Cerebrovascular Hypertension by John Dickinson and Julian Paton

CEREBROVASCULAR HYPERTENSION
CEREBROVASCULAR
HYPERTENSION
John Dickinson
with chapters by Julian F R Paton
Book Guild Publishing

Sussex, England
First published in Great Britain in 2012 by

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Contents
Preface
Part I
1
2
3
4
The Enigma of Essential Hypertension
A Personal Historical ReviewHarvey Cushings

Experiments
1
3
The Evidence for a Neurogenic Increase of Heart Rate,

Cardiac Output and Peripheral Arteriolar Resistance in
Essential HypertensionCurrent Views of its Cause
21
Can Essential Hypertension be Fully Explained by

What is Already Known About that Disease?
32
Anatomy and Post-Mortem Measurements of Flow

Resistances in the Main Human Cerebral Arteries; their
Relation to Ante Mortem Blood PressureInuence of
Chronic Renal Disease
67
Mechanisms of Blood-Pressure Control in Humans

Compared With Those in Other MammalsCerebral
Autoregulation
92
Cerebral Oxidative Metabolism in Essential Hypertension 100
Neural Mechanisms for Blood-Pressure Control
113
Structures and Mechanisms Subserving Blood-Pressure

Control by the Brainstem (by Julian F R Paton)
115
The Hypertensive Brainstem (by Julian F R Paton)
136
Part II
7
ix
Secondary Causes of Hypertension and their Relation to

the Cerebral Circulationthe Inuence of the Brain on
the Kidneys
Part III
Stroke: the Commonest Cerebrovascular Disorder
157
175
10
The Cause of Strokes in Cerebrovascular Hypertension

What Causes Bleeding into the Brain?
177
11
Management and Treatment of Cerebrovascular

Hypertension
196
Epilogue: a Century of Research into Essential

Hypertension and Strokes
211
12
References
217
Index
255
vi
Acknowledgements
My rst must be to the late Drew Thomson, the friend with whom I
collaborated in the pathology department of the former Middlesex
Hospital, and to Jack Howell, for his advice and criticism and for his
independent blood pressure assessments. Since my retirement from
the Chair of Medicine at St. Bartholomews Hospital Medical
School, Nick Wright (the Warden of Queen Marys Medical School
of the University of London) and Nick Wald (the Director of the
Wolfson Institute) have provided the ideal environment for continuing scientic research. I have been encouraged to plunder a lot of
time that their computer and secretarial staff might have better
spent. I am particularly grateful to Neville Young, Dallas Allen and
Maria Gkori at Queen Mary. Many others have helped by reading
and criticising individual chapters, especially Ben Sacks, who has
encouraged me, corrected the worst of my literary lapses and very
kindly read the proofs. My many other helpful critics include Isobel
Barnes, Eric Beck, Gus Born, Pierre Bouloux, Caroline Dickinson,
Mark Dickinson, David Galton, Abe Guz, Jerry Kirk, Malcolm
Law, Graham Mitchell, Stan Peart, the late John Vane, Nick Wald
and Joanna Wardlaw. I remain grateful to those patients of the
former Middlesex Hospital and to their relatives, who gave permission for the post-mortem examinations without which I could not
have even begun to nd the cause of essential hypertension. I am
also grateful to my wife Elizabeth, who has kindly accommodated
my frequent absences while I was writing this book.
I am delighted that Julian Paton has written two chapters
describing new work on vascular control systems of the rats brain.
This has shed unexpected light on the cause of human high blood
pressure, as he will explain in Chapters 7 and 8. Julian wishes
gratefully to acknowledge the nancial support of the British Heart
Foundation, the Wellcome Trust and the National Institutes of
Health (grant HL033610-18). He has also received a Royal Society
Wolfson Research Merit Award.
vii
Preface
This book continues work I began in 1958, to discover the cause of
the most common kind of human high blood pressure. It almost
exclusively affects middle-aged men and post-menopausal women
living in towns and cities in developed countries. It seldom appears in
children or in any of our usual experimental animals, unless they
have been fed unnatural diets or have been selectively inbred. The
disease should have been called idiopathic because its cause was
unknown, but we are stuck with the description essential hypertension until we have established its cause and given it a better name.
Harvey Cushing, the great American neurosurgeon, knew that
people with expanding brain tumours often had an unduly high
blood pressure. He investigated its possible cause in animals, because
of its importance in the treatment of human brain tumours. He
discovered that if the pressure inside the head of an anaesthetised
dog was articially increased its blood pressure went up in strict
proportion, so that there was always enough blood owing to keep
the brain alive. Cushing tracked the physiological structures
responsible to a receptor at the back of the brain and to an effector
that was part of the sympathetic nervous system in the upper spinal
cord. Cushing himself, and many clinical scientists since, speculated
that this mechanism (as he called it) might explain the common
occurrence of spontaneous so-called essential hypertension if the
blood supply of the hindbrain was inadequate. Many people,
impressed by Cushings observations, tried to create an animal
model for human hypertension by tying off one or more main
arteries to the brain, in the hope that an animal model could be used
to improve understanding and treatment of a common disease. Most
attempts failed. If animals survived, their blood pressure could only
be raised for a week or two. New collateral arteries grew in, and
existing arteries grew larger. Unfortunately this does not seem to
happen in human adults.
ix
But while working at the former Middlesex Hospital in London I

attended many human necropsies. I often saw white lumps of
atheroma thickening the walls of the vertebral and internal carotid
arteries in the necks of cadavers. The lesions narrowed and sometimes even blocked these important blood vessels. I already knew
that extensive atheroma of the main human cerebral arteries was
strongly associated with high blood pressure. I also knew that many
clinical scientists had been impressed by Cushings observations and
had suggested that narrowing of the four main arteries to the brain
might reduce its blood ow and thus raise the systemic arterial blood
pressure. My colleague Drew Thomson and I decided that some
measurements were needed. In Chapter 4 I shall describe how we
measured the ow resistance of the four main cerebral arteries of
ninety-four cadavers. We were astonished to nd an almost incredibly close negative correlation between the fastest possible rates of
uid ow in each of our subjects main cerebral arteries (ow-rates
added together) and each subjects previous blood pressure, recorded
in the hospital notes. The maximal ow-rates of the two vertebral
arteries added together had a particularly strong negative correlation
with ante-mortem blood pressure.
Our initial observations were published as a Preliminary Communication in The Lancet in 1959. Our two nal reports appeared in
Clinical Science in 1960 and 1961, accompanied by tables of all our
raw data. Despite our claim that our observations explained essential
hypertension, they aroused little interest at the time. Everyone was
certain that small arteries of 50300 mm internal diameter comprised
the only important cause of increased cerebral vascular resistance.
And most people thought either that a genetic fault in the kidneys
caused the disease, or that it had some vague kind of psychosocial
origin.
Then the late Seymour Kety, one of the most famous neurologists
in the worldjustly celebrated for having devised, with Carl
Schmidt, a way of measuring cerebral blood-ow in humans
reported that total human cerebral blood-ow (CBF) was the same
in individuals with essential hypertension as in normal people. This
apparent constancy of CBF laid the cornerstone of the next thirty
years of research into essential hypertension. But many new measurements of CBF have shown that Ketys observations were inadvertently misleading. His human volunteer subjects were not studied
in restful conditions. All recent work shows that total cerebral bloodx
PREFACE
ow in resting subjects with essential hypertension is decreased

roughly in proportion to the elevation of their blood pressure. My coauthor Julian Paton has discovered that the inbred spontaneously
hypertensive rat developed by Aoki and Okamotorecognised the
world over as the ideal animal model for human essential hypertensionhas narrowed main cerebral arteries, which are functionally
identical with the same arteries that Drew Thomson and I had found
narrowed by plaques of atheroma in people with essential hypertension. Julian has also found that this rats main cerebral arteries
are not only congenitally narrow, but are also narrowed by inammatory thickening of their walls.
Julian and I suggest that the inappropriate description essential
hypertension should be abandoned. The condition is not essential in
any normal meaning of the word. Strictly and accurately, it is Cerebrovascular Hypertension, which is the title of our book. We hope
that our ideas will initiate a change in the way in which the academic
community thinks about this disease. New techniques will eventually
allow the diagnosis of cerebrovascular hypertension to be made
explicitly, rather than by exclusion of less common causes of raised
blood pressure. They will also profoundly inuence prognostic
indicators, screening and the choice of drugs to lower blood pressure
and to prevent strokes. Prophylactic surgery of the internal carotid
artery is now regularly used to deal with transient cerebral ischaemic
attacks; but we envisage that new methods of preventing or reducing
other kinds of excessive cerebrovascular resistance will be developed.
Because the blood supply of the brain is shared between four large
arteries this situation will not often arise, but there are exciting
possibilities ahead.
John Dickinson
Wolfson Institute of Preventive Medicine,
Queen Mary, University of London
xi
Part I
The Enigma of Essential Hypertension
1
A Personal Historical ReviewHarvey
Cushings Experiments
Writing under the title Pathogenesis of essential hypertension: historical paradigms and modern insights, Richard Johnson and his
colleagues recently reviewed more than a century of clinical research,
concentrating mainly on renal mechanisms (Johnson et al., 2008).
They had to admit that the cause of essential hypertension was an
unsolved problem, even though the disease was common and comprised (in their words) a current epidemic. A year earlier, Paul
Korner (2007) had published a comprehensive account of Essential
Hypertension and its Causes. The subtitle of his monograph described
Neural and Non-neural Mechanisms.
These are just two examples of many dedicated reviews of dierent
aspects of this extraordinary subject that have been published in the
last century. George Pickering (1961), who wrote several of them,
concluded that because essential hypertension could only be
arbitrarily dened, talk about its age of onset was meaningless.
Speculation about its cause was equally meaningless. But skewness
in the frequency distribution of blood pressure was apparent in data
that he had helped to collect (Hamilton et al., 1954). For systolic
pressure, skewness began to appear in the data of their 3039 age
groups. For diastolic pressure, it appeared in their 4049 age groups.
This indicated that a new factor was making its appearance at about
this time of life.
Evelyn (1954) and Perera (1955) placed the average age of onset,
or of rst diagnosis of essential hypertension, at age 32. The data of
Master et al. (1950) suggested that the coecient of variation of
blood pressure (a measure of the lack of homogeneity in a population) begins to increase by the fourth decade. Available data are
consistent. We can say that essential hypertension is a disease of
human adults, which can appear in the fourth decade of life,
3
THE ENIGMA OF ESSENTIAL HYPERTENSION
sometimes earlier. Thereafter it becomes more common and more

severe. A small genetic predisposition to hypertension operates
during childhood, but is quantitatively insignicant. Michael de
Swiet (1986) summarised the tracking coecients for blood pressure
at dierent ages, each coecient measuring the persistence of a rank
order of blood-pressure measurements in a dened group, studied
over time. The coecient rose from 0.1 in the rst year of life to 0.4
after age 4, eventually reaching 0.7 at age 18. From his long
experience and careful records, a general medical practitioner in
Wales recommended a robust approach to hypertension in childhood. He suggested that screening children for hypertension was
pointless, unless there were symptoms or signs of another disorder
(Hart, 2008). Paediatricians can usually identify secondary causes for
hypertension in children referred to doctors with suggestive symptoms. In nine out of ten cases, kidney disease is present, or endocrine
causes or aortic coarctation can be found (Londe, 1978).
A personal introduction to the neural control of the cardiovascular

system
After I had spent two years as a medical student at Oxford, David
Whitteridge, my former tutor, invited me to take a year out of my
course to work on vascular baroreceptors in his laboratory. David
was a dynamic and inspiring man, already well known from his work
on aerent nerves arising from the lungs and from the vascular
system. The specic task that David set me was to record from
individual baroreceptor nerve endings in the cats right atrium, while
simultaneously recording uctuations in right atrial pressure. Most
of my time was taken up making apparatus and getting it to work,
but I was eventually able to show that these low-pressure aerent
baroreceptors red o bursts of impulses during each a- and v-wave
of atrial pressure uctuations. Within each cardiac cycle there was a
quantitative relation between each small elevation of atrial pressure
and the consequent rate of discharge of impulses from the lowpressure receptors (Dickinson, 1950a). David Whitteridge was an
ideal supervisor. I enjoyed the challenge that he had set me. I was
also stimulated to produce a technical manual describing Electrophysiological Technique (Dickinson, 1950b), only to be disappointed
when all my nice thermionic valve circuits were supplanted by
4
A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS
transistors. But many years later I was able to make use of my

physiological experience with David to propose that an anomalous
burst of aerent atrial baroreceptor nerve activity (collapse ring)
was the cause of fainting in normal healthy people (Dickinson,
1993). This hypothesis has so far stood the test of time. It is consistent with all available data and has not been disproved.
The challenging problem of human essential hypertension

This experience of scientic research got me interested in the brains
control of the cardiovascular system. After qualifying in medicine in
1952, I spent a year in junior clinical posts in London at University
College Hospital. In my second post, my chief was Max Rosenheim,
an experienced physician with a special interest in diseases caused by
unduly high blood pressure. Many of his patients were diagnosed
with essential hypertension, after renal and endocrine causes had
been ruled out. Nobody knew the cause of the condition, although
there had been international conferences to discuss it. I became
fascinated by the disease and resolved to understand it. I read as
much literature as I had time for. Max introduced me to Horace
Smirk, a visitor from New Zealand, who was one of the rst people
to emphasise the importance of measuring basal blood pressure,
preferably during sleep. Raised basal blood pressure was much better
correlated with later illness and with shortened life-expectancy, than
were casual readings of blood pressure (Smirk, 1957). Smirk was also
one of the rst people to breed rats selectively to develop hypertension (Smirk and Hall, 1958). He should be remembered as one of
the most original clinical scientists to have worked in this eld. I owe
him a personal debt of gratitude for having emphasised the importance of basal blood-pressure control. This has been the keystone of
all my thinking about the cause of essential hypertension.
After leaving Max, I extended my clinical experience for a year as
Resident Medical Ocer at University College Hospital (UCH)
where I had immediate responsibility for all acute medical and surgical admissions. Then I was conscripted into the British Army for
two years as a Junior Medical Specialist, after which I was appointed
a medical registrar at the former Middlesex Hospital in London. At
last I could return to research. The cause of essential hypertension
presented the most exciting intellectual challenge available at the
time. There had to be a solution. I approached the subject by an
5
extensive literature search, mostly conducted in the dusty basement

of the comprehensive medical library of the Royal Society of Medicine and in the old Reading Room of the British Museum.
I was astonished to discover that there was no accepted animal
model for this common condition. The systemic arterial pressures of
dogs, for example, occupied a narrow frequency distribution. When
high blood pressure was found, chronic pyelonephritis was usually
present (McCubbin and Corcoran, 1953; Goldblatt, 1958; Wakerlin,
1959). Many investigators had observed that hypertension produced
in dogs by constricting the main renal artery, or by inducing cellophane perinephritis, could not be distinguished haemodynamically
from human essential hypertension. But no comparable renal
abnormalities could be found in the human disease, at least in its
early stages.
So I reviewed the early German literature. Owsjanniko (1871)
and Dittmar (1873) had identied bilateral centres in the cerebral
medulla of dogs which raised systemic blood pressure when stimulated and which lowered blood pressure when ablated. Science needs
measurement. I was excited to read Harvey Cushings account of his
classic observations, which were strictly quantitative. They seemed to
point the way towards a possible neurogenic animal model of human
essential hypertension. Cushing later became the worlds most
famous neurosurgeon, but after graduating in medicine from Harvard in 1895, and before joining the permanent sta of Johns
Hopkins Hospital in Baltimore, he travelled to Europe to complete
his postgraduate training by physiological study of the cerebral circulation. He already knew that blood pressure went up when the
brain was compressed by a tumour or (in animals) by an inated
rubber bag. When working in Theodore Kochers physiology
department in Bern, he investigated the phenomenon further. He
quantied it by injecting saline under pressure into the subarachnoid
space of a dog and wrote: The fact that cerebral compression
occasions a rise in blood pressure is universally known but it does not
seem to have been recognised that the degree of this elevation occurs
pari passu with the degree of compression (measured in millimeters of
mercury) to which the medullary centres are subjected. The fact that
the arterial tension is a variable quantity which regulates itself so as to
overcome the eects of the increased intracranial pressure never seems
to have received attention. A simple and denite law may be established, namely that an increase of intracranial tension occasions a rise
6
of blood pressure which tends to nd a level slightly above that of the

pressure exerted against the medulla (Cushings italics: Cushing,
1901).
Modern authors are sadly reluctant to use italics to emphasise
observations that they deem particularly importantas these certainly were. In his Mutter Lecture, published in the following year,
Cushing described further investigations in dogs given morphine and
lightly anaesthetised with ether. His paper is illustrated by his
original records, which show that systemic blood pressure was
maintained at all times about 20 mmHg above the applied intracranial pressure. His experiments sounded to me physiological rather
than pathological. For example: In the experimental conditions,
when the intracranial tension about the bulb [medulla] is slowly and
gradually brought to the neighbourhood of the blood pressure the
latter may rise to counteract its eects, without the production of the
slow vagus pulse and deliberate respiration almost invariably seen in
more rapid processes (Cushing, 1902). This seemed a long way from
describing the phenomenon as a last ditch response, which is the
way that most people since have looked upon it. My colleague Julian
Paton has used Cushings own word to describe the response as a
manifestation or component of Cushings mechanism.
Cushing investigated the responsible structures subserving the
mechanism in anaesthetised dogs. These structures were in the
hindbrain and were activated by medullary ischaemia. The pressor
response was mediated through the upper spinal cord after a delay of
3060 s. Cushings observations challenged clinical scientists to
create an animal model by tying o or narrowing the main cerebral
arteries of many dierent animals in many dierent ways, hoping
thereby to establish a state of chronic (neurogenic) hypertension,
which would be a good model for human essential hypertension.
Most attempts failed. If treated animals survived without infarcting
their brains, their blood pressure often went up, but it came down
again within a week or two because collateral arteries opened up and
restored the brains blood supply.
Despite its apparent low sensitivity, the response suggested to
many distinguished clinical scientists, notably Ernest Starling, that
gross lesions in arterial trunks might diminish the average pressure
in the Circle of Willis and in the small arteries of the brain and raise
blood pressure by producing cerebral ischaemia. This condition is
well known (Starling, 1925). But at about this time, Hering (1924),
7
followed by Corneille Heymans (review by Heymans and Neil, 1958),

discovered systemic arterial pressure detectors (baroreceptors) in the
carotid sinus and in some other places. Their aerent nerves terminated in the brainstems control centres. When stimulated by changes
in endosinus pressure, these receptors stabilised systemic arterial
pressure by negative feedback through the autonomic nervous system. Despite this discovery, interest in the brains relation to
hypertension continued. There was strong (though indirect) evidence
that peripheral arterial baroreceptors soon adapted their working
range of pressure to any maintained blood-pressure level. This
seemed to make them unsuitable receptors to stabilise blood pressure
in the long term. Eventually, baroreceptor resetting in renal hypertensive dogs was directly conrmed by McCubbin et al. (1956).
Between 1925 and 1970 there were many sporadic and sometimes
partly successful attempts, mainly in dogs and rabbits, to create what
might be described physiologically as chronic cerebrovascular
hypertension. Cutting the aerent arterial baroreceptor nerves
produced big blood-pressure uctuations, but only slightly increased
the mean blood-pressure level. It was dicult either to eliminate or
allow adequately for arterial baroreceptor eects. The most convincing single experiment was that reported by Nastev et al. (1968).
They followed a dog for four years, during which its blood pressure
was repeatedly measured by the atraumatic technique of van Leersum (1911). After they had ligated both vertebral arteries and one
internal carotid artery, blood pressure rose, but fell after extirpation
of the carotid sinus on the ligated side. Blood pressure crept up
slowly during the next eighteen months, until the dog died with a
cerebellar haemorrhage. At necropsy it had cardiac hypertrophy and
nephrosclerosis. These ndings closely matched those of end-stage
human essential hypertension. The authors specially noted that, until
its terminal cerebrovascular accident, the dog appeared normal in
every way. This unique experiment does not seem to have been
exactly repeated. Essential hypertension is a common but insidious
condition, developing over many years. We should not necessarily
expect to create a realistic animal model in a few days or weeks.
Long ago I listed and summarised some twenty of the early papers
(Dickinson, 1965, pp 1214). At that time a readily reproducible and
consistent animal model of cerebrovascular hypertension had not
been established. Twenty years later the situation had not changed.
Animal experiments of this kind seemed to have stalled, although
8
Jannetta et al. (1985) had devised an ingenious primate model of

human neurogenic hypertension by arranging looping arteries to
press on the left lateral medulla oblongata. But this model could not
explain more than rare occasional cases in which essential hypertensive patients had similar arterial abnormalities.
The eld of animal experimentation was transformed after Aoki
and Okamoto had created the spontaneously hypertensive rat
(SHR) by selectively inbreeding WistarKyoto rats with progressively higher blood pressures. I confessed my dismay when it
seemed that investigation of the SHR was taking clinical scientists
attention away from the study of human essential hypertension
(Dickinson, 1991). But I was excited after Julian Paton had shown,
by animal experiments (some of which he will describe in Chapters 7
and 8), that it is possible to unify the whole eld of long-term
mammalian blood-pressure control in terms of a Cushing mechanism
in the brainstem.
The most comprehensive recent survey of this confusing eld was
published by Paul Korner (2007), who rejected the mainly renal
causes that others had espoused. Korner was impressed by the strong
evidence for a neurogenic origin for most cases of essential hypertension, even though he had to attribute the elevation of blood
pressure to an undened and mysterious psychosocial aetiology.
When I rst began to take an interest in the subject, I determined to
nd an organic cause for the disease, i.e. one whose attributes could
be measured by conventional physiological techniques.
Steps towards a new idea about the cause of essential hypertension

The great William Osler once wrote that there would always be a
place in medicine for those who had attended fty necropsies. Indeed
my own idea about the cause of essential hypertension came directly
from my study of human necropsies at University College Hospital
and at the Middlesex Hospital. Unfortunately this experience has
now become dicult to obtain, in Britain and in most other developed countries: fewer necropsies are being performed. Absurd and
almost hysterical protests about the retention of bits of dead bodies
continue, stirred up by the popular press. This is already greatly
damaging medical research.
I count myself fortunate that between 1952 (when I graduated in
9
medicine) and about 1980, post-mortem examinations were still

being routinely performed in every hospital in which I worked. I saw
many necropsies from people who had died with strokes. When their
brains were examined and the main cerebral arteries exposed, I saw
many large arteries, notably the basilar, irregularly thickened by
white lumps of atheroma. I recalled the published accounts of the
animal work, which I have just described. Experimenters had found
it dicult and frustrating to restrict the arterial supply of the brain
by just the right amount to raise the blood pressureafter which
collaterals developed and the blood pressure went down again. The
astonishing ability of dogs to grow new arteries had been known ever
since the great surgeon Astley Cooper (1836) had successively ligated
all four main cerebral arteries of a pet, which later became his own
house dog. This animal was preserved in the Museum of the Royal
College of Surgeons in London, where all four complete ligations
were clearly displayed. Robert Lowe (1962) demonstrated that rabbits could do the same as dogs. He successively ligated all four main
cerebral arteries in rabbits without being able to produce chronic
hypertension, until he had also denervated the carotid sinuses. His
article is illustrated by resin casts of the exuberant collateral arteries,
which maintained an adequate cerebral blood supply after he had
tied the main cerebral arteries.
But while looking at many human brains at necropsy, I had a new
idea. It dawned on me that perhaps a solution to the apparently
intractable problem of the cause of essential hypertension lay in a
natural human experiment, rather than in an articial animal one. I
envisaged that obstruction of the main human cerebral arteries by
atheroma might raise the lowest (basal) blood pressure, during sleep,
which the brain could tolerate without activating a Cushing-type
pressor mechanism. My study of many necropsies made it obvious
that adult human beings lacked the same ability that dogs and
rabbits had to grow new arteries to bypass arterial obstructions.
An extensive survey of a large number of publications (mainly in
journals of pathology, see Chapter 3) satised me that there was
astonishingly strong pathological evidence from human necropsies
to support my idea. I was also encouraged that Brobeil et al. (1954)
had reported that angiographically-identied narrowing of human
main cerebral arteries by plaques of atheroma was correlated with
increased cerebrovascular resistance determined by Kety and
Schmidts cerebral blood-ow technique (see below). But to test my
10
idea I needed a quantitative estimate of the least resistance that the

main cerebral arteries might have presented, in life, under basal
conditions. This might then allow me to compare these estimates of
resistance with previously recorded measurements of blood pressure
in the same individuals, if I could obtain these.
I was very lucky to meet Drew Thomson, with whom I collaborated for three years. We approached the problem in the post-mortem
room of the former Middlesex Hospital in London. We identied
ninety-four former patients of the hospital for whom one or more
blood-pressure readings had been recorded in the hospital notes
before death, and whose cadavers we had the opportunity and permission to examine. We deliberately chose to study former patients
whose ante-mortem blood pressures covered as wide a range of
pressure as possible, only omitting those with evidence of previous
heart disease. I shall describe in Chapter 4 how we rst fully dilated
the four main cerebral arteries of each cadaver with dilute ammonia,
then perfused each artery with water under pressure to allow us to
estimate the resistance that each main artery might have presented in
life. Our technique deliberately took no account of any possible
resistance presented by distal small arteries and arterioles. We had
assumed (I should rather say hypothesised) that these small vessels
would be fully relaxed and dilated during sleep. This assumption
stimulated us to measure the resistance created solely by large, main
arteries and by atheromatous deposits in their walls. The basilar
artery was relatively short, but also often had atheromatous plaques
in its walls. Although such lesions were specially abundant and
severe in former hypertensive patients, the basilar artery was too
short to be realistically perfused. But, as it was close to the meeting
point of the four main cerebral arteries in the skull, at the Circle of
Willis, its resistance seemed less important than that of the four
main cerebral arteries in the neck and skull base. We therefore
concentrated our attention on them. The congenital size of these
large arteries was very variable but all could develop atheromatous
plaques in their walls.
Soon after we had started to make our resistance measurements of
the main cerebral arteries, our results became unexpectedly spectacular. The ow resistance of these large brain arteries was strongly
and positively related to the former patients blood pressures, which
had previously been recorded in the hospital notes. We felt sure that
we had made a great discovery, which perfectly explained the cause
11
of essential hypertension. We dispatched a Preliminary Communication to The Lancet suggesting that the kind of arterial cerebrovascular resistance we had measured could completely account for
essential hypertension.
I was disappointed that nobody accepted our views about the
cause of essential hypertension, but nobody could prove them
wrong. Nobody seemed prepared to believe that the stenotic lesions
we had seen, and the increased ow resistance that they had produced, and which we had measured, had any relevance to the blood
supply of the human brain. Everyone was condent that the brains
blood supply was more than adequate, whatever the main arteries
looked like. So after I had established my credentials as an academically qualied physician, I was itching to make use of my previous
animal physiological experience to investigate the Cushing
mechanism further. I hoped that I might be able to extend Cushings
observations to allow them a place in normal basal blood-pressure
regulation. The award of a Rockefeller Travelling Fellowship (by the
British Medical Research Council) gave me the opportunity to work
somewhere where everyone was thinking about, and working on,
hypertension. I approached Irvine Page in Cleveland, Ohio, because
of the denitive work that had already been done there in the
Research Division of the Cleveland Clinic Foundation. I managed to
exchange our home with an American academic wanting to work in
London. My wife and I, accompanied by our three small children,
were made welcome by Irvine, and especially by Jim McCubbin, who
became a close friend and collaborator.
A meeting with Arthur Guyton

While in the USA, I visited many people, notably John Stirling
Meyer in Detroit and ES Crawford in Houston, Texas. Both were
regularly performing four-vessel cerebral artery angiography on
people with strokes. I watched both of them, fascinated. Both
recognised the frequency and severity of stenotic lesions of the main
cerebral arteries in the human neck. In Philadelphia, I participated in
a Hahnemann Symposium on hypertension, presided over by JH
Moyer. After I had presented a paper decribing our work with
cadavers, I was asked if it proved that the cause of essential hypertension lay in atheroma of the main cerebral arteries. Since I believe
that science advances by a process of conjectures and refutations
12
(Popper, 1963), and that there is no such thing as a certain proof of

anything, I said no. My ideas were not pursued further. But I also
took the opportunity, while in the USA, to attend the Young Turks
annual meeting of clinical scientists in Atlantic City, where I met
Arthur Guyton, whom I had always regarded as the worlds most
exciting and original cardiovascular physiologist. Later I visited his
department in Jackson, Mississippi, several times and he visited me
in London. We met at many international symposia. I stayed with
him and Ruth in Jackson and corresponded with him for many years
until his death more than forty years later. Despite his unwillingness
to accept my views about the neurogenic aspects of hypertension, I
always enjoyed crossing swords with Arthur. To the end of his life he
never lost his conviction that the kidney was the culprit in essential
hypertension, particularly because it was the only organ that possessed what he described as innite gain in its blood-pressure
control system. In many reviews he always conceded the immense
power of the Cushing response, but also dismissed the phenomenon
as only a last-ditch mechanism to save a critically ischaemic brain.
He regarded the kidneys as the prime mover in essential hypertension (Guyton, 1948; Guyton et al., 1984), and once wrote: I personally doubt that essential hypertension occurs regularly in persons
who do not have some hereditary abnormality that makes the kidneys more susceptible to permanent functional changes (Guyton,
1988). We never reconciled our dierent points of view; but Guytons towering scientic reputation, his books and many of his
exciting original observations on renal mechanisms probably dissuaded many clinical scientists at the time from allowing a major role
to the brain in causing essential hypertension.
There were also other problems. In the 1940s, Seymour Kety had
devised an ingenious and fairly non-invasive way to measure total
cerebral blood-ow (CBF) in humans, using the (relatively) inert gas,
nitrous oxide. A substantial body of work was published using this
method. The results were consistent in showing that CBF was the
same in essential hypertensive as in normal individuals (Kety et al.,
1948a). Reported values averaged 55 ml. 100 g brain-1. min-1. Niels
Lassen (1959) commented in an inuential review: The cerebral
perfusion is apparently regulated in such a way as to maintain
scrupulously [my italics] the normal chemical milieu of the brain. This
observation suggests the inuence of a regulatory mechanism governed by the metabolic demands of the cerebral tissues, i.e. metabolic
13
control. Figure 1.1 is borrowed from Niels Lassens review. It

summarised average values for CBF (in cc.100 g brain weight-1. min-1.)
in eleven dierent groups of 376 individuals, spanning a wide range
of blood pressures. The points labelled #5 and #6 came from normotensive men and women; points #9, #10 and #11 were from essential
hypertensive individuals. The cerebrovascular resistance (CVR) in
these hypertensive people was proportionately increased, so that
total CBF remained normal. Furthermore, total cerebral blood-ow
appeared not to rise above what might be described as a virtual
ceiling.
Fig. 1.1 The celebrated classic relationship between total cerebral blood-ow and mean
systemic arterial pressure in 376 individual determinations in human subjects. Points 1,
2: drug-induced severe hypotension; 3, 4: drug-induced moderate hypotension; 5, 6:
normal pregnant women and normal young men; 7: drug-induced hypertension; 8:
hypertensive toxemic pregnancy; 9, 10, 11: essential hypertension. (Reproduced with
permission from Niels Lassens 1959 Physiology Review 39 183238).
Almost everyone acts as if high blood pressure is the primary

abnormality in essential hypertension, however scientically inaccurate and unsatisfactory this has to be while its aetiology remains
undiscovered. Any increase of CVR is looked upon as a secondary
consequence of a rise in systemic arterial pressure. In 1968, Seymour
14
Kety dismissed my observations with Drew Thomson because CVR

could be reduced with drugs. In Chapter 3, I shall review newer
observations made during the last twenty-ve years. These show that
constancy of cerebral blood-ow in hypertension is not scrupulously maintained at all. We know now that cerebrovascular resistance is often disproportionately elevated. But my unorthodox views
and necropsy estimates of main cerebral artery resistances received
little interest and no detailed criticism from fellow hypertensiologists, although I had several opportunities to present them in public.
I met Kety at the 6th Princeton Conference on Cerebrovascular
Diseases, at which he explained why he thought my views were
wrong. In the published record of the lively discussion that followed
my oral presentation at the conference, Kety admitted that there had
been complacency concerning the older hypothesis of the origin of
essential hypertension as being a response to cerebral ischemia. He
could only accept it as an explanation for rare cases, because, he
said: when one reduces . . . hypertension . . . with drugs or better still
with sympathetic blockade . . . one nds that the cerebral vascular
resistance quickly relaxes and the cerebral blood ow tends to be
preserved. Discussion time at the conference was limited. I was not
able to make the point that cerebrovascular resistance has two
components, in series. They should be added and considered together.
Kety was only interested in one componentthe resistance of the
smallest so-called resistance arteries and arterioles. This can
change rapidly. It can thus subserve cerebral autoregulation and
accommodate postural blood-pressure changes. But there is another
component that most people forget, but it was one that Kety himself
had recognised. He said that in one or two . . . patients who had
previous evidence of peripheral arteriosclerosis, and probably cerebral
involvement as well, the cerebral blood ow did not quickly adjust to
the induced fall in blood pressure to normal levels. These patients
showed a signicant reduction in venous oxygen tension and clinical
symptoms of cerebral ischemia . . . In these patients the hypertension
may have been a compensatory adjustment to cerebral vascular
stenosis and cerebral ischemia . . . But I nd it dicult to be convinced that this relationship holds in uncomplicated essential
hypertension (Kety, 1968). I shall return in Chapter 6 to Ketys
awkward and disturbing calculations of the subnormal cerebral
respiratory quotient in essential hypertension (p 111).
As I shall describe in Chapter 4, Drew Thomson and I examined
15
the four main cerebral arteries of ninety-four cadavers, 376 large

arteries in all. We saw three internal carotid and three vertebral
arteries completely blocked by atheroma. One vertebral artery was
vestigial, without any lumen. Many of the other main cerebral
arteries contained multiple plaques of atheroma, which narrowed the
lumen. Hutchinson and Yates (1957) described the sometimes gross
lesions of these large arteries as comprising carotico-vertebral
stenosis. Drew and I could not believe that any amount of dilatation
of distal small arteries could always have restored and maintained a
normal blood supply to the brain, unless the individuals aected had
a much increased systemic arterial pressure. Even the late John
Swales, who reviewed my second monograph and accepted that there
was a strong neurogenic basis for essential hypertension, thought
that I had proposed that the characteristically late development of
essential hypertension was due to ischaemia of the brainstem vasomotor centre as a result of atheroma of the vessels which supply it.
He would only concede that I had made a persuasive case for the
progressive skewing of the blood pressure distribution curve. . .with
ageing (Swales, 1991). Both Seymour Kety and John Swales misinterpreted my idea. I had never suggested that cerebral ischaemia,
i.e. reduction of blood ow to the brain, was the cause of essential
hypertension. My hypothesis is slightly more complicated, but it is
straightforward and explicit:
Any primary unrelaxable or structural increase of cerebral
arterial resistance sets a lower limit of perfusion pressure below
which the brain will not allow blood pressure to fall during sleep.
This will be at a level just short of that which would begin to activate
the Cushing mechanism.
Unless my readers have seen gross atheromatous diseasewhich
can be severe enough sometimes to close a major cerebral artery
completelythey may continue to think that increased cerebrovascular resistance can only be due to constrictive, hypertrophic or
eutrophic modelling changes in small arteries and arterioles. But
careful examination of many necropsies of sixty-year-old adults in
any developed country should convince sceptics that atheromatous
lesions of large arteries within the skull or in the neck, must inevitably have often presented signicant resistance to blood ow to the
brain.
16
Other criticisms
Almost all those who are trying to nd the cause of essential
hypertension assume that the small artery and arteriolar component
of increased cerebrovascular resistance comes about by a myogenic
reaction to increased distending pressure, the so-called Bayliss
eect. In other words, high blood pressure is the problem. At rst
sight this seems reasonable. A sharp increase of distending pressure
can certainly make arteries constrict (the so-called myogenic reaction) and thus acutely increase their ow resistance. It is more difcult to show that sustained hypertension increases arterial and
arteriolar resistance in the long term, unless there is present a circulating vasoconstrictor agent, such as noradrenaline or angiotensinII. None has been found.
I need to ask how systemic arterial hypertension can really be primary in the normal meaning of that word. Certainly most body organs
and tissues exposed to high arterial pressure for months or years can
develop small artery and arteriolar changes, which can increase their
ow resistance. The idea that a primary increase of cerebrovascular
resistance could be the causeindeed the sole causeof essential
hypertension was ignored at the time that Ketys observations were
published. There are several reasons why it should be re-examined.
I shall take the single Goldblatt kidney as my rst example.
Stable long-term hypertension can be established in a dog with only
one kidney by constricting the main artery to that kidney, or by
inducing perinephritis. Three groups of investigators (Schroeder and
Steele, 1940; Corcoran and Page, 1942; Warthin and Thomas, 1942)
reported that, after these manoeuvres had established stable longterm hypertension, renal blood-ow could return almost exactly to
the level it was before the renal manipulations. In all these cases,
increased renal vascular resistance came rst. Hypertension followed. Some critics, e.g. Stamey (1963), tried to dismiss these results
as inaccurate. But even if statistically signicant reduction of renal
blood-ow had been shown in every case, it could only have been
very slight. Yet the increased renal vascular resistance clearly caused
the hypertension, which remitted when (for example) a clip constricting the main renal artery was removed. By analogy, the nding
of a normal cerebral blood-ow in essential hypertension can be
explained if a primary increase of cerebral arterial resistance comes
rst and hypertension follows.
17
My second reason for suspecting that much of the increased CVR

of essential hypertension might be due to atheromatous lesions of the
large cerebral arteries is the failure to cure the condition by prolonged hypotensive drug treatment. Paul Korner and his collaborators (Korner, 1982; Jennings et al., 1984) treated their rst
thirteen patients with moderate essential hypertension with hypotensive drugs for a year and were disappointed to nd that, although
blood pressure stayed down for a week after stopping treatment, it
was soon back again to its former level: The most remarkable
nding was the speed at which hypertension redeveloped after
stopping the drugs in this and subsequent studies (Korner, 2007,
p 92). In a large study conducted under the auspices of the British
Medical Research Council, hypotensive drug treatment of (mild)
essential hypertensive patients for six years failed to cure them.
Blood pressure soon went back to its previous level when the drugs
were stopped (Medical Research Council Working Party, 1985).
Recent investigations into cardiovascular control by the rats

brainstem
Yet another reason to suspect that a primary increase of CVR might
be the cause rather than the result of hypertension is now coming
from studies of the spontaneous hypertensive rat (SHR). My former reservations about the burgeoning study of this animal were
allayed after Julian Paton and his colleagues had demonstrated
grossly narrowed main brainstem arteries supplying the brain in the
SHR, even before the blood pressure had gone up (Paton et al.,
2007). So I am delighted to have joined Julian and Graham Mitchell
in a hot topic review in Experimental Physiology in which we
invoked the Cushing mechanism to account for long-term bloodpressure regulation in rat, human and girae (Paton et al., 2009).
Summary
An adult man or post-menopausal woman living in a town or city in
a developed country, and having a systemic arterial pressure at or
above 140/90 mmHg, is said to have primary essential hypertension, if there is no evidence of a secondary cause for the condition.
There is also no agreed primary cause. Nearly two centuries ago it
18
was known that ligating the main cerebral arteries of animals raised
their blood pressure, providing that the brain was not critically
deprived of blood, but hypertension produced in this way could not
be sustained for more than a few weeks after new and collateral
arteries had appeared and dilated. Harvey Cushing restricted the
blood supply to a dogs brain by injecting uid into the cerebral
ventricles or subarachnoid space. This raised blood pressure in exact
proportion to the applied intracranial pressure and inversely to the
consequently decreased cerebral blood-ow. Cushing identied the
brainstem as the detector site. The pressor eect was mediated by
the spinal cord. Seymour Kety made comparable chronic observations in patients with cerebral tumours, in whom systemic arterial
pressure was increased in proportion to the elevation of their
intracranial pressure.
Attention turned to the kidneys, because chronic kidney disease
often raised blood pressure. Harry Goldblatt had thought that
constrictive changes in small renal arteries might be the primary
cause of essential hypertension because he had seen established
constrictive changes in the renal arterioles of people dying with
longstanding essential hypertension. He was able to produce stable
chronic hypertension in animals by constricting the main renal
arteries. The hormone renin had been identied in the kidneys. This
led to the generation of the octapeptide, angiotensin-II, identied by
Stan Peart. This was a powerful pressor agent when infused intravenously but there seemed to be not enough to cause chronic
hypertension. Jim Lawrence and I found that very small concentrations of angiotensin-II could produce sustained hypertension if
it was infused continuously over several days, during which the
blood pressure slowly went up to a hypertensive level.
The cause of essential hypertension is not yet established or
agreed. There are many interlocking mechanisms, any of which
might be playing some part in the disease. Although a possible
Cushing mechanism in the brainstem remained a popular explanation for the disease, it became less popular after Hering and his
followers had demonstrated arterial nerve endings in the carotid
sinus and elsewhere. These arterial baroreceptors sent nerve
impulses to the brainstem every second, signalling the current level of
blood pressure. The brainstem continuously reacted to this and
stabilised blood pressure through eectors in the sympathetic nervous system. The arterial baroreceptors were found to adapt and
19
reset their sensitivity to any sustained level of blood pressure, high or

low. A similar long-term adaptation of sensitivity was also found in
the secretion of renin by the kidneys. None the less, many people
continued to believe that a congenital genetic renal abnormality was
the cause of essential hypertension.
The heart and circulation in people with essential hypertension is a
tightly controlled system. There is a logical need to identify a xed
and stable mechanism controlling blood pressure in the long term.
From research into the voluminous hypertensive literature, and by
my study of many human necropsies, I had concluded that the
internal carotid and vertebral arteriesoften congenitally small and/
or narrowed by atheromamight themselves comprise a xed and
stable additional resistance in the blood supply of the human brain.
This might account for essential hypertension; but proper
measurements were needed.
To measure the total eective resistance, which these four main
cerebral arteries might have presented in life, I collaborated with
Drew Thomson in the Middlesex Hospital Medical School in London. Our results are described in detail in Chapter 4. I have been
excited recently that Julian Paton has identied changes in the blood
supply of the brain in the spontaneously hypertensive ratthe
closest animal model for essential hypertensionwhich seem to be
functionally identical to the atheromatous lesions that Thomson and
I identied in former patients with essential hypertenison.
20
2
The Evidence for a Neurogenic Increase of
Heart Rate, Cardiac Output and Peripheral
Arteriolar Resistance in Essential
HypertensionCurrent Views of its Cause
Men and women with essential hypertension have long been known
to have, on average, a faster heart rate than normotensive people,
matched for age and sex, even when all other factors have been
controlled and taken into account (Julius and Conway, 1968; Sannerstedt, 1969; Gillum, 1988). In a series of eighty-eight young men
(aged 2632), Paenbarger et al. (1968) noted that increased heart
rate, by itself and independently of blood pressure at the time, predicted the development of hypertension in later life. Increased heart
rate in early adult life provides the rst clue that the blood pressure is
probably being raised by increased activity of the sympathetic nervous system. This has now been rmly established by a large variety
of observations and techniques. I shall not attempt to summarise all
the data here, but refer to previous reviews by Dickinson (1991),
Esler (2004) and Grassi and Mancia (2004). These take into account
many methods of assessing sympathetic nerve activity, by recording
eerent sympathetic nerve impulses, measuring plasma catecholamines, urinary catecholamines, catecholamine metabolites and
spillover.
In Chapter 8, Julian Paton has taken the opportunity to bring upto-date further evidence for a neurogenic aetiology of the wellaccepted rat model for human essential hypertension.
The cardiac output of young essential hypertensive individuals is
on average signicantly (1520%) greater than in matched normotensive controls (Bolomey et al., 1949; Safar et al., 1976; LundJohansen, 1980), although cardiac output diminishes in older
patients. Increased output can be brought down to normal levels by
21
cardiac blockade with atropine and propranolol (Julius et al., 1975).

This seems to rule out any primary, organ-specic, non-neurogenic
inuence on the heart itself as a cause of hypertension. All these
observations suggest that sympathetic nerve activity is increased and
vagal inhibition diminished in essential hypertension (Julius et al.,
1971). There is heightened sympathetic nerve activity to both the
vasculature (Smith et al., 2002) and the heart (Neumann et al., 2005).
In a review, Grassi (2004) went so far as to say: the sympathetic
system has moved towards centre stage in cardiovascular medicine
. . . data in both animal and human studies unequivocally show that
sympathetic activation characterises the hypertensive state and participates in the development, maintenance and progression of elevated blood-pressure values. In humans, the levels of muscle
vasoconstrictor sympathetic nerve activity in both borderline and socalled white coat hypertensive patients is raised even before their
blood pressure has gone up.
There is substantial innervation of the kidneys by the sympathetic
nervous system. Increased sympathetic nerve impulses to the kidneys
could obviously raise blood pressure by constricting arterioles and
increasing renin secretion from the juxta-glomerular apparatus.
Indeed, Katholi et al. (1983) produced and maintained hypertension
simply by infusing low concentrations of noradrenaline continuously
into the renal arteries of dogs. Noradrenaline spillover into the
venous euent of an organ during sympathetic stimulation has
been observed ever since Peart (1949) rst demonstrated it for the
spleen. Since then rened techniques have been applied to humans
(Esler, Blombery, Leonard, Jennings and Korner, 1982; Esler et al.,
1984). These have shown the important contribution that the sympathetic nervous innervation of the kidneys can make to elevated
noradrenaline concentrations in essential hypertension (Esler et al.,
1988). Ablation of the sympathetic nerve supply to the kidneys
without interfering with any other part of the autonomic nervous
systemcan reduce substantially the systemic arterial pressure of
patients with severe and resistant essential hypertension (Chapter 9,
p 170).
22
THE EVIDENCE FOR A NEUROGENIC INCREASE OF HEART RATE. . .
Current explanations for increased sympathetic nervous activity in

essential hypertension
Most clinical scientists who have arrived at this point feel obliged to
attribute increased sympathetic nervous activity to psychosocial
stress of some kind, derived from emotions arising in, or reaching,
the hypothalamus before being transmitted to cardiovascular centres
in the brainstem (e.g. Korner, 2007). There have been many suggestions about the nature of the stress. The higher prevalence of
essential hypertension in black adult Americans, compared with
whites, has often been attributed to suppressed racial hostility. There
have also been comparisons between relatively primitive or impoverished people living in the countryside and town dwellers of the same
genetic stock. Such comparisons consistently demonstrate that socalled development of a community tends to raise the blood pressure of its adult residents.
The studies by Cruz-Coke (1960) and Cruz-Coke et al. (1964)
elegantly revealed the inuence of environment on blood pressure.
They examined Easter Islanders in their traditional habitat in the
Pacic Ocean and observed that blood pressure remained low
throughout life. But when the same inbred communities moved to
the mainland of Chile, the blood pressures of their adult members
rose to levels comparable with those of the American black population. A similar change was reported by Sever et al. (1980) in urban
blacks in South Africa, whose blood pressure at all ages was higher
than in the rural black population. Poulter, et al. (1984) observed
virtually no rise of blood pressure with age in adult rural Kenyans.
But when rural Kenyans moved into the city of Nairobi, their blood
pressure went up. This change was not due to selective urban
immigration of people with higher pressures (Poulter et al., 1988).
Increased body weight and increased dietary sodium probably
acount for some of the dierences, but the associated rise in heart
rate suggests the additional involvement of autonomic sympathetic
nervous mechanisms (Poulter et al., 1985).
Over twenty years, Timio et al. (1985) compared the blood pressure of a group of 126 lay women with that of a group of 138 nuns
living in a secluded religious order. The two groups were matched for
weight, height, cholesterol and triglycerides throughout the study.
Diet was unrestricted in both groups. The nuns, who spent most of
their time isolated in prayer and silence, showed no average blood23
pressure elevation with age (128/79 went to 127/80 after 20 years).

But the average blood pressure of the group of lay women rose from
128/81 to 167/95 after 20 years. The inuences of smoking, dietary
salt and other factors were neither excluded nor controlled, but the
study is as striking as that of a more recent study by Cruz-Coke
(1987) of Chilean population groups. He attributed the environmental inuence on blood pressure to a process that he called
acculturation. This seems to happen when individuals from primitive communities move into towns. Szklo (1986) observed that,
although blood pressure steadily rises during childhood in all
populations, its later rise in adult life is mostly conned to urban
populations. It is easy to think of dierences between urban and
rural living, but dicult to quantify or explain why urban life raises
blood pressure. Sever and Poulter (1989) suggested that the stress of
urban living produced a defence reaction, which increased sympathetic drive, especially to heart and kidneys. In the short term this is
certainly plausible. Whether the level of emotional stress in cities is
ever enough to cause chronic, sustained hypertension is dicult to
determine. Within dened populations it has never been convincingly shown to do so. The long siege of Stalingrad by the Germans
in 1942 did not lead to an epidemic of hypertension in its
inhabitants.
The authors of all these epidemiological studies were trying to
identify a nebulous train of neuropsychological events that might,
somehow, impinge on the brainstems cardiovascular centres. The
studies have sometimes been inconsistent because genetic factors
have to be taken into account, even in behavioural studies in animals. For example, Rothlin et al. (1956) reported that a laboratory
strain of rats, cross-bred between a Sandoz strain and a wild Norwegian strain, became signicantly hypertensive two months after
exposure to repeated bells, hooters and ashes of light, with a
maximum elevation at four to ve months. Blood pressure remained
up for a month after stopping the stimulation, then slowly fell. But
rats bred in the Glaxo laboratories did not become hypertensive even
after a year of exposure to this unpleasant-sounding experience. JP
Henry has published many studies that show the hypertensive eects
of various kinds of social stress on mammals. For example, Henry
and Stephens (1988) reported that social stress could be such a
potent cause of neurogenic hypertension that it could be produced in
mammals despite quite severe sodium restriction.
24
Neurological involvement in secondary forms of hypertension

In Chapter 9 I shall review well-established secondary causes of
human hypertension associated with normal or increased sympathetic system overactivity. These include most kinds of so-called
renal hypertension, such as salt and water overload due to chronic
renal glomerular failure, renal artery stenosis and a primary excess of
renin, aldosterone, cortisol or catecholamines. After months or years
of hypertension, all these conditions can eventually produce widespread renal arteriolar hypertrophy or contracture, left ventricular
hypertrophy or renal glomerular injury. Such changes may then
allow hypertension to persist, even when its primary cause has been
removed. A more subtle possible cause of persistent hypertension
could be resetting of the renal renin release threshold (Kaneko et al.,
1967, 1968), though I guess that this secondary eect could be
eventually reversed by prolonged hypotensive drug therapy.
The long-term eect of all these changes is that less and less
inuence, whatever it may have originally been, is eventually needed
to maintain hypertension. What started as neurogenic hypertension
may now, on the surface, appear to be unrelated to any sympathetic
overactivity (Julius, 1988). The proposition that essential hypertension is neurogenic initially, but eventually becomes self-sustaining
by mainly non-neurogenic means, seems entirely reasonable. This is
not the same as saying that essential hypertension must have a
neurogenic cause. There are some conditions that closely resemble it,
e.g. primary hyperaldosteronism (Conns syndrome) and primary
hyperreninaemia (haemangiopericytoma), in both of which the primary cause undoubtedly lies outside the nervous system. However,
measurements of increased sympathetic activity in essential hypertension are entirely compatible with the hypothesis of a neurogenic
initiation of the blood-pressure elevation.
Bjorn Folkow (1982) pointed out that structural reinforcement of
hypertension can take place over a period of time. He commented:
Neurogenic mechanisms seem to be a great pathogenetic inuence
[my italics] in early phases of most types of primary hypertension,
though probably elicited in dierent ways in dierent variants.
However, the early involvement of the structural factor may soon
more or less mask these neurogenic contributions (Folkow, 1989).
Many changes might allow the maintenance of raised blood pressure
without the need for continuing high levels of sympathetic
25
vasoconstrictor activity. But I am not aware that anyone, or any

group, has been able to produce chronic hypertension in any animal
by behavioural means alone and which is still detectable six months
after the behavioural stimulus has been withdrawn. Clinical scientists
are still seeking a credible identity for Folkows great pathogenetic
inuence in the early phases of most types of primary hypertension.
I was disappointed that no clinical scientist before Julian Paton was
interested that Drew Thomson and I had already suggested a credible identity for the great pathogenetic inuence, which Folkow was
looking for fty years ago.
Acute non-neurogenic causes for increased peripheral arterial

resistance in essential hypertension
Increased peripheral systemic arterial resistance, often called total
peripheral resistance (TPR), can have non-neurogenic causes, as
well as those associated with increased activity of the sympathetic
nervous system or with excess circulating catecholamines. For
example, TPR can be increased by circulating renin, the protein
secreted by the kidney when its blood supply is inadequate. I shall
discuss renal hypertension and other forms of secondary hypertension in Chapter 9. But at this juncture I need to point out that no
mysterious pressor substance has ever been found in individuals with
essential hypertension. There is a curiously persuasive but illogical
school of thought that high blood pressure is itself the primary
problem in essential hypertension. After all, we are quite good at
treating it. Is that not enough? Why must we look for a cause?
The eect of maintained stretch on smooth muscle

The reason is that clinical scientists have known for many years that
small arteries can change their structure and function after they have
been exposed to increased intraluminal pressure for months or
longer periods of time. In acute experiments Bayliss (1902) noted
that vascular smooth muscle from dogs, cats and rabbits tended to
contract when stretched. He dened normal vascular tone as that
resistance remaining after acute sympathetic nervous block had been
eliminated. He recognised that increased intraluminal pressure can
make living arteries constrict. When they are already constricted, a
26
reduction of distending pressure may allow them actively to dilate.

He suggested that these reactions had evolved to keep ow constant
in the face of changes in arterial pressurea pattern of behaviour
that we describe today as autoregulation. After acutely distending
an artery, Bayliss sometimes observed what he called reverberation
in arterial dimensions, with a cycle length of 15 s. These eects could
even persist in isolated arteries for several hours. For cerebral
arteries, he thought that this myogenic response could make arteries
more rigid and so permit the increased velocity of ow, due to
increased pressure, to produce its desired eect in providing a more
abundant blood supply to the cerebral tissue. To me this sounds like
the opposite of autoregulation! But he realised that the general
system required central nervous control, otherwise every rise of
pressure would cause a further rise, and every fall a fall, i.e. a vicious
circle, in the absence of any regulatory functions of the vasomotor
centres (Bayliss, 1902).
Slower metabolic changes might also facilitate autoregulation.
Wol and Forbes (1928) observed that, if cerebral arteries were
squeezed (i.e. had their internal diameter reduced) by an acute elevation of cerebrospinal uid pressure, they soon started actively to
dilate. Fog (1937) conrmed this and also reported that they actively
constricted when at their distending pressure was increased (Fog,
1939). Meyer and Denny-Brown (1957) examined the cerebral collateral circulation in Macaque monkeys. They considered that the
myogenic Bayliss eect (as they named it) probably derived more
from changes in intraluminal pressure rather than from changes in
local gas tensions of O2 and CO2, or in pH, because they occurred
within a few seconds of a change in distending pressure. Johnson et
al. (1960) examined the pressure/volume relationships of small
arterial segments. They observed that in vitro the segments invariably
expanded when intraluminal pressure was increased, but in vivo,
surrounded by other tissues, their volume rst increased but after
30 s started to decrease. Folkow (1952) reviewed the contributions of
myogenic and metabolic factors to autoregulation. He concluded
that the normal tone of smooth muscle was mainly of myogenic
rather than of metabolic origin. However, he later wrote that the
metabolic factor acts as a powerful and important brake on the
myogenic mechanism. A brake of some kind is a logical necessity to
prevent a vicious circle of unrestrained widespread vasoconstriction
appearing once a stimulus has set vasoconstriction in motion.
27
Chronic changes
Long-term exposure of arterioles to increased intraluminal pressure
may eventually induce apparent hypertrophy of smooth muscle in
their media walls (Kernohan et al., 1925; Moritz and Oldt, 1937).
Proximal constriction of the main renal artery can prevent such
changes developing in small, distal renal arteries (Byrom and Dodson, 1949; Bauer and Forbes, 1952). Folkow (1975) noted that small
arteries exposed to increased intraluminal pressure over days or
weeks developed changes that looked like medial hypertrophy and
could eventually turn into hyaline degeneration. Such changes could
narrow the lumen and increase ow resistance. Sodium and water
content of arterial walls also increased. Hollander et al. (1968)
reported that the sodium content of the arterial wall proximal to a
constriction might increase but that no such change developed distal
to a constriction. Longstanding secondary hypertension, e.g. in
Cushings and Conns syndromes, or in phaeochromocytoma, can
induce hypertrophic changes in the media of arterioles (ONeal et al.,
1970).
I imagine that chronic changes of this kind in the arteriolar bed of
many organs could be part of the structural factor that Folkow
envisaged could eventually take over from an initially neurogenic
hypertension. The general proposition that essential hypertension is
neurogenic initially, but eventually becomes self-sustaining by nonneurogenic means, seems entirely reasonable. The experiments of
Wilson and Byrom (1941) showed that if a constricting clip is put on
the main renal artery of a rat, to produce a Goldblatt type of
hypertension, this can produce small artery or arteriolar changes in
the opposite kidney, which could soon create enough increased
resistance to renal blood-ow to maintain hypertension, even after
the originally clipped kidney had been removed.
To come back to the question I posed earlier: why do we need to
look for another cause for the increased TPR of essential hypertension when we know that increased systemic arterial pressure itself
can undoubtedly increase the resistance of arterioles and the smallest
arteries? My answer is that I expect that this type of increased
resistance, which high blood pressure itself can create, will have been
programmed in the course of evolution to be held in abeyance during
sleep or when it is playing a part in so-called autoregulation. This
would prevent an animal wasting energy (hence food) through
28
maintaining an unnecessarily high blood pressure during sleep. That

is the time at which stenotic or occlusive atheromatous lesions of
large arteries are most likely to inuence the basal level of blood
pressure.
Are the changes true hypertrophy or are they only contracture or

eutrophic remodelling?
The idea that chronic spasm of small arteries and arterioles might
provide a long-term increase in ow resistance, without there being
true medial smooth muscle hypertrophy, was rst put forward by
Conway (1958) and developed by Short (1968). Both had been stimulated by Folkows analysis, but they were also inuenced by the work
of van Citters et al. (1962), who had shown how misleading the
geometry of arterioles could be in ordinary stained sections of vessels
xed in an undistended state. David Short was a senior academic
colleague of mine at the Middlesex Hospital Medical School. I
watched his careful measurements of the total cross-sectional area of
the media of small arteries and arterioles in the small intestinal
mesentery of six essential hypertensive patients, comparing them
with vessels of similar size in six normotensive controls of similar
age. After relaxing all post-mortem spasm with a warm ammoniacal
solution, he xed the vessels in a distended state under pressure, and
measured the cross-sectional area of the medial muscular wall. The
lumina of arterioles from his essential hypertensive individuals were
smaller than those from his normotensive controls. The media walls
were thicker. In life, such arterioles must have contributed more
resistance to blood ow. However, Short wrote that though the
wall/lumen ratio of the intestinal arterioles is increased in hypertension, the cross-sectional area of the wall is not increased. There is
therefore neither hypertrophy nor hyperplasia of these vessels. He
described this widespread narrowing of intestinal arteriolar lumina
as contracture, i.e. a state of chronic spasm of their muscular walls
(Short, 1968). I am sad that this nice descriptive term is no longer
used. Most inuential scientists like Mulvany, Baumbach, Aalkjaer,
Heagerty, Korsgaard, Schirin and Heistadt (1996) prefer the
Greek-derived description eutrophic remodelling, presumably so
that it can be contrasted with hypertrophic remodelling. I prefer
contracture because it implies the reduced internal diameter of the
vessels, but nobody agrees.
29
I remember David Short well from the time that we were both
working at the Middlesex Hospital. I was grateful to him for suggesting to me the use of dilute ammonia to relax all post-mortem
arterial spasm in the necropsy study I shall describe in Chapter 4. His
pioneer work was an important correction to the almost universal
assumption that longstanding essential hypertension necessarily
causes true structural changes of medial hypertrophy in systemic
arterioles. He explained to me that one way of looking at arteriolar
contracture was in the same way that we think about the contracture
of skeletal muscle in paralysed limbs. If a muscle is somehow prevented from passively stretching to its natural length it will eventually become permanently shortened. Short felt that the same could
happen to the circular smooth muscle comprising the media of small
arteries and arterioles.
Similar observations have been reported in hypertensive animals,
e.g. in the rat study by Baumbach and Heistadt (1988) on elderly
stroke-prone spontaneously hypertensive rats. But whatever name
we use to describe the phenomenon, it helps to explain how functional small artery and arteriolar changes can eventually sustain a
longstanding increase in peripheral arterial resistance.
Some generalisations about the cause of essential hypertension

In Chapter 4 I shall describe the primary, tangible and measurable
structural abnormalities that Drew Thomson and I identied in
every cadaver we examined of patients who had died with apparently
essential hypertension. We suggested that our observations provided an entirely plausible explanation for the increased sympathetic
nervous activity that underlies and appears to be the main cause of
that disease. I would like my readers to bear in mind some useful
generalisations, though there are exceptions to every rule. Essential
hypertension (i.e. hypertension without an identiable cause) is not
found in wild animals, unless they have been articially and selectively inbred. It rarely, if ever, aects children; it does not occur in
primitive populations or in those who spend all their time living a
simple life in the countryside, away from towns, or in closed religious
communities. I can summarise the epidemiological evidence thus:
30
The unique victim of essential hypertension is an adult man or

post-menopausal woman living in a town in a developed country.
Summary
The heart rate, cardiac output and total peripheral arterial resistance
are higher in individuals with essential hypertension than in normotensive controls. Eerent sympathetic nervous activity is
increased. Many suggestions have been made about its cause, e.g.
genetic predisposition, especially in respect of renal function,
acculturation of people living in towns and cities, inter-racial hostility or an acquired decrease in arterial baroreceptor sensitivity. A
chronic increase in eerent sympathetic nervous activity can eventually lead to non-neurogenic structural changes in the cardiovascular system. Small arteries can develop and sustain an increase in
ow resistance, without necessarily developing thicker muscles in
their walls, but the muscles of the heart can become thicker and
stronger.
The blood ow to the brain normally shows autoregulation, i.e.
stability of total cerebral blood-ow, despite changes in perfusion
pressure, but this facility may be diminished in established essential
hypertension.
31
3
Can Essential Hypertension be Fully
Explained by What is Already Known About
that Disease?
In the previous chapters I have explained that human so-called
essential hypertension is associated with increased sympathetic
nervous activity and that it is commonly associated with the widespread deposition of plaques of atheroma in the four main arteries
supplying blood to the brain. An extensive post-mortem study of
these main arteries revealed that, when narrowed, they must have
substantially impeded the blood supply of the brain. Could these
facts be brought together by invoking Cushings mechanism (p 6),
even though total cerebral blood-ow (CBF) had been reported to be
normal in essential hypertension? They couldbecause Harry
Goldblatt had produced long-term hypertension in dogs by constricting their main renal arteries and others had shown that total
renal blood-ow could return to normal in this situation (p 17). By
analogy, there was no logical reason why long-term human hypertension might not be accounted for by narrowed main cerebral
arteries, even though total cerebral blood-ow was normal.
This chapter will describe how essential hypertension can be
explained by answering a set of questions that I shall consider in
order:
(1) Is the epidemiology of main cerebral artery atheroma and its
relation to hypertension the same as that for coronary artery
disease and hypertension?
(2) How much does extensive atheroma increase the resistance of
the main cerebral arteries?
(3) What are the blood requirements of the human brain? How
much do they change during 24 h?
32
CAN ESSENTIAL HYPERTENSION BE FULLY EXPLAINED?
(4) What is the pressor eect of restricting the blood supply of the
brain?
(5) What is the resistance of small cerebral arteries and arterioles in
dierent kinds of systemic hypertension?
(6) What are the special attributes of the vasculature of the human
brainstem and its pathology?
In my rst monograph on this subject (Dickinson, 1965), I reviewed
the extensive literature concerning stenotic and occlusive disease of
the four main cerebral arteries in humans, and its close association
with so-called essential hypertension. Much of the work was published half a century ago. It has nearly all been forgotten. That is a
pity, because the association is by far the best pathologically correlated of all the abnormalities that have ever been considered as
possible causes of essential hypertension. It is extraordinary that
such a close association has been overlooked or ignored by most of
those who have tried to understand the disease. To help readers
without easy access to some of the early work, I shall briey review
the epidemiology.
(1) Is the epidemiology of main cerebral artery atheroma and its

relation to hypertension the same as that for coronary artery disease
and hypertension?
The great Charles Miller Fisher was one of the rst neuropathologists to recognise that stenosis and occlusion of the main cerebral
arteries in the human neck could cause senile dementia and strokes
of all kinds. Fisher et al. (1965) examined many human necropsies in
which they reported complete occlusion of the internal carotid artery
in twenty-eight cases (6.5%), and severe arterial stenosis in three
(3%). In their necropsy studies, Hutchinson and Yates (1956) paid
particular attention to the vertebral arteries in the neck. They coined
the term carotico-vertebral stenosis to describe their ndings
(Hutchinson and Yates, 1957). Hypertension had often been present
in life, but the association was not quantied. For reasons I have
already explained, I collaborated with the late Drew Thomson in the
pathology department of the former Middlesex Hospital Medical
School to investigate the resistance that these human cervical cerebral arteries could have oered in life to the brains blood ow, even
33
when they were fully dilated. In what follows I shall review the
epidemiology of large cerebral artery atheroma and its very close
association with high blood pressure.
In their pathological study of seventy cases of carotid and vertebral artery disease, McGee et al. (1962) reported: Hypertension
was found to correlate with carotid-vertebral disease, and this correlation was on the basis of the vertebral artery disease. This would
support Dickinsons evidence that hypertension is related to vertebral artery stenosis. This referred to a paper that Thomson and I
(Dickinson and Thomson, 1960a) had published in Clinical Science.
Many people continued to draw attention to the close association
between atheromatous cerebrovascular disease and hypertension.
But Thomson and I were lone voices suggesting that the large artery
disease came rst and that this had increased blood pressure.
Fisher et al. (1965) conrmed the close association of cervical and
intracranial cerebral artery disease with hypertension in a large
unselected necropsy series. They specially noted the relationship with
the basilar artery and wrote: Hypertension aggravates (sic) cerebral
atherosclerosis in general and basilar atherosclerosis and stenosis in
particular. This was in striking contrast to aortic atheroma, which
was almost equally extensive at necropsy, when previously hypertensive and normotensive patients of the same age were compared.
In another investigation, Fisher reported that in his series of 1,042
consecutive necropsied brains, he saw 114 small deep cerebral
infarcts, which he called lacunes. These were the commonest cerebrovascular lesions. Evidence of preceding hypertension was present in 111 (97%) of these cadavers.
Baker et al. (1967) noted dierent racial predispositions to
atheroma at dierent sites and said that, Most published reports
suggest that atherosclerosis, particularly of the coronary arteries, is
very uncommon among orientals . . . this was not found to be true in
the case of the cerebral arteries in a Japanese population. With
identical coding techniques, atherosclerosis of the arteries of the
circle of Willis, age group for age group, was found to be at least as
severe in the Japanese as in the Minnesota population and . . . it is
likely that it is actually somewhat more severe. There are striking
dierences in atheroma distribution between countries and between
dierent racial groups. Neser et al. (1971) noted the special predisposition of American blacks to cerebral arterial disease and strokes.
Solberg and McGarry (1972) compared the incidence, severity and
34
distribution of atheroma in 2,166 necropsies of blacks and whites.

They observed: Negroes have more atherosclerosis in the intracranial arteries and as much or more in the cervical arteries, while
Caucasians have more atherosclerosis in the aorta and coronary
arteries . . . Hypertension appears to exert a strong atherogenic
inuence (sic) especially on intracranial arteries, increasing the risk
of infarction. Cooper (1985) noted that the prevalence of hypertension ran in parallel with that of cerebral arterial atheroma and
was more common in American blacks than in American whites.
Divergence of atheroma severity between blacks and whites in the
USA begins between the second and third decades of life (Voors et
al., 1979) or between the third and fourth decades (Gillum, 1988).
The same applies to high blood pressure (Newman et al., 1986).
Racial dierences are also seen in ischaemic heart disease, which is
much less common in blacks than in whites (Williams, 1985). Similar
dierences have also been observed in Birmingham (England) by
Beevers and Cruickshank (1981), who reported that black people
there suered nearly twice as many strokes, but only about half as
many heart attacks than whites, matched for age and sex.
In a large series of men between 40 and 50, hypertension was
correlated with lipid abnormalities (Abernathy et al., 1988). In a
recent study of 1,669 Chinese peasants by Jinzhen et al. (2009), 358
(21%) were reported to have isolated hyperlipidaemia, 257 (15%)
had isolated hypertension and 189 (11%) had both conditions. The
ndings suggested the presence of many common risk factors. Such
results would be expected if lipid abnormalities can cause or increase
atheroma and if atheroma of the cerebral arteries causes hypertension. Bjurulf (1964) contrasted the prevalence of hypertension with
the prevalence of coronary artery atheroma and the prevalence of
arterial atheroma elsewhere: The systolic blood pressure shows a
signicant correlation with atherosclerosis of all the cerebral vessels,
and of two parts of the aorta. On the other hand no correlation
could be demonstrated with the atherosclerosis of the coronary
vessels . . . The diastolic pressure showed a correlation with atherosclerosis of all cerebral vessels, but none with atherosclerosis of any
other vascular area [my italics]. Bjurulf singled out the basilar and
posterior cerebral arteries, whose correlation of atherosclerotic
severity with hypertension reached P<0.01 signicance, while it only
reached P<0.05 signicance for carotid and middle cerebral artery
atheroma. In a comparison of 6,688 patients with coronary artery
35
lesions, with 2,119 atheroma-free patients, Vliestra et al. (1980)

reported very little dierence in mean blood pressure between the
two groups. After adjustment for other risk factors, the dierence
disappeared altogether, except in one sub-group of 4665-year-old
women.
The special predisposition of vertebral/basilar atheroma to

hypertension
The extremely weak relation between coronary artery atheroma and
hypertension makes a striking contrast to that between vertebral/
basilar arterial atheroma and hypertension, which is extremely
strong. There can be racial predisposition to atheroma in general and
to cerebral artery atheroma in particular. Resch and Baker (1964)
and Resch et al. (1967, 1969) made an international comparative
study of 6,000 necropsies. They wrote that atheroma of large arteries
contributing to the Circle of Willis was visible in a Japanese population as early as the second decade of life, and in a North American
population in their early twenties. They also wrote: Atheroma
increases rapidly in both populations after the age of 35. The
hypertensive Japanese population has a specially high incidence of
atheroma in the large cerebral arteries within the skull. The Japanese populations liability to intracranial main artery atheroma was
strongly conrmed in the second paper by Resch and others (1969),
which reported that atheroma of large arteries contributing to the
Circle of Willis was visible in a Japanese population as early as the
second decade of life. In an exceptionally detailed study (published
as a substantial supplement to a Scandinavian journal of pathology),
Sternby (1968) wrote: In this [his] series the presence of hypertension
was associated with increased atherosclerosis of all arteries in both
sexes. The increase was, however, most marked in the cerebral
arteries and most obvious at ages below 70. Sternby particularly
mentioned the basilar artery (see his g. 75): In diabetics, a dierence between the hypertensive and normotensive subjects with
reference to atheroma was only demonstrable in cerebral atheroma.
Giertsen (1966) used cholesterol/phospholipid ratios in arterial
specimens to quantify atheroma. He observed a correlation coecient
of age/aortic disease of +0.66 and about +0.42 in respect of age/
cerebral arterial disease; but he also commented that the relationship
of large cerebral artery atheroma to hypertension was just as
36
pronounced in old as in younger age . . . Only in hypertensive individuals does cerebral atherosclerosis reach approximately the same
severity that aortic and coronary atherosclerosis may reach in normotensive individuals. This was in striking contrast to aortic
atheroma, which was of almost the same severity in hypertensive and
normotensive patients of similar age. Baker et al. (1969) reported the
close association of intracranial atheroma with raised blood pressure
in life, rather than simply with increased heart weight or left ventricular thickness at necropsy.
Bouthier et al. (1985) compared 38 hypertensives with 38 agematched controls and reported increased rigidity of the common
carotid arteries in the hypertensive group. Van Merode et al. (1987)
reported that carotid distensibility and cross-sectional compliance
was signicantly less than normal in young (2035) borderline
hypertensives. Laurent et al. (1988) reported similar changes and
wondered whether the changed viscoelastic properties of the carotid
arteries were simply the result of hypertension, or whether widespread change in physical properties could even be a cause of
hypertension. Girerd et al. (1989) compared average large artery
pulse wave velocity in young (1824) borderline hypertensives with
that in age-matched normotensive controls. They reported that, even
when their subjects and controls were compared at a time when their
blood pressures were identical, the hypertensive group had signicantly increased pulse-wave velocity. This suggested that young
essential hypertensives already had stier large arteries than their
normotensive controls. Changes were already beginning to develop
by the end of the second decade. Van Merode et al. (1993) reported a
faster rate of deterioration in these arterial attributes in people with
essential hypertension than in normotensive individuals.
In an extensive search of the literature I have found no epidemiological evidence dissociating the incidence of cerebral arterial
atheroma from that of essential hypertension. There are renal,
endocrine and other causes of hypertension, which can obviously
exist without increased cerebral atherosclerosis, e.g. in children. But
extensive atheroma of the main cerebral (especially vertebral)
arteries simply does not occur in adults unless hypertension, as
usually dened, has been present for several years. The only exception is that which can arise when associated heart disease has lowered previously raised blood pressure (Fishberg, 1925). I cannot
resist pointing out that all the epidemiological and pathological
37
evidence falls into place if large cerebral artery narrowing causes

essential hypertension.
(2) How much does extensive atheroma increase the ow resistance

of the main cerebral arteries?
The resistance of the main cerebral arteries must rst depend on their
natural size, which is genetically determined. Later, the deposition of
atheromatous plaques can augment the ow resistance of any of the
main cerebral arteries, especially those that begin life congenitally
small. In a magisterial review, Agabiti-Rosei et al. (2008) classied
and dened the nomenclature of those structures that comprised the
total peripheral resistance (TPR). They said that the main drop in
hydrostatic pressure occurred in small resistance arteries of (350
100 mm internal diameter), in arterioles (<100 mm internal diameter),
and in capillaries (about 7 mm internal diameter). Between 45% and
50% of the TPR was contributed by teminal arteries and arterioles,
12% to 30% was in capillaries, 3% to 4% in small veins (venules)
and nally 3% was in the large veins. All these estimates were for
supine individuals. Like almost everyone else who has written on the
subject, the authors failed to mention large cerebral artery resistance.
This omission helps to explain why the cause of essential hypertension lay undiscovered for so many years.
The rst intimation of the great importance of large cerebral
artery resistance came from studies of young adults, who can usually
tolerate short periods of complete occlusion, either of one internal
carotid or of one vertebral artery, without suering brain damage. In
young adults, an occluded main cerebral artery may provide a stimulus for the development of collateral arteries. Necropsies and
angiographic observations suggest that this facility is lost by most
people reaching their thirties or forties. Many investigators have
recorded pressures in the internal carotid artery immediately above
an acutely occluding clamp. Continuous records show that pulsation
almost disappears, and intraluminal pressure falls to about half its
former value when the clamp is applied. Sweet and Bennett (1948)
continuously recorded pressures just above the clamp in patients
with dierent initial systemic arterial pressures. In ve of their
patients, the recorded pressures, in mmHg, fell from 140/100 to
80/65, from 210/100 to 85/65, from 185/82 to 70/52, from 170/70 to
38
80/56 and from 160/100 to 80/55. Clamping the external carotid

artery at the same time made little dierence to the pressure recorded
in the internal carotid artery. These consistent results should help to
dispel any idea that the main cerebral arteries have plenty of spare
functional capacity, to allow stenotic lesions in the internal carotid
and vertebral arteries to be ignored. With the skull open, Bakay and
Sweet (1952) directly recorded the cortical temporal artery pressure
of a 56-year-old man as 135/83 mmHg during free blood-ow, while
blood pressure in his arm, recorded at the same time, was 158/106.
Some large arteries supplying the heart muscle, the kidneys, the
other main abdominal organs and the limbs take a nearly rightangled turn at their origins, but thereafter they usually follow
straight or gently curved paths. Measurements of intraluminal
pressure at the distal ends of large arteries, before they have split into
arterioles, usually provide values within a few mmHg of mean aortic
pressure, except when ow is much increased, as in an exercising
limb. However, the usual course of each of the four main human
cerebral arteries is both twisted and tortuous. In particular, the
vertebral arteries follow a twisted path and almost double-back on
themselves half-way up the neck. This is well shown in Fig. 3.1. This
is a diagram of the main human vertebral/basilar arteries drawn by
John Stirling Meyer, based on his own series of retrograde vertebral
arteriograms. When Stirling Meyer showed me many of his cerebral
arteriograms in Detroit in 1962, he had no doubt that atheromatous
large arteries provided highly signicant resistance to blood ow.
Several of his angiograms showed a complete occlusion of one of
these large arteries by atheroma or organised clot. Fisher (1954) had
noted 6.5% complete occlusions of the internal carotid artery in his
human necropsy series. The sometimes convoluted and twisted
course of the vertebral arteries, and the partly convoluted course of
the internal carotid arteries, are well shown in the X-ray photographs of the injected and distended cerebral arteries that Drew
Thomson and I obtained from three cadavers in our necropsy series,
after we had removed half the neck and half the skull base as a single
mass of bone and tissue. I shall describe and illustrate these specimens in my next chapter and also summarise the measurements that
Thomson and I made of the ow resistances of the main cerebral
arteries of ninety-four cadavers.
With the skull open, Woodhall et al. (1952) made several measurements of the pressure in small human cerebral arteries by direct
39
Fig. 3.1 Composite diagram of the human vertebral arteries traced by Stirling Meyer et
al. from several subclavian-vertebral arteriograms: 1, left subclavian a; 4, innominate a;
8, common carotid as; 9, internal carotid a; 17, vertebral as; 21, basilar a; 24, posterior
cerebral as. The two posterior cerebral arteries join at their ends to the two internal
carotid arteries, to make the posterior part of the Circle of Willis (Fig. 3.2). Branches
from the ends of the posterior cerebral arteries join the ends of the internal carotid
arteries to make the posterior part of the Circle of Willis. Reproduced with permission
from Archives of Neurology (1960) 2 2745. (Copyright 1960, American Medical
Association. All rights reserved.)
puncture. They estimated that the mean circle of Willis pressure was
usually about 60% of systemic arterial pressure. Many direct readings of the pressure in small cerebral arteries with internal diameters
greater than 350 mm should correct the widespread misapprehension
that the resistance of the main cerebral arterial trunks is trivial and
can be ignored.
40
(3) What are the blood requirements of the human brain? How much
do they change during 24 h?
The four main arteries supplying the human brain are anatomically
and functionally dierent from all other large arteries. I have already
explained why I expected that most, or all, relaxable neural or
chemical constriction of the brains blood supply would have evolved
to be suspended during sleep, to prevent the wasteful consumption of
energy, if blood pressure was needlessly high at this time. Darwinian
thinking along these lines made me conclude that unrelaxable
structural resistance of the main cerebral arteries is likely to be the
main determinant of cerebral blood-ow (CBF) during sleepand
thus of basal systemic arterial pressure. This expectation led me to
guess that, when the brain nds itself getting signicantly short of
blood during deep sleep, it will rst relax all its small resistance
arteries and arterioles, using the many neural and chemical
mechanisms available to it. But when no further relaxation is
possible, it will prevent any possibly injurious further fall of cerebral
blood ow by stabilising systemic arterial pressure, probably by the
Cushing mechanism (p 7), until equilibrium is reached and an
adequate CBF is restored.
Once Seymour Kety and Carl Schmidt had devised a method of
measuring total cerebral blood-ow in human beings, in life, using
the (relatively inert) gas, nitrous oxide, the next two decades were
occupied by a multitude of published measurements of total CBF in
almost every possible human activity. The metabolic rate, oxygen
consumption and total blood-ow of the human brain were found to
change very little during healthy adult life. In young adults, the
values for total cerebral blood-ow diminish signicantly during
deep sleep (Zoccoli et al., 2002), but they transiently return to
waking levels during episodes of rapid-eye-movement (REM) sleep
(Kotajima et al., 2005). Each such change was accompanied by a
small rise in glucose and oxygen uptake. In instrumented newborn
sleeping lambs, each REM-sleep episode was associated with a shortlived blood-pressure elevation and a burst of increased sympathetic
vasoconstrictor nerve activity (Cassaglia et al., 2009). The authors
speculated that simultaneous constriction of small arteries and
arterioles might protect the brain from damage by blood pressure
surges.
Recent estimates concur that total CBF and oxygen consumption
41
hardly change while human beings undertake mental tasks. Mental

arithmetic has been observed to reduce total CBF slightly, probably
because of hyperventilation, which reduces arterial PCO2 (Debreczeni et al., 2009), while cerebral lactate production may slightly
increase (Madsen and Vorstrup, 1991). Even muscular exercise has
no signicant eect on CBF, even though heart rate, cardiac output
and blood pressure increase (Critchley et al., 2000).
It is now common knowledge, from a large number of regional
blood ow (rCBF) measurements, that, although local cortical blood
ow frequently changes according to what a subject is thinking
about or doing, such changes are small and do not much aect total
cerebral blood-ow. Many studies of rCBF in patients with temporal
lobe epilepsy have shown locally-increased cerebral blood-ow
during epileptic seizures and reduced brain perfusion between seizures, but even during seizures, blood ow is usually adequate for
metabolic demand (Duncan, 1992). Single photon emission computed tomography (SPECT) measurements of rCBF in many
patients with idiopathic generalised epilepsy have recorded mainly
reductions of blood ow rather than increased ow. Joo et al. (2008)
even reported: No brain regions in IGE [idiopathic generalised
epilepsy] patients had increased rCBF. So even when inter-neuronal
nerve trac must (presumably) be much increased, CBF is little
changed.
Circle of Willis pressure

To measure the eective resistance of the four main cerebral arteries,
we need to know the blood pressure in the Circle of Willis, where the
ends of the internal carotid and basilar arteries meet (Fig. 3.2). This
pressure is dicult to determine. The vessels are very inaccessible
beneath the brain. The choice of a sampling site must be arbitrary.
The posterior communicating arteries, like every other part of the
Circle of Willis, vary considerably in size. The thin intracranial
arteries are fragile. Surgeons are reluctant to puncture them to
measure their internal pressure. I am not aware of any comprehensive attempts to measure average small cerebral artery pressures in a
substantial series of subjects with and without essential hypertension.
The measurements would have to be made in conscious subjects, to
avoid the inuence of general anaesthesia on cerebral blood-ow.
Readers who have followed my work will realise that I predict and
42
Fig. 3.2 Diagram of the main component arteries meeting at and comprising the Circle
of Willis beneath the human brain.
expect that Circle of Willis pressures will be found to be not signicantly increased in patients with uncomplicated essential hypertension, because pressure in the main arteries will already have fallen
by the time that blood reaches the smaller vessels that make up the
Circle of Willis. One day, determined clinical scientists will perhaps
take a leaf from the book opened by Damiano Rizzoni, who took
advantage of planned craniotomies for cerebral tumours to examine
the dimensions of small resistance arteries and arterioles in brain
tissue from normal and essential hypertensive patients. I shall return
to his imaginative and important work later in this chapter. But
those who believe that the only signicant cerebrovascular resistance
is provided by tiny arteries and arterioles should stand back and
reect upon the extraordinary diculties that our ancestors brains
had to overcome in their evolutionary development.
43
There is an important deduction to be made from the relative

constancy of total cerebral blood-ow under many conditions. A
Darwinian physiologistas I am proud to beis entitled to assume
that all the main arteries supplying blood to the human brain will
have evolved to be of the appropriate size for their function in life. If
they are too big, they will hold an inconveniently large volume of
blood. If they are too small, they will increase ow resistance and
elevate blood pressure unduly. It is reasonable to assume that Homo
sapiens will have established, during evolution of the species, the best
compromise solution for all the interacting variables, given the
environment at the time. If the environment changes, the interacting
variable functional properties will doubtless also change. I hypothesised that the small cerebral resistance arteries and arterioles should
be fully dilated during sleep, to minimise the waste of energy if blood
pressure was needlessly high at that time. But relaxation and dilation
of the large cerebral arteries of adults will necessarily be limited by
their brous structure. Furthermore, elderly people often develop
unrelaxable calcication of atheromatous plaques in their main
cerebral arteries.
Kety (1950) found it dicult to believe that atheromatous plaques
could seriously increase cerebrovascular resistance enough to impair
cerebral blood-ow, even though he had reported that chronic elevation of blood pressure could result from cerebral tumours
chronically raising cerebrospinal uid (CSF) pressure, thus reducing
cerebral blood-ow and raising systemic arterial pressure by Cushings mechanism (Kety et al., 1948b). He was sure that, if the resistance of large cerebral arteries was increased by atheromatous
plaques, small cerebral resistance arteries and arterioles would simply
dilate and prevent any signicant decrease in cerebral blood-ow. He
had regularly seen this happen when sympatholytic hypotensive
drugs had been infused. I contend that this expectation may not
apply in deep sleep, if the small resistance arteries and arterioles are
already fully dilated at this time. The brains need for blood would
inevitably raise basal blood pressure by the Cushing mechanism.
This would then also raise casual blood pressures during the following day.
There is no reason to expect that the vertebral and internal carotid
arteries, either congenitally or in the teens and early twenties, will
have grown any larger than they need to be to carry the large
quantity of blood that the brain needs. Any small increase of ow
44
resistance produced even by the smallest intrusive plaque of atheroma will necessarily limit, to an equivalent degree, the fall of cerebral
blood-ow in sleep. I therefore suggest that every intrusive deposit or
plaque of atheroma in a main cerebral artery that increases CVR can
contribute to systemic arterial hypertension. This hypothesis is difcult to prove; but it ts all the available data much better than any
other explanation.
A revolution in measurements of total blood ow to the human brain

Niels Lassens classic graphical presentation of the consistency of
human CBF in many dierent situations (Fig. 1.1, p 14) suggested
that our species may have evolved physiological mechanisms to
preserve an adequate supply of blood to the brain, to prevent it from
falling below its usual value of about 55 ml. 100 g brain-1. min-1.
Figure 1.1 also suggests that the human race may have evolved other
mechanisms to prevent cerebral blood-ow from rising above its
usual ceiling value, which also seems to be set at about 55 ml. 100 g
brain-1. min-1. The conrmed stability and constancy of cerebral
blood-ow has been the cornerstone of our collective misunderstanding of essential hypertension. Seymour Kety inadvertently laid the groundwork when he reported sixty years ago that
twelve of his patients with essential hypertension had the same total
cerebral blood-ow as had eighteen normotensive adults (p 13).
Time has moved on. It is now clear that Ketys patients were studied
under somewhat stressful conditions. Their cerebral blood-ow was
probably raised to its ceiling value by excitement or apprehension.
I have tried to identify the moment that our collective errors were
corrected. I suggest that the rst crack in our misunderstanding
appeared some 25 years ago when Shaw et al. (1984) published their
study of benign ageing in 130 healthy hypertensives. They reported
that the average total cerebral blood-ow values were signicantly
less than those in matched normotensive control patientrs. Their
total CBF values declined at an average rate of 0.5 ml. 100 g-1. min-1.
each year. I should also like to acknowledge the earlier observations
of Raab (1931), who had reported that the brains arterial-tocerebral venous oxygen content dierence was greater in people
with essential hypertension than in normotensive control patients.
Raab inferred that cerebral blood-ow was less than normal
and suggested that a Cushing mechanism might have raised
45
blood pressure. Raabs subjects were elderly and some were short
of breath. His observations were unjustly forgotten after Seymour
Kety had used the nitrous oxide technique to report that CBF in
essential hypertension was the same as in normal people (p 13). But
clinical investigators have since been unable to conrm Ketys
observations when their subjects were resting and not stressed in
some way.
The apparent constancy of CBF also arises because high levels of
blood pressure in normal waking life create a balancing myogenic
increase of cerebrovascular resistance provided by arterioles and
small resistance arteries. This ensures that its blood ow is not more
than the brain needs. Lasssen and Klee (1965) used radioactive
85
krypton to measure rates of cerebral saturation and desaturation
and thought that the early CBF measurements may have been
slightly overestimated. Most CBF measurements published since
then have used a dierent and more convenient radioactive gas,
133
xenon. This also has the advantage of allowing duplex comparative studies to be made using stable xenon. Modern measurements of
cerebral blood-ow are now consistent, but also devastating. I use
that word advisedly. The new work has shattered the cosy certainty
of those who believed that the whole problem posed by essential
hypertension was that some mysterious psychosocial mechanism
raised blood pressure by increasing sympathetic nervous activity.
Recent investigators using 133xenon are now regularly reporting
lower than expected CBF values in people with essential hypertension, as well as in patients with manifest cerebrovascular disease.
This makes it dicult to maintain that hypertension comes rst and
proportionately elevates cerebrovascular resistance (CVR). We now
acknowledge that CVR is disproportionately increased, so that cerebral blood-ow falls below its normal value. For example, Rodriguez et al. (1987) reported slight reductions in both total and
regional cerebral blood-ows in essential hypertension and a signicant inverse correlation between systemic arterial pressure and
CBF (r = 0.43, P<0.01). Nobili et al. (1993) examined 101 severe
essential hypertensive patients and reported that diuse cerebral
hypoperfusion was present even in neurologically asymptomatic
patients, especially when untreated. Both regional and global cerebral
blood-ow reductions were observed in about one-third of their
patients. Thulin et al. (1993) reported that all their measurements of
total CBF in a series of severe hypertensive patients fell between 25
46
and 53 ml. 100 g-1. min-1. These were all less even than average values
of CBF in normotensive individuals.
Another set of regional cerebral blood-ow measurements has
been made using positron emission tomography (PET). Fujii et al.
(1990) used PET to examine eight hypertensives with previous transient ischaemic attacks. They reported diminished regional bloodows in several supratentorial structures, including striatum and
thalamus. Lambert et al. (1994) reported relative underperfusion of
cortical brain regions in patients wih essential hypertension. Nakane
et al. (1995) reported that regional cerebral blood-ow in severely
hypertensive patients with cerebral infarcts was diminished, but it was
also reduced in cortex and deep grey matter, even in patients without
infarcts. In their review of many studies using PET, Fujishima et al.
(1995) conrmed that regional cerebral blood-ows in essential
hypertensives were often diminished, especially in the cortex and
basal ganglia. In the same review, they also drew attention to similar
studies in spontaneous hypertensive rats (SHR). These rats also had
diminished regional blood ows in cortex and thalamus, together
with diminished glucose utilisation in many regions of the brain.
More recent PET studies in human essential hypertension conrm
that blood ow is reduced in many cortical regions. Waldstein et al.
(2010) used single photon emission tomography (SPECT) and
reported that generally healthy men between 54 and 83 years with
higher levels of blood pressurenone at the time on hypotensive
drugshad reduced regional cerebral blood-ows (rCBF) in all the
thirteen brain regions they examined, most to a signicant degree.
The outow from the internal jugular vein in a group of essential
hypertensives was less than that in control patients. There was also a
signicant reduction in cerebral oxygen utilisation in cortical regions
(Lambert et al., 1996). Troisi et al. (1998) measured mean middle
cerebral artery blood-ow velocity by a trans-cranial Doppler
method in young hypertensive patients and compared their results
with those in matched normotensive control patients. This conrmed
that middle cerebral artery blood-ow velocity was reduced in
hypertensive individuals. In a recent study, Dai et al. (2008) used
continuous arterial spin-labelled magnetic resonance imaging to
compare otherwise normal elderly subjects with matched normotensive controls. They reported regional reductions of cerebral
blood-ow in cortical regions and also in limbic and paralimbic
structures in hypertensive subjects.
47
The total blood ow of the brain compared with that in other organs
Many people nd it hard to believe that the mass of jelly, which
comprises the human brain, has a normal blood-ow through it
of more than a pint of blood each minute. The relative constancy of
total CBF makes a striking contrast to the blood requirements
of most other organs of the body, in which blood ow always
increases when the organ becomes more active. This applies as much
to the pancreas and to the salivary glands, as to the muscles of the
limbs and of the heart. Most estimates of the coronary artery bloodow of resting adults are that it is about 0.8 ml. g heart weight-1. min-1,
which equates to about 250 ml/min for an average-sized heart of 300
g. The most accurate measurements I know are those by Wieneke et
al. (2005), who measured average ow velocity and luminal crosssectional area of the proximal segments of all three coronary arteries
in twenty-eight resting patients without coronary arterial lumen
irregularities. They reported that the average global coronary ow
for all three coronary arteries added together was 197 ml/min. To
simulate the changes with exercise, they could increase this with
adenosine-induced hyperaemia to an average of 637 ml/min. To
emphasise the disparity between the blood ow needs of the brain
and those to the heart muscles of an adult at rest, I like to point out
that the human brain continuously uses about four times more blood
than the muscles of the beating heart.
The arteries of the brain have to supply enough blood at an
adequate pressure to a most inconveniently placed organ, which
demands a large blood ow. The human brain is a tremendously
active chemical factory and telephone exchange. It has to maintain
resting membrane potentials in millions of nerve cells, despite the
inevitable slow leaks of charged ions across cell membranes by diffusion. It has to accommodate macromolecule turnover, membrane
and vesicle tracking, axonal transport, neurotransmitter synthesis
and a host of other energy-requiring activities. Although it is highly
ecient, the human brain consumes the same amount of energy and
produces about the same amount of heat as an old-fashioned 20-W
lament light-bulb. A rapid cerebral blood-ow is needed to dissipate this heat whether the owner of the brain is asleep, awake or
taking strenuous mental or physical exercise. In Chapter 6, I shall
review cerebral oxidative metabolism, but will mention now that
about 25% of the total adenosine triphosphate (ATP) of the brain is
48
broken down every second to provide energy (McIlwain and

Bachelard, 1985). Doubtless the same amount of ATP has to be
synthesised every second to replace it.
Readers of the rst chapter of the present book, and of my second
monograph (Dickinson, 1991), will appreciate that all my work on
hypertension has been concerned with the blood supply of the brain.
I believe that most hypertensiologists would now concede that
preservation of an adequate blood supply to the brain has an even
higher priority than the blood supply of the kidneys, although the
late Arthur Guyton might not have agreed. But he would certainly
have agreed that essential hypertension had to have a physical cause,
even if it had not yet been found. As a clinical scientist I nd it
intolerable to live with the absurd categorisation of the commonest
variety of human hypertension as essential. My identication of
atheromatous stenoses of the four main cerebral arteries as its cause
may be wrong, but at least has the merit of suggesting experimental
tests. Proponents of psychosocial causes should be challenged to do
the same.
(4) What is the pressor eect of restricting the blood supply of the
brain?
The work I reviewed in the last chapter strongly suggested that the
variety of human high blood pressure called essentialfor want of
a better namewas associated with increased activity of the sympathetic nervous system. This slightly increased the heart rate, cardiac output and peripheral small artery constriction. Leaving aside
improbable psychosocial primary causes for these changes, I shall
consider instead the blood supply of the brain, bearing in mind
Harvey Cushings classic observations that restricting the blood
supply of a dogs hind brain, by increasing cerebrospinal uid
pressure, activated the sympathetic nervous system in a reproducible
and quantitative manner.
In a previous book (Dickinson, 1991, p 36) I reproduced g. 3.1,
which was a personal continuous 30-h record of the blood pressure
of a conscious rabbit. The animal was moving about its cage, eating,
cleaning itself and resting at intervals during the long period of
observation. When I continuously infused intravenous angiotensinII at 0.0025 mg.kg-1. min-1. into a previously inserted right vertebral
49
artery catheter, the animal immediately developed, and sustained, an

elevation of 30 mmHg in its lowest levels of blood pressure, recorded
from another previously-implanted catheter in the femoral artery.
The 4-h record demonstrated the exquisite sensitivity of mammalian
blood-pressure control during a drug-induced cerebral vasoconstrictor or direct central neuronal stimulus. I suggest that hindbrain
arteries grossly narrowed by atheromatour plaques might elevate
human basal blood pressure in a way similar to that described for the
now well-accepted animal model for essential hypertensionthe
spontaneous hypertensive rat (SHR), in which Paton et al. (2007)
have identied narrowed and congenitally small vertebral and basilar arteries.
Could human basal blood pressure be raised in a comparable way?
Seymour Kety and his colleagues showed that it could. In a series of
patients with brain tumours, they reported that the higher the cerebrospinal uid pressure, the lower was the total cerebral blood-ow
and the higher was the (resultant) systemic arterial pressure. This
convincingly demonstrated the Cushing mechanism operating in
humans. Figure 3.3 shows the excellent correlation (r = +0.86)
between intracranial pressure and mean arterial pressure. However,
there is one dierence between this relationship in patients chronically exposed to an increased cerebrospinal uid pressure and the
acute Cushing phrenomenon. In the experimental animal counterpart, blood pressure did not begin to rise until cerebrospinal uid
pressure closely approached it. Kety had noted the excellent correlation . . . between intracranial pressure and the acute Cushing
phenomenon . . . The acuteness of the animal experiments and the
depressant eect of anaesthesia may possibly explain the dierence
(Kety et al., 1948).
But in another paper in the same volume of the Journal of Clinical
Investigation, Ketys clinical investigators had compared the average
total cerebral blood-ow of eighteen normotensive people with the
average total cerebral blood-ow of twelve people with essential
hypertension and reported that average total CBF in both groups
was the same: 55 ml. 100 g. brain weight-1. min-1. (Kety et al., 1948a).
This was an unexpected, amazing and epochal observation. In Ketys
eyesand in the eyes of the rest of the worldit appeared that the
blood supply of the human brain was subserved by an ecient
autoregulation mechanism, which controlled the calibre of small
resistance arteries and arterioles and kept total CBF constant.
50
Fig. 3.3 The relation between cerebrospinal uid pressure and simultaneously recorded
mean systemic arterial pressure in a set of patients with cerebral tumours (Kety et al.,
1948b). Reproduced with permission from the Journal of Clinical Investigation (1948) 27
493499.
After Seymour Kety had reported this nding he wrote: A

number of possibilities present themselves by which to explain this
inordinately high tone of cerebral vessels and the hypertension. The
increased resistance may be primary and the hypertension a compensatory adjustment brought about by cerebral anoxia. This is
unlikely, since there is no evidence of a restricted cerebral circulation
in essential hypertension, whereas in other conditions, such as high
intracranial pressure or cerebral arteriosclerosis, in which the
hypertension is probably compensatory, some degree of cerebral
ischemia exists to initiate and maintain this mechanism (Kety,
1950). The apparent normality of cerebral blood-ow in essential
hypertension means that cerebrovascular resistance (CVR) must be
proportionately increased. Almost everyone has assumed for years
and most people still assumethat the increased CVR in essential
hypertension is of the same nature as the increased vascular resistance in other organs, i.e. contributed by the smallest arteries or
arterioles. Everyone has also assumed that the increased CVR has
somehow been created by the primary but mysterious blood-pressure
elevation itself.
Ketys conclusion, cited above, was almost identical to his later
criticism of a presentation that I made to a Princeton conference on
cerebrovascular diseases (Dickinson, 1968). I should rst take issue
51
with his statement that there is no evidence of a restricted cerebral

circulation in essential hypertension. We can be sure, from more than
a century of physiological observations in many animals, and some
also in humans, that nobodys blood pressure during deep sleep falls
as low as it would fall if the autonomic eector system of the upper
spinal cord was anaesthetised or otherwise put out of action. There is
always a detectable residual amount of sympathetic nervous vasoconstrictor tone present during sleep. Therefore there is always some
active restriction of the cerebral circulation during deep sleep.
Next, I should go back to Horace Smirks insistence on the great
importance of basal blood pressure, i.e. that maintained during
complete rest and sleep once its lower limit has been reached. The
current hypertensive literature is full of accounts of dippingthe
tendency for the blood pressure of virtually all normal and many
hypertensive individuals to fall, or dip, at night. I dont like this silly
term at all. It suggests a duck diving for sh rather than what
happens to blood pressure as most people go to sleep. Why does
blood pressure gently fall to a trough level during sleep and remain
there for 34 h, though with minor perturbations during body
movements and rapid-eye-movement sleep?
Recently there has been published an important multiple author
and multinational review of the curiously-named condition: isolated
nocturnal hypertension (INH) by Fan et al. (2010). This showed,
with a very high degree of certainty and signicance, that some
individuals whose blood pressure, recorded by ambulatory measurements in daylight hours was within normal limits (<135/85 mmHg)
had a poor prognosis if they also had an unduly high basal blood
pressure level, during rest and sleep, which reached or exceeded
120/70 mmHg. These observations suggested a worse eventual
cardio-vascular outcome, in terms of hard endpoints, than that of
individuals with lower INH values. This interesting detailed review
has supported the old observations of Smirk (1957) concerning
blood pressures during sleep.
Average diurnal blood pressure changes in men and women with

dierent casual blood pressures
Figure 3.4 is reproduced from the superb and important paper by
Imai et al. (1997) published in the Journal of Hypertension. It showed
pooled records of mean systolic and mean diastolic blood pressures,
52
with standard deviations (SDs), of three large groups of Japanese

men and women during each hour of the day, starting from midday
and continuing for the next 24 h. The 72 men in group (a) had an
average systolic pressure equal to or less than 119 mmHg; the 147
men in group (b) had a systolic pressure between 129 and 139
mmHg; and the 55 men in group (c) had systolic pressures equal to
or greater than 140 mmHg. The three groups of women in Imais
study had comparable results. All had stable but slightly lower blood
pressures than the men in each of the three groups. I describe Yutaka
Imais investigation as superb because it provides strong evidence
that basal blood pressure, i.e. the trough level maintained during
sleep, probably determines the pattern of blood pressure during the
following day. The large number of men and women in each of the
three groups in Fig. 3.4 makes it clear that the higher the nocturnal
(basal) blood pressure of each group, the higher is the daytime level
and more uctuant is the pattern of daytime blood pressures (shown
by the larger standard deviations of each groups mean value). We
know that the elevated basal blood pressure of essential hypertensive
patients is closely related to the severity of their hypertensive organ
damage (Tochikubo et al., 1998). In Chapter 6 I shall review evidence that the essential hypertensive brain uses dierent energyproviding fuels than are used by the normal brain.
Men and women in Imais groups (b) and (c) had mild (b) or
moderate (c) essential hypertension. Individuals in both these
groups must have had a substantial restriction of their cerebral
circulation during sleep. In both groups, basal blood pressure during
sleep was maintained for 3 or 4 h at a higher level than that in the
normotensive individuals who comprised the (a) groups. We already
know, from a large body of classic physiological work, that the
blood pressure of both men and women in any of the groups, even in
those in groups (a) could be reduced by sympathetic blocking drugs
or by anaesthetising the spinal cord. We do not have to discover
evidence of ischemia to appreciate that during sleep something must
have restricted the cerebral circulation in all these groups. We
could, of course, postulate that three dierent levels of sleep might
have caused these three dierent stabilised basal levels of blood
pressure, but this seems most unlikely. It stretches credibility much
less to assume that the neural processes underlying sleep are much
the same in all the large groups of Japanese men and women studied
by Imai. But it is obvious that men and women in groups (b) and (c)
53
Fig. 3.4 Five-year records of mean two-hourly circadian blood-pressure records

obtained from three groups of Japanese men (upper graphs) and three groups of
Japanese women (lower graphs) by Yutaka Imai et al (1997), at three dierent daytime
blood pressure levels. All values are shown as means SD at each 2 hours of the 24-h
day. n = number of subjects in each group; SDP, systolic blood pressures; DBP,
diastolic blood pressures. Note the relative stability of basal pressure (during sleep) in
each of the three groups in each sex. For both men and women a higher than average
basal pressure is associated with higher casual and uctuant waking pressures.
Reproduced with permission from the Journal of Hypertension (1997) 15 456460.
54
must have received an additional restrictive but blood-pressure

raising stimulus of some sort. The most likely source is Cushings
mechanism. Certainly some mechanism must have arrested the fall of
blood pressure with sleep at a higher blood pressure level than in the
(a) groups, presumably because they had greater levels of unrelaxable cerebrovascular resistance. I suggest that everyones blood
pressure is programmed to fall in sleep to a basal level determined by
the minimal cerebral arterial resistance, unless a renal, endocrine or
other mechanism prevents this. I suggest that everyones systemic
circulation is, in a real sense, restricted during sleep.
Thinking along these lines has made me suggest that one of the
long-sought functions of sleep in any terrestrial mammal is to
identify and establish the most energy-economical way of living, i.e.
the lowest possible basal blood pressure supplying the respiratory
centres in the brainstem and in all other vital organs, while all the
cerebral arteries of every natural size remain as fully dilated as
possible, to allow the very high rate of brain metabolism to continue
almost unabated during sleep.
All the lower than expected values that I have described for CBF
in essential hypertension, in many regions of the brain, mean that the
CVR is disproportionately increased. Conventional thinking is (1)
that hypertension increases CVR (which is what everyone has
assumed for the last thirty years or more); and (2) that increased
CVR raises blood pressure, which it must do if an adequate bloodow to all other tissues is to be maintained; but (3) the resulting
hypertension increases CVR still further. Something is wrong with
the logic!
All these observations t much better with my simple proposition:
that a primary increase of CVR raises blood pressure. They cannot
be reconciled with currently accepted wisdom: that the primary
abnormality in essential hypertension is a rise in blood pressure,
which induces cerebral arteriolar changes, which in turn increase
CVR. The anticipated hypertrophic or remodelled changes cannot be
found in the brains arterioles and small arteries, even though they
are found in all other systemic vascular territories exposed to elevated blood pressure. All investigations conrm that the primary
abnormality in essential hypertension is a disproportionately
increased cerebrovascular resistance. Even the elevated blood
pressure is not able to restore normal blood-ow to the brain under
basal conditions.
55
(5) What is the resistance of small cerebral arteries and arterioles in

dierent kinds of systemic hypertension?
General anaesthesia in experimental animals reduces CBF (in line
with cerebral metabolic rate) to about half its normal value
(McDowall et al., 1963). Animal evidence suggests that intracranial
arterial pressures are lower than those previously reported and that
the large neck arteries contribute a very substantial part of the total
CVR (Kontos et al., 1978). The hypertensive community is slowly
beginning to realise that large arteries (greater than 200 mm internal
diameter) make a substantial contribution to total cerebrovascular
resistance:
According to Baumbach and Heistad (1983): An emerging concept is that large arteries are important determinants of cerebral
vascular resistance. Large-artery resistance in rabbits and cats
accounted for approximately 40% of total cerebral vascular resistance. Harper et al. (1984) reached similar conclusions in rats.
Mayhan et al. (1980), after reviewing the results in several species,
made a similar generalisation. Farachi et al. (1987), used a servo-null
pressure-measuring device applied to a basilar artery branch in
pentobarbitone-anaesthetised cats and reported that 31% of the
total arterial resistance was made up by the neck arteries. Changes in
large-artery resistance with changed PCO2 were about two-thirds
greater than the changes in small-artery resistance. Faraci et al. also
pointed out that large as well as small arteries, contribute to the
regulation of blood ow to the brainstem.
I referred in the last chapter to the hypertrophic changes in small
cerebral arteries and arterioles in stroke-prone spontaneously
hypertensive rats (SHR-SP). The appearance and functional properties of these vessels in various animal models of hypertension has
been extensively studied by Baumbach and his colleagues. For
example, Baumbach and Hajdu (1993) compared the dimensions of
arterioles in anaesthetised normotensive WistarKyoto rats with
those in anaesthetised renal hypertensive (one-clip, one kidney) rats,
and with those in classic inbred spontaneously hypertensive rats
(SHR). However, I shall leave furher discussion of the nature of
cerebral vascular resistance in SHR to Julian Paton, in Chapters 7
and 8.
56
Is there a contradictory view?

Until 2009 I was not aware of anyone who seriously disagreed with
my viewderived from much published literaturethat the small
cerebral resistance arteries and arterioles in people with essential
hypertension did not develop hypertrophic changes or eutrophic
remodelling, to suggest that they had been exposed to an unduly
high intraluminal pressure. Such changes as had been seen were
ascribed to chronic hypoxia. However, at this point I should
acknowledge the work of Rizzoni et al. (2009). Their investigation
was an astonishing and imaginative tour de force. It involved
handling and measuring the structural and functional properties of
fresh, small human cerebral arteries of internal diameter 100
350 mm. It bears importantly on the views that I have consistently
maintained: that stenosis of the main cervical cerebral arteries is the
cause of essential hypertension. If I am right, small intracerebral
arteries and arterioles from essential hypertensive patients should be
spared the hypertrophic or remodelled changes that might otherwise
be expected to develop from long-sustained high intraluminal
pressure. If I am wrong, and intracerebral arterioles behave like
small resistance arteries in every other part of the body, we should
expect to nd evidence of medial hypertrophy, contracture or
increased media thickness in relation to internal lumen diameter
what Rizzoni describes as the M/L ratio, in small cerebral arteries.
Rizzoni and his colleagues were able to obtain small portions of
macroscopically normal cerebral cortical tissue adjacent to both
benign and malignant brain tumours. This allowed them to compare
microvessel density in fresh brain tissue from thirteen essential
hypertensive patients, with that from fteen normotensive individuals. The microvessel density of the hypertensives cerebral arterioles
was slightly less than that from normotensive controls. However,
Rizzoni opined that an increased M/L ratio of small resistance
arteries was the most reliable measure of previous exposure to
high intraluminal pressure. He reported that the M/L ratio of
average small cerebral resistance arteries from essential hypertensive
patients was signicantly greater than that of similar arteries from
normotensive controls: 9.4% compared to 8.5%; P<0.05. However,
this conclusion was based on two measurements (media wall thickness and internal luminal diameter), neither of which was signicantly dierent from average values. The series was small. I have
57
argued, in a letter published in the Journal of Hypertension (Dickinson, 2009), that Rizzonis observations do not upset the overwhelming pathological evidence that I have summarised. The
increase in longstanding small artery or arteriolar resistance could
obviously come from a renal pressor component, such as might be
due to increased circulating concentrations of angiotensin-II, but
there is no evidence to support this possibility.
I suggest that Rizzonis results should be regarded as having
excluded signicant hypertrophic or eutrophic remodelled changes in
small cerebral resistance arteries and arterioles in essential hypertension. Although his observations were made on fresh tissue, there
is no obvious reason why hypertrophic or remodelled changes in
fresh tissue should disappear with xation. None the less, Damiano
Rizzoni and his colleagues deserve great credit for showing the
hypertensive community a way in which it is possible to investigate
the inaccessible cerebral microcirculation.
(6) What are the special attributes of the vasculature of the human
brainstem, and its pathology?
The ne detail of the brains vasculature was comprehensively
examined and described by Henri Duvernoy (1978). To prepare his
magnicent atlas, he injected the vasculature of human cadaver
hindbrains with Indian ink. In my second monograph I reproduced
one of Duvernoys beautiful illustrations, a paramedian sagittal
section of the medulla (Dickinson, 1991, his g. 7.3). This demonstrated the course of the multiple tiny parallel branches of the basilar
and other main arteries running upwards towards the oor of the 4th
ventricle, wherein lies the nucleus of the solitary tract, one of the
main relay stations for central autonomic blood-pressure control. It
is evident that the solitary tract and adjacent nuclei lie at the end of
the line, as far as their blood supply is concerned. Foix et al. (1925)
commented: Nothing is more impressive than to see the thinness of
these arteries and arterioles and one can only wonder how the supply
of blood of such important regions of the brainstem is assured by
these remarkably thin blood vessels. Duvernoy (1978) also emphasised another feature that is displayed by his injection studies.
Although there is an extensive capillary network in the medulla, he
commented: No internal arterial anastomoses, either between
58
arteries belonging to separate groups, or between those of the same

group were present. Thus, the internal arteries of the brainstem can
be classied with the other cerebral end arteries. The integrity of the
central cardiovascular and respiratory neural control mechanisms is
therefore crucially dependent on an adequate supply of blood from
these end-arteries.
Long ago, Fishberg (1925) noted that, although sustained hypertension conmonly induced hypertrophic changes in all other small
systemic arteries, those in the brain were strangely spared. At
necropsy, he reported changes in cerebral arterioles in only 6 out of
31 (19%) of individuals previously diagnosed with essential hypertension. The changes were not those of hypertrophy, but rather of
atrophy and replacement brosis. In their pathological study,
Bordley and Baker (1926) wrote: The changes we have observed [in
the small arteries of the brain in essential hypertension] are certainly
not hypertrophic in character if we correctly understand the meaning
of hypertrophy. We would be inclined to think that, at least in some
of our cases, the changes more nearly represent the end stage of some
slowly progressive necrotic process. Tuthill (1931) reported nding
similar changes in 50% of patients previously hypertensive, but in
none whose blood pressure in life had been normal. Baker (1941)
published the results of an extensive study of large and small cerebral
arteries in the brains of fty-three formerly hypertensive patients and
wrote: One is impressed by the paucity [my italics] of actual alterations occurring within the small cerebral arteries and arterioles in
cases of longstanding hypertension . . . The larger cerebral arteries
often show far advanced atherosclerotic changes . . . but hypertension may exist for years with little or no eect on the small arteries.
AB Baker conrmed his interesting ndings to me personally when
we met at the 6th International Cerebrovascular Diseases Conference
in Princeton, NJ (Dickinson, 1968), but he did not regard the lack of
hypertrophic changes in the small cerebral arteries of the brain in
longstanding hypertension as anything more than a curiosity, though
I found it dicult to account for logically. Why should essential
hypertension not produce medial hypertrophy (or eutrophic remodelling) in small cerebral arteries and arterioles, when it is known to
do so in arterioles in every other systemic vascular territory?
Scheinker (1943, 1945) also could not nd hypertrophic changes in
small cerebral arteries and arterioles in hypertensive individuals. All
the changes were in capillaries and veins. Baker and Iannone (1959)
59
observed some changes in the media of cerebral arterioles, which

appeared to be leading to progressive brosis and hyalinisation.
Ross Russell, in his study of cerebral arterioles in elderly individuals,
noted that there were degenerative changes in muscular and elastic
tissues, which were more marked in the brains of hypertensive
people, but wrote: there is no evident hypertrophy of muscular
tissue (Russell, 1963). Roggendorf et al. (1978) observed that cerebral arterioles in essential hypertensives of at least three years
duration showed thickening of basement membranes, atrophy and
deformity of smooth muscle cells, but there was no evidence either
of smooth muscle hypertrophy or of Shorts contracture. Many
other authors have made similar observations.
Anticipating the discussion of my presentation to a forthcoming
conference on cerebral vascular diseases, I was stimulated to make a
small pilot study of my own, so that I could more intelligently
contribute to the discussions. I used the technique of Short (1968) to
examine small artery and arteriolar dimensions from mesentery and
brainstem of nine previously normotensive subjects (four men, ve
women, mean age 60, with diastolic pressures less than 100 mmHg),
comparing them with the dimensions of these vessels from ve
essential hypertensive subjects (two men, three women, mean age 53,
with previous diastolic pressures greater than 120 mmHg). I tied my
cannulas into branches of the superior mesenteric artery or into a
vertebral artery within the skull, dilated all vessels fully with 5%
aqueous ammonia, tied o all small branches, then lled the vessels
with a hot gelatin solution containing nely powdered barium sulphate. This was held at 140 mmHg internal pressure until the gelatin
had cooled and set. Then I cut all tissues across their arterial lengths
and prepared microscopic slides of transverse sections of the small
arteries and arterioles in both the brainstem and in the gut mesentery. My analysis of mesenteric arterial transverse sections followed
exactly that devised by Short (1958) for his analysis of small
mesenteric arteries and arterioles. These are shown in the upper-right
panel of Fig. 3.5. After I had xed and stained all the arteries, I
measured the internal diameters and media wall thickness of as many
small arteries as possible, both from the mesentery and from the
brainstem. Then I ranked these, exactly as Short had done, in ten
equal groups in descending order of wall thickness/internal lumen
diameter ratio, with the same number of small vessels analysed in
each group.
60
Fig. 3.5 Comparisons of wall/lumen ratios of arterioles from human mesentery and
brainstem of normotensive people and those with essential hypertension. Analysis follows the technique of Short (1958, 1968), who measured wall/lumen arterial ratios in
mesenteric arteries and arterioles from normotensive and essential hypertensive cadavers
(shown in the right-upper panel. Panels on the left show my results from nine normotensive cadavers (diastolic pressures less than 100 mmHg) and from ve cadavers with
previous essential hypertension (diastolic blood pressures greaterthan 120 mmHg). My
results from mesenteric arteries are similar to those of Short. In both panels, small
arteries and arterioles were rst ranked in order of lumen diameter, then divided into ten
groups in descending order of size, with the same number of vessels in each 10% group.
My results from mesenteric vessels in the left-upper panel were similar to those of Short
(right-upper panel); but my results from brainstem blood vessels (left-lower panel) are
similar for both sites. This suggests that brainstem vessels from essential hypertensive
subjects had almost identical size relationships as those from mesenteric vessels, i.e. they
had no evidence of hypertrophic thickening of their walls (Dickinson, 1991).
61
David Shorts results for mesenteric small arteries appear in the

right upper panel of Fig. 3.5. My results are in the upper left-hand
panel. They are almost the same as Shorts. Both our measurements
from people with previous essential hypertension are widely separated from those from normotensive control subjects. Small mesenteric arteries and arterioles all had substantially increased wall
thickness/lumen diameter ratios. However, my analysis also extended to a similar study of the small cerebral arteries and arterioles
arising from the basilar artery and passing upwards towards the
nuclei of the XIIth cranial nerve and of the solitary tract in the oor
of the 4th ventricle. Henri Duvernoy (1978) and his publisher kindly
allowed me to reproduce one of his superb injected sagittal sections
of the human medulla (Dickinson, 1991, p 96). The straight course of
these small arteries allowed me to capture them in cylinders of brain
tissue with a cork borer, as I reported to the 6th Cerebrovascular
Diseases Conference in Princeton (Dickinson, 1968, g. 2, p 126).
My analysis of small artery and arteriolar structure followed exactly
the technique used by Short. It appears in the lower-left panel of Fig.
3.5. Photographs of two typical representative arteriolar transverse
sections of 96 and 64 mm internal diameter also appeared in the same
publication. Like Short, I was easily able to identify medial hypertrophy, contracture or eutrophic modelling in small arteries or
arterioles in the mesentery of the small intestine from essential
hypertensive patients, but I observed no evidence of comparable
changes in brainstem arterioles. I regret not having presented these
results properly in a full paper, but my pilot study suggested that,
although medial hypertrophy, contracture or eutrophic modelling
was easily demonstrable in mesenteric small arteries and arterioles
from former patients with essential hypertension, I could nd no
similar changes in the hindbrain vessels of such patients.
Cook and Yates (1972) compared and measured small renal and
cerebral arteries of 10500 mm diameter in the presence of hypertension associated with chronic renal disease. They reported that
renal hypertension had induced medial hypertrophy in all sizes of
artery in brain, as well as in kidney. They made no comment on the
relative contributions of smooth muscle, hyaline deposition and
brous tissue to the increased wall thickness. But my generally
negative ndings in the small cerebral arteries of essential hypertensive patients support my views about the cause of that disease. If
essential hypertension results from increased cerebrovascular
62
resistance in the hindbrain, and if most or all of this is contributed by

stenoses in the large arteries, brainstem arterioles should be spared
the changes of medial hypertrophy or eutrophic remodelling which
characterise arterioles in other vascular territories.
Some reviewers lump together human observations with those in
rats, suggesting that they could or should be considered together.
Here is an example from a paper by Barry and Lassen (1984): As in
other vascular beds in man and animals, the basis for the increased
[cerebrovascular] resistance appears to be structural changes in the
smaller resistance vessels [my italics]. Of the eleven references cited
by these authors to support this statement, four concern spontaneous hypertensive rats, one concerns renovascular hypertension,
one is a paper about intracerebral microaneurysms and three are
same author duplicates. None concerns arterioles in the brainstem of
human essential hypertensive patients. Even in the most spectacular
animal model, the stroke-prone spontaneously hypertensive rat
(SHR-SP: Yamori, 1984), intracerebral arterioles do not show the
same structural changes that are seen in the larger extracerebral
arteries, probably because they have not been exposed to high
pressure but rather to hypoxic damage, which causes necrotic
changes (Yamori et al., 1985).
Summary
In every minute, the adult human heart pumps about 1 pints of
blood through the jelly, which comprises the brain. This is about
four times more than the amount of blood that is needed by (and
supplied to) the muscles of the beating heart of an individual at rest.
Cerebral bloodow (CBF) diminishes slightly during deep sleep but
is little changed by mental activity, or even by epileptic seizures,
although small rapid changes in local cortical blood ow accompany
changes in mental activity. In the last century, total CBF was measured many times in people with essential hypertension and reported
to be normal; but in the last twenty-ve years, new techniques have
gradually revealed that cerebral blood-ow is less than normal in
most resting subjects with essential hypertension. It is now apparent
that any primary increase of total cerebrovascular resistance (CVR)
can reduce cerebral blood-ow, unless subjects are excited or
stressed.
63
The international hypertensive research community has so far

taken little notice of this important revelation, even though it
destroys the current but absurd idea that high blood pressure can
itself be the primary fault in essential hypertension. The primary
fault is that cerebrovascular resistance is abnormally increased. This
probably reduces basal cerebral blood-ow and thus (potentially)
activates what Cushing described as a blood-pressure raising
mechanism located in the brainstem. Any threat to basal cerebral
blood-ow will be resisted by a proportional elevation of systemic
arterial pressure. This situation can account for essential hypertension, as will be explained in the next chapter.
The brains diculty in securing a normal basal cerebral bloodow in essential hypertension is revealed indirectly by its signicantly
subnormal respiratory quotient, the meaning of which I shall discuss
in Chapter 6. The variable resistance of the four main human cerebral arteries is evident in X-rays of the lled and distended internal
carotid and vertebral arteries from three cadavers in our series
(e.g. Fig. 3.6). It is important to note that the smooth muscle in
all these arteries was fully relaxed with aqueous ammonia before
the vessels were lled with a hot gelatin solution containing a suspension of powdered barium sulphate. This was held at a distending
pressure of 140 mmHg until the gelatin had set and the X-rays taken.
These three injected specimens of the internal carotid and vertebral
arteries illustrate the varied natural size of these arteries, and the
extensive narrowing of the lumen that plaques of atheroma can
produce. Chapter 4 gives full details of the techniques used at
necropsy to measure the minimal ow resistance of these main
arteries.
The incidence and severity of coronary arterial atheromatous
disease has almost no association with hypertension. Hypotensive
drugs provide almost no protection against myocardial infarction.
But there is overwhelming epidemiologial and pathological evidence
that the incidence and severity of cerebral atheromatous disease is
much the same as the incidence and severity of hypertension in
individuals with so-called essential disease. Because the four main
cerebral arterial trunks supply most or all the increased cerebrovascular resistance of essential hypertensionas I suggestthe
distal small arteries and arterioles should be protected against
hypertrophic or remodelled changes due to an unduly high intraluminal pressure. All the pathological literature conrms that the
64
Fig. 3.6 Photographs of one side of the neck of three vertebral and internal carotid
arteries in our published series, prepared as described in the text. All six arteries in these
specimens were rst fully dilated with aqueous ammonia, before being lled with a hot
powdered barium sulphate suspension in gelatin, held at 140 mmHg distension pressure
until the gelatin had set and these photographs taken.
small cerebral arteries and arterioles in patients with essential

hypertension do not develop the remodelled or hypertrophic changes
that are well-recognised to develop in all other vascular beds,
although such changes have often been observed in small cerebral
arteries in renal and other secondary forms of hypertension in man
and animals.
I suggest that increased resistance of the four main cerebral
arteries in the neck and skull base may be particularly important
under basal conditions, particularly during sleep, when all the
relaxable resistance of small arteries and arterioles is likely to be at
its minimum. The intraluminal pressure at the Circle of Willis is
probably only slightly greater than half of systemic arterial pressure.
There must normally be substantial resistance in the proximal main
cerebral artery trunks. Even complete occlusion of a single main
cerebral artery has been found in about one in twenty cadavers in
most human necropsy series.
The human brainstem is supplied by very small end arteries and is
65
the site of many neural structures controlling the mammalian cardiovascular system, which Julian Paton will describe in Chapters 7
and 8.
66
4
Anatomy and Post-Mortem Measurements
of Flow Resistances in the Main Human
Cerebral Arteries; their Relation to Ante
Mortem Blood PressureInuence of
Chronic Renal Disease
All the measurements and data recorded in this chapter were published by Drew Thomson and me fty years ago, but there are several reasons for revisiting our old observations. New ethical
guidelines would not allow seriously hypertensive patients to remain
untreated. When we began our work, hypotensive drugs were
regarded as experimental, and were seldom used. But this situation
provided us with a unique opportunity to compare unmodied antemortem blood-pressure records with our later necropsy observations.
As I explained at the end of chapter 3, Drew Thomson and I had
made necropsy/perfusion measurements of the unrelaxable main
cerebral artery resistances in a large series of cadavers. We had
reported that a primary increase in this resistance could very exactly
explain essential hypertension (p 11). In his discussion, after I had
presented our observations to an international meeting on cerebrovascular disease, Seymour Kety (1968) rejected our claim, not
because our measurments were wrong, but simply because he had
found that cerebral blood-ow (CBF) remained constant even after
blood pressure had been slightly reduced by drugs (p 12). But, as I
pointed out in the last chapter, Ketys measurements of CBF have
since been shown to have been inadvertently misleading. His subjects
cannot have been at rest when his measurements were made. Later
investigators have consistently reported that measurements either of
total or regional cerebral blood-ow are signicantly less than normal
in patients with essential hypertension, provided that subjects are not
67
excited or stressed. The time has come to overturn Ketys objections

and revisit our old necropsy/perfusion measurements. These still
provide a complete explanation for a common but important human
disease.
Our measurements also threw unexpected light on the cause of
spontaneous intracerebral haemorrhage (ICH): they suggested that
this lesion was almost always ischaemic and that it had little directly
to do with high systemic arterial pressure.
In this chapter I have tried to give readers all the raw data that
they might need to repeat or re-analyse our old results, for which I
now claim the patina of history.
Darwinian thinking about normal cerebral blood-ow and the size of

the brains main arteries
I invoked Darwin to construct my hypothesis that during sleep all
the small resistance arteries and arterioles supplying the human brain
would have evolved to be fully relaxed. We now know that total
cerebral blood-ow (CBF) changes very little during the 24 h (p 41).
But it seemed likely that during the evolution of every racial group,
appropriate dimensions for the main trunks of the vertebral and
internal carotid arteries in the neck and skull base would have been
determined by natural selection. If these arteries were too big, blood
volume would also be unnecessarily big. If they were too small, or
actively constricted, basal systemic arterial pressure would have to
rise unduly to preserve an adequate basal blood ow to the brain. I
assumed that the natural dimensions of human main cerebral
arteries probably represented an evolutionary compromise.
This banal thought process suggested that atheromatous stenoses
of the main cerebral arterial trunks could be the elusive and longsought cause of essential hypertension. Stenotic atheroma is only
rarely seen in animals unless they have been selectively inbred or fed
unnatural diets. Although atheroma is common and found in all
developed populations, it seemed unlikely that a selective evolutionary process would yet have had enough time to have made big
changes in the genetic inheritance of human main cerebral arteries.
Although atheromatous plaques in these main arteries can produce
an unrelaxable increase of cerebrovascular resistance, this mainly
arises after the reproductive years.
68
ANATOMY AND POST-MORTEM MEASUREMENTS
The obvious next step was to measure main cerebral artery resistance in a series of cadavers, so that these measurements could be
compared with the previously recorded blood pressures of each
subject during life.
The anatomy of the paired main human cerebral arteries

The vertebral arteries arise from the rst part of the subclavian
artery on each side, then run upwards and backwards behind the
common carotid arteries. Each ascends through foramina in the
transverse processes of the upper-six cervical vertebrae. Each winds
behind the lateral mass of the atlas vertebra and enters the cranial
cavity through the foramen magnum. Then it runs vertically until it
passes through the transverse process of the axis bone, then runs
upwards and laterally to the foramen transversarium of the atlas and
curves backwards behind the lateral mass of the atlas. It then lies in a
groove on the upper surface of the posterior arch of the atlas and
enters the vertebral canal covered by the semispinalis capitis muscle.
It pierces the dura and the arachnoid membranes and unites with the
vessel of the opposite side to form the basilar artery at the lower
border of the pons. John Stirling Meyers superb diagram of the
human vertebral-basilar systerm (Fig. 3.1, p 40) was compiled from
his own series of subclavian-vertebral angiograms. Even without any
atheromatous narrowing of these large important vessels it is
obvious that their convoluted twisted and sometimes looping course
might already contribute a signicant resistance to blood ow.
The internal carotid arteries on each side arise at the bifurcation of
the common carotid artery in the neck at the upper border of the
thyroid cartilage. The cervical part is usually straight, but can
occasionally be exceedingly tortuous. It ascends in front of the
transverse processes of the upper three cervical vertebrae. Its petrous
continuation enters the carotid canal in the temporal bone then
curves forwards and medially. It leaves the canal between the lingula
and the petrous process of the sphenoid bone. Its cavernous portion
lies in the cavernous sinus, covered by the latters lining endothelium.
It then ascends upwards towards the posterior clinoid process and
passes forwards at the side of the body of the sphenoid. Each artery
then curves upwards again on the medial side of the anterior clinoid
process and perforates the dura mater, which forms the roof of the
cavernous sinus. Its cerebral portion turns backwards below the
69
optic nerves and eventually divides at the anterior perforated substance at the medial end of the lateral cerebral sulcus. There it gives
o the ophthalmic artery and many smaller branches and divides
into the anterior and middle cerebral arteries.
Anatomical variants of the main cerebral arteries and the eects of

atheromatous disease
Both vertebral and internal carotid arteries run almost uninterrupted
courses to the brain, with very few changes in lumen diameter
throughout their course in the neck and skull base, and with only a
few tiny tributaries and no collaterals. There is tremendous variation
in the congenital size of these main arteries, even in the long and
tortuous course they pursue to allow rotation, exion, extension and
lateral movements of the neck without compressing or tearing any
artery. The human cervical spine and the four large arteries that it
contains and protects, is a marvel of evolutionary engineering. Many
anatomists have been surprised that a young man or woman can
continue to supply blood to their brain in all possible positions of the
neck. But neurologists know that atheromatous vertebral arteries
can be compressed and partly occluded in certain positions of the
neck, producing the symptoms of intermittent vertebro-basilar
insuciency. In the presence of atheromatous obstruction of the
rst part of the subclavian artery, the alliterative (but ungrammatical) syndrome of subclavian steal can arise, when blood ow in a
vertebral artery is acutely reduced or even reversed when blood ow
to the arm from the subclavian artery is acutely increased, e.g. while
combing the hair.
The original pressure/perfusion technique used to measure main

arterial resistances
I now reiterate my apology to readers. The rest of this chapter will
simply describe in detail the measurements that Drew Thomson and
I made in ninety-four cadavers in the post-mortem rooms of the
former Middlesex Hospital Medical School. None the less, our
measurements and conclusions enabled us to suggest how all ideas
then current about the cause of essential hypertension could be
overturned and replaced by a plausible and testable explanation for
70
that disease: that increased ow resistance in the main cerebral

arteries was the primary cause of essential hypertension. However, at
this time everyone believed that increased cerebrovascular resistance
resided exclusively in very small arteries and arterioles, and that
unduly high systemic arterial pressure (from some unidentied
source) must have created it by some myogenic process. As I
explained in the last chapter, the new observations of CBF are not
compatible with these old ideas, though they are perfectly compatible with my alternative ideathat a primary increase of cerebrovascular resistance from stenotic main cerebral arterial trunks can
completely account for essential hypertension.
I tested my hypothesis by studying the cadavers that often came to
the Department of Pathology of the Middlesex Hospital Medical
School, where I was working in 1957. Post-mortem examinations of
the hospitals former patients were being regularly carried out to
determine the cause of death, to teach the medical students and to
discover whether the medical or surgical care of each former patient
had been appropriate. Technicians opened the rib cage of each
cadaver and removed and weighed the heart. They sawed around the
skull to remove the vault and thus exposed the brain. This was then
removed by one of the pathologists, without damaging the main
cerebral arterial trunks.
I sought the help of the late Drew Thomson, the pathologist who
had immediate charge of the post-mortem rooms. We examined the
cadavers of former hospital patients who had many dierent diseases
and as wide a range of previously recorded blood pressures as possible. We tried to avoid studying any patient with manifest heart
disease, which might have made previous blood-pressure readings
unreliable and potentially misleading. We also eliminated any
patient who had received, or was receiving, drug treatment for
hypertension. This was possible in London sixty years ago (in the
1950s) because, at that time, hypotensive drugs were only seldom
given to hypertensive individuals. Drew and I were together able to
select former patients whose hospital notes recorded a wide range of
ante-mortem blood pressures. We devised a perfusion technique to
measure ow resistance of the main cerebral (and of some femoral)
arteries, which we could apply to each large artery in turn, in each of
the ninety-four cadavers in our nal series.
The measurement of the ow resistance of an artery, even after
death, is more dicult than it sounds. It is considerably more
71
tedious. The eective resistance presented to uid owing through a

tube can be determined by knowing its rate of ow while measuring
the pressure dierence between two separated places along its length,
knowing also the uids viscosity and that signicant turbulence did
not occur. I wanted to avoid introducing any unrealistic extra
resistance or damaging the arteries in any way. Routine hospital
necropsies involved opening the chest and removing the heart with
its attached main vessels. To make possible a standard measurement
of ow resistance in each large artery, I therefore made six cannulas
in stainless steel, each with close-tting removable steel rods with
rounded ends (Fig. 4.1). These covered a wide range of sizes. Table
4.1 shows the dimensions of each of our six cannulas and the maximal ow-rate that could be obtained from each cannula in our
perfusion system with no artery attached. Cannulas #1 to #3 were
used for the vertebral arteries, cannulas #2 to #6 for the internal
carotid arteries, and cannulas #3 to #6 for the femoral arteries. The
use of a set of cannulas allowed me to cannulate the origin of each
artery without tearing or splitting it or unrealistically narrowing the
Fig. 4.1 The set of six stainless steel cannulas used throughout the pressure/perfusion
study of Dickinson and Thomson (1960a, 1961). Each numbered calnnula was equipped
with a close-tting steel introducer. The dimensions of each cannula are shown in
Table 4.1 (p 74). In the raw data tables of Dickinson and Thomson (1960a, 1961) the
small superscript numbers above each recorded ow-rate identify the numbered cannula
used for each main artery perfusion.
72
origin. On two occasions I was unable to introduce my smallest steel

cannula (#1) into the origin of a vertebral artery because the origin
was virtually a pinhole. In these cases I tied cannula #1 into the
vertebral artery, as close to its origin as possible, though recognising
that in life the artery concerned would probably have produced more
resistance than we were able to measure.
The other problem we encountered was that our perfusing uid
could sometimes travel from the end of either internal carotid artery
into the ophthalmic artery and thence into the face. To prevent this
happening we routinely inserted a brass plate into a saw cut behind
both orbits (Fig. 4.2). I cannulated the internal carotid arteries on
Fig. 4.2 Photograph of the anterior part of the skull base, after removal of the brain, to
show the position of the at, brass plate inserted into a saw cut behind both orbits, to
prevent perfusing uid from the internal carotid arteries entering the ophthalmic artery
and hence the face of each cadaver. I.C.: the cut ends of the two internal carotid arteries.
73
each side from their origin at the common carotid bifurcation. We

also cannulated fty-two femoral arteries of our subjects so that the
resistance of these often atheromatous arteries could be compared
with that of similarly diseased main cerebral arteries.
Table 4.1 Details of cannula sizes and introducers for each; all in stainless steel
Cannula
number
Length
(mm)
Int diameter
(mm)
Ext diam
(mm)
(greatest)
1
2
3
4
5
6
35
37
50
50
50
50
2.18
3.18
3.97
4.78
5.56
6.35
3.45
4.75
5.59
6.55
7.24
8.46
Maximal
ow-rate (ml/s)
as described in
the text
17.5
31.5
40.0
50.3
55.0
62.5
We cut o the distal end of each cerebral artery within the skull, the
vertebrals before they joined together to form the basilar and the
internal carotids, where they split into anterior and middle cerebral
artery branches. We used a realistically high perfusion pressure
within the clinical range (140 mmHg) so that non-adherent antemortem clots would be ejected and the arteries studied in a realistically distended state. The ends of the internal carotid arteries,
within the skull, were cut across before they joined the Circle of
Willis, and the vertebrals, before they came together to make the
basilar artery. We also cannulated a femoral artery of fty-two
cadavers just distal to the origin of the profunda femoris branch and
cut across each femoral artery in the popliteal fossa, at the level of
the upper border of the patella. Perfusion uid was allowed to run
o all arteries at atmospheric pressure. Each cannula in turn could
be connected by wide-bore rubber tubing to a graduated constantpressure container lled with a measured amount of aqueous
ammonia. This could be hauled up to a height close to the ceiling (R
in Fig. 4.3). It provided a pressure of 140 mmHg at the level of the
necropsy table. The container could also be lowered so that its
residual volume could be measured. A realistic mean systemic
arterial pressure of this order would be produced in life by a clinical
blood pressure of about 200/110 mmHg.
For more than two years we measured the maximal ow-rate that
we could obtain from each of the four main cerebral arteries of all
74
Fig. 4.3 Photograph of the author in the post-mortem room of the former Middlesex
Hospital Medical School, perfusing one of a cadavers main cervical cerebral arteries, as
described in the text. The constant pressure container with 5% aqueous ammonia has
been hauled up to the ceiling (see R), to provide a uid perfusion pressure equivalent to
140 mmHg at the level of the cadavers neck on the necropsy table.
our cadavers, after fully dilating each with 5% aqueous ammonia

(MacWilliam, 1902). Figure 4.3 shows my youthful self, engaged in
this activity in the post-mortem room of the former Middlesex
Hospital Medical School. I am opening and closing the rubber tube
of our perfusion system with a spring clip, using a stop-watch to
control timing, while my assistant holds a jug in the cranial cavity to
collect the euent uid from the cut ends of each artery. I have
included this photograph, and also that of our cannulas (Fig. 4.1), to
remind readers that the measurement of the ow resistance of an
artery, even after death, was a tedious procedure, however simple
our technique may seem to have been.
75
Drew Thomson and I realised that we might be accused of bias in

our initial selection of patients and in our choice of the cannula size
used to connect each artery to our pressure-perfusion system. We
took care that each cannula was always the largest that could be
admitted without splitting the arterial wall. We had deliberately
chosen to study former patients with as wide a variety of previous
blood pressures as possible. At the conclusion of the study we
gathered all the hospital notes together and presented them for
independent scrutiny to Jack Howell, a helpful friendlater Professor of Medicine at Southamptonwho very kindly read the notes
and wrote down for each subject an ante-mortem blood-pressure
value, which seemed to him best representative of the blood pressure
in life. This was always a value or a mean value measured and
recorded in the absence of any vasoactive drug, well before each
subjects death, and (in subjects with strokes) always before the
stroke had occurred.
All our measurements and results were published in three papers
(Dickinson and Thomson, 1959, 1960a and 1961). The rst was a
Preliminary Communication in The Lancet. The last two articles
were published in Clinical Science and contain full details of our
techniques and measurements. The last two articles also contain
complete printed tables of all our raw data, even including the
designated numbered cannula used for the perfusion of each artery
in our series. To help readers without easy access to old Clinical
Science journals, I have described our main ndings in enough detail
to give those who have criticised or disagreed with my conclusions
the opportunity of showing where we went wrong or were misled.
I have retained all our original case records, which I would be happy
to show to interested parties or lodge in a departmental library.
I have republished all our data in this chapter because it has now
become impossible to repeat all our observations exactly, because
hypotensive therapy cannot ethically now be withheld from patients
who need it. But there should be no problem in repeating our
pressure/perfusion measurements providing care is taken to prevent
perfusion damage to the face.
76
The results of a necropsy perfusion study comparing measured ow

resistances of the main cerebral arteries of ninety-four cadavers with
independently recorded ante-mortem blood pressures
Our ndings and conclusions are now being re-examined and taken
more seriously than when Drew Thomson and I reported them fty
years ago. What follows is a brief description of our ndings, all of
which were recorded in our published papers together with all our
raw data. I have described them again in this book, to give those who
want to challenge our conclusions the opportunity to re-interpret our
data and tell me what we did wrong. It has now become dicult to
assign an appropriate ante-mortem blood pressure to former hospital patients. Physicians cannot ethically withhold treatment from
severely hypertensive patients, so that their representative untreated
blood pressure can be determined. Drew and I completed our study
only just in time. We could not have done it today with the same
certainty that we had enjoyed concerning the true (untreated) blood
pressure of each of our subjects. Thus I believe that our techniques
and measurements, however na ve my readers may consider them,
remain as relevant today as they were when we rst presented them.
As far as I am aware they have never been repeated.
At the end of Chapter 3, Fig. 3.6 (p 65) showed the complete
length of one vertebral artery and one internal carotid artery on the
same side from three cadavers in our series. It is obvious that the
vertebral and internal carotid arteries can dier greatly in their
natural congenital size, as well as being subject to stenotic atheromatous lesions. I was not able to examine more than a few neck
arteries in this way, because this was administratively very dicult to
arrange. However, the injected arteries of Fig. 3.6 show that the
lumina of these main human cerebral arteries in the neck and base of
skull vary considerably in their natural congenital size. Clearly they
can develop widespread stenotic lesions, which could interfere with
the blood supply of the brain. In our standard pressure/perfusion of
the vertebral artery illustrated in Fig. 3.6c, the maximal ow-rate we
achieved through that particular artery, despite a 140 mmHg perfusion pressure, was only one-seventh of that through the larger and
normal-looking vertebral artery in Fig. 3.6b.
We did not try to identify or classify arterial lesions. We were only
interested in the ow resistance that each artery must have provided
in life, after any possible residual constrictive spasm had been
77
removed by dilute ammonia. At rst we found it dicult to believe

the enormous range of ow rates we obtained from our series of
ninety-four cadavers. There was an astonishing extent and severity of
stenoses caused by atheromatous plaques distributed along the
course of many of these large vital arteries. Many plaques grossly
narrowed the arterial lumina and considerably restricted ow rates,
even at our high perfusion pressure. Because the main cerebral
arteries are paired, our ninety-four cadavers should have provided us
with twice that number of vertebral arteries to study, but one was
absent, one was vestigial, and three were completely blocked by
organised atheroma or preformed clots. Thus we were only able to
report perfusion measurements on 183 vertebral arteries in all. All
188 internal carotid arteries were present but three were completely
blocked by organised atheroma or organised clots. Occasional nonadherent ante-mortem clots were expelled during our perfusions.
Completely blocked arteries can be identied in the published tables
of all our raw data by having zero ow-rates. Measurements of the
ow rate of each main artery individually allowed us to add the ow
rates of pairs of arteries together and also to add together the ow
rates of all four main cerebral arteries, thus making what I have
called a summated ow-rate. This seemed the best way of dealing
with parallel resistances.
In their necropsy study, Hutchinson and Yates (1957) had cut
these arteries across in many places to examine luminal diameters.
They had made careful structural measurements of diseased arteries
at necropsy. But our work provided, and still provides, the only
measurements ever made (or at least ever published) of the ow
resistances of a large number of the main human cerebral arteries in
the neck and skull base. This subject has now become academically
red-hot. As I explained in Chapter 3, we can now put our old
observations and the new techniques and discoveries together. We
now know that human cerebral blood-ow is not the constant it was
believed to be fty years ago. It declines slowly with age, and more
rapidly in people with essential hypertension and with most kinds of
cerebrovascular disease.
Many aspects of our study are now unfortunately dicult to
repeat in any developed country. Most hypertensive patients today
receive hypotensive drugs. This makes it impossible to estimate what
the true ante-mortem blood pressure of each hypertensive subject
would have been in life in the absence of drug treatment. However,
78
all our old necropsy pressure/perfusion measurements can, of course,

be very exactly repeated.
Our results aroused little interest amongst the community of
hypertensiologists when they were published fty years ago. This was
not because our observations were thought to have been wrong or
inaccurate. They were simply deemed to be irrelevant to the aetiology of essential hypertension. Even the published opinions of distinguished clinical scientists like Seymour Kety (1968) and John
Swales (1991), made it clear that both men thought that the four
main cerebral arteries in the human neck were always large enough
to supply plenty of blood to the brain, despite the existence of many
plaques of atheroma in their walls. The smaller distal arteries and
arterioles could always dilate and restore normal blood-ow to the
brain.
But the vitally important large cerebral arteries are extraordinary
in many ways. Their normal blood-ow is rapid; and some arteries
pursue a tortuous and sometimes twisted course (e.g. see the subclavian-vertebral systems in Fig. 3.1, p 40). Figure 3.6 (p 65) is a
photograph of the whole length of three vertebral and internal carotid
arteries, from one side of the neck of three subjects in our series
(#34, #54 and #43). Readers will appreciate that these X-ray photographs were dicult to arrange. I had to saw out half of the skull
base of each cadaver and also saw vertically down the length of the
cervical spine, so that I could remove half of it as a single piece of
bone and tissue, still attached to half the skull base. The whole
specimen contained the entire length of the vertebral and internal
carotid arteries on one side of each subject. That left enough support
for the head to prevent distortion of the normal appearance of each
cadaver and prevented damage to any part of either main cerebral
artery.
I perfused each vessel with 5% aqueous ammonia under pressure
until the ow rate in each vessel was constant, then lled and distended each vessel with a hot powdered barium sulphate/gelatin
solution, held at an internal pressure of 140 mmHg until the gelatin
had cooled and set and the X-rays taken.
I regret that these X-rays of representative main human cerebral
arteries have previously been published only twice: once in my rst
monograph (Dickinson, 1965, p 31) and once in the Proceedings of
the 6th Princeton Conference on Cerebrovascular Diseases (Dickinson, 1968, p 125). The natural size of these arteries is very variable
79
and is presumably genetically determined, but it is obvious that both

main arteries can be narrowed by deposits of atheroma. Plaque
lesions indent the lumina of these vitally important arteries and
substantially increase their ow resistance, as in Fig. 3.6c. Close
inspection, even of the upper part of the fairly normal-looking
vertebral artery in Fig. 3.6a, reveals a hemispherical lling defect
across half the width of the lumen. I did not try to get any more of
these X-ray pictures, because they were administratively so dicult
to arrange. But those in Fig. 3.6 are enough to show that the natural
and congenital size of these important vessels is very variable. They
can be grossly narrowed, even over their whole length, by extensive
stenotic atheromatous plaques.
Because of the fast rate of blood ow in all the main arteries
supplying the human brain it is easy to appreciate that stenotic
lesions, such as those of the vertebral artery shown in Fig. 3.6c
(p 65), must have produced a devastating impairment of the subjects
cerebral blood supply. They did so in this former patients case (#43
in the series of Dickinson and Thomson, 1960a). This womans other
main cerebral arteries contained many atheromatous deposits. Her
hospital notes revealed that she had grossly increased blood pressure
(260/130 mmHg), had suered several previous strokes and had
complained of giddiness for the previous twenty-ve years, with
recent headaches and failing vision. It is dicult to imagine that any
amount of downstream small artery or arteriolar dilation could
possibly have oset the manifestly gross impairment of the blood
supply of this unfortunate womans brain by her diseased main
arteries.
Assessment of main cerebral artery resistance by determining the

maximal rate of ow of water through each artery under standard
conditions
When Drew Thomson and I made our necropsy measurements in a
series of cadavers, we were only just in time. Routine necropsies were
still being regularly performed in UK teaching hospitals. Our aim
was simply to estimate the least resistance that each of the four main
cerebral arteries in each of our ninety-four cadavers might have
presented in life. We made the reasonable Darwinian assumption
that all possible chemical and neurological constrictor mechanisms
80
in arterial walls would surely have evolved to be adequately relaxed

during physical rest and sleep, to minimise the wasteful consumption
of energy, if cerebral perfusion pressure or cerebral blood-ow had
been unduly great at this time. We therefore tried to simulate these
conditions as closely as possible at necropsy by dilating all arteries
fully with aqueous ammonia before making any pressure/perfusion
measurements of maximal ow-rates.
Our summated ow-rates, especially those for the vertebral
arteries, were closely correlated (negatively) with values of blood
pressure previously recorded in the hospital notes and assessed by
our independent observer. Mean blood pressure was taken to be
diastolic plus one-third pulse pressure. The following Figs 4.44.7 all
come from our rst originally published main article (Dickinson and
Thomson, 1960a). All gures are reproduced here with the permission of The Biochemical Society, (website: http://www.clinsci.org).
Figure 4.4 shows the highly signicant relation between ante-mortem
blood pressure and the summated uid ow-rates for both vertebral
arteries added together for all available former patients at that time,
excluding cases of malignant-phase hypertension and those with
inadequate blood-pressure records (P<0.001).
Because at the time of our study, Thomson and I knew that many
people believed that hypertension was the main cause of atheroma,
we also pressure/perfused a standard length of fty-two of our
cadavers femoral arteries. Many of these were grossly atheromatous, though none was completely blocked. The maximal owrate of the femoral arteries in our perfusion system was only weakly
(inversely) related to ante-mortem blood pressure of each subject
(r = 0.15), whereas that obtained from vertebral arteries on the
same side of each cadaver (r = 0.58) was considerably more closely
related to ante-mortem blood pressure (P<0.001).
In retrospect I realise that what seemed to be an almost absurdly
close correlation between two apparently dierent measurements
(vertebral artery uid-carrying capacity and ante-mortem blood
pressure) proved too incredible and dicult for most people to
believe or take into account. So nobody did take any notice of our
results for more than fty years, much to my frustration. Drew
Thomson and I also reported signicant correlations between antemortem blood pressure and the total summated ow-rates for all
four cervical cerebral arteries added together (Fig. 4.5). This gure
identies subjects dead from strokes, which I shall further discuss in
81
Fig. 4.4 The close relationship rst established between the maximal ow-rate of both
vertebral arteries (added together) and the mean ante-mortem blood pressure, for all
available subjects, only omitting seven former patients with malignant phase hypertension. The correlation coecient r = 0.732, P<0.001. This gure, and Figs 4.54.7,
all come from Dickinson and Thomson (1960a), pp 513538, and are all reproduced
with the permission of The Biochemical Society (website: http://www.clinsci.org).
Chapter 10, but it also identies cases of chronic renal disease (Fig.
4.6).
The inuence of chronic renal disease on the relation between

summated vertebral artery resistances and ante-mortem blood
pressures
We anticipated that chronic renal disease or renal artery narrowing
might have increased basal and casual blood pressures for any preexistent increased resistance of the main cerebral arteries. I shall
82
Fig. 4.5 The relation between total summated-ow rate for all four main cerebral
arteries, for all cases available at the time and the mean ante-mortem blood pressure of
all available subjects. The slope and signicance (r = 0.818, P<0.001) of our
measurements are almost the same as for both vertebral arteries alone.
consider these conditions in Chapter 9, taking care not to attribute

the necropsy ndings of so-called benign nephrosclerosis to primary chronic renal disease, because this type of renal damage is
usually attributable to the long-term pathological eects of essential
hypertension. Our expectation that chronic renal disease might make
an independent additional contribution to ante-mortem blood
pressure was, to a limited extent, borne out by our necropsyresistance measurements, which suggested that chronic renal disease
had made a small additional hypertensive contribution to blood
pressure already elevated by cerebrovascular lesions (Dickinson and
Thomson, 1960a). Although both renal and non-renal cases were
signicantly correlated with mean ante-mortem blood pressure and
with the summated ow-rates of both vertebral arteries added
together, Fig. 4.7 shows that there was a possibly signicant
83
Fig. 4.6 The relation between the summated ow-rates of both vertebral arteries taken
together and ante-mortem blood pressure, showing the position of subjects with some
form of pre-existent renal disease other than glomerulonephritis.
510 mmHg dierence between the positions of the two calculated

regression lines for cadavers with and without evidence of chronic
renal disease (P<0.02). Although the dierence was small, it suggested the blood pressure of people with chronic renal disase could
be elevated partly in the way I have envisaged for essential hypertension, but also partly by an additional renal increment, which
might have derived from circulating angiotensin, as I shall discuss in
Chapter 9.
Technical criticisms
The viscosity of blood in large vessels is between two and four times
greater than that of water (Dintenfass, 1971). I have tried to estimate
to what extent the ow resistances measured by Drew Thomson and
myself in our cadavers main cerebral arteries had values that might
have been comparable to those appropriate in life. As I have already
mentioned (p 45), the total cerebral blood-ow (CBF) of human
adults was measured by Kety and Schmidts nitrous oxide method
and conrmed by numerous other techniques, which I described in
84
Fig. 4.7 Statistical treatment of the dierence between renal and non-renal cases, in
respect of total ow rates of both vertebral arteries and mean ante-mortem blood
pressures (t = 2.62, P<0.02).
the last chapter. The generally accepted value for normal adults is
55 ml. 100 g brain-1. min-1. For a brain of average weight (1,400 g)
this gave an average total ow of 770 ml/min, or 13 ml/s. When
perfusing arteries with water rather than blood, we might expect to
nd ow rates about three times faster than this, i.e. about 40ml/s.
This is within the range of blood ow-rate estimates from the gures
of magnetic ow-meter rates obtained from the internal and vertebral arteries during surgical operations. Hardesty et al. (1960)
reported that human internal carotid artery blood-ow in life was
between 210 and 460 ml/min for each artery, and Hardesty et al.
(1963) reported that it was between 18 and 42 ml/min for each
vertebral artery ow rate. These gures provide a range of total
CBF, in all four arteries, of between 456 and 1,004 ml/min, i.e.
85
between 9 and 17 ml/s. Using water instead of blood, we might expect

values about three times greater, between about 23 and 50 ml/s.
Figure 4.5 (p 83) showed the relation between average summated
ow-rates from all four main cerebral arteries and the ante-mortem
blood pressures of all patients with adequate records. Summated
ow-rates ranged between 21 and 112 ml/s, values that are within the
range of our maximal summated necropsy perfusion rate measurements (12112 ml/s).
The average values for our summated necropsy perfusion rates
with aqueous ammonia were about 50 ml/s. All our perfusions used
the same high proximal perfusion pressure (140 mmHg) and deliberately took no account of the distal resistance of the small arteries
and arterioles, between the Circle of Willis and brain tissue,
becauseas I have explainedwe assumed that these classic resistance vessels would be fully dilated during basal pressure measurements. Estimates in humans have been that the Circle of Willis
pressure is about 60% of systemic arterial pressure. If so, this may
partly explain why our necropsy perfusion-rate measurements were
unrealistically rapid and therefore why they must have underestimated the total eective cerebrovascular resistance of the main
cerebral arteries in the neck and base of skull. However, our perfusions of some large cerebral arteries with aqueous ammonia
sometimes produced obvious turbulence, which was probably not
present in life when a more viscous uid was owing. This could
have led us slightly to overestimate the eective cerebrovascular
resistance in life during normal blood-ow. The two inaccuracies
might partly cancel out. But it is dicult to deny that our necropsy
perfusion technique must have measured something relevant and
signicant, else how could total vertebral artery ow rates in Fig. 4.4,
and our total summated ow-rates in Fig. 4.5, have possibly related
so closely to the ante-mortem blood pressures of our subjects?
The summated ow-rates of the four main cerebral arteries

We added ow rates together to calculate the eective resistance of
both vertebral arteries and added in the ow rates of both internal
carotid arteries. This allowed us to calculate total eective ow-rates
and thus total eective main cerebral artery resistances for each
subject. This was possible because all proximal pressures were
86
identical (140 mmHg). Although distal pressures doubtless varied in

life, all distal pressures in our perfusion system were identical, at zero
mmHg, because the cut ends of each artery were necessarily held at
atmospheric pressure. Our total maximal summated ow-rates for
dilute ammonia in our perfusion system ranged between 21 and
112 ml/min (Fig. 4.5). We were astounded to realise how much
ow resistance multiple distributed atheromatous lesions could
create.
Robert Lowe (1961) criticised my use of dierent cannulas within
a range of sizes to connect arteries of variable sizes to the rubber
tubing of our perfusion system. This was necessary to take account
of congenital, as well as atheromatous, narrowing of the arterial
origins. Stung by Lowes criticism, I plotted the relation between
ante-mortem blood pressure and the ow rates of both vertebral
arteries (added together) for all those cadavers in which we had used
the identical steel cannula (#2) for every vertebral artery perfusion in
our series. The eect was only to enhance our correlation coecient
for the relationship from 0.78 to 0.84, as I demonstrated in the
published summary of our work (Dickinson, 1965, g. 18, p 65).
Other critics might have worried that the main cerebral arteries on
each side had collateral branches, but there were only a few tiny
ones. The X-rays illustrated in Fig. 3.6 demonstrate that, although
the vertebral and internal carotid arteries run long and partly tortuous courses, their calibre is reasonably uniform along their lengths,
except in places where the lumen is partly occupied by atheromatous
lesions (e.g. Fig. 3.6c, p 65).
Only the small ophthalmic artery presented a problem, which I
mentioned earlier and solved by inserting a metal barrier behind the
orbit to prevent unsightly damage to the face from leakage of very
small amounts of uid from ophthalmic artery branches (Fig. 4.2,
p 73). We were always able to check for unusual leaks by comparing
the volume of uid lost from the reservoir during a perfusion with
that recovered from the receiver in the skull. The small amount of
perfusion uid lost either from the walls of the internal carotid, or
vertebral arteries themselves, was negligible. In any case it should
have been much the same in all our perfusion studies. In the course
of developmental evolution of the human brains blood supply, it
seems that nature has taken care not to divert a lot of blood destined
for the brain into irrelevant accessory collateral arteries.
We encountered one exceptional subject who proved to have
87
extraordinary main cerebral arteries, which were unusual but

understandable. Subject #23 in the series of Dickinson and Thomson
(1960a) was a 35-year-old man who had congenital cyanotic heart
disease (Fallots tetralogy), with polycythaemia. He had died from a
cerebral abscess. When we perfused his vertebral arteries with dilute
ammonia at 140 mmHg pressure, the base of his skull resembled a
watering can, with water rushing out of numerous small holes, each
of which must have contained small collateral arteries alongside the
main vertebral artery trunk. This cadaver made a complete contrast
to all our other vertebral artery perfusions. In every other case each
vertebral artery ran its long, complex course without any signicant
collateral branches. Evidently a lifetimes exposure to hypoxic
arterial blood in this mans case had supplied a powerful stimulus for
collateral arterial development.
Because Thomson and I knew that that almost everyone believed
that hypertension could cause, or at least aggravate, large artery
atheroma, we decided to extend our perfusion measurements to look
at ow resistances in an artery not thought to have any causal
relation to blood pressure control, but one commonly aected by
stenotic atheromatous lesions. We chose the right femoral arteries,
comparing them with the right vertebral arteries, in the same cadavers. We used the femoral artery from the origin of its profunda
branch to its bifurcation behind the knee joint. Although there was a
small negative correlation coecient of femoral artery ow-rate with
ante-mortem blood pressure in our standard perfusion system (r =
0.15), this was much smaller than that for the right vertebral artery
(r = 0.58). The dierence of correlation coecients was highly
signicant (P<0.001).
A pause in our perfusion study

After Drew Thomson and I had examined and perfused the cerebral
arteries of our rst group of cadavers, using the methods and techniques I have just described, we stopped to take stock. We were
excited because thus far our results strongly supported the new
idea, which I described earlier: that atheromatous narrowing of the
four main cerebral arteries in the neck and skull base was the cause
of essential hypertension. When we added together the ow rates we
had obtained from the four main cerebral arteries of each cadaver (a
quantity that I have described as a summated ow-rate), we were
88
amazed to nd that the summated ow-rates in our rst fty-eight

cadavers were almost sensationally correlated (negatively) with our
subjects ante-mortem blood pressures, recorded in the hospital
notes. Although we knew that much of the cerebral arterial resistance was provided by relaxable small arteries and arterioles, it
seemed obvious that extensive atheromatous plaques must often
have provided serious ow-resistance: a completely satisfying
explanation for essential hypertensionsomething that had been
sought in vain for more than a century. In a state of great excitement
we sent our paper o to The Lancet, where it was accepted
unchanged and published as a Preliminary Communication (Dickinson and Thomson, 1959). In due course this was followed by our
two denitive papers (Dickinson and Thomson, 1960a and 1961),
which contained all the details of our techniques and all our raw
data.
In retrospect, I should not have been surprised that very few
people took any notice of our work. I do not believe that most
people thought that we had cheated by inventing data that supported
my ideas. There were several other problems. Everybody thought
that the four nice big arteries in the human neck were more than
adequate to supply blood to the brain, however many atheromatous
plaques they might contain. In any case, atheromatous plaques were
at least partly created and denitely aggravated by high blood
pressure itself. Large cerebral-artery resistance could be ignored
because the small cerebral resistance arteries and arterioles would
simply relax and surrender more of their autoregulatory reserve, if
this was needed to bring cerebral blood-ow back to normal. So
nobody believed that our careful resistance measurements explained
essential hypertension. Nobody before had ever tried to measure the
minimal ow-resistance of these inconveniently inaccessible cervical
arteries. Nobody has tried since. The technique was tedious and
time-consuming. It may have been considered na ve, at best. It was
undoubtedly unaesthetic. And at the time, almost everyone thought
that some abnormality in the kidneys caused essential hypertension,
even if it had to operate through the nervous system.
Many people before us had classied atheromatous lesions of
human cervical cerebral arteries. Many have done so since. They
have sometimes cut these arteries across in many places to examine
luminal diameters. But my hypothesis about essential hypertension
demanded measurements of resistance, which Drew Thomson and I
89
supplied. Fifty years later, I am pleased to have been able to describe

in this book many new observations, which are entirely compatible
with my original idea. They are also entirely consistent with Julian
Patons observations of the blood supply to the brain in the
generally-accepted animal model of essential hypertension: the
spontaneously hypertensive rat (SHR). Several competing
theories can now be laid to rest. Julian and I await the judgement
of history.
Summary
This entirely technical chapter contains full details of the necropsy/
perfusion study of ninety-four cadavers carried out by Drew
Thomson and myself. It was inspired by Darwinian thinking and
extensive literature research, from which we conjectured that the
small human cerebral resistance arteries and arterioles would be
fully dilated during sleep, thus leaving total cerebrovascular resistance entirely dependent on their congenital resistance, together with
any additional resistance created by atheromatous plaques narrowing the two internal carotid and the two vertebral arteries in their
long, convoluted courses in the neck and skull base. This assumption
has not been proved, but it contradicts no reliable published
measurements.
In each cadaver, we successively cannulated the origin of each of
these arteries with the help of stainless steel cannulas, each tted with
rounded introducing plugs. Each artery was connected in turn to a
constant-pressure reservoir containing aqueous ammonia. This
could be hauled up to ceiling level, providing a pressure of
140 mmHg at the level of the necropsy table. Maximal ow-rates
were determined by timed opening and closing the spring clip on a
wide-bore rubber tube connected to each main artery cannula in
turn. All perfusions were repeated until ow rates became constant.
Our two main papers were published in Clinical Science. We
concluded that the four main arteries in the neck and skull base often
supplied a substantial unrelaxable resistance to uid ow. This
varied over a ve-fold range, which went from a fast, smooth ow to
what could best be described as a trickle. Individual maximal owrates represented minimal individual ow-resistances, which we
found were directly related to the previously recorded ante-mortem
90
blood pressure of each subject. These measurements provided a

complete and plausible explanation for essential hypertension.
They also explained several apparent anomalies in the causation of
spontaneous strokes, as will be described in Chapter 10.
91
5
Mechanisms of Blood-Pressure Control in
Humans Compared With Those in Other
MammalsCerebral Autoregulation
Adult human hypertension is dened by the World Health Organisation as a systemic arterial pressure at or above 140 mmHg systolic
and 90 mmHg diastolic. Hypertension can be regarded as a disease
that shortens average life-span in proportion to the extent to which
these upper limits are exceeded. As I said in my rst chapter, Horace
Smirk, Professor of Medicine in Otago (New Zealand) was one of
the rst people to emphasise the importance of measuring basal
blood pressure, preferably during sleep. Elevated basal blood
pressure was better correlated with later illness and shortened lifeexpectancy than were elevated casual readings of blood pressure
(Smirk, 1957). The superb epidemiological survey of large groups of
Japanese men and women by Imai et al. (1997) provided pooled
records of mean systolic and mean diastolic blood pressures at
hourly intervals of 24 h. These clearly demonstrated that groups of
individuals with three dierent nocturnal basal blood pressure levels
were strongly associated with the later patterns of increased casual
blood-pressure readings during the day, in each of the three groups
(Fig. 3.4, p 54). The strong prognostic signicance of basal blood
pressure is now generally acknowledged, e.g. Fagard et al. (2008).
Most epidemiological evidence suggests that the cause of hypertension is less important than its severity, which quantitatively
determines its pathological ill-eects. Almost every clinical study has
shown that reducing blood pressure in hypertensive patients by any
means, reduces hypertensive symptoms and also improves lifeexpectancy, providing that the reduction in blood pressure is not too
great. In Chapter 9 I shall briey summarise the well-established
secondary causes of hypertension, most of which are either renal or
endocrine. But the elephant in the room has to be essential
92
MECHANISMS OF BLOOD-PRESSURE CONTROL IN HUMANS
hypertension, the cause of which remains mysterious. Can animal

studies help?
Hypertension in giraes
Adult giraes have the highest blood pressure of any mammal.
Hitchens (1982) attributed this to successive mutations in thousands
of generations, which equipped this vegetarian animal with unique
selective advantages in obtaining food from the tops of trees.
However, elongation of the neck began early in the giraes evolutionary history, and was gradual, not punctate (Mitchell and Skinner, 2003). Giraes have main cerebral and renal arterial blood
vessels, which are anatomically comparable to those in most other
terrestrial mammals (van Citters et al., 1969). The high systemic
arterial pressure of giraes appears to relate to their size. It rises in
proportion to growth (Hargens et al., 1988). The exactly proportional rise of blood pressure with increasing neck length in the girae, and the proportional development of other changes, such as left
ventricular hypertrophy and hypertrophy of arterial media, are most
plausibly ascribed to the operation of the Cushing mechanism in the
hindbrain (Paton et al., 2009; Mitchell and Skinner, 2010).
Hypertension in rats
The late Horace Smirk was not the only clinical investigator to
inbreed WistarKyoto rats deliberately and selectively to develop
higher and higher values of systemic arterial pressure. Many others,
notably in North America, Japan, Italy and Australia, have also
developed hypertensive rat strains. The most celebrated of these is
the spontaneous hypertensive rat (SHR) of Aoki and Okamoto.
This animal is generally accepted as the ideal model for human
essential hypertension. In the second edition of my monograph
(Dickinson, 1991), I listed many international varieties of spontaneous hypertensive rats, notably one that was stroke-prone. I was
able to identify thirteen main points of resemblance between SHR
and human essential hypertension. I have even wondered whether
someone will characterise the well-known bad temper of SHR-SPs as
evidence of a psychosocial predisposition.
93
However, spontaneous hypertensive rats have well-recognised

structural abnormalities in their cerebral arterial blood-supply. The
vertebral and basilar arteries of young SHRs have thickened walls
and much reduced internal luminal diameters, even before hypertension has developed (Paton et al., 2007). The SHR must have
independently developed narrowed main hindbrain arteries. Julian
Paton describes in detail, in Chapters 7 and 8, the structural and
functional anatomy of the main brainstem nuclei of SHR and
illustrates in which structures the hypertensive predisposition arises.
Cerebral autoregulation
Moyer and Morris (1954) used Ketys nitrous oxide method in
humans to examine cerebral autoregulation: the stability of cerebral
blood-ow (CBF), despite changes in cerebral perfusion pressure.
Carlyle and Grayson (1956) used direct methods in animals. No
more recent work has much changed the conclusion that in all
mammals studied, providing that surgical trauma has been minimal
and anaesthesia not too deep, cerebral blood-ow remains remarkably constant over a wide range of arterial pressures. Holmes et al.
(1971) measured CBF in humans before and after acutely ligating
one common carotid artery (in the course of treatment of a subarachnoid haemorrhage). They observed that, even in the ipsilateral
hemisphere, there was only a brief reduction of blood ow. Wholebrain blood-ow was back to normal after thirty minutes. However,
heroic management of this kind has only been tried in young adults,
as a last resort.
Hypotensive drugs have been used to determine the lower limit of
cerebral autoregulation, with or without head-up tilt. The trouble
with this technique is that the drugs themselves may independently
reduce tonic cerebral vascular resistance (CVR) and thus give the
impression of natural intrinsic autoregulation where none really
exists. In rats, CVR in both normal and hypertensive animals can be
reduced by cervical sympathectomy (Hart et al., 1980). Altered
sympathetic vasoconstrictor tone of cerebral vessels could, therefore,
play some part in producing autoregulation in the brains circulation. This conclusion is supported by experiments, such as those
reported by Shiokawa et al. (1988), who observed some impairment
of cerebral blood-ow autoregulation after -blockade with
94
propranolol, -blockade with phenoxybenzamine or cholinergic

blockade with atropinesuggesting that the autonomic control of
brain blood-vessels is highly complex! Edvinsson and McCulloch
(1987) have edited a useful review of peptidergic control systems in
the cerebral circulation. Except in the case of angiotensin-II, which is
probably a vasoconstrictor in its normal concentration range, we
do not know whether the naturally-occurring low circulatingconcentrations of most other vasoactive agents are great enough to
have any signicant physiological eect.
It has long been known that carbon dioxide is a cerebral vasodilator, both directly and indirectly, by its inuence on the autonomic
nervous system. A reduction in cerebral blood-ow, unaccompanied
by a reduction in metabolic rate, must increase local PCO2, whose
local vasodilator action may allow some autoregulation independently of nervous inuences. No doubt there are many other chemical inuences on cerebral blood-ow, which could contribute to
autoregulation. In addition, the brains enclosure in a rigid bony box
has the potential for some degree of mechanical autoregulation.
The lower cerebral autoregulatory threshold for cerebral blood-ow

In the young normotensive adult, compared with the young essential
hypertensive individual
The blood pressure of an average, t, young adult at rest and in sleep
might well fall tolet me say90/60 (= 70 mmHg mean pressure).
According to Meyer et al. (1965) 6070 mmHg is the critical mean
systemic arterial pressure, below which there is a risk that cerebral
autoregulation might fail and threaten brain infarction. A value of
this order is about 1015% higher than a lower mean valuelet me
suggest 55 mmHgbelow which cerebral blood-ow autoregulation
would usually fail and cerebral blood-ow (CBF) begin to fall. I shall
call this the lower cerebral autoregulatory threshold (LCAT). Let
me contrast a normotensive individual with someone with essential
hypertension and a blood pressure of 170/110 (corresponding to a
mean systemic arterial pressure of 130 mmHg) and an LCAT 15
20% less than this, say, 115 mmHg.
Figure 1.1 (p 14) was taken with permission from Niels Lassens
classic review (Lassen, 1959). It shows the average cerebral blood95
ow in thirteen groups of 376 human adults, plotted against the

average values of systemic arterial pressure of each group. Points
labelled #1, 2, 3 and 4 came from groups of patients with druginduced hypotension; points #5 and 6 from normal pregnant women
and normal young men; points #7 and 8 were from people with
secondary (renal) hypertension; and points #9, 10 and 11 were from
three dierent groups of patients diagnosed with essential
hypertension.
Even if blood pressure was lowered to the LCAT value
(115 mmHg) in one of the people in the hypertensive groups, there
would still be a considerable margin of safety left for further bloodpressure reduction. Physicians trade on this margin of safety when
lowering blood pressure in hypertensive patients. Only unduly large
and sudden reductions of blood pressure threaten cerebral infarction. In his review, Lassen wrote prophetically: It has been clearly
shown that patients with essential hypertension are abnormal in so
far that they cannot tolerate a blood-pressure reduction to as low
pressure levels as are seen in normotensive subjects. This indicates
that the cerebral blood vessels are unable to relax normally, presumably because of increased rigidity . . . It is of considerable interest
to know whether prolonged ecient anti-hypertensive treatment
would normalise the tolerance to hypertension. In his review of
cerebral blood-ow in hypertension, Barry (1985) compared the
cerebral arterial vasodilator eect of increased carbon dioxide tension in essential hypertension with that seen in normal subjects. He
wrote: The attenuated response to CO2 inhalation observed may be
due to structural changes in the vascular wall from longstanding
hypertension, to the process of ageing itself, or to both of these.
I shall discuss the merits of blood-pressure reduction more fully in
Chapter 10, where I shall review the evidence that reduction of blood
pressure prevents, or alleviates, heart failure and might protect
against strokes. The benets are inversely proportional to the bloodpressure reduction achieved. Within obvious limits, the lower the
blood pressure, the greater the improvement in morbid symptoms
and in life-expectancy. The ideal treatment for essential hypertension
would appear to be lowering blood pressure to the lower cerebral
autoregulatory threshold (LCAT), but the inevitable unevenness of
cerebral perfusion in most people makes this a counsel of perfection.
Many claims have been made that long-term anti-hypertensive
drug treatment of essential hypertensive patients can reset the LCAT
96
back to its normal level. Strandgaard (1978) wrote: Of the patients

studied twice only one or two appeared to have shifted his autoregulation towards normal during antihypertensive treatment.
Fortunately there is a close parallel between the value of basal blood
pressure and the lower limit of cerebral blood-ow autoregulation.
This suggests that the blood ow to some critical site determines
both phenomena. It might, therefore, be worth discovering whether
long-term hypotensive drug treatment can lower the basal blood
pressure during sleep. This seems a more practicable objective than
trying to measure more LCATs before and after long-term hypotensive drug treatment. Nobody has yet been able to show convincingly that, although CVR can be reduced by all our powerful
hypotensive drugs, the LCAT seems, so far, to have resisted all
attempts to lower it, except in animals (see below). This follows
naturally if we accept that the LCAT is xed by the congenital small
size and atheromatous lesions narrowing main human cerebral
arteries.
Cerebrovascular resistance is made up of two components, in
series: (a) that due to unrelaxable atheromatous lesions or congenital
small size, and (b) that due to arteriolar and small artery changes due
to medial muscular spasm, hypertrophy or eutrophic remodelling.
Resistance (b) can be reduced or removed by our powerful hypotensive drugs, and (as I showed in Chapter 4) was completely
eliminated by ammonia during my necropsy perfusion studies. But
resistance (a) cannot be changed, except by surgical dilation,
reconstruction or by arterial stents.
In spontaneous hypertensive rats (SHR and SHR-SP)

The cerebral arteries of the SHR seem to have greater spontaneous
vasomotor activity than those of WKY rats. This might contribute
to increased cerebrovascular resistance. In contrast to the failure of
any investigators convincingly to lower the LCAT in essential
hypertensive patients, no authors have experienced comparable difculty in reducing LCAT in spontaneously hypertensive rats. For
example, Barry et al. (1984), Harper (1987) and Torup et al. (1993)
have all reported resetting of the LCAT to normal after long-term
anti-hypertensive treatment of SHRs. Vorstrup et al. (1984) have
done the same for renal hypertensive rats. In due course it will be
interesting to nd whether the LCAT of SHR-SP can be reduced by
97
long-term hypotensive treatment, because Julian Patons recent work

suggests that the main cerebral arteries of these rats are congenitally
narrow.
In other animal models

It is interesting that in a primate model of hypertension and cerebrovascular disease, produced by cholesterol feeding and aortic
coarctation, Prusty et al. (1988) observed that anti-hypertensive
treatment had twice precipitated a stroke. Hollander et al. (1968)
commented that in this animal model with treatment of hypertension readaptation [of the cerebral autoregulatory threshold] to more
normal levels is reported to be inconsistent and slow to develop. It is
tempting to suggest that the authors on this occasion had got very
close to producing an accurate animal model of human essential
hypertension.
The higher cerebral autoregulatory threshold for cerebral bloodow: an apparent ceiling
Human cerebral blood-ow has been measured many times by many
people, ever since Kety rst reported that it averaged 55 ml. 100 g
brain-1. min-1. and that it was the same in people with essential
hypertension, as in normotensive individuals. Niels Lassens famous
graph (Fig. 1.1, p 14) emphasised this but also suggested that there
may be a ceiling for CBF, which is seldom exceeded. Even in
hyperthyroidism, when blood ow to many parts of the body was
increased, total CBF did not also rise (Sokolo et al., 1950).
There have been many attempts in animals to increase total
cerebral blood-ow by administering vasoconstricting drugs to
elevate blood pressure. Meyer et al. (1960) reported that in cats they
could induce arteriolar vasospasm by this means. Mackensie et al.
(1976) reported a sudden breakthrough of autoregulation in cats
when systemic arterial pressure was raised by angiotensin infusion
above a threshold at about 170 mmHg. This could sometimes
produce a sausage-string appearance of cerebral arterioles by segmental dilations. However, Fog (1939) had acutely raised arterial
pressure in cats by clamping the thoracic aorta just distal to the
cerebral arterial origins and was able to induce pial arteriolar spasm
even without the administration of a vasoconstrictor drug.
98
I doubt whether such experiments are relevant to realistic clinical

situtations. I guess that the brains enclosure within a rigid bony box,
creates an eective upper limit for cerebral blood-ow most of the
time. A rise of systemic arterial pressure must distend the proximal
arterial tree slightly. This will inevitably increase intracranial
pressure towards a cerebral blood-ow ceiling, above which compression of the brains venous drainage will be the other limiting factor.
This mechanical type of cerebral autoregulation is dicult either to
prove or even to investigate, but I strongly suspect that when Ketys
original essential hypertensive subjects had their cerebral bloodows measured by the nitrous oxide method, their cerebral bloodow had already been raised to its natural ceiling by excitement or
apprehension.
Summary
Autoregulation in the cerebral circulation of humans, giraes and
rats is briey summarised. Some apparent autoregulation in all these
species is due to the drugs chosen to raise or lower perfusion
pressure. However, there is a xed unadaptable and unrelaxable
lower cerebral autoregulatory threshold in patients with essential
hypertension. This may be unique in the animal kingdom.
99
6
Cerebral Oxidative Metabolism in Essential
Hypertension
My rst opportunity for clinical, i.e. applied, research came in 1957,
when I was appointed a medical registrar at the former Middlesex
Hospital in London. That was where I met, and collaborated with,
Drew Thomson in the human necropsy study I described in Chapter
4. But I also had the pleasure of meeting and collaborating with
Moran Campbell, who had just returned from a year in Baltimore,
working with Dick Riley. Moran and I had desks in the same
laboratory. I learnt a great deal about human respiration from him.
We discovered a strong mutual interest in clinical physiology and
jointly edited a multi-author textbook of applied physiology
(Campbell and Dickinson, 1959), which eventually ran to ve
editions. Moran later helped me design and publish my digital
computer model of human respiration (Dickinson, 1977).
Equipped with this background in human respiratory physiology,
and with my previous interest in blood-pressure regulation and
hypertension, I was intrigued to come across a strange and unexpected observation recorded in the classic paper by Kety et al.
(1948a) published in the Journal of Clinical Investigation. That was
the rst occasion in which Kety and Schmidts nitrous oxide method
was used to compare the average cerebral blood-ow (CBF) of a
group of twelve patients with essential hypertension and an average
blood pressure of 159 mmHg (corresponding to a clinical blood
pressure of about 220/130 mmHg), with that of a control group of
eighteen normotensive subjects with an average blood pressure of
86 mmHg (corresponding to a clinical blood pressure of about 110/
75 mmHg). The average cerebral blood-ow (CBF) of the essential
hypertensive patients was 54 ml. 100 g-1. min-1., which was the same
as that of the normotensive group. The cerebral oxygen uptake was
also the same for both groups. Although we now know that Ketys
100
CEREBRAL OXIDATIVE METABOLISM IN ESSENTIAL HYPERTENSION
measurements of CBF were inadvertently misleading (p 46), I

became interested in another observation recorded in Ketys original
paper.
The average cerebral respiratory quotient (RQ) of Ketys normotensive control patients had the usual expected value (0.99), whereas
the average cerebral RQ of his group of patients with essential
hypertension was considerably less than unity (0.90). Kety and his
colleagues calculated that the dierence between the respiratory
quotients of the two groups was signicant at P<0.01 level, but they
did not try to explain the dierence in the text of their article.
I was alerted and fascinated by this observation. In my rst
chapter, I explained how I came to conceive the idea that increased
atheromatous structural resistance in the four main arteries
supplying the human brain might be the cause of so-called essential
hypertension. This hypothesis explained why that disease was unique
to humans. It also explained why all attempts to produce a stable
animal model of the disease, by constricting or ligating the main
cerebral arteries, had failed. Unless animals are fed an atherogenic
diet, to promote atheromatous deposits, there is nothing to prevent
the animals eventually developing new collateral arteries bypassing
any obstructions to their main cerebral arteries. I envisaged that the
lower than expected cerebral respiratory quotient of essential
hypertensive patients might have been an indirect marker suggesting
that their brains might have sometimes been short either of glucose
or oxygen and had gradually turned to the use of some fuels other
than glucose, perhaps also making some use of so-called anaerobic
metabolism. Before going any further I will explain, for readers
unfamiliar with the subject, the meaning and the signicance of the
respiratory quotient of the brain.
The signicance of an organs respiratory quotient

When an organic substrate is oxidised in an organ to provide energy,
some of its carbon becomes carbon dioxide. The respiratory quotient
(RQ)more helpfully called the respiratory exchange ratioof an
organs metabolism relates the amount of carbon dioxide produced
to the amount of oxygen consumed when a substrate is oxidised
(dehydrogenated) to produce energy. In the chemical equation for
the oxidation of glucose to carbon dioxide and water:
101
C6H12O6 + 6O2 g 6CO2 + 6H2O

the same number of molecules (or volumes) of carbon dioxide are
produced by the same number of molecules (or volumes) of oxygen.
In that case, the respiratory quotient:
Volume of CO2 produced
Volume of O2 consumed
should be unity. Within the limits of experimental error this is the
case when glucose is the substrate for mammalian brain suspensions,
brain tissue slices and for the perfused mammalian brains of cat, dog
and monkey (review by Dickinson, 1995). The consistent nding of a
cerebral RQ of unity in all these situations is strong evidence that the
brain uses glucose predominantly. Gibbs et al. (1942), in their classic
study of fty healthy young men (mostly medical students), reported
that their average cerebral RQ was 0.99 with a SEM of 0.01 (my
calculation from the Gibbs published data table). The rate of oxidation of glucose by brain slices, weight for weight, is faster than
that of glucose oxidation by hepatic, cardiac or renal slices. In
contrast with many other tissues, the brain does not need insulin to
metabolise glucose, although insulin does have small, but measurable,
eects on central nervous system function.
Measurement of the RQ of the brainbrain metabolism in adult

mammals
The determination of cerebral RQ demands four separate measurements of blood gas contents, two for oxygen and two for carbon
dioxide, in blood owing both to and from the brain. In a steady
state, the respiratory quotient of the brain can be determined by the
ratio:
(Jugular venous arterial) CO2 content dierence
(Arterial jugular venous) O2 content dierence

All available evidence suggests that the energy needs of the adult
human brain in situ can be fullled completelyand are normally
fullled completelyby the oxidation of glucose. The situation in
the mammalian foetus is dierent. The foetal brain tolerates
102
hypoxaemia and makes considerable use of ketones to provide

energy. l-lactate can enter the foetal brain readily, and may even be
the preferred substrate for energy production following a period of
anoxia. But in terrestrial mammals there is a gradual shift during
development from ketone body utilisation by the brain to predominant glucose utilisation. We do not know the evolutionary
reason for this change. My guess is that it may be a metabolic change
that reduces the brains oxygen requirements and perhaps also the
production of heat.
Calculations are dicult. The energy stores of the brain are very
small in relation to its high metabolic rate. Pooled data from several
sources suggest that at the maximum observed rate of change, 10 to
15% of the total amount of oxygen and glucose in the adult brain is
reacting every second. The maximal rate of consumption of adenosine triphosphate (ATP) is faster still. About 25% of the total ATP
of the brain can be metabolised every second (McIlwain and
Bachelard, 1985). General anaesthetics have profound eects on
oxidative metabolism, reducing both glucose uptake and glycolysis
by the brain. The brain is capable of metabolising sugars other than
glucose much less well. The penetration of substances from blood
into brain can be measured by the brain uptake index (BUI). If this
is set at 100% for (tritiated) water uptake during a single passage
following carotid artery injection, the BUI for d-glucose is 32% and
that for l-glucose uptake is unmeasurable. The uptake of d-glucose is
highly specic and carrier-mediated (Oldendorf, 1971). Metabolism
is either through the EmbdenMeyerhof pathway (EMP) or the
hexose monophosphate pathway (HMP). The HMP is more
important in the young animal, whereas the EMP is mainly used for
energy production in the adult brain. Lactate and pyruvate are
relatively impermeable compared to glucose, but both can be
transported across the bloodbrain barrier by saturable stereospecic transport mechanisms. In newborn animals, acetoacetate is
metabolised by the brain at the same rate as glucose, though in adult
animals glucose is metabolised about three times faster than
acetoacetate. The dierence may reect the relatively high levels of
ketones in the blood at birth, and perhaps the low foetal tissue
oxygen tension. If hypoglycaemia is produced in human adults by
the intravenous administration of insulin, the intravenous infusion
of ketones allows lower blood glucose concentrations to be tolerated
without the appearance of symptoms or of the hormonal responses
103
associated with severe hypoglycaemia (Amiel et al., 1991). In general,

the higher the concentration of ketone bodies in the plasma, the
higher their rate of metabolism by the human brain. Although
ketones can substitute for up to about 50% of oxidisable substrate
necessary for neuronal function, the presence of small amounts of
glucose has a disproportionately large facilitating eect on the
brains ability to catabolise ketones. Brain tissue can oxidise several
fatty acids, but normally does so only on a small scale. The brain can
also metabolise amino-acids (Lajtha and Toth, 1961). Labelled
14
CO2 can be produced within the brain from 14C-labelled aminoacids; but no amino-acid can fully replace glucose as an oxidisable
energy-yielding substrate.
Glucose uptake appears to be related to specic parts of the brain.
GLUT1 is the glucose transporter of the bloodbrain barrier. It is
mainly located on the abluminal side of brain capillaries (Stewart et
al., 1994). When glucose is oxidised by the brain, only some 50% of
14
C-labelled glucose can be recovered in cerebral euent blood as
labelled CO2 and HCO3. It is therefore likely that glucose carbon
equilibrates in the brain with a metabolic carbon pool, which
includes glutamic, N-acetylaspartic and -aminobutyric acids, glycogen and glutamine. This makes it dicult to determine how much
glucose is oxidised in any particular part of the brain, and how much
has become part of the metabolic carbon pool. There are not enough
data about cerebral fuel utilisation to assign any specic meaning or
spatial location to the observation of a lower than normal cerebral
RQ in essential hypertension; but it may be useful to consider in
which conditions the adult cerebral RQ has been reported to be less
than unity.
The signicance of the adult human brains respiratory quotient

Single organs, unlike the body as a whole, are not closed systems. To
take a simple example, if some incoming glucose is oxidised to
pyruvic acid within the brain, according to the general equation:
C6H12O6 + O2 g 2C3H4O3 + 2H2O
and if pyruvate leaves the brain without undergoing further change,
oxygen would have been consumed within the brain and energy
released without the evolution of any CO2. This would obviously
104
lower the apparent RQ. The oxidation of substrates other than

glucose produces an RQ less than unity: about 0.71 for fats and
about 0.81 for amino acids. For the whole human body at rest,
consuming an average Western diet, the RQ is 0.82 (Lennox, 1931).
So the unexpected nding of a reduced cerebral RQ in essential
hypertension tells us that all is not completely well with the energy
supply of the essential hypertensive brain. The brain must have been
using some fuel additional to glucose to provide energy.
Hafkenschiel et al. (1954) substantially conrmed Ketys original
ndings that there was a signicant dierence between normal
people and those with essential hypertension. In their study, thirtyfour normotensive patients had an average cerebral RQ of 0.99
( 0.02), but the average RQ of 101 patients with essential hypertension and an average mean blood pressure of 134 mmHg was 0.90
( 0.01).
I wanted to get more information about this dierence and about
the possible inuence of age. So I examined as many published
human studies as possible in which cerebral respiratory quotients
were either recorded or (more usually) could be calculated from the
published full tables of raw data. This possibility arose as a byproduct of Kety and Schmidts method for measuring cerebral
blood-ow. This required collection of blood from an internal
jugular vein, as well as from an artery, which allowed measurements
of oxygen and carbon dioxide contents in blood going to and coming
from the brain. After 1961, human cerebral blood-ow was
measured using radioactive inert gases, notably 133xenon. No further
measurements of cerebral RQ became available in the published
literature or could be calculated from raw data tables. But I was able
to nd enough data in sixteen studies published before 1961 of 223
subjects, with a wide variety of blood pressures and raw data,
without using any of the data from the published papers I have
already mentioned above.
These reports gave me enough further data to allow me to
undertake a meta-analysis of these later papers (Dickinson, 1995).
Fortunately all the necessary blood gas measurements in the reports
I reviewed were made using the Van SlykeNeill technique, and most
authors had been trained in Ketys laboratory. Once again the results
conrmed that people with moderately severe essential hypertension
had, on average, a cerebral RQ signicantly less than unity (0.91 .
0.02; table 2 from Dickinson, 1995). Figure 6.1 shows all the available
105
Fig. 6.1 The relation between mean systemic arterial pressure and the cerebral
respiratory quotients of all 378 available individual measurements for all cases in which
measurements could be obtained from the published literature (see text). Patients with
grades III and IV fundal changes are separately identied by open triangles. Although
the results are collectively confusing (because each point was derived from four separate
published oxygen and carbon dioxide content measurements), the calculated regression
equation (illustrated) is signicantly less than unity (r = +0.91, P<0.001). Reproduced
with permission from Dickinson (1995) Journal of Hypertension 13 653658.
data points I collected, relating cerebral RQs to blood pressure.

There is a great deal of scatter, but that is only to be expected
because each individual cerebral RQ estimation involved four
separate determinations of blood gas contents.
Clearly the metabolism of the brain of an individual with essential
hypertension is abnormal. In those people with the higher blood
pressures, the brain must have been using a substantial proportion of
non-glucose fuels to provide energy. This seemed to t with my idea
that essential hypertension was the bodys adaptive response to a
xed and unrelaxable increase in resistance of the large arteries
supplying the brainstem. I can make this claim with condence
because comparably reduced cerebral RQs have usually been
reported in patients with clinically-manifest cerebrovascular disease,
i.e. in those with completed strokes or transient ischaemic attacks. In
such cases, average cerebral RQ values have all been considerably
less than unity, e.g. 0.90 (Novack et al., 1953) and 0.88 (Shenkin et
al., 1953). There has even been one study that estimated an average
cerebral RQ of 0.79 (Reinmuth et al., 1966). All the twenty-two
106
patients reported by Reinmuth and colleagues had evidence either of

cerebral infarcts or recent focal ischaemia.
In a study of fourteen arteriosclerotic patients, Gottstein et al.
(1965) were able to elevate the average cerebral RQ from 0.88 to 0.99
by the intravenous infusion of glucose. They suggested that, in
vascular disease of the brain, the cerebral metabolism of noncarbohydrates was increased as a consequence of disturbed
permeation or utilisation of glucose. I suggest that a minor defect in
cerebral oxygen supply in basal conditions had probably long-term
eects on the fuels used to supply energy to the brain. Some
disturbance in fuel supply or fuel utilisation is obviously present in
essential hypertension, which could be regarded as a step in a
progression towards overt cerebrovascular disease. After severe and
prolonged brain anoxia in conscious patients with permanent brain
damage, cerebral glucose consumption may be only 75% of normal.
It may be as low as 50% of normal in patients in a vegetative state
(de Volder et al., 1990).
Rats subjected to a short episode of global cerebral ischaemia have
impaired oxidative metabolism of glucose in many areas of the brain.
Morphological changes occur in brain mitochondria. Glycolysis is
impaired for more than 24 h and brain lactate concentration remains
elevated for up to seven days after the acute ischaemic episode
(Sutherland et al., 1990). It is interesting that even the small rat brain
may take days to recover from an ischaemic or hypoxic episode.
Long-term memory eects on the metabolism of a creature as
small as the sea snail Aplysia californica have been intensively
studied by Eric Kandel and his collaborators (e.g. Pittenger and
Kandel, 2003; Lee et al., 2008). Their studies have revealed the
gradual steps by which long-term memories are established by new
protein synthesis. I was particularly intrigued that long-term
memory storage can be mediated in Aplysia not only by positive, but
also by negative regulatory mechanisms, suggesting that there are
genetic mechanisms with a memory suppressor function (Abel and
Kandel, 1998). This allows me to imagine that, if the human brain is
subjected night after night to the threatened impairment of oxygen
or glucose supply during sleep, it might in the end accumulate longterm memory changes to consolidate the use of non-glucose fuels in
the braineven though during most of the waking day the oxygen
and glucose consumption of the brain were normal.
107
What may we conclude about oxidative metabolism in the essential

hypertensive human brain?
Within the last two decades, as I mentioned in Chapter 3, total
cerebral blood-ow has many times been recorded to be signicantly
reduced in essential hypertensive individuals with substantial elevation of blood pressure. The same applies in heart failure. There are
many other similarities in pathophysiology between heart failure and
essential hypertension, which I have discussed elsewhere (Dickinson,
1991, chapter 14). So it is worth remarking that the cerebral RQ in
heart failure was long ago noted to be signicantly less than normal
(Moyer et al., 1952; Novack et al., 1953).
Clearly there is something unusual going on in the human essential
hypertensive brain. Although the alteration in cerebral oxidative
metabolism might in some way have been brought about by the rise
of blood pressure per se, it is much more likely that the metabolic
changes and the elevation of blood pressure both arise from a less
than ideal blood supply to the brain. Within the last two decades, as
I mentioned in Chapter 3, total cerebral blood-ow has many times
been recorded to be signicantly reduced in essential hypertensive
individuals with substantial elevations of blood pressure. I guess that
the change in brain fuel usage has been gradually brought about
during sleep, when blood pressure is at its normal lowest level, at
which time the brain has to make some use of so-called anaerobic
metabolism.
Although positron emission tomographic (PET) human studies do
not suggest that in the absence of hypertension and manifest cerebrovascular disease there is much reduction in the cerebral metabolic
rates of glucose and oxygen with increasing age, elderly senile
patients with symptomatic cerebrovascular disease have signicantly
reduced cerebral blood-ow compared with the young. Oxygen
consumption can be 22% less (Dastur, 1985). Patients who have
suered unilateral cerebral infarction have reduced cerebral glucose
metabolism, not only in the damaged regions, but also in some
contralateral and more remote regions, possibly because of disturbances of the neural network by retrograde neuronal degeneration. It is not known for certain what fuels, other than glucose, the
brain uses in these situations. Reduced oxidative metabolism (i.e.
reduced oxygen consumption) has been demonstrated in most conditions with impaired mental function, together with a reduction in
108
total cerebral blood-ow. Energy-providing metabolism, particularly

of carbohydrates, is reduced in patients with cerebrovascular disease
and chronic mental disorders (Sacks, 1959).
Cerebral metabolism in the spontaneously hypertensive rat

Many of the pathophysiological changes in essential hypertension
have parallels in the spontaneous hypertensive rat (SHR) and in its
stroke-prone derivative (SHR-SP). Such rats have an impaired cerebral blood supply. Infarctions are easily produced by arterial
occlusions, which have little adverse eect on WKY rats. SHR and
SHR-SP also have reduced cerebral glucose utilisation. The Cushing
mechanismthreatened medullary ischaemia activating sympathetic
vasomotor centrescould be the means by which chronic borderline
cerebral circulatory inadequacy activates sympathetic eerent nervous activity, either directly or through altered brain metabolism.
Despite the SHR brain being some 10% smaller than the brain of the
WKY rat (Nelson et al., 1993), with larger cerebral ventricles and
appreciably fewer neurones per brain structure (Tajima et al., 1993),
its brains blood supply is precarious. A comparison of SHR with
essential hypertension reveals similar abnormalities in cerebral vascular resistance, oxidative metabolism and vulnerability to ischaemia. The vertebral and basilar arteries in young SHR are much
smaller than in WKY rats at the same age (Paton et al., 2007).
Carotid artery ligation in SHR or SHR-SP produces a higher incidence, or greater extent, of ischaemic damage than in WKY, with
much higher levels of internal jugular venous blood lactate
(Fujishima et al., 1975; Katayama et al., 1986). Glucose utilisation
has been reported to be reduced in SHR (Wei et al., 1992). Although
neither SHR (nor SHR-SP) suer from the stenotic or occlusive
cerebral atheroma seen in human hypertension, it is clear that SHR
hasin common with essential hypertensiona precarious cerebral
arterial supply.
The obvious and universally-accepted interpretation of these and
other experiments is that the rise of blood pressure in itself causes
structural arteriolar changes in the SHR. The obvious and universally
accepted interpretation is mostly wrong. A major and signicant part
of the cerebral circulatory inadequacy of SHR and SHR-SP is
undoubtedly genetic rather than caused by the rise in blood pressure
(Suno et al., 1981), as are some of the metabolic dierences.
109
An evaluation of the Dickinson hypothesis

I have already described my meta-analysis of papers published
between 1948 and 1961 reporting that the cerebral RQ of essential
hypertensive patients was less than unity, by an extent proportional
to their blood-pressure elevation (Dickinson, 1995, g. 1 and table 1,
p 656). Gavin Lambert and his colleagues did me the honour of
comparing cerebral metabolism and sympathetic nervous activity in
twenty-ve essential hypertensive patients with twenty-eight normotensive volunteers, in a paper that included in its title Evaluation
of the Dickinson hypothesis (Lambert et al., 1996). These authors
were able to establish that their hypertensive patients had reduced
internal jugular vein blood ows and reduced oxygen utilisation, but
the average cerebral RQs of their hypertensives (0.98 0.03) was
not signicantly less than that of their normotensives (1.00 0.04).
However, the authors would certainly have acknowledged that the
hypertension of their hypertensive patients was mild (with average
mean arterial pressure of only 118 mmHg), whereas the average
mean blood pressure of the 151 hypertensive patients, which I
collected for my meta-analysis, was 152 mmHg. A mean pressure of
152 mmHg would be expected from a clinical blood pressure
of about 210/120 mmHg.
I suggest that a minor defect in cerebral oxygen supply in basal
conditions has long-term chronic eects on the fuels used to supply
energy to the brain. Some disturbance in fuel supply or fuel utilisation appears to be present in essential hypertension, which should
be regarded as a step in a progression towards overt cerebrovascular
disease. After severe and prolonged brain anoxia with permanent
brain damage, cerebral glucose consumption in conscious patients
may be only 75% of normal. It may be as low as 50% of normal in
patients in a vegetative state (de Volder et al., 1990).
Although I had speculated that the fault in essential hypertension
might be a primary change in cerebral oxidative metabolism, I
thought it much more likely that the primary fault was increased
cerebrovascular resistance, which had brought about the change in
cerebral oxidative metabolism. The Dickinson hypothesis is not
that essential hypertension is due to a primary change in cerebral
metabolism, which increases sympathetic nervous activity. Rather I
now believe that the change in cerebral metabolism and the increased
sympathetic nervous activity are both secondary consequences of a
110
primary increase of arterial resistance. This limits the fall of blood

pressure during sleep to a higher than normal value. However, the
meticulous study by Gavin Lambert and his colleagues has added to
the diculty of attributing the increased blood pressure of essential
hypertension to some undenable essential cause when the evidence
is increasing that it is a secondary eect of a less than perfect supply
of blood to the brain. New evidence is steadily emerging that
cerebral blood-ow is not maintained at normal levels in essential
hypertension. Its progressive decline with age, as cerebrovascular
resistance increases, is yet further evidence against false ideas
about essential hypertension that have held sway for more than a
century.
Summary
The respiratory quotient (RQ) of the brain relates its production of
carbon dioxide to its consumption of oxygen. Because normal adult
terrestrial mammals oxidise glucose almost exclusively to provide
energy to their brains, the RQ of the brain is at or close to unity. If
fuels other than glucose are used, or if energy release is in part
anaerobic, the brains RQ will be less than unity. When total cerebral
blood-ow (CBF) was rst measured (by the nitrous oxide method)
in conscious human subjects with essential hypertension, their
average cerebral RQ was signicantly less than unityabout 0.91
as was the brains RQ of people with strokes. This suggests that,
although total cerebral blood-ow was normal at the time of
measurement, it had probably been less than normal in less stressful
resting situations, especially during sleep.
Because the values for total gas contents of oxygen and
carbon dioxide in blood owing to and coming from the brain
were all published in the early papers reporting CBF measurements
by the nitrous oxide method, it was possible to use the published
values of cerebral RQs as an indicator of the kind of fuels that
the brain had been using. A larger and dierent series of measurements of severe essential hypertensive patients conrmed Ketys
observations. These all suggested that the cerebral blood supply of
these patients had sometimes failed to meet normal energy
requirements, most probably during sleep. Even lower values of
cerebral RQ have been reported in patients with established
111
strokes and with other evidence of cerebrovascular disease. A

meta-analysis revealed a signicant negative relation between
systemic arterial pressure and the respiratory quotient of the human
brain.
112
Part II
Neural Mechanisms for Blood-Pressure
Control
7
Structures and Mechanisms Subserving
Blood-Pressure Control by the Brainstem
(by Julian F R Paton)
Overview
Not enough emphasis can be given to the importance of the control
of blood ow to vascular beds. Arterial pressure is simply a means to
drive ow. The regulation of blood ow is essential for circulatory
homeostasis and must be adjusted appropriately to the level of
activity in each organ, or even within dierent parts of a single
organ. Dierential control of ow is key to maintaining a sucient
pressure head to maintain perfusion. To achieve this there has to be
a sophisticated structural organisation within the autonomic nervous
system to ensure that adequate perfusion of organs is maintained by
the appropriate modication of arterial pressure. Thus, arterial
pressure must be maintained within relatively ne limits and this for
most mammals is a mean of around 90 mmHg, a pressure that
appears optimal for maintaining perfusion of vital organs. The
cardiovascular system has an armoury of eector systems to combat
excursions in arterial pressure, including fast responses mediated by
changes in both vascular resistance and cardiac output, as well as
slower, longer term responses, such as changes in hormonal secretion
and water and solute reabsorption at the level of the kidney and
gastrointestinal tract. Feedback signals arising from strategically
placed cardiovascular receptors, such as arterial baroreceptors, target the medulla oblongata and play a major role in modulating
cardiovascular motor outputs. The cardiovascular neural control
circuitry lying within the spinal cord, medulla oblongata, pons and
hypothalamus has been identied. Gross intra-nuclear connectivity
and the functional roles of specic brain sites have revealed how
115
NEURAL MECHANISMS FOR BLOOD-PRESSURE CONTROL
homeostatic regulation of blood pressure is maintained. Such

knowledge is vital before considering essential hypertension. This
chapter summarises our understanding of central cardiovascular
control with reference to the changes that may underpin hypertension.
Cardiovascular central nervous control network: the basics

The following description starts peripherally and works its way back
into the central nervous system.
Sympathetic Nervous System

Most cardiovascular target organs (e.g. the heart and arterioles)
receive innervation from post-ganglionic sympathetic neurones
located in the paravertebral chain that runs parallel with the spinal
cord. One exception is the adrenal glands that receive sympathetic
pre-ganglionic neurone innervations. The pre-ganglionic sympathetic neurones are localised segmentally within the intermediolateral cell column of the thoracic and upper lumbar spinal
cord (Janig, 2006). There is some organisation with vasomotor
neurones distributed throughout the thoraco-lumbar segments,
whereas those that inuence cardiac activity are in thoracic T1T4
segments only. Each pre-ganglionic neurone can innervate up to ten
post-ganglionic neurones.
Based on their ongoing ring patterns and reex evoked activations, sympathetic post-ganglionic nerves have been functionally
identied as muscle vasoconstrictor, cutaneous vasoconstrictor,
pseudomotor and piloerector (Wallin and Elam, 1994; Janig and
Habler, 2003). These patterns of discharge may be important for
optimising eector organ activation based on transmitter release and
post-junctional receptor sensitivity. To achieve these patterns means
that the connectivity of post-ganglionic and their antecedent preganglionic sympathetic neurones, as well as descending supra-spinal
inputs, must be highly well-organised. It is likely that pre-ganglionic
neurones receive descending drives from specic subsets of phenotypically distinct supra-spinal sympathetic pre-motor neurones (i.e.
neurones that are pre-synaptic to the pre-ganglionic neurones). The
origins of pre-motor sympathetic neurones has been well documented using retrograde and anterograde tracing and retrograde
116
STRUCTURES AND MECHANISMS SUBSERVING BLOOD-PRESSURE...
trans-synaptic viral tracers (Strack et al. 1989a, 1989b; Janssen et al.,

1995). Descending inputs to the adrenal medulla (Strack et al.,
1989b) and kidney (Schramm et al., 1993) originate from hypothalamic, midbrain, pontine and medullary cell groups (Fig. 7.1). The
phenotypes of these supra-spinal neurones are distinct, based on
their neurochemical content and therefore may subserve specic
functions. For example, transmitter substances in the supra-spinal
terminals forming close appositions with pre-ganglionic sympathetic
neurones include: glutamate, GABA, glycine, noradrenaline, adrenaline, dopamine, serotonin, substance P, encephalin, oxytocin,
vasopressin and purines, which may be co-released (reviewed by
Pilowsky and Goodchild, 2002). The neurochemicals involved in
mediating baroreex sympathoexcitatory responses include tyrosine
hydroxylase, serotonin, substance P, enkephalin, neuropeptide Y
(NPY), phenylethanolamine-N-methyl transferase (PNMT) and
galanin with some segmental distribution (Minson et al., 2002). The
idea is that the physiological signicance of these phenotypically
distinct innervations may provide the substrate for activating specic
populations of pre-ganglionic sympathetic neurones, allowing differential control of blood ow, as occurs during exercise and the
ght or ight response. The location and properties of pre-motor
sympathetic neurones that connect to the sympathetic pre-ganlionic
neurones is now discussed. Most of our current knowledge is based
on the glutamatergic, adrenaline/noradrenaline and serotonincontaining neurones of the ventral medulla, and so emphasis will be
put on these sub-groups.
The rostral ventrolateral medulla (RVLM)

A major source of excitatory input to sympathetic pre-ganglionics
originates from the rostral ventrolateral medulla (RVLM; Fig. 7.1)
and may represent the classical vasomotor centre (Guyenet, 2006).
However, this is based on anaesthetised animal data. The situation
may be dierent in conscious animals and the RVLM is not the only
source of excitatory synaptic input to sympathetic pre-ganglionic
neurones; midline raphe, A5 and PVN are other drivers (Fig. 7.1).
The dierent descending controls may be more or less important,
dependent on state and behaviour.
Spinally-projecting RVLM neurones, located caudal to the facial
nucleus, comprise both glutamate-containing cells that express
vesicular glutamate transporter 2 (VGLUT 2) mRNA. These are
117
Fig. 7.1 Pre-motor sympathetic neurones. Descending drives to the sympathetic preganglionic motor neurones (located within the intermediolateral cell column, IML)
originate from the lateral (LH) and paraventricular hypothalamic nuclei (PVN), the A5
noradrenergic cell group in the caudal ventrolateral pons, the rostral ventrolateral
medulla (RVLM), the rostral medial medulla or midline raphe (pallidus, magnus and
obscurus, Rob), as well as spinal segmental interneurones within laminae of the dorsal
horn at cervical, thoracic and lumbar levels. Other abbreviations: LC, locus coeruleus;
LF, lateral funiculus; LPG, lateral paragigantocellular nucleus; PB, parabrachial
nucleus; PY, pyramid; sp5, spinal trigeminal tract; 3V and 4V, third and fourth ventricle, respectively. Modied from Janig (2006) with permission.
118
intermixed with adrenaline-containing neurones that are

immunopositive for tyrosine hydroxylase or phenylethanolamine Nmethyltransferase and comprise the C1 group (Guyenet, 2006, for
review). It has been estimated that between 50% and 70% of RVLM
neurones are C1 cells but that 80% of C1 neurones also express
VGLUT 2 mRNA (Guyenet, 2006). Ultrastructural evidence has
shown direct monosynaptic connections of RVLM neurones with
both the soma and dendrites of sympathetic pre-ganglionic neurones
(Zagon and Smith, 1993). The RVLM region is sympathoexcitatory
in function because application of glycine on to the rostroventrolateral medullary surface produced profound falls in arterial
pressure (Guertzenstein and Silver, 1974), whereas direct intraparenchymal injection of glutamate evoked hypertension in anaesthetised animals (Dampney et al., 1982). Discrete loci could be
identied within the RVLM that aected dierent sympathetic
motor outows in the cat (Dampney and McAllen, 1988). This was
consistent with the idea of a viscero-topographical representation
within the RVLM, which was analogous to the motor homunculus in
the cortex, and may provide the ability for dierentially controlling
sympathetic motor outow. Moreover, RVLM spinally-projecting
neurones have properties indicative of a sympathoexcitatory function: (1) they have a strong cardiac rhythm in their ongoing discharge due to a pulsatile inhibitory input from arterial baroreceptors;
(2) their ring is related to the level of arterial blood pressure; (3)
spike-triggered averaging shows a strong correlation with postganglionic sympathetic nerve activity (Sun 1996; Guyenet, 2006).
Guyenets group have studied the functional role of the C1 neurones
in blood pressure control. Using photostimulation to activate C1
neurones selectively, blood pressure increased by 15 mmHg (Abbott
et al., 2009). Using a selective neurotoxin to destroy C1 cells resulted
in a slight fall in arterial pressure and reduced evoked pressor
responses from the RVLM (Schreihofer et al., 2000), underpinning a
role for this cell group in maintenance of arterial pressure, at least in
the anaesthetised rat. However, the level of arterial pressure following RVLM lesions can normalise with time (Cochrane and
Nathan, 1994) suggesting the presence of other descending pathways, as well as other mechanisms, such as vasopressin and angiotensin-II. In spinal-transected rats, the isolated cord generates
impressive levels of sympathetic discharge that correlate with dorsal
horn neurone activity (Chau et al., 2000). The isolated spinal cord is
119
quite capable of generating substantial excitatory responses to

aerent inputs (Bravo et al., 2004) and ischaemia (Braga et al., 2007).
In quadriplegic humans, hypertension is a severe issue and involves
diuse sympathetic discharge (Wallin, 1986).
The origin of activity of RVLM pre-motor sympathetic neurones
has fascinated investigators and only now has a consensus been
reached. Historically, using an in vitro slice preparation, spinally
projecting RVLM cells were described to have metronomic beating
activity due to an intrinsic pacemaker current (Guyenet, 2006).
However, Lipski et al. (1996) provided a contrary view. In in vivo
rats they noted that each action potential of RVLM neurones was
preceded by a fast excitatory post-synaptic potential, suggesting that
they are synaptically driven. RVLM neurones clearly do have the
capability to generate discharge via pacemaker currents. RVLM
pacemaking may become critical under conditions of brain ischaemia, when synaptic transmission is known to fail. Such a mechanism
would assist in maintaining adequate arterial pressure in conditions
when oxygen supply is reduced. This is supported by the ndings
that the persistent sodium current, which is attributed to respiratory
neuronal pacemaking within the ventrolateral medulla (Paton et al.,
2006), is present in RVLM pre-sympathetic neurones (Kangrga and
Loewy, 1995) and is activated by hypoxia. In terms of synaptic
inputs to RVLM neurones, there are a number of possible origins for
these inputs, including pontine structures, hypothalamic and amygdaloid regions essential for the coordination of a behavioural
response (ght-and-ight versus play dead: Spyer, 1994). An additional excitatory input comes as cross-talk from the medullary
respiratory network, which is interwoven with the RVLM. The
expiratory Botzinger cells and inspiratory pre-Botzinger cells lie
juxtaposed to the RVLM and may contribute to the central
respiratory modulation of RVLM neurones and hence provide the
substrate for central cardiorespiratory coupling that undermines the
matching of cardiac output with minute ventilation (Sun et al. 1997;
Simms, 2009; 2010; Toney et al., 2010).
In summary, RVLM neurones play a major role in sympathetic
motor outow based on their direct connectivity to pre-ganglionic
sympathetic neurones, their ongoing activity, the integration of
synaptic drives from other CNS regions regulating cardiovascular
activity and reex pathways, such as baroreceptor (below), peripheral chemoreceptor and nociceptive inputs (Guyenet, 2006). There
120
may be viscerotopography within RVLM, and the type of neurotransmitter released onto pre-ganglionic sympathetic neurones from
RVLM axonal terminals may be either vascular bed or statedependent specic. A major input to the RVLM is from the arterial
baroreceptors that provide one of the major restraining controls over
sympathetic nerve activity. This input comes via the caudal VLM
(CVLM).
The caudal ventrolateral medulla (CVLM)

A major source of the inhibitory input to RVLM sympathoexcitatory neurones that is evoked by the arterial baroreceptors originates
from GABA-containing neurones in the caudal ventrolateral
medulla (CVLM; Fig. 7.2). The CVLM projects to the RVLM and in
turn receive a major projection from baroreceptor-activated glutamatergic neurones located in the intermediate nucleus of the solitary
tract (NTS), the central site of termination of many visceral aerents
(Izzo and Spyer 1997; Weston et al., 2003; Fig. 7.2). The NTS also
mediates the peripheral chemoreceptor reex, which produces sympathoexcitation and depends on a direct excitatory projection from a
dierent part of the NTS (commissural) to RVLM, thereby
bypassing the CVLM (Koshiya and Guyenet, 1996).
It is established that the CVLM plays a major role in controlling
the activity of RVLM neurones. Blessing (1988) demonstrated that
stimulation of the CVLM produced profound depressor responses
dependent upon GABAergic transmission in the RVLM. Later,
Jeske et al. (1993) demonstrated that CVLM neurones with projections to RVLM were excited by baroreceptor stimulation thereby
completing a central arc of the baroreex (Fig. 7.2). More recently,
CVLM neurone activity has been shown to be pulse modulated,
presumably by baroreceptors, tightly coupled to arterial pressure
and inversely coupled to sympathetic discharge (Schreihofer and
Guyenet, 2002). These cells express an enzyme necessary for production of GABA (i.e. contain GAD67 mRNA; Schreihofer and
Guyenet, 2003) and therefore full the criterion for a sympathoinhibitory CVLM neurone. Many CVLM neurones have respiratory
modulation (Schreihofer and Guyenet, 2002; Mandel and Schreihofer, 2006), which could explain the respiratory-related discharge of
RVLM neurones and, as such, provide another access point for
coupling of sympathetic and respiratory systems.
121
Fig. 7.2 The baroreceptor reex arc. Baroreceptor aerents terminate in the nucleus
tractus solitarii (NTS). Whether these same neurones project out of NTS directly to the
nucleus ambiguus (NA) and caudal ventrolateral medulla (CVLM) is not known (Fig.
7.3 and Deuchars et al., 2000). It is likely that there are separate NTS neurones projecting to the nucleus ambiguus and CVLM (Simms et al., 2007 and Fig. 7.5). Both the
latter projections are excitatory and involve glutamate acting on ionotropic receptors.
The CVLM sends inhibitory GABAergic projections to the rostral ventrolateral medulla
(RVLM), which is a pre-motor site driving sympathetic pre-ganglionic neurones (Fig.
7.1). Increased arterial pressure excites NTS causing inhibition of sympathetic activity
and excitation of cardiac vagal outows. This reexly-evoked reciprocal pattern of
autonomic activity is strongly related to the baroreceptor reex (Paton et al., 2005).
Other abbreviations: AP, area postrema; CC, CE and CI, common, external and
internal carotid arteries; DLF, dorsolateral funiculus; DMNX, dorsal vagal motor
nucleus; PY, pyramid; Rob, raphe obscurus; X, vagus; 4V, fourth ventricle. Modied
from Janig (2006) with permission.
122
Cardiac vagal pre-ganglionic motoneurones

Cardiac vagal pre-ganglionic neurones are located within both the
external formation of the nucleus ambiguus, located in the ventrolateral medulla (VLM; Fig. 7.2), and in the dorsal vagal nucleus
(Standish et al., 1994; Izzo and Spyer, 1997). The function of the
latter group is less well-dened. The cardiac vagal motoneurones
located in the nucleus ambiguus have B-bre axons that control
chronotropism (Jones et al., 1994; 1995). However, there appear to
be spatially distinct sub-groups of ambiguual neurones with dierent
cardiac functions (e.g. chrono-, dromo- and iono- tropism; Gatti et
al., 1996) but whether all these functions are mediated by B-bres is
not known. This organisation is reected in the cardiac ganglia,
which contain the post-ganglionic cardiac vagal motoneurones.
Stimulation of dierent cardiac ganglia aect beat rate or contractility or conduction speed (Gatti et al., 1995; Sampaio et al., 2003).
This suggests a highly organised level of neural control. The dorsal
vagal cardiomotor neurones have C-bre axons in most species, but
in the rabbit, B bres also arise from these vagal motoneurones.
While activation of cardiac vagal motor cells with C-bres produces
bradycardia, this eect is smaller than observed after activating Bbre axons originating from the nucleus ambiguus and with a
dierent time course and pharmacology of action within the cardiac
ganglion (Jones et al., 1994). C-bre cardiac vagal motoneurones
located in the dorsal vagal motor nucleus may control cardiac
functions other than chronotropism, which could include chronotropic, coronary blood ow and atrial naturetic peptide functions.
Unlike B-bre type cardiac vagal motoneurones, the majority with
C-bres appear not to be modulated by baroreceptor, lung ination
or central respiratory inputs (Jones et al., 1998). However, they
receive a powerful excitatory input from unmyelinated vagal aerents with endings in the pulmonary vascular bed that are sensitive to
oedema. When stimulated with a setonergic type-3 receptor agonist
(phenylbiguanide) they participate in a vagal C-bre-to-C-bre
reex. This reex may be triggered in heart failure when pulmonary
congestion is present. A coronary vasodilating role for the C-bre
dorsal vagal motoneurones innervating the heart is a plausible
suggestion and one that requires testing.
There are multiple inputs to the nucleus ambiguus, but these are
not exclusive to this region as they also innervate the RVLM and
123
include: bed nucleus of the stria terminalis; substantia innominata;

central nucleus of the amygdala; paraventricular hypothalamic
nucleus; dorsomedial hypothalamic nucleus; lateral hypothalamic
area; zona incerta; posterior hypothalamus; mesencephalic central
grey; mesencephalic reticular formation; the parabrachial nucleus,
including the KollikerFuse nucleus; the NTS and the medullary
reticular formation. This illustrates a high degree of convergence and
reects the multiple roles and states that vagal control of heart rate is
involved in.
A particularly powerful source of aerent input to the nucleus
ambiguus arises from the NTS (Fig. 7.2), and ultrastructural studies
have shown monosynaptic connections from the NTS to vagal (but
not necessarily cardiac) neurones of the nucleus ambiguus (Izzo and
Spyer, 1997). Similarly, evidence shows that cardiomotor vagal
neurones are contacted by synaptic boutons containing 5-HT (Izzo
et al., 1993) that when activated, excite cardiac vagal motoneurones.
This is mediated by a 5-HT1a receptor (Wang and Ramage, 2001)
and evokes powerful bradycardia (Dutschmann et al., 2009). It is
clear that serotonin plays a major role in regulating cardiac vagal
motoneurone excitability and likely originates from multiple sources.
The NTS and baroreceptor reex control of the cardiovascular

system
The primary site of termination and interaction of visceral aerents
is within the NTS (Fig. 7.2) and as such this structure provides a
most powerful site for modulation of reex activity (Spyer, 1994;
Paton, 1999; Andresen and Paton, 2011). In addition to a vast array
of aerent inputs, the NTS outputs to numerous supra-medullary
inputs, including pontine nuclei, hypothalamic, thalamic and cortical
structures, such as the insular cortex. This massive connectivity
emphasises the major role the NTS has in the integration of visceral
and somatic nervous systems. The immune system also communicates with the NTS via vagal aerents or across the bloodbrain
barrier allowing appropriate adjustment of cardiovascular autonomic activity.
Several groups of peripheral receptors contribute to the reex
control of circulation. The most important of these include the
arterial baroreceptor and chemoreceptors, and receptors within the
124
heart as well as the airways and lungs (Daly, 1997; Hainsworth,

1991; Spyer, 1994). Baroreceptors exist within the walls of the aorta
and internal carotid artery and are dened by increased elastin tissue, making the regions more compliant, allowing for pressuresensing. Carotid sinus and aortic nerves innervate the carotid sinus
and aortic arch, respectively, and via their peripheral sensory aerent
neurones terminate within the NTS.
The basic autonomic central reex arc is contained within the
medulla oblongata (Fig. 7.2) and involves NTS projections to the
cardiomotor neurones of the nucleus ambiguus and the CVLM
neurones, which project to inhibit the RVLM. There are also excitatory inuences on vasopressin release when pressure at the baroreceptors is reduced, indicating connections from baroresponsive
NTS neurones to the hypothalamic paraventricular and supra-optic
nuclei. The baroreceptor reex is unusual in that it produces a
reciprocal response in parasympathetic and sympathetic motor
outows to the heart. Many other visceral reex responses studied
appear to co-activate both autonomic limbs innervating the heart
irrespective of the polarity of the heart rate change (Paton et al.,
2005).
Neurophysiological studies have shown that dorsolateral and
dorsomedial regions of the NTS receive innervation from the arterial
baroreceptors (myelinated and unmyelinated bres), and that these
same regions also receive innervation from other aerents, such as
the arterial chemoreceptors and gastrointestinal aerents (Fig. 7.3).
There is evidence that NTS neurones excited by arterial baroreceptors (Fig. 7.4) receive convergent excitatory inputs from other
reex inputs that exert qualitatively similar reex response patterns
(Dawid-Milner et al. 1995; Paton, 1998; Deuchars et al., 2000). Also,
NTS neurones that are excited by baroreceptor stimulation are
inhibited by chemoreceptor aerent inputs (Silva-Carvalho et al.
1995a; Paton et al., 2001a). One interpretation of this is a functional
organisation of neurones within the NTS based on their projection
targets to, for example, cardiac vagal versus CVLM versus RVLM
neurones. Intracellular labelling of baroresponsive NTS neurones
showed that the majority (including those shown to receive direct
aerent inputs) project out of the NTS into ventrolateral medullary
regions, including ambiguus and CVLM (Fig. 7.3; Deuchars et al.,
2000). Within a sub-region of the NTS, neurones receiving inputs
from functionally distinct aerent inputs (baroreceptor,
125
Fig. 7.3 Absence of viscerotopography of functionally identied NTS neurones in the

NTS. Montage of intracellularly labelled NTS neurones activated by baroreceptor,
chemoreceptor and abdominal vagus nerve aerent inputs. Despite their dierent
functions, these cells are neighbours, suggesting an absence of viscerotopographical
organisation in NTS. The baroreceptor responsive neurones mostly projected out of
NTS to the ventrolateral medulla with some exhibiting axonal collaterals within NTS
(Deuchars et al., 2000; Fig. 7.2).
chemoreceptors and gastrointestinal receptors) all reside as neighbours (Fig. 7.3). However, this should not imply a lack of functional
organisation. Clearly, spatial or viscerotopic organisation is lacking
in the NTS, but selective targeting of aerent inputs to and projection targets from, the NTS neurones is proposed. This is supported
by recent studies in an arterially perfused decerebrate rat preparation, which allows control of systemic pressure and demonstrates
distinct pressure thresholds for barorecepotor reex-mediated vagal
bradycardia (*83 mmHg) versus sympathoinhibition (*65 mmHg;
Simms et al., 2007; Fig. 7.5). This supports the idea of separate
channels of information leaving NTS destined for each limb of the
autonomic nervous system. It may be that these separate channels of
126
Fig. 7.4 Baroreceptive neurones in the NTS are under a restraining inhibitory tone.
Intracellular recordings of baroreceptive neurones from rat. A, depicts a typical
adaptive response where the peak depolarisation and ring response occurs before the
maximal stimulus, in this case a rise in carotid sinus pressure (arrowed). Note the after
hyperpolarisation that reduces the electrical excitability of the neurone to subsequent
baroreceptor inputs. B, the ring response of another baroreceptive neurone showing an
adaptive response in control (i) and after (ii) bicuculline, a GABAA receptor antagonist.
A mechanism for driving this inhibition is from angiotensin-II and nitric oxide (Fig. 7.6
and text for discussion). Modied from Paton, 1999; Paton et al., 2001c.
communication exist within the baroreceptor aerents themselves

and are already dedicated to driving vagal versus sympathetic outows at this level. This degree of organisation is supported by the
observation that numerous neuromodulators, acting within the
NTS, aect preferentially the cardiac vagal component of the baroreceptor reex and not the sympathetic component (Pickering et al.,
2003). These data lead to the prediction that, within the NTS, there
are dedicated pre-motor cardiac vagal neurones and pre-CVLM
neurones and that these form completely separate entities that provide exibility for independent modulation as is seen, for example,
during exercise (e.g. Raven et al., 2006). Similar observations have
been found in humans in which muscle vasoconstrictor sympathetic
nerve activity is sensitive to increases in arterial pressure that are
without eect on heart rate (Eckberg et al., 1988). The baroreceptor
control of renal sympathetic nerve activity is better correlated to
127
Fig. 7.5 Distinct pressure threshold for the cardiac vagal and vasomotor sympathetic
limbs of the baroreceptor reex. The eect of sequential lowering baseline perfusion
pressure (i.e. arterial pressure) on the responses (heart rate and lower thoracic sympathetic nerve activity) to transient rises in perfusion pressure to stimulate arterial baroreceptors is depicted. (a) From an initial baseline pressure, the pressure challenge evokes
a baroreex-mediated bradycardia and sympathoinhibition. The subsequent equivalent
perfusion ramps from the lowered baselines (bd) produce striking baroreex sympathoinhibition but a progressive attenuation (b, c) and then complete loss of the
baroreex bradycardia (d). Note that the progressive reductions in baseline pressure
were associated with a marked increase in the ongoing SNA, but comparatively little
change in heart rate. Fluctuations in sympathetic activity are respiratory modulated.
Data from Simms et al. (2007).
cardiac output, rather than to the absolute level of arterial pressure

in humans (Charkoudian et al., 2005), suggesting that baroreceptors
are designed to detect changes in blood ow. It has been previously
shown that carotid sinus baroreceptors are sensitised under conditions of altered ow and pressure, rather than by static pressure
changes alone, such that they exhibit lower thresholds for discharge
(Hajduczok et al., 1988). Ultimately it is blood ow that organs care
about and baroreceptor modulation of vascular resistance is probably providing a means to accurately control this.
The role of baroreceptors in long-term control of arterial pressure
has been debated recently (Dickinson, 2004; Sleight, 2004). Conventionally, arterial baroreceptors have long been thought to buer
arterial pressure on a moment-by-moment basis (Cowley et al.,
1973). When baroreceptor aerents were sectioned, there was no
change in mean levels of arterial pressure, although it did become
labile (Cowley et al. 1973). (If baroreceptor and other vagal aerents
128
are sectioned, this does produce hypertension, although this has only
been studied acutely; Persson et al., 1988.) However, Lohmeier et al.
(2004) showed that persistent baroreceptor stimulation caused a
well-maintained hypotension (>1 week) that can last up to three
weeks (Lohmeier et al. 2010). Conversely, Thrasher (2004) has
shown that preventing baroreceptor stimulation causes a persistent
pressor response that is maintained for days (Thrasher, 2004) supporting a chronic role in regulating arterial pressure set-point. Barrett et al. (2003) has raised systemic arterial pressure chronically with
i.v. infusions of angiotensin-II and found that renal sympathetic
nerve is depressed (via the baroreceptor reex) and that this remains
for days in instrumented conscious rabbits, again supporting a
chronic role. On closer examination, at least in the dog, chronic
baroreceptor unloading induced hypertension that persisted for two
weeks only; thereafter it declined back to control levels (Thrasher,
2005) suggesting adaptations to the reex. The conclusion based on
the current data is that baroreceptors alone can inuence the setpoint of arterial pressure but this is time-limited to days, rather than
weeks and months. Therefore, other reex aerent inputs, such as
renal aerents (Krum et al., 2009), and/or neuro-humoral and cerebral perfusion, must all contribute (Osborn, 2005; Paton et al.,
2009).
Modulation of cardiovascular function at the level of the NTS

Modulation of NTS circuitry sub-serving cardiovascular and
respiratory reexes probably inuences autonomic motor activity
signicantly. A major transmitter that is important in modulating
neural activity in the NTS is gamma-amino butyric acid (GABA). It
is well known that GABA, acting on GABAA receptors, plays a
major role in the NTS to depress baroreceptor reex function (Fig.
7.4).
GABA and the defence response

NTS neurones that are excited by baroreceptor stimulation receive
an inhibitory GABAA receptor mediated input on stimulating within
the hypothalamic defence area; this can be antagonised by the iontophoretic application of bicuculline (Spyer, 1994). The descending
pathways from the hypothalamus are likely to be glutamatergic and
converge on local NTS GABAergic neurones (Silva-Carvalho et al.
1995b). The resulting inhibition of NTS neurones mediating the
129
baroreceptor reex contributes to the profound tachycardia and

pressor response that characterises the ght-or-ight response.
Nociception and exercise

Activation of somatic nociceptors produces reex tachycardia and
synpathoexcitation; the former is mediated in most part through the
NTS (Boscan and Paton, 2001). This nociceptor reex response is
concurrent with an inhibition of the cardiac vagal component of the
baroreceptor reex (Pickering et al., 2003), which allows the tachycardia and increased cardiac output to ensue. This is again dependent upon GABAA receptor activation. Boscan et al. (2002) showed
that nocieptive aerent stimulation released substance P in the NTS
that acted on neurokinin type 1 (NK1) receptors that stimulated
GABAergic interneurones to depress the baroreceptor reex. A
similar mechanism operates for resetting the baroreceptor reex
during exercise (Potts et al., 2003, 2006).
Angiotensin-II and nitric oxide
Much attention has been given to the actions of angiotensin-II (A-II)
within the NTS because of its potential central role underpinning
neurogenic hypertension. A-II acting in the NTS inhibits the baroreceptor reex, including both its cardiac vagal and cardiac sympathetic components (Paton and Kasparov 1999; Boscan et al., 2001;
Polson et al., 2007). This is dependent upon activation of GABAA
receptors. However, the eect of A-II on GABAergic transmission
involves nitric oxide release. A-II activates endothelial nitric oxide
synthase (eNOS) contained within the endothelium to release nitric
oxide and subsequently stimulate soluble guanylyl cyclase in
GABAergic interneurones (Paton et al., 2001b, 2006; Wang et al.,
2006, 2007). This led to the notion of vascular-neuronal signalling in
the NTS (Fig. 7.6; Paton et al., 2002, 2006), a novel form of paracrine signalling in the brain. Chronic inhibition of eNOS, using
virally mediated gene transfer to knock down eNOS activity specically in NTS. Improved baroreceptor reex gain in conscious rats
(Waki et al., 2006) suggesting that NO tonically restrains the baroreceptor reex at the level of the NTS. The idea that bioactive
molecules such as A-II circulating within the blood through the NTS
can release signalling molecules from the endothelium to aect
neuronal transmission (Fig. 7.6) suggests there is a new dimension
for central autonomic control of the cardiovascular system.
130
Fig. 7.6 Vascular-neuronal signalling in the NTS regulates cardiovascular function. A

dierential interference contrast image of living NTS depicting a capillary full of erythrocytes. Recent ndings indicate that angiotensin-II (blood-borne or of central origin), acting on angiotensin-II- type-1 receptors, expressed on the endothelium activates
endothelial nitric oxide synthase (eNOS) to release nitric oxide that diuses into the
NTS to enhance release of GABA, which depresses baroreceptor reex function (Paton
et al., 2001b, 2002, 2006; Wang et al., 2006, 2007). Further, chronic blockade of eNOS
in the NTS of conscious rats increases baroreceptor reex gain and in the spontaneously
hypertensive rat also lowers arterial pressure (Waki et al., 2006). Thus, eNOS activity
plays a chronic role in the regulation of baroreex gain and the set-point of arterial
pressure. I am grateful to S. Kasparov for the image.
Central coupling of cardiovascular motor outows with the

respiratory oscillator
Naturally occurring oscillations in heart rate and blood pressure
include those that are respiratory modulated. These can be detected
using power spectral analysis and some are used clinically as diagnostic indicators for cardiovascular disease. The coupling between
the systems involves a central component dependent upon synaptic
connectivity between respiratory and cardiovascular brainstem
neurones. The close spatial proximity of these neurones within the
131
brainstem assists in this tight coupling. Here, the physiological

mechanisms and functional relevance of respiratory modulation of
both heart rate and blood pressure are discussed.
Respiratory sinus arrhythmia and TraubeHering waves

Heart-rate variability (respiratory sinus arrhythmia) and Traube
Hering waves are good examples of how closely the respiratory and
cardiovascular brainstem control networks are coupled. Anrep and
his colleagues rst demonstrated that sinus arrhythmia was a consequence of respiratory inuences on the vagal outow to the heart
and that this included a central component (Anrep et al. 1936a,
1936b; Figs 7.5 and 7.6). The central mechanism involves a direct
synaptic regulation of cardiac vagal motoneurones exerted by a
subset of those brainstem neurones that are responsible for generating the respiratory rhythm (Richter and Spyer, 1990). Cardiac
vagal pre-ganglionic motoneurones are actively hyperpolarised
during inspiration by a wave of chloride-dependent inhibitory postsynaptic potentials (Gilbey et al., 1984). Hence, any inuence that
increases inspiratory drive will lead, by this process, to both a suppression of vagal eerent discharge and a reduced sensitivity of these
neurones to other excitatory inputs, whether central or reex in
origin. The outcome is a tachycardia in inspiration.
Respiratory patterning of cardiac vagal outow is mirrored by
similar changes in the excitability of sympathetic pre-ganglionic
motoneurones (Fig. 7.7; Richter and Spyer, 1990), which causes
respiratory related waves in arterial pressure (Traube-Hering waves;
Simms et al., 2009; Fig. 7.7). There is evidence that neurones in the
CVLM and RVLM have their activity modulated by respiratory
activity, which could account for the respiratory related discharge of
post-ganglionic sympathetic nerves, but it also remains a distinct
possibility that a portion of the respiratory discharge of sympathetic
pre-ganglionic neurones is mediated by direct connections from
spinally-projecting medullary respiratory neurones (Richter and
Spyer, 1990).
Functional relevance of the coupling

Why are the cardiac vagal and sympathetic vasomotor systems
coupled to respiration? It may link ventilation to breath-by-breath
variations in cardiac output and distribution of blood ow, which
132
Fig. 7.7 Common cardiorespiratory neurones in the medulla. Simultaneous recordings

of arterial pressure (AP), heart rate (HR) in beats per minute (bpm), integrated thoracic
sympathetic chain activity (SNAth), integrated phrenic nerve activity (PNA) and two
ventrolateral medullary expiratory neurones from the Botzinger complex during steadystate conditions and a baroreceptor-reex challenge. The three phases of breathing are
clearly demarked (horizontal lines) as inspiration (I), post-inspiration (PI) and expiration (E), based on the ring of PNA and the two respiratory cells. Note the sinus
arrhythmia (open arrow) as well as the Traube-Hering waves in the arterial-pressure
trace (solid arrow); the latter are mediated by the respiratory-related increases in
sympathetic discharge (coincident with the inspiratoryexpiratory transition). During
the transient rise in arterial pressure, to stimulate the baroreceptor reex, both heart
rate and SNA are reduced (*). This also activates the post-inspiratory neurone (PostInsp) and inhibition of the expiratory augmenting (Exp-Aug) neurone, suggesting an
inhibitory connection between these cells. Note the accentuated sinus arrhythmia
(double open arrows) after the stimulus, which reects an increased excitability of
cardiac vagal motoneurones; the post-inspiratory neurone also exhibits heightened
excitability reected by its higher peal discharge frequency (square head arrows). The
pattern and phase of ring of the post-inspiratory neurone is similar to ambiguual
cardiac vagal motoneurones with B-bre axons (Gilbey et al., 1984; Wang and Ramage,
2001), which are also excited by baroreceptor reex activation forming the idea of
common cardiorespiratory neurones (Richter and Spyer, 1990). Unpublished data from
D Baekey, T Dick and JFR Paton.
optimises oxygen delivery and carbon dioxide removal, making the

system ecient through saving of heart beats (Hayano et al., 1996).
Alternatively, the coupling may provide a mechanism to reduce
uctuations in blood pressure due to respiratory phase-related
changes in venous return. During expiration, venous blood-ow to
the heart is reduced by the relative increase in intrathoracic pressure,
whereas during inspiration, venous return is enhanced due to both
133
the negative intrathoracic pressure and increased abdominal pressure, as the diaphragm moves downwards. During expiration, when
venous return is reduced, the cycle of respiratory sinus arrhythmia
produces a slowing of heart rate that allows longer ventricular lling
time, helping to maintain stroke volume and hence blood pressure.
This vagally mediated bradycardia during expiration also assists
with coronary blood-ow by prolonging diastole and also perhaps
by reducing ventricular contractility and producing coronary dilatation. The physiological role of respiratory uctuations in sympathetic activity to produce TraubeHering waves in arterial pressure
may play a role in the optimal matching of blood delivery to lungs
and active muscle groups. This may be particularly important during
periods of exercise, which produce enhanced respiratory-sympathetic
coupling to direct blood away from inactive muscle groups towards
those whose activity-evoked local vasodilation opposes the sympathetic drive (Habler et al., 1994). This role in optimising perfusion is
also consistent with the proposal that slow vasomotor oscillations
such as TraubeHering waves can increase vascular conductance and
enhance ow to potentially ischaemic tissues (Nilsson and Aalkjaer,
2003).
Summary
The brainstem organisation of nervous control of the cardiovascular
system circuitry has been described. When discussing the nervous
control of the circulation, it is necessary to emphasise that
mechanisms are needed to co-ordinate blood ow to multiple vascular beds simultaneously. A fundamental design principle appears
to involve a tight central nervous coupling of respiratory and cardiovascular regulation, which provides a neat intrinsic way to elevate
cardiac output and respiration that is appropriate to a change in
behavioural state. Because of its predominating role in cardiovascular control, the baroreceptor reex and its modulation under different physiological conditions was discussed. Modication of
baroreceptor reex function, which can be exerted by rostral
brainstem and subcortical areas, may provide an indication of
potential mechanisms whereby stress and emotion can cause profound changes in the cardiovascular system. Whether these normally
acute, and clearly reversible, changes may be converted, on
134
repetition, to prolonged and irreversible alterations in gene expression

and subsequent protein function contributing to cardiovascular
disease, remain to be determined. However, it is clear that baroreceptors are essential for buering sharp changes in arterial pressure
but, based on current data, less likely to regulate the long-term setpoint of arterial pressure. Other reex aerents, neuro-humoral and
cerebral perfusion were all suggested as participating in the longterm control of the set-point of arterial pressure via modulation of
the sympathetic nervous system. This argument is further discussed
in the next chapter.
135
8
The Hypertensive Brainstem
(by Julian FR Paton)
Overview
There is unequivocal evidence of a positive association between
hypertension and elevated sympathetic activity in animal models and
human hypertensive patients (Fig. 8.1). The central question of why
sympathetic nerve activity (SNA) is raised in these conditions of
hypertension includes explanations of putative central mechanisms
that may contribute to the excessive sympathetic genesis. It is concluded that there may be multiple drivers of sympathetic activity in
hypertension, which revolve around the issues of enhanced angiotensin-II (A-II) activity, inammation and brainstem hypoperfusion.
The discussion attempts to address the issue of causation between
these alterations.
Human hypertension: the size of the clinical problem

It is estimated that by 2025 there will be more than 1.56 billion
hypertensive patients (Kearney et al., 2005). Since hypertension leads
to coronary heart disease, cardiac failure, renal failure and stroke,
this represents a massive nancial burden. This is worsened by the
fact that, despite the impressive armoury of anti-hypertensive medication, there appears to be an alarming 4555% failure rate of
current pharmacological regimes to normalise arterial pressure in
hypertensive patients (Burt et al., 1995; Mann, 2003). This prompts
the questions whether we fully understand what controls blood
pressure in clinical conditions of hypertension. And are we treating it
optimally? Clearly some patients avoid their medication due to the
intolerable side-eects, supporting the need for new forms of anti136
THE HYPERTENSIVE BRAINSTEM
Fig. 8.1 Raised sympathetic activity in human hypertensives. Original multiunit

recordings of post-ganglionic sympathetic vasoconstrictor activity innervating skeletal
muscle in a leg (Muscle SNA). The recordings were made using the microneurography
technique applied to the peroneal nerve in two men of comparable age. Note the greater
bursting frequency in the hypertensive individual relative to the normotensive control.
(Hart, Joyner and Charkoudian, unpublished data).
hypertensive therapy that have less severe side-eects. Drug intolerance aside, there is an urgent need to gain a better understanding
of the control of blood pressure in conditions of hypertension. Here,
an account of some of the changes within the autonomic nervous
system is presented in the development and maintenance of
hypertension.
Human hypertension: relationships between SNA, arterial pressure,

sex and ageing
Ageing is associated with a gradual augmentation of arterial blood
pressure and SNA (Sundlof and Wallin, 1978a). Furthermore, SNA
is increased and arterial pressure rises proportionately in older men
and women (Narkiewicz et al., 2005; Hart et al., 2009a; Fig. 8. 1).
This relationship is not observed in either young normotensive men
or women (Hart et al., 2009a). As humans age, there is an increased
risk of developing hypertension (Burt et al., 1995; Wiinberg et al.,
1995), which is (in most cases) associated with increased sympathetic
activity (Sundlof and Wallin 1978b; Schlaich et al., 2004). Interestingly, the risk of developing hypertension is greater in postmenopausal women, than in men of the same age (Burt et al., 1995).
The relationship between SNA and arterial pressure becomes steeper
137
in older women, than in older men (Narkiewicz et al., 2005), suggesting that decreased circulating female sex hormones modify the
relationship of SNA to arterial pressure. In this context, recent data
indicate that men and women regulate resting arterial pressure differently (Hart et al., 2009b). In young, normotensive men, a reciprocal balance between cardiac output and TPR appears to be a key
factor in normal arterial-pressure regulation (Charkoudian et al.,
2005, 2006; Hart et al., 2009b). There is a positive relationship
between SNA and TPR, and an inverse relationship between SNA
and cardiac output in young men. Together, these relationships
minimise the eect of high sympathetic outow on arterial pressure.
In contrast to men, there is no relationship of SNA to TPR or
cardiac output in normotensive women. This suggests that the
transduction of SNA into vasoconstrictor tone is modulated in
young women. As men age, the relationships observed in their youth
are abolished (Hart et al., 2009b). In summary, ageing and hypertension are associated with elevated SNA, the aetiology of which
may be sex specic. In healthy individuals and normotensive animals, the baroreceptor reex operates to buer changes in arterial
pressure, although this is unlikely to be a major long-term
mechanism for determining the set-point of arterial pressure.
The baroreceptor reex in hypertension

In Chapter 7, I discussed the role of the baroreceptor reex in the
long-term regulation of arterial pressure. The conclusion arrived at
was that the available evidence did not support a role in the longterm regulation of arterial pressure in the normotensive animal.
Notwithstanding, electrical stimulation of the carotid sinus region in
the conscious dog lowered arterial pressure for days (Lohmeier et al.,
2004) and showed no sign of adaptation over three weeks (Lohmeier
et al., 2010). This has led to a clinical trial in refractory hypertensives, where an implantable stimulator is used to excite the carotid
sinus, with each stimulator being tuned to the requirements of the
patient for optimising the anti-hypertensive eect (Scheers et al.,
2010). The ability to lower blood pressure with such an approach has
persisted for two years without adverse eects and, as such, presents
a possible way to control arterial pressure. So, what do we know
about the baroreceptor reex in hypertension?
138
In the juvenile, pre-hypertensive SHR, the cardiac component of

the baroreex resets to a higher pressure range relative to the Wistar
rat and the cardiac baroreex gain is reduced four-fold in the SHR
(Simms et al., 2007; Fig. 8.2). In addition, in mature SHR there is
also a selective suppression in the cardiac vagal component of the
heart rate response with preservation of the sympathetic baroreceptor reex (Head and Adams, 1988, 1992; Salgado et al., 2006;
Fig. 8.2). This is surprising given that resetting of the peripheral
baroreceptor aerents was described in the SHR (Andresen et al.,
1978; Chapleau et al., 1988). Thus, the changes in the baroreceptor
reex precede the hypertension in the SHR. It is interesting to
speculate that this selective resetting of the cardiac baroreex may
permit the increase in heart rate that precedes (and predicts) the
development of hypertension in SHR (Dickhout and Lee, 1998).
Similarly, in human hypertension there are selective alterations in the
cardiac vagal component of the baroreex with a shift to higher
pressures, a decreased gain and a reduced range (Mancia and Mark,
1983; Grassi et al., 1998).
The location within the baroreex arc where these dierential
changes occur and the mechanisms in hypertension are unknown.
However, it may involve nitric oxide, GABA and phosphoinositol-3
kinase. Additionally, it is not known whether the two limbs of the
baroreceptor reex receive the same information from the baroreceptors themselves or if there is segregation and dierential
processing of this aerent trac before the split downstream in the
nucleus tractus solitarii (NTS) and beyond into cardiac vagal versus
vasomotor sympathetic, for example. One plausible explanation is
that the processed baro-output from the NTS may be more eective
at exciting the neurones of the caudal ventrolateral medulla
(sympathetic limb) than the cardiac vagal preganglionic neurones
(parasympathetic) and thus the dierent thresholds reect the differences in the integrative properties of these groups of neurones,
which may change accordingly in hypertension. Under this model,
both limbs of the reex would receive the same information from the
NTS. However, there are indications that dierential processing of
the baroreex information may originate in the periphery, such as
the observation of dierences in the pressure responsiveness of the
aortic versus the carotid baroreceptors in dogs (Donald and Edis,
1971) and the observation of a dominant role for the aortic baroreceptors in the cardiac component of the reex in conscious rats
139
Fig. 8.2 Altered baroreex function in hypertension. In the immature, pre-hypertensive

SHR, both the sympathetic (A) and cardiac gains (B) were right-shifted to operate over
higher pressure ranges. The approximate sympathetic PP50 was 20 mmHg higher,
whereas the cardiac PP50 was 14 mmHg higher in SHR compared to WistarKyoto
rats. In (C), the baroreceptor reex gains, derived from the slope of the baroreceptor
reex function curves, indicate that the cardiac gain (bpm. mmHg-1) is signicantly
attenuated in the SHR (n = 8) compared to normotensive (n = 9) rats (*P<0.05,
Students unpaired t test), whereas there is no dioerence in the sensitivity of the
sympatheic component. Sympathetic nerve activity was recorded from the thoracic
chain. Note: these are primary changes in the SHR independent of the hypertension.
Data are from Simms et al. (2007).
140
(Dworkin et al., 2000). There are also dierences in the heart rate
and vascular responses to selective A- and C-bre stimulation of
baroreex aerents, such that A-bres appear critical in the generation of baroreex heart rate responses (Fan et al., 1999). Additionally, within the NTS, barosensitive neurones exhibit dierent
single cell responses (Zhang and Miin, 2000; Paton et al., 2001c)
and suggest that the limbs of the baroreex have dierential pharmacological sensitivity (e.g. Pickering et al., 2003; Simms et al.,
2006). These lines of evidence suggest that the transduced pressure
information may be specically tailored for the output limbs of the
baroreex by the NTS, or perhaps even earlier in the reex arc, in the
organisation and functional properties of the baroreceptor aerents
themselves. However, how hypertension aects these latter
mechanisms is not known but could involve inammatory processes.
Sympathetic overdrive in hypertension

Animal models of hypertension, whether induced (Goldblatt twokidney, one-clip) or genetically driven (spontaneously hypertensive
rats, SHR), show elevated increased noradrenaline release (Judy and
Farrell, 1979; Lundin et al., 1984) and SNA (Simms et al., 2009;
Oliveira-Sales et al., 2010). Furthermore, neonatal sympathectomy
prevents the SHR from developing hypertension and limits vessel
and cardiac hypertrophy (Cabassi et al., 1998). Simms et al. (2009)
have shown that SNA is elevated in young SH rats prior to the
development of hypertension, again consistent with a role in the
development, as well as the maintenance of hypertension and in end
organ damage.
The ndings in the animal hypertensive models are mirrored by
studies in human patients with essential hypertension. They have
elevated plasma noradrenaline concentrations (Esler et al., 1977;
Goldstein, 1983), and excessive noradrenaline spillover resulting
from active sympathetic terminals in the heart and kidneys (Esler et
al., 1990). In addition, eerent post-ganglionic SNA to skeletal
muscle vasculature is also raised (Grassi, 1998). The issue of what
came rst is unresolved. The notion that sympathetic activation
could play a causative role in triggering the hypertensive state has
been suggested previously (Abboud, 1982; Grassi, 2004; Grassi and
Mancia, 2004). Augmented SNA is seen in individuals with white
141
coat hypertension (Smith et al., 2002, 2004), borderline hypertension

(Smith et al., 2004) and in normotensive individuals with a family
history of hypertension (Yamada et al., 1988), indicating that elevated SNA pre-dates the hypertensive condition. In cross-sectional
patient studies, the degree of sympathetic over-activity has been
shown to be related to the magnitude of hypertension (Grassi, 1998),
thus supporting the role of the sympathetic nervous system in the
maintenance of hypertension. It is notable that, aside from a role in
the development of hypertension, sympathetic over-activity has been
implicated in the initiation and progression of numerous pathophysiological processes independent of increases in blood pressure,
such as cardiac and vascular hypertrophy, atherosclerosis and glomerulosclerosis (Burns et al., 2007; Fisher et al., 2009). An important
point is the need not simply to lower blood pressure, but to also
lower sympathetic tone.
All told, it appears that the relationship between central sympathetic over-drive and the hypertensive state is not simply associative,
but the increase in SNA plays a signicant role in both the initiation
and the development of hypertension (Abboud, 1982; Anderson et
al., 1989; Grassi, 1998; Grassi 2004; Smith et al., 2004) and end organ
damage (Burns et al., 2007). As such, the sympathetic nervous system
constitutes an important potential target for arresting the progression of hypertension (Grassi and Mancia, 2004), but to develop
eective countermeasures, it is essential to identify the neural
mechanisms driving the sympathetic over-activity (Grassi, 2004).
Putative generators of sympathetic overdrive in the hypertensive

brainstem
Central coupling to the respiratory oscillator
As discussed in the last chapter, heart-rate variability (respiratory
sinus arrhythmia) and Traube-Hering waves are products of central
respiratory coupling to brainstem cardiovascular control networks.
Whilst the loss of respiratory sinus arrhythmia of heart rate is a
known prognostic indicator of cardiovascular disease, including
hypertension, there is an augmented coupling between respiration
and sympathetic activity that occurs in hypertensive animal models.
The coupling between respiration and blood pressure may have
142
been rst noted by Harvey Cushing, who showed that elevated

intracranial pressure caused an augmentation of Traube-Hering
waves that accompanied the development of severe hypertension
(Cushing, 1901). Recently, abnormal respiratory-sympathetic coupling has been associated with hypertension. Respiratory-sympathetic
coupling was found to be augmented in the juvenile pre-hypertensive
SHR (Simms et al., 2009; Fig. 8.3). In this later study, it was shown
that SNA was enhanced during the end of phrenic discharge and the
start of expiration and contributed functionally to raising vascular
resistance. In another model of hypertension, induced using chronic
intermittent hypoxia to mimic sleep apnoea, there was a change in
respiratory pattern consisting of abdominal pumping or forced
expiration; sympathetic activity coupled to this emergent expiratory
activity (Zoccal et al., 2008). In human sleep apnoea the respiratory
pathology is accompanied by increased levels of SNA (Homann et
al., 2004). Altered breathing patterns have been demonstrated to
induce short-term decreases in blood pressure in patients with
essential hypertension (Joseph et al., 2005). Presently it is not known
whether human hypertensives show increased respiratory sympathetic coupling. An essential question is what are the possible
Fig. 8.3 Sympathetic overdrive in the SHR and dependence on the respiratory rhythm
generator. In pre-hypertensive SHR we found greater respiratory- (phrenic nerve
PNA) related sympathetic discharges than in normotensive, age- and sex-matched
WistarKyoto rats. There was no signicant change in phrenic activity leading us to
recognise enhanced central respiratory-sympathetic coupling in the SHR. We showed
that this translated to a greater increase in vascular resistance than the coupled activity
in the normotensive rat. Data from Simms et al. (2009).
143
brainstem mechanisms driving the increased sympathetic activity in

hypertension?
Enhanced A-II-phosphoinositol-3 kinase (PI3k) signalling in the

rostral ventrolateral medulla (RVLM) in hypertension
The RVLM contains pre-motor sympathetic neurones that drive the
sympathetic pre-ganglionic neurones in the thoracolumbar segments
of the spinal cord. This is a major brainstem site for convergence of
multiple aerent inputs and a site for generating SNA (see Chapter
7). Within the RVLM there is a greater density of angiotensin type 1
receptors (AT1 receptors; Hu et al., 2002). A-II acting on AT1
receptors in the RVLM exerts powerful sympathoexcitation.
Antagonising this receptor subtype reduces arterial pressure in the
SHR but not in the normotensive rat. This is indicative of a tonic
angiotensinergic drive unique to the SHR (Ito et al., 2002). A source
of this tonic drive may descend from the hypothalamic paraventricular nucleus (PVN; Ito et al., 2002). Further, Allen (2002) has
shown that inactivating the hypothalamic paraventricular nucleus
produced a larger fall in arterial pressure in the SHR than in the
normotensive control, suggesting greater neuronal activity within the
PVN driving RVLM pre-motor sympathetic neurones in the SHR.
An alternative source of increased angiotensinergic drive to the
RVLM might originate locally within the RVLM itself, since
Yamazato et al. (2007) found decreased levels of angiotensin converting enzyme-2 (ACE-2) in the RVLM of SHR compared with
WistarKyoto rats. ACE-2 breaks down A-II to angiotensin1-7; the
latter peptide osets the pro-hypertensive eects of AT1 receptor
stimulation. If ACE-2 levels in the RVLM of the SHR are increased
by site-specic lentiviral-mediated expression, mean arterial pressure
is lowered by *17 mmHgan eect that is seen in the SHR but not
normotensive control rats (Yamazoto et al., 2007). Thus, functional
re-instatement of ACE2 in the RVLM of the SHR assists in reducing
arterial pressure. These data all support increased A-II activity in the
RVLM of the SHR but what does this do?
Raizadas group have shown that, in the RVLM, there is an
additional signalling pathway involving PI3k that is driven by A-II
acting on AT1 receptors (Veerasingham et al., 2005). Antagonising
PI3k signalling in the RVLM reduced arterial pressure in the SHR
but was without eect in the normotensive control rat (Seyedabadi et
144
al., 2001). The RVLM also appears to have increased levels of

superoxide, which could result from AT1 receptor activation of
nicotinamide-adenine dinucleotide phosphate oxidase (NADPH).
Lowering superoxide levels in the RVLM of the SHR also reduces
arterial blood pressure, an eect that is greater than that seen in
normotensive rats (Tai et al., 2005). Superoxide levels are also
upregulated in the RVLM of the Goldblatt-induced hypertensive rat
(Oliviera-Sales et al., 2010). How this occurs is unclear but by
reducing superoxide levels, arterial pressure is completely normalised
(Oliviera-Sales et al., 2010). This shows both the ubiquity and
importance of superoxide in RVLM in hypertensive animal models
for maintaining high blood pressure.
A-II, PI3k and eNOS in nucleus tractus solitarii (NTS) in

hypertension
Similar to the RVLM, the mRNA expression levels of some PI3k
catalytic subunits of adult SHR relative to WistarKyoto rats were
enhanced in the NTS (Zubcevic et al., 2009; Fig. 8.4). However,
chronic blockade of PI3k signalling in the NTS of the SHR increased
systolic pressure and its low-frequency component, indicative of
elevated sympathetic vasomotor tonean eect not seen in the
WKY rat (Fig. 8.4). Thus, although both the NTS and RVLM of the
SHR both have elevated endogenous levels of A-II-PI3k signalling,
the functional eect on arterial pressure levels is opposite (NTS:
sympathoinhibitory; RVLM: sympathoexcitatory), indicative of sitespecic eects. In addition, PI3k also appears to modulate the baroreceptor reex and provides a mechanism for its central re-setting:
Sun et al. (2009) demonstrated that depression of the baroreceptor
reex by A-II within the NTS involved both PI3k and protein kinase
C signalling in the SHR, whereas in the WKY, only PKC signalling
was important. Therefore, an additional PI3k pathway exists in the
NTS of the SHR that, via nicotinamide adenine diphosphate
(NADPH)-generated superoxide, plays a signicant role in mediating A-II eects on the baroreceptor reex function; such a pathway
was inactive in the WKY rat (Sun et al., 2009).
The depressant eects of A-II on the baroreceptor reex in the
NTS also involve release of nitric oxide from endothelial nitric oxide
synthase (eNOS) and stimulation of GABA release from GABAergic
terminals, at least in normotensive rats (Paton and Kasparov, 1999;
145
Fig. 8.4 Enhanced PI3k activity in the hypertensive brainstem. In the SHR the PI3k
subunit-p110 is upregulated in the NTS (A). Using lentiviral mediated gene transfer to
knock down the expression of this enzyme in catecholaminergic neurones in the NTS
(A2 cell group; B) resulted in an elevation of arterial pressure (C), accompanied by an
elevation in low-frequency spectra of systolic blood pressure, indicative of an increase in
sympathetic vasomotor activity (D). Elevated PI3k appears to play a restraining role on
arterial pressure in SHR but not normotensive rats. Cardiovascular variables were
recorded using radio-telemetry. Data from Zubcevic et al. (2009).
Paton et al., 2002, 2006; Wang et al., 2006, 2007). In the NTS of the
SHR, eNOS was upregulated compared to normotensive control rats
(Waki et al., 2006; Fig. 8.5). Based on the acute depressant eect of
nitric oxide in the NTS on the baroreceptor reex in normotensive
rats (Paton and Kasparov, 1999), the hypothesis that chronic knock
down of eNOS would increase baroreceptor reex function and
heart rate variability was tested. Chronic adenoviral-mediated overexpression of a dominant negative protein to block eNOS activity in
the NTS not only elevated baroreceptor reex gain and heart rate
variability, but also lowered arterial pressure in the SHR (Waki et
al., 2006; Fig. 8.5). The inference from these data is that excessive
eNOS activity in NTS contributes to the maintenance of the cardiovascular autonomic dysfunction of the SHR, including excessive
sympathetic activity. Whether this involves nitric oxide signalling
146
Fig. 8.5 Endothelial nitric oxide synthase (eNOS) activity in the NTS contributes to the
hypertensive state in the spontaneously hypertensive rat (SHR). A, using real-time
quantitative PCR, the level of eNOS mRNA in the SHR was greater than that in the
normotensive, WistarKyoto rat. B, group data (n = 6) showing that chronic blockade
of eNOS activity in the NTS lowered blood pressure. Cardiovascular variables were
recorded remotely via radio-telemetry. eNOS activity was reduced by adenoviralmediated expression of a dominant negative (truncated eNOS) protein. The inset
shows a transduced capillary endothelium expressing enhanced green uorescent protein induced by the viral vector strategy. Data from Waki et al. (2006).
itself or its oxidised products, such as peroxynitrite or superoxide,

remains unresolved.
The NTS and set-point control of arterial pressure

One possible role for A-II and PI3k signalling is in the regulation of
catecholamine release from central catecholaminergic neurones
(Kasparov and Teschemacher, 2009). Such neurones in the NTS
express AT1 receptors (Healey et al., 1989) and in the SHR have
increased PI3k signalling relative to the catecholaminergic neurones
in WKY rats (Sun et al., 2009). It has been suggested that this A-IIAT1 receptor-PI3k signalling in catecholaminergic neurones of SHR
is essential for enhanced ring and release of transmitter substance(s)
that contribute to the hypertensive condition, at least at the level of
the RVLM (Veerasingham et al., 2005). However, this function is
again specic for the brainstem area, as genetically induced electrical
silencing of NTS catecholaminergic neurones resulted in hypertension that was greater in the SHR compared to the WKY rat and
independent of a change in baroreceptor reex function (Duale et al.,
2007). These data support the notion that activity generated by these
147
NTS neurones is higher in the hypertensive animal (perhaps due to

greater AT1 receptor activity) and functions to restrain arterial
pressure from rising further. Moreover, the data are similar with the
eect of chronically blocking PI3k activity in the NTS of the SHR,
but not WKY rat (Zubcevic et al., 2009) and support the belief that
the PI3k pathway operates in catecholaminergic neurones in the
SHR (Veerasingham et al., 2005). Thus, taken together, the NTS
plays a major role in the determination of the set-point of arterial
pressure and this seems more important in the SHR than in normotensive rats. The evidence presented suggests that this is likely to
be independent of eects on the neural circuitry controlling baroreceptor reex function.
Summary
To summarise, a number of changes revolving around increased A-II
signalling appear to exist in brainstem cardiovascular control nuclei.
A condition of raised A-II activity clearly leads to oxidative stress
and altered intracellular signalling including PI3k. Another result of
elevated AT1 receptor activity is its pro-inammatory function (da
Silveira et al., 2010). The next section reviews briey the evidence
that the brainstem microvasculature is inamed in the SHR and this
has detrimental consequences for arterial pressure control.
Brainstem inammation in hypertension

It has been recently proposed that a major conspirator for essential
hypertension is inammation (Montecucco et al., 2010). Although
this review focused on the kidney, a similar proposal is made here for
the brainstem. It is likely that both circulating and centrally produced A-II can trigger release of pro-inammatory cytokines in
brain regions regulating arterial pressure. This eect may involve
activation of microglia in the brain that subsequently release cytokines and chemokines, which can modulate neuronal ring and
synaptic transmission, as well as reactive oxygen species, such as
superoxide, that is also pro-inammatory. Rodent models of
hypertension show a condition of inammation in brain areas
involved in central control of arterial pressure (e.g. NTS; Waki et al.,
2007; Fig. 8.6). The NTS is characterised by an elevated pro148
Fig. 8.6 Adhesion molecule (junctional adhesion molecule-1; JAM-1) is over-expressed

in the NTS of the SHR and causes hypertension. Over-expression of JAM-1, using an
adenovirus in the NTS of a normotensive rat, triggered hypertension (A). In the NTS of
the SHR, the microvasculature is full of leukocytes (B), which are absent in normotensive animals. Note that JAM-1 is upregulated in the NTS of the SHR (Waki et al.,
2007). Inammation within the NTS is pro-hypertensive. Data are from Waki et al.
(2007).
inammatory cytokine prole, particularly in the brainstem and the

hypothalamus (e.g. Hirooka, 2008; Shi et al., 2010; Waki et al., 2007,
2009, 2010b). Waki et al. (2007) showed upregulation of a vascular
adhesion molecule (junctional adhesion molecule-A) in the NTS of
the SHR that has a primary role in attracting leukocytes (Fig. 8.6B).
Inducing leukocyte adhesion to the NTS microvasculature of the
normotensive rat, by expressing JAM-1, produced hypertension
(Fig. 8.6A). This is likely to be mediated by pro-inammatory
cytokines and chemokines.
In the NTS, several cytokines and chemokines were expressed
dierentially in the SHR compared to the WistarKyoto (WKY) rat
149
(Waki et al., 2010b). A microinjection of the pro-inammatory

interleukin-6 (IL-6) in NTS depressed the cardiac baroreceptor reex
gain in the rat (Takagishi et al., 2010), consistent with the notion that
cytokines and chemokines can modulate neuronal circuitry subserving the baroreceptor reex. Others have also shown a strong link
between IL-6 levels and A-II-induced hypertension (e.g. Coles et al.,
2007), suggesting a novel pro-inammatory role for A-II within the
brainstem. Similarly, A-II elevates expression of an array of proinammatory cytokines, including IL-6, IL-1a and TNF-a in the
paraventricular nucleus of the hypothalamus (Kang et al., 2009).
Specic and localised microinjection of IL-1a or IL-1b into the PVN
caused elevation in blood pressure in the rat, which was attenuated
by AT1 receptor blockade (Kannan et al., 1996; Lu et al., 2009). On
the other hand, intra-cerebroventricular viral over-expression of an
anti-inammatory cytokine (IL-10) is sympathoinhibitory in the rat
(Yu et al., 2007). Similarly, virally-mediated over-expression of the
migratory inhibitory factor (MIF), an anti-inammatory factor, in
the PVN, ameliorated hypertension in the SHR (Li et al., 2008). Proinammatory agents operating within central cardiovascular control
sites exist in the SHR and contributes to its pathology. Their activity
seems coupled with that of A-II.
The close association between excessive A-II activity and inammation in hypertension can be demonstrated by attenuating the
central sympathoexcitatory eect of A-II by expressing antiinammatory cytokine -IL-10 in the PVN (Shi et al., 2010).
Furthermore, intra-cerebroventricular infusion of minocycline, an
anti-inammatory antibiotic that inhibits microglia activation,
ameliorated A-II-induced hypertension, cardiac hypertrophy and
reduced plasma noradrenaline levels (Shi et al., 2010). This was
accompanied by reduction in the expression of pro-inammatory
IL-6, IL-1b and TNF- in the PVN (Shi et al., 2010). These studies
conrm a major novel pro-inammatory role of A-II, whether from
periphery or generated centrally, in sympathetic overdrive contributing to the aetiology of neurogenic hypertension.
A critical question emerges as to what triggers the inammatory
condition within the hypertensive brain? If it is A-II, then what
drives its expression? Since poor perfusion/ischaemia of the brain
can trigger both increases in A-II activity (Lakova, 1980; Saad et al.,
2010) and inammation (Fisher, 2008; Rodr guez-Yanez et al., 2008;
Soriano and Piva, 2008; Tuttolomondo et al., 2009), the next section
150
discusses the possibility that the hypertensive brainstem is

hypoperfused.
Brainstem perfusion: does the Cushing mechanism contribute to the

set-point of arterial pressure?
In human patients and SHR there is an increase in cerebral vascular
resistance, but blood ow to the brain is unchanged compared to
normotensive controls (Oseka and Kozniewska, 1997; Granstam et
al., 1998). In addition, in some hypertensive individuals, regional
cerebral blood-ow was attenuated relative to normotensive controls
(Granstam et al., 1998). In SHR, elevated cerebral vascular resistance may be due, in part, to: (1) leukocyte adhesion within the
brainstem microvasculature causing clogging of microvessels (Waki
et al., 2007); (2) elevated levels of prostanoid induced vasoconstriction (Oseka and Kozniewska, 1997); (3) morphological changes in
the arteries supplying the brainstem including thicker walls of both
the vertebral and basilar arteries and lower lumen to wall thickness
ratio (Harrap 1990; Harrap et al. 1990; Paton et al., 2007; Cates et
al., 2011). The latter is equivalent to that found in human hypertensives (Dickinson and Thomson, 1960a). Thus, localised and/or
transient hypoxic episodes within the brain could trigger or compound the inammatory condition in the hypertensive brainstem (see
Fig. 8.6B) leading to sympathetic over-activity, as discussed above.
However, inammation may not be the only driver of sympathetic
activity in a hypoperfused brainstem. There may also be a direct
sympathoexcitatory response mediated by specic groups of brainstem neurones capable of sensing low oxygen levels. Potential
transduction mechanisms are discussed later in this section.
The changes in the cerebral vasculature in the hypertensive
brainstem described above have hitherto been assumed to be a result
of hypertension. However, it is possible that increased cerebral
vascular resistance might actually precede hypertension. Recent data
from Simms et al. (2009) indicated that increased SNA occurred
before the onset of hypertension in SHR (Fig. 8.3) and that these
immature animals also showed a signicant vertebral and basilar
artery wall thickening and vascular resistance (Paton et al., 2007;
Cates et al. 2011; Fig. 8.7A, B). This is reminiscent of the nding of a
positive correlation between ante-mortem arterial pressure and post151
Fig. 8.7 Elevated brainstem vascular resistance and exacerbated Cushing response in
pre-hypertensive SHR. In (A), the ow-pressure relationships of the isolated in vitro
brainstem are shown for immature (34 week) pre-hypertensive SHR and normotensive
rats. The data indicate elevated vascular resistance in the SHR brainstem at all ow rates.
(B) shows the morphology of the basilar and vertebral arteries including a thicker media
in pre-hypertensive SHR compared to controls. The Cushing response evoked sympathetic and vascular responses elicited by bilateral vertebral artery and unilateral common
carotid artery occlusion are depicted in (C) (opposite page). Note that the Cushing
response was augmented in the pre-hypertensive SHR compared to the normotensive
Wistar control rat. Data in (B) from Paton et al. (2007). Data in (A) and (C) from Cates
et al. (2010).
152
mortem vertebral artery ow-resistance in human essential hypertensives (Dickinson and Thomson, 1960a). However, before measuring post-mortem ow resistances of the main cerebral arteries in
cadavers, Dickinson and Thomson (1960a) removed all residual
spasm by perfusing the arteries they studied with dilute ammonia
(p 75).
In the SHR, a potential driver for these morphological changes is
the increased sympathetic activity itself and this is supported by a
predominance of adrenergic receptors on the vertebral, basilar and
Circle of Willis vessels (Handa et al., 1992; Mitchell, 2004) and/or
A-II (see Harrap, 1991; Harrap et al., 1990). Occlusion of one of the
vertebral arteries in the pre-hypertensive SHR produced profound
sympathetic activation not seen in normotensive age-matched rats
153
(Cates et al.; Fig. 8.7C); this resulted in a greater increase in arterial

pressure and vascular resistance (Fig. 8.7C). The latter suggest limited capacity to tolerate reductions in blood ow in the SHR and a
low threshold for initiating a Cushing response. Consequently,
oxygen debt in the brainstem may increase both SNA and systemic
arterial pressure to maintain cerebral perfusion and oxygenation.
This remains a hypothesis to be tested. It is known that reductions
in either blood ow restricted to the NTS (Waki et al., 2011) or in
oxygen to the RVLM (Reis et al., 1997), can both cause increases
in arterial pressure and SNA. Moreover, in the rat, the sympathoexcitatory response to ischaemia can be evoked from both an isolated medulla-spinal cord, as well as an isolated spinal cord (Braga et
al., 2007), suggesting multiple sites for the detection of hypoperfusion/hypoxia and generation of sympathetic discharge. To date, the
transduction mechanism(s) await verication but could include
neurones that are sensitive to hypoxia, as has been shown for those
in the RVLM (Reis et al., 1997). This may include heme oxygenase
as the sensing or transducing protein (Sunderram et al., 2009).
Consistent with the notion of inadequate perfusion, preliminary
data indicate that, in the SHR brainstem, there is a shift from
aerobic to non-oxidative metabolism (Toward et al., 2008). For
example, enzymes such as phosphofructokinase are upregulated, an
enzyme essential in the anaerobic production of ATP. This is analogous to reports in human essential hypertensives of a change in
cerebral fuel usage (Dickinson, 1995). In addition, brainstem tissue
oxygen levels are normal in the SHR but when arterial pressure is
dropped to normotensive levels, the rat becomes severely hypoxic
suggesting that it has become dependent on the systemic hypertension to maintain normal levels of oxygen in the brainstem (Potts et
al., 2009). Thus, a modest lowering of blood pressure in the SHR
could result in hypoperfusion of the brainstem. With a right shift in
the cerebral blood-ow autoregulatory curve the problem of insufcient blood ow is accentuated. The latter could provide a major
stimulus to the generation of sympathetic activity via the Cushing
mechanism (Paton et al., 2009). This would provide a robust
mechanism to ensure cerebral perfusion was maintained and therefore dictate the level of the systemic circulation. In this context, in
regions where CVR was increased, cerebral blood-ow in SH rats
was not dierent from normotensive rats. However, in regions where
CVR was not altered, cerebral blood-ow was higher compared to
154
the normotensive rats (Granstam et al., 1998). Thus, it is argued that

a Cushing mechanism exists (as distinct from the Cushing response)
and is a major physiological mechanism for the determination of the
set-point of arterial pressure in both health and disease states, when
it contributes to the hypertensive condition (Paton et al., 2009).
Moreover, we hypothesise that it drives the physiological hypertension in the girae (Paton et al., 2009). Thus, Cushings mechanism
may operate in the hypertensive condition to overcome gravity
(girae), as well as increased cerebral vascular resistance (SHR,
hypertensive humans), thereby elevating sympathetic activity to
produce a sucient perfusion pressure to maintain blood ow to the
brain. The strategy of lowering peripheral vascular resistance in
hypertensive patients can be detrimental to cerebral blood-ow
(causing potentially a stroke or dementia), resulting (via the Cushing
mechanism) in a further heightening of sympathetic activity that
would accentuate end organ damage. Clearly, such treatment should
not be too aggressive but given in moderation to prevent such catastrophic outcomes.
Summary
This chapter has described a number of changes that occur within
the central nervous system of the SHR rat. It is clear that the renin
angiotensin system gures heavily in this and all evidence supports
an increase in AT1 receptor signalling. Endogenous mechanisms that
are in place to quench A-II activity, such as ACE2, appear suppressed in the SHR brainstem. High tissue levels of A-II appear to
drive additional pathways that further excite pro-hypertensive
neurones controlling sympathetic activity. The hypertensive brainstem is inamed and it is suggested that this is caused by elevated
levels of A-II activity and reactive oxygen species, as well as its
hypoperfused state. The knock-on eect of this is the production of
pro-inammatory cytokines and chemokines released from adhered
leukocytes on to brainstem microvasculature and from activated
microglia. Anti-inammatory treatment in the SHR has produced an
anti-hypertensive eect, supporting the viewpoint that brain
inammation is driving up blood pressure in the SHR. The confounding issue of vascular inammation and leukocyte adhesion
plugging of the microvasculature, coupled with an altered
155
morphology of posterior cerebral arteries, produce an increased

cerebral vascular resistance and hypoperfusion in the SHR brainstem; this also exists in hypertensive humans (see Dickinson and
Thomson, 1960a). A radical working hypothesis has been proposed
that the increased posterior cerebral vascular resistance occurs
before the hypertension (as seen in the pre-hypertensive SHR;
Fig. 8.7B) and is a major driver of sympathetic activity, end organ
damage and high blood pressure.
The issue of causality between hypertension, A-II activity,
inammation and poor perfusion of the brainstem has been aired but
remains equivocal. It will be essential to address what comes rst, in
order that one can get to the root cause of the problem and break a
number of positive-feedback loops that are driving up blood pressure. Getting closer to the primary cause may present a more
eective means to clinically treat hypertension. The evidence presented herein proposes that excessive A-II activity, inammation and
poor cerebral perfusion are likely to be primary cause candidates
occurring before the onset of hypertension, and not a consequence of
it. They do appear linked and it is therefore proposed unlikely that
they all change simultaneously in parallel. Both A-II and hypoperfusion can induce inammation. A-II could induce hypoperfusion
through its vasoconstrictor function and hypertrophic eect on
brainstem conduit arteries. However, hypoperfusion/ischaemia may
elevate the activity of the brain renin/angiotensin system (Lakova,
1980; Saad et al., 2010). It is time now to disentangle this interdependency in order to assess who triggers whom. Based on the
evidence given, a major next step must include strategies to improve
brainstem blood-ow in the SHR and establish if this reduces
arterial pressure, and whether it is related to reductions in inammation and activity of the renin-angiotensin system.
156
9
Secondary Causes of Hypertension and their
Relation to the Cerebral Circulationthe
Inuence of the Brain on the Kidneys
In the rst edition of Neurogenic Hypertension I wrote (Dickinson,
1965):
There must be a two-way link between the kidneys and the
brain in the control of blood pressure . . . Suppose that the brain
determines that systemic arterial pressure should be increased
and the kidney has no information transmitted to it. The basic
behaviour of the kidneys is to excrete more uid when arterial
pressure rises, and less when arterial pressure falls. In practice,
neurogenic inuences on the kidneys restrict the excretion of
uid, despite the rise in blood pressure. The other necessary link
is the inuence of the kidneys on the brain. Angiotensin might
perhaps provide this link, by its constricting eect on the cerebral vasculature.
I shall develop this theme later, paying special attention to the
slowly developing pressor eects of small amounts of angiotensin-II
and also bring up-to-date the ways in which understanding essential
hypertension helps the understanding of renal and other secondary
types of hypertension.
I have proposed that essential hypertension is initiated by a rise in
basal blood pressure brought about by increased sympathetic nervous system activity (SNA), necessitated by a primary increase of
resistance in the main cerebral arteries. This limits the fall of blood
pressure during deep sleep to a basal level, which will be just short of
that which would begin to activate the Cushing mechanism and
increase SNA. A basal regulated level of blood pressure is
157
characteristic for any individual human being and appears to set the
average level of casual blood pressures during the following day.
This was very convincingly shown by the superb studies of Imai et al.
(1997), reproduced (with permission) as Fig. 3.4 (p 54). These
demonstrated the stability of blood-pressure control during the night
in each of three groups of patients with initially dierent casual
blood-pressure levels. It also shows, in both sexes, the relation
between the nocturnal blood-pressure values during sleep and the
higher values and increased variability of casual blood-pressure
levels during the following day. Because most kinds of renal
hypertension are also associated with maintained or increased levels
of SNA, there is probably a link between essential and renal
hypertension. Sympathetic nervous activity is relevant in both
situations. I doubt whether there is ever complete absence of SNA,
except in people with rare genetic neurological defects. Patients with
any kind of renal or other secondary forms of hypertension usually
respond to some extent to sympathetic neurone blockade. Elevation
in their basal blood-pressure level can come from their main cerebral
arteries being congenitally smaller than usual and sometimes narrowed by atheromatous constrictions. But proximal cerebral-artery
resistance can also be increased by a secondary renal component
such as that contributed by circulating angiotensin-II.
Renal hypertension
Most hypertensiologists recognise three main categories of renal
hypertension: (1) renal retention of sodium and water, (2) excess of a
renal blood-pressure-raising hormone, (3) deciency of a renal
blood-pressure-lowering hormone.
(1) Renal retention of sodium and water: the long-term regulation

of body sodium contentdietary sodium inuences on blood
pressure
Selkurt (1951) and Thompson and Pitts (1952) recorded the direct
relationship between renal perfusion pressure and sodium excretion.
Jon Thompson and I (Thompson and Dickinson, 1976) perfused
twenty rabbit kidneys with blood from a donor animal and quantied the relationship. There was an intercept at about 55 mmHg
158
SECONDARY CAUSES OF HYPERTENSION
mean perfusion pressure, below which no urine was secreted, and a

steep exponential rise at higher pressures, with no easily determinable upper-limit to the rate of sodium excretion (Fig. 9.1). Very small
changes in perfusion pressure within the normal range can produce
large changes in sodium excretion rate (Guyton et al., 1984). In many
publications, Guyton showed that the curve in intact animals and
humans was almost vertical. Guyton et al. (1972) emphasised the
relation between body uid volume control and long-term bloodpressure regulation. Any change in the renal perfusion pressure/
sodium excretion relationship necessarily dictates a corresponding
change in blood pressure for any particular dietary intake. A renal
function curve of this kind shifted to the right characterises
established hypertension from virtually any cause. Although it might
appear that all the hypertension associated with sodium excess and
increased extracellular uid volume is due to whole-body autoregulation (as envisaged by Borst and Borst-De Geus, 1963), there
are several lines of evidence that sodium-loading is associated with
increased arterial vasoconstrictor tonenot, as might be expected,
with a decrease (Mark, 1986).
Fig. 9.1 Relation between systemic arterial pressure and the excretion rate of single
rabbit kidneys, perfused with blood under pressure (drawn from the data of Thompson
and Dickinson, 1976).
159
Desoxycorticosterone acetate (DOCA)/salt hypertension is, in

eect, a kind of renal hypertension. The renal retention of salt and
water is due to the mineralocorticoid excess. This condition also
depends on the integrity of the central nervous system. Increased
sympathetic nervous activity (SNA) has been demonstrated in this
condition (De Champlain et al., 1969; De Champlain and Van
Amerigen, 1980). In Dahl salt-sensitive rats, a high-salt diet facilitates peripheral adrenergic function and increases peripheral sympathetic tone. In addition, there are enhanced pressor responses to
central neural stimuli. Pharmacological sympathectomy by 6hydroxydopamine, which puts noradrenergic neurones and probably
also dopaminergic neurones permanently out of action (Takeshita et
al., 1979), prevents salt-induced hypertension (Okuno et al., 1983).
If the kidneys retain sodium, or if renal hormonal factors inuence
cation transport across cell membranes, this might indirectly alter
the function of the vasomotor regulatory centres of the brainstem. It
is striking that while blood pressure falls with acute sodium depletion,
and sympathetic vasoconstrictor tone and plasma noradrenaline
concentrations are increased, long-term sodium depletion in humans
is associated with a reduction in plasma noradrenaline concentration. This suggests some eect of body sodium content on central
vasomotor centre function (Kjeldsen et al., 1986). It is also
interesting that arterioles from rats on a high-sodium diet exhibit
increased smooth muscle contraction in response to a given
concentration of noradrenaline (Rankin et al., 1981). This suggests
that there is peripheral facilitation of arterial contractile responses,
as well as facilitation at a central level. Conversely, sodium
restriction reduces blood pressure in SHR, partly by decreasing the
pressor eect of sympathetic nervous activity (Toal and Leenen,
1987). There is also a larger quantal release of noradrenaline
transmitter at sympathetic terminals in animals on a high-sodium
diet, and a smaller transmitter release in individuals on a low-sodium
diet. De Champlain et al. (1969) reported that the turnover of
catecholamines was increased in the SHR. Renal denervation acutely
lowered blood pressure and increased sodium excretion (Stella et al.,
1986), but once hypertension was well-established it had little eect
(Katholi et al., 1983).
160
Mineralocorticoid hypertension
Distler et al. (1985) studied this kind of hypertension in human
volunteers given mineralcorticoids Although plasma noradrenaline
concentration was reduced, reactivity to exogenous noradrenaline
was increased. Urinary noradrenaline was increased, suggesting that
renal sympathetic drive might be specically enhanced. There was
also a decreased number of a2 and 2 binding sites on platelets and
lymphocytes. I have personally cared for a woman of 35 with a
history of three pregnancies and well-documented 120/80 bloodpressure records, but who arrived at my clinic with a blood pressure
of 200/120. She had a low plasma potassium, a low renin and a high
aldosterone, but responded very well to bethanidine (an adrenergic
nerurone-blocking drug). Oral bethanidine controlled her hypertension for more than a year. Then it was still better controlled by
spiralactone, until eventually the hypertension was permanently
cured by the removal of an aldosterone-secreting adrenal adenoma.
This sort of experience of the neurogenic component of primary
mineralocorticoid hypertension, and of its neurogenic maintenance,
is commonplace. In primary hyperaldosteronism with hypertension,
plasma noradrenaline concentration has been reported to be normal,
with a normal rise with head-up tilt (Tarazi et al., 1973). But I have
to agree with Distler and his colleagues (see above) that despite a
large variety of available data, the precise role of the sympathetic
nervous system in the development of mineralocorticoid hypertension is still poorly understood. The point is worth making that, if
mineralocorticoid hypertension was simply due to blood volume
expansion and whole-body autoregulation, sympathetic vasoconstrictor tone should denitely be diminished. On the contrary it
appears to be either normal or increased.
The importance of dietary sodium
In Dahl salt-sensitive rats, a high-salt diet facilitates peripheral
adrenergic function and increases peripheral sympathetic tone.
According to Mark (1986), even borderline hypertensive patients
have increased vascular resistance and increased SNA during saltloading. In patients with renal glomerular disease, plasma noradrenaline concentrations are positively correlated with blood
pressure (Ishii et al., 1983). It seems that increased SNA may play an
important part in the associated hypertension. In SHR and in its
stroke-prone derivative (SHR-SP), additional dietary salt increases
161
eerent sympathetic activity still further. It also increases renal

sympathetic nervous activity during stress (Oparil et al., 1989). The
quantal release of sympathetic transmitter per nerve impulse in rats
is related directly to dietary salt intake (Folkow and Ely, 1987). We
do not know why the sympathetic nervous system should be activated by salt-loading, but there is likely to be a central eect of the
sodium and perhaps also the chloride ion on the brain itself.
Man int Veld et al. (1983) made an elegant study of a few patients
with gross autonomic neuropathy and virtually denervated kidneys.
The perfusion-pressure/sodium-excretion curve (Fig. 9.1) was shifted
to the right during an intravenous aldosterone infusion, so that for
any particular blood-pressure level, less sodium would be excreted.
The authors inferred that the same would happen with chronic
aldosterone excess. This would clearly necessitate a higher renal
perfusion pressure, i.e. systemic hypertension, to maintain sodium
balance. Hall et al. (1986) wrote: Chronic hypertension appears to
be an essential homeostatic response that permits sodium and water
balance to be maintained despite various abnormalities which tend
to decrease renal excretory capability. Graham MacGregor has been
an eloquent and persuasive advocate of the importance for human
beings of reducing dietary salt intake, to lower blood pressure (He
and MacGregor, 2007). However, the role of the sodium ion itself
may have been overemphasised. Many publications suggest that the
chloride ion is of equal or of greater importance in inuencing the
sympathetic nervous system (e.g. Kurtz and Morris, 1985;
Motoyama et al., 1988).
There are several possible reasons why DOCA/salt hypertension
could be predominantly neurogenic. There is also some evidence that
increasing dietary potassium may lower blood pressure (MacGregor
et al., 1982). Many comparative studies indicate that hypertensive
populations eat less potassium than do comparable populations with
lower blood pressures (review by Tobian, 1988). Unfortunately it is
extremely dicult to identify a low-potassium intake as an independent risk factor for hypertension, though it may well have some
inuence.
A characteristic attribute of essential hypertensive patients is that,
when given a load of saline by mouth or injection, they excrete it
faster than do normotensive subjects (Lowenstein et al., 1970),
probably because of a reduction of renal proximal tubular sodium
reabsorption. This allows enhanced sodium clearance in proportion
162
to the total renal blood-ow (London et al., 1984). The circulation

seems to be tighter than normal. People with essential hypertension
behave as if there were an overabundance of blood and extracellular
uid, even though the blood volume is usually some 10% less than
normal (Tobian, 1960). At present we simply do not know whether
there is a single mechanism that explains the accelerated saline
diuresis in essential hypertension, and (if so) whether it is mediated
through widespread sympathetic arteriolar vasoconstriction, intrinsic renal changes, vagal aerents, increased cardiopulmonary blood
volume, atrial natriuretic peptide, by a combination of these, or
perhaps by an as yet undiscovered mechanism.
(2) Excess of a renal blood-pressure-raising hormone

The steps that led to the identication rst of renin and later of
angiotensins I and II are now part of the history of research into
hypertension. So too is Harry Goldblatts classic work in which he
simulated the narrowing of all aerent renal glomerular arterioles by
putting constricting clips on one or both main renal arteries of
mammals. I do not want to bore my readers by going over this
familiar eld, but because I had concluded that essential hypertension derives from the human brainstem under basal conditions of
rest and sleep, when its blood supply was threatened by atheromatous narrowing of the main cerebral arteries, I was keenly
interested in the central neurogenic action of angiotensin. John
Stirling Meyer was one of the rst clinical scientists to use synthetic
angiotensin-II (A-II) after CIBA had made it available. Meyer and
Gotoh (1961) noted that after blood pressure had been raised by
intravenous injection of A-II, constricted cerebral arteries might
remain constricted after blood pressure had gone down.
Careful measurements of plasma renin concentrations in experimental renal artery constriction showed that renin was increased in
the early stages, but later the increase was small or undetectable
(Koletsky and Pritchard, 1964). The renin/angiotensin system has
many links with the sympathetic nervous system. For example, the
renal vascular activity of A-II depends in part on sympathetic neurotransmitter release (McGi and Fasy, 1965). Low concentrations
of A-II are known to enhance sympathetically-mediated vasoconstriction (McCubbin and Page, 1963). Centrally-mediated sympathetic nervous stimulation after intravenous infusion of A-II
163
probably accounts for the constriction of peripheral vein segments

and for the failure of the blood-pressure elevation to slow the heart
as much as might be expected. It may also help to account for the
slowly developing pressor response to the continuous intravenous
infusion of very small amounts of angiotensin-II.
The slowly-developing pressor response to initially sub-pressor

intravenous administration of angiotensin
I discovered this unexpected but remarkable phenomenon after I had
constructed an automatic servo system to infuse intravenous
angiotensin continuously into a conscious rabbit, at a rate inversely
proportional to the animals arterial pressure at any moment. I was
trying to simulate what I guessed might be happening in chronic
renal hypertension. The result was spectacular. During three days
observations, the initial infusion rate of A-II progressively fell from
0.13 mg.kg-1. min-1. to a rate of about 0.006 mg.kg-1. min-1., while
blood pressure was maintained at a steady constant value some 30
mmHg above its initial value at the start of the experiment. Later my
colleagues and I found it much easier initially to infuse just subpressor amounts of angiotensin-II continuously at a constant rate,
thus avoiding the considerable diculties of setting-up and maintaining the servo system. Jim Lawrence, Richard Yu and I consistently observed that low concentrations of intravenous A-II
(initially sub-pressor) could progressively raise blood pressure and
maintain it (Dickinson and Lawrence, 1963; Dickinson and Yu,
1967). I thought at rst that an initially sub-pressor infusion of
angiotensin might have had an indirect neurogenic action on basal
systemic arterial pressure by its constrictive eect on the cerebral
medullary circulation. The real explanation was simpler: A-II
directly stimulated the brainstem.
Ng and Vane (1967) had demonstrated that angiotensin-I could be
converted to A-II within the brain. Angiotensin-binding sites have
been located in several areas of the brainstem, including the nucleus
of the tractus solitarius (NTS), the inferior olivary nucleus and
(notably) the area postrema, where binding sites are present in
greatest density (Israel et al., 1984). Microinjection of A-II at these
sites raises blood pressure (Casto and Phillips, 1984). Its eect on the
NTS is probably inhibition of normal tonic inhibitory drive. There
are numerous angiotensin receptors in the C1 area of the rostral
ventrolateral medulla (RVLM) and A-II is probably a cotransmitter
164
from the area postrema to the C1 area (Allen et al., 1988). Andreatta
et al. (1988) reported that blood pressure rose in cats after the local
application of A-II to the so-called glycine-sensitive area, from which
depressor responses can be obtained by local application of glycine.
This coincides with the C1 group of neurones. Bickerton and
Buckley (1961) had demonstrated, in cross-perfused dogs, that high
concentrations of A-II infused into the cerebral circulation raised
blood pressure by a direct action on the brain. Later I reported that,
in conscious rabbits, infusions of extremely small amounts of A-II
into the vertebral arteries had a greater pressor eect than infusions
elsewhere (Dickinson and Yu, 1967).
The progressive pressor response to angiotensin-II in other species

Cowley and McCaa (1976) had observed that the progressive rise of
blood pressure with low concentrations of infused angiotensin could
be prevented by baroreceptor denervation. Yu and I observed that
adrenergic neurone blockade with bethanidine greatly enhanced the
immediate pressor response to very low concentrations of A-II. It
also eliminated the progressive rise in pressure (Dickinson and Yu,
1967). Yu and I also observed that low rates of A-II infusion did not
change urinary sodium excretion, despite the rise in blood pressure.
It is clear that sodium retention is not responsible for the progressive
rise in blood pressure. It is more reasonable to ascribe much of the
progressive pressor response to slow baroreceptor resetting over the
three-day experiment. The known time-scales correspond well.
I believe that the experiments I performed with Jim Lawrence
(Dickinson and Lawrence, 1963) were the rst in which any
vasoactive material had ever been infused into the vertebral artery of
any animal. Jim McCubbin and Carlos Ferrario wanted to verify my
rabbit observations in dogs and invited me to Cleveland to demonstrate the phenomenon. I felt some of the same excitement that an
animal physiologist a century ago might have felt when challenged to
demonstrate an unusual phenomenon in public. The demonstration
was a success. The three of us observed, and later reported, the
progressive pressor response to initially sub-pressor amounts of
angiotensin-II in dogs (Ferrario et al., 1970). It was clear that A-II
could raise blood pressure by its direct action on the brainstem
without producing any signicant change in blood ow. Our results
have been conrmed by many others. Ablation experiments have
suggested that the phenomenon is mediated through the area
165
postrema, a part of the medulla in which noradrenaline- and serotonin-containing neurones are both present
Another indirect way in which the kidneys can inuence the brain
also depends on angiotensin-II. This polypeptide is a stimulus both
to thirst and to vasopressin release (Epstein, 1978). In the malignant
phase of hypertension, the high levels of circulating A-II may contribute to the increased thirst, which is sometimes a feature of that
condition. In so far that it increases thirst and releases vasopressin,
A-II can expand body uid volume and thus contribute to hypertension. Other observations have since been reported in dogs (Bean
et al., 1979) and in monkeys (Forsyth et al., 1971). All these observations explain how very low circulating concentrations of angiotensin can maintain an elevated blood pressure in the chronic phase
of the two-kidney, one-clip model of experimental hypertension, and
in various forms of chronic renal hypertension in humans. Whether
there is any additional long-term pressor eect of angiotensin exerted
through its cerebral vasoconstrictor eect remains an open
question.
Local eects of angiotensin on the brainstem

The pressor response from the brainstem, brought about by angiotensin arriving from the blood circulation, may be only an accidental
feature of vasomotor centre design. Local neuropeptinergic actions
are normally dominant. For example, Bravo and Tarazi (1979)
observed that the hypotensive eect of angiotensin-convertingenzyme (ACE) inhibitors is not related at all closely to the plasma
level of A-II. The local action of ACE inhibitors in the brain may be
at least as important as their general systemic actions. The reduction
of blood pressure by ACE inhibitors in nephrectomised animals can
be actually greater than in animals with intact kidneys. Messenger
RNA (mRNA) coding for renin is present in the hypothalamus of
the rat, and is identical with mRNA in the kidney. Angiotensinogen
is also present in various parts of the brain. The area postrema
probably has the main role in mediating the central nervous pressor
response to vertebral artery infusion of angiotensin (Joy and Lowe,
1970).
The kidneys can inuence the vasomotor centres in other ways.
Sensory aerent nerves from the kidneys pass directly to the lower
brainstem where they terminate in the nucleus of the solitary tract.
Their function is not known, but the eerent limb of the reex path
166
involves systemic vasoconstriction, renal vasoconstriction and

reduction in sodium and water excretion (Golin et al., 1984).
The relationship of plasma renin concentrations to other measurements in essential hypertension

Plasma renin concentrations in essential hypertension are variable.
In normotensive people they bear an inverse relationship to dietary
and excreted sodium. On average the values are not notably dierent
in people with hypertension, but the spread of values is wider
(Brunner et al., 1972). In addition, hypertensive patients seem less
able than normotensive controls to reduce their plasma renin concentration when dietary sodium is increased (Sealey et al., 1988). The
renal threshold for renin release as renal-perfusion pressure falls is
set at a higher level in the untouched kidney of an animal with one
renal artery clipped, or in the equivalent human situation. It is also
elevated in essential hypertension in both kidneys (Kaneko et al.,
1968). There is a negative correlation between plasma renin and
ltration fraction (Schalekamp et al., 1970), suggesting that the local
renal renin-angiotensin system is stimulated when ltration fraction
falls, i.e. when glomerular ltration rate (GFR) is unduly low in
relation to renal blood-ow. This would be in keeping with a putative role for renin in maintaining GFR and with the propensity of
angiotensin-converting enzyme inhibitors to reduce GFR, especially
when GFR is already low.
There is a negative correlation between plasma renin concentration
and plasma sodium concentration (Brown et al., 1965), which is
perhaps most plausibly attributed to the stimulation of thirst and
vasopressin release by A-II. The hyponatraemia of renin excess in
severe hypertension and heart failure is usually correctable by giving
ACE inhibitors (Packer et al., 1984), though such treatment can also
lead to a catastrophic fall of blood pressure.
(3) Deciency of a renal blood-pressure-lowering hormone: the
renal medullary depressor system
There is strong evidence for the existence of a renal medullary lipid
system (medullipin I, II) with depressor properties. This probably
contributes both to normal blood-pressure regulation and to the fall
of blood pressure after releasing a constricting renal artery clip in
experimental renovascular hypertension. Renal medulla-derived
platelet-activating-factor and prostaglandin E2 may also be involved.
167
The renal depressor hormone medullipin II has some central sympathetic-inhibitory action, as well as direct vasodilator properties
(Muirhead, 1983; Gothberg and Thoren, 1986).
The inuence of the sympathetic nervous system on the kidneys

There are several possible ways in which the kidneys might aect
blood-pressure control. There might be imbalance between dilator
and constrictor prostaglandins (Grose et al., 1983), renal production
of kallikrein might be altered (Margolius et al., 1976) or a putative
saluretic hormone might initiate hypertension (De Wardener and
MacGregor, 1980). None of these hypotheses has been worked out in
enough detail to allow rigorous tests and predictions to be made
from them. In none has the sympathetic nervous system been
invoked.
The renal sodium excretion/perfusion pressure curve (Fig. 9.1) can
be shifted to the right by various means, including circulating A-II,
sympathetic nervous activity and mineralocorticoids. McGi and
Fasy (1965) suggested that angiotensin itself was the message that
passed from a clipped kidney with a narrowed renal artery to the
normal kidney on the other side, instructing it to hold back
natriuresis and to let the blood pressure rise. This interpretation was
supported by DeClue et al. (1978), who observed that, despite the
large rise of pressure slowly but eventually produced by initially subpressor amounts of A-II, the pressure natriuresis, which would be
expected, did not occur. The authors concluded that the tendency for
the kidneys to retain sodium under the inuence of angiotensin was
probably caused mainly by a direct eect of angiotensin on the
kidneys themselves.
A chronic eect of angiotensin on the untouched kidney may
explain the shift to the right in the perfusion pressure/sodium
excretion curve which Jon Thompson and I (Thompson and Dickinson, 1976) observed in two-kidney, one-clip hypertension in
rabbits. Hall et al. (1980) very beautifully demonstrated the eects of
A-II on the perfusion pressure/sodium excretion curve (Fig. 9.1) in
dogs. They reported a shift to the left in animals given angiotensinconverting-enzyme (ACE) inhibitors and a shift to the right in dogs
infused with synthetic angiotensin-II. The inuence of angiotensin
on the kidneys appears to require the cooperation of the sympathetic
168
nervous system because it is impaired or prevented by adrenergic

blockade (McGi and Fasy, 1965). Other factors may play a part in
changing the function of an untouched kidney contralateral to a
clipped one. For example, Himmelstein et al. (1986) observed an
early rise of thromboxane and a later fall of prostacyclin production
in the contralateral kidney from rats made hypertensive by a single
renal artery clip.
Alberto Zanchetti (Zanchetti, 1986) has summarised the literature
concerning the sympathetic innervation of the kidneys, which can
inuence renal blood-ow, renin release and sodium and water
excretion. For example, electrical stimulation of pressor regions of
the brainstem of cats produces a rapid increase in renin release and a
fall in renal blood-ow in an innervated kidney, but not in a
denervated one. Chronic electrical stimulation of the renal sympathetic nerves raises blood pressure (Kubicek et al., 1953), as also does
long-term infusion of noradrenaline into the renal artery of a dog
with only one kidney (Katholi et al., 1977).
Malmejac (1934) was probably the rst to look upon the carotid
sinus reex eects on the kidneys as a part of the volume-regulating
mechanism of the organism, though later work has focused more
attention on the low-pressure baroreceptors of the atria and great
veins. Renal denervation can attenuate or retard the development of
several types of experimental renal hypertension (Katholi, 1983;
Jansssen et al., 1987), presumably by reducing the ability of the
nervous system to maintain an elevated blood pressure in the face of
increased sodium and water loss. This may well be the result of a
shift in the perfusion pressure/sodium excretion curve, but a change
in the threshold for renin release could also play some part in the
response (Davis and Freeman, 1976).
Essential hypertension develops slowly, over years rather than
months. Current knowledge of renal sodium excretory function
indicates that the brain can only maintain hypertension of neurogenic origin (such as that which Julian Paton and I envisage for
essential hypertension) if there is resetting of renal sodium handling.
Initially this will be by sympathetic vasoconstriction of renal aerent
arterioles, but in due course this will be succeeded by permanent
structural changes. These are principally narrowing of vessels
changes that comprise part of the pathological picture of benign
nephrosclerosis. Renal medullary depressor activity will probably
also be reduced in the presence of the pathological changes evident in
169
benign nephrosclerosis. Thus when a new, perfectly functioning

kidney is grafted into a chronically hypertensive patient, a big
diuresis of salt and water would be expected and indeed is often
observed. When it is not seen, I imagine that the kidney is already
damaged in some way. A grafted kidney is necessarily sympathetically denervated, though some degree of re-innervation eventually
takes place. Furthermore, normally functioning kidneys should be
able to maintain a normal secretion rate of medullary depressor
substances, which would also help to keep blood pressure from
rising.
Unilateral renal denervation in anaesthetised animals causes
diuresis and natriuresis from the ipsilateral kidney (Bello-Reuss et
al., 1975). Chronic electrical stimulation of the renal sympathetic
nerves raises blood pressure (Kubicek et al., 1953), as also does long
term infusion of noradrenaline into the renal artery of a dog with
only one kidney (Katholi et al., 1977). Guyton et al. (1972) have
stressed the importance of the kidneys in long-term blood-pressure
regulation and in the maintenance of hypertension. The brain can
only raise blood pressure over long periods of time if it can bring
about a change in the functional characteristics of the kidneys. It is
obvious that neurogenic constriction of aerent glomerular arterioles will reduce glomerular ltration pressure and therefore glomerular ltration rate. If tubular sodium reabsorption does not
change, sodium excretion will fall. However, increased sympathetic
tone can increase renal tubular reabsorption of sodium without
aecting GFR (Gill and Casper, 1969) by a direct eect on tubular
transport (Bello-Reuss et al., 1976). All these are examples of
cooperation between kidneys and brain.
The clinical application of renal sympathetic denervation

Renal sympathetic denervation needs now to be taken seriously as an
eective way of treating patients with severe drug-resistant hypertension, because it can now be accomplished by a catheter-based
technique. As I write (in 2011), the carefully-controlled trial by
Murray Esler and his colleagues (Esler et al., 2011) has shown that a
sustained (six-month) reduction of blood pressure can be achieved
by destruction of the renal sympathetic nerves in severely hypertensive patients. I admire this interesting clinical application of basic
physiological principles to therapeutic blood-pressure reduction.
170
Time will be needed to assess the long-term safety and long-term

eectiveness of this interesting treatment. Although such treatment
does not dilate stenoses in the main cerebral arteries, the same can of
course be said about hypotensive drug treatment.
Natriuretic peptides
The cardiac origin of what is now known as atrial natriuretic peptide
(ANP) was established by De Bold et al. (1981), who prepared atrial
myocardial extracts that had a potent natriuretic eect on the rat
kidney when injected intravenously. The renal eects are mainly
mediated by a powerful functional antagonism of the reninaldosterone system and inhibition of A-II-driven proximal tubular
sodium reabsorption. According to Laragh (1986): ANP promptly
reduces renin secretion, it relaxes angiotensin-constricted vessels, it
blocks angiotensin-induced aldosterone synthesis by the adrenal
cortex and, by its natriuretic action, it opposes the renal action of
aldosterone. ANP is expressed in the brain, where it probably acts
as a specic neurotransmitter at several sites, and as an antagonist of
A-II action. Nilsson et al. (1987) observed in 717 people no dierence in ANP concentrations between normotensive and hypertensive
subjects. It probably plays no specic part either in causing or
preventing hypertension.
The same can probably be said of two other related natriuretic
peptides: B- (of cardiac ventricular cell origin) and C- (of endothelial
origin). Specic receptors have been identied for each (Nakao et al.,
1993). Neseritide is a recombinant form of human BNP, and has
been used to treat heart failure, with many of the immediate vasodilator eects of nitroglycerin but with additional diuretic properties.
BNP concentrations have been used to diagnose and assess heart
failure and its response to treatment (Isaac, 2008).
Renal transplantation
Bianchis technically astonishing cross-transplantation experiments
between spontaneously hypertensive rats of the Milan hypertensive
strain (MHS) and normotensive rats, clearly demonstrated the
transmission of a hypertensive predisposition through the sole
agency of the kidney (Bianchi et al., 1974). Similar results have since
been obtained in SHR (Kawabe et al., 1978). It is likely that a shifted
perfusion pressure/sodium excretion curve probably contributes to
171
hypertension in all rat models. Curtis et al. (1983) removed the

kidneys from six patients with end-stage renal failure complicating
what had appeared to be essential hypertension, sometimes in the
malignant phase. When a kidney from a normotensive donor was
grafted in, blood pressure came down and, in the six reported cases,
remained normal for an average of three years. On the face of it,
these observations, and generally similar observations by others,
might lead one to suppose that the renal origin of essential hypertension is thereby established. That is not so. Such an interpretation
ignores both the time-scale of essential hypertension and the
sympathetic nervous control of renal function. An analogy may help
to explain why I cannot accept that observations of crosstransplantation of human kidneys in any way prove a renal origin or
initiation of essential hypertension. As Julian Paton has described in
Chapters 7 and 8, there are several pressor areas in the brainstem
that lower blood pressure if they are damaged. All the animal
evidence suggests that these eects would still occur in, for example,
the severe hypertension and renal failure of terminal chronic
glomerulonephritis. It would be manifestly absurd to claim that this
proved a primarily neurogenic origin for the hypertension.
Summary
This chapter briey reviews the well-known secondary causes of
hypertension. These need to be considered as contributing potential
increments to any pre-existing cerebrovascular (esssential) level of
hypertension.
The kidneys can increase systemic arterial pressure both directly
and indirectly. If blood volume and the static pressure in the blood
vessels of the body increase, the renal excretion rate of sodium and
water also increase. The kidneys contain the hormone renin, the
secretion of which increases when the kidneys are ischaemic. Renin
can indirectly release the octapeptide angiotensin-II, a powerful
pressor material, from a circulating precursor. Low and initiailly
sub-pressor concentrations of this hormone can also exert a direct
neurogenic action on brainstem nuclei to elevate blood pressure. An
increase of dietary salt can also raise blood pressure signicantly.
Mineralocorticoids, notably aldosterone, can sustain high levels of
blood pressure by neurogenic means. Natriuretic peptides from the
172
heart and elsewhere can antagonise the pressor inuence of mineralocorticoids. The kidneys also contain a blood-pressure-lowering
hormone, medullipin, deciency of which is also a potential cause for
hypertension.
It is well-established that the kidneys inuence neurogenic blood
pressure-controlling mechanisms in the brainstem. The sympathetic
nervous system directly controls renin secretion and indirectly
inuences renal glomerular pressure and glomerular ltration rate by
its vasoconstrictor innervation of the renal vasculature.
173
Part III
Stroke: the Commonest
Cerebrovascular Disorder
10
The Cause of Strokes in Cerebrovascular
HypertensionWhat Causes Bleeding into
the Brain?
In the rst chapter of this book I described the Preliminary Communication that Drew Thomson and I sent to The Lancet in 1959.
That was the rst account of the necropsy perfusion studies of the
main human cervical cerebral arteries, which we had presented to the
British Medical Research Society the year before. Even at an early
stage in our study we were revealing an astonishingly close negative
correlation between the maximal ow-rates of water (under pressure)
through both vertebral arteries (ow rates added together), and the
ante-mortem blood pressures of the rst fty-eight of our subjects,
whose blood-pressure records were available. The correlation coefcient was highly signicant (r = 0.59, P<0.001). When six cases
of malignant-phase hypertension were excluded, and another eight
cases with possibly unreliable records of ante-mortem blood pressure
were also excluded, forty-four cadavers remained. We observed that
their summated vertebral artery ow-rates were almost incredibly
closely correlated with their ante-mortem blood pressures, independently obtained from the hospital notes (Dickinson and Thomson,
1959; g. 1b, p 49, r = 0.78, P<0.001). When we added in the
measured ow-rates for both internal carotid arteries, to make what
I have described as the summated maximal ow-rate of all four
cerebral arteries for each subject, we found that these values were
almost as closely associated (negatively) with the blood pressures of
each subject previously recorded in the hospital notes, as were the
ow rates from both vertebral arteries alone. All this was exciting.
We thought that we had identied the long-sought mysterious cause
of essential hypertension. Previous chapters in this book have
described many new observations that have strengthened this belief.
177
STROKE: THE COMMONEST CEREBROVASCULAR DISORDER
However, received wisdom at the time was that the increased cerebral arterial resistance in people with essential hypertension came
from small arteries and arterioles, sometimes assisted by a circulating
pressor inuence from the kidneys. The brain and its large arteries of
blood supply had nothing to do with the case.
But now I want to change tack and revisit unexpected observations about strokes, which began to emerge from the same original
necropsy pressure/perfusion measurements that I described in
Chapter 4. Figure 10.1 comes from our Lancet paper, reproduced
with the publishers permission. On the ordinate scale it showed our
Fig. 10.1 Copy of gure 2 from the Preliminary Communication to The Lancet from
Thomson and myself, showing our initial measurements of the maximal total summated
ow-rates, in our pressure/perfusion system, from cadavers with evident spontaneous
strokes (on the right side) and those with otherwise normal brains (ordinate scale on the
left side), for all four main cerebral arteries added together. There was a clear line of
separation between normal and stroke subjects, leaving aside cadavers with evident
malignant hypertension and those with relevant hypotensive cardiovascular complications. Our results were so surprising and were so clearly relevant to the cause of
strokes that we decided to extend the series until we had equal numbers of former
patients with and without strokes. Reproduced from Dickinson and Thomson (1959) in
The Lancet ii 4648, with the permission of Elsevier.
178
THE CAUSE OF STROKES IN CEREBROVASCULAR HYPERTENSION
pressure/perfusion rate measurements of the summated ow-rates

obtained from all four main cerebral arteries (added together) in two
groups of cadavers: forty-four former patients without strokes, on
the left side, and nineteen former patients with macroscopically
visible strokes, on the right side.
It was obvious that the main cerebral arteries of each individual
who had died with, or from, a stroke had a summated uid-carrying
capacity that was only about half that of individuals whose brains were
macroscopically normal at necropsy. I shall not further consider
three former patients with strokes who also had evidence of
malignant-phase changes (papilloedema and retinal haemorrhages).
Malignant hypertensive changes are generally recognised as qualitatively dierent from benign hypertension and I shall not further
consider these former patients here. Four cerebral infarcts in our
series were clearly due to co-existant circulatory problems: one with
acute post-operative bleeding, one with a massive pulmonary infarct,
one with congestive heart failure, and one with an associated cerebral tumour. The remaining stroke subject (Case #61) also had an
old cerebral infarct (a large cyst in his left internal capsule) but
otherwise had almost no evidence of stenotic atheroma of his main
cerebral arteries. His hospital notes revealed that he had been
admitted eight years earlier with an acute right hemiplegia that
developed during an episode of severe bronchopneumonia. We
assumed that his stroke had probably been precipitated by a welldocumented prolonged hypotensive episode, which was recorded at
the time in his hospital notes from the Intensive Care Unit.
That left eleven people who had died with, or from, strokes, all of
which could be described as spontaneous. In ten of these we could
nd no obvious acute arterial obstructions to explain them. Four
cadavers had cerebral infarcts (CIs), two had intracerebral haemorrhages (ICHs) and four cadavers had died with both types of
stroke. Only in Case #4 did we nd an ante-mortem thrombus in a
small artery, which appeared to have supplied the damaged part of
the brain, but even that individuals main cerebral arteries had also a
much reduced summated uid-carrying capacity. Drew Thomson
and I repeated all our pressure/perfusion measurements with watery
ammonia until each ow rate could be increased no further. Those
who nd it dicult to believe that atheromatous disease of the main
human cerebral arteries can seriously obstruct ow should look at
the distended and xed vertebral artery in Fig. 3.6c, p 65. Even in the
179
otherwise normal-looking vertebral artery (Fig. 3.6a) there is a large

hemispherical lling defect at the distal (upper) end of this vessel.
This was caused by a round mass of atheroma which obstructed half
the lumen.
In earlier chapters I described the work of John Stirling Meyer and
his colleagues, and that of Hutchinson and Yates. All had recognised
that stenotic atheromatous lesions of the main cerebral arteries were
strongly associated with spontaneous strokes and must have played
some part in their causation. But Thomson and I were the rst to
estimate the minimal resistance of the main cerebral arteries. I have
explained in Chapter 4 how we overcame the problem of parallel
resistances contributed by these vessels. This allowed us to estimate,
for each cadaver, what I described as the summated maximal owrate for all four main arteries. This was a crude inverse measure of
their total eective resistance. When Stirling Meyer showed me his
magnicent cerebral arterial angiograms, he did not doubt that
atheromatous lesions of the large cerebral arteries often caused
strokes, either by slowing down blood ow or by promoting blood
clots on plaques of atheroma. Only in the single case I mentioned,
did Drew Thomson and I nd an acute ante-mortem clot obstructing
a main cerebral artery at necropsy.
I should acknowledge today that I tried (and failed) to persuade
John Stirling Meyer that stenotic large cerebral artery lesions were
the cause of essential hypertension. He admitted the possibility, but I
recall his insistence that there were too many exceptions in people
without hypertension. I would now suggest that such individuals
blood pressures might have been reduced by co-existent heart disease, but the matter remained unresolved when I drove back to
Cleveland.
How often do acute clots obstruct the main arteries of the brain?
Long ago I summarised the extensive world literature describing
cerebral infarcts unaccompanied by obstructions of the relevant
arteries (Dickinson, 1965, p 93). And later, when I reviewed the
necropsy measurements of main cerebral artery resistances in the
forty-seven stroke patients in our whole series (see above), Drew
Thomson and I found only nine main cerebral arteries blocked by
atheroma or by adherent clots. In only a single subject (Case #4) did
180
we nd a small recent cerebral artery clot blocking an artery supplying an infarcted area.
Our almost comprehensive failure to identify acutely occluding
clots causing spontaneous strokes made me think that circulating
thrombolytic agentsor just the passage of timemight have
already lysed clots by the time of our necropsy perfusion study. We
knew that acute clots often locally obstructed one of the main coronary arteries, causing an acute myocardial infarction, but acute
local clots seldom obstruct the main cerebral arteries, probably
because the rate of blood ow is too fast for a local thrombus to
form. Preformed clots could obviously act as emboli, but we did not
nd any in our study. When I had cannulated and connected each of
the main cerebral arteries to our reservoir of ammoniated water at
ceiling levela height that provided a pressure of 140 mmHg at the
necropsy table (Fig. 4.3, p 75)the pressure was great enough
immediately to expel all non-adherent clots.
Are cerebral infarcts due simply to lack of blood or is there a more

subtle cause? How much blood does the human brain need?
Drew Thomson and I began our necropsy perfusion work with no
intention of studying strokes. Apart from recognised causes, such as
a leaking berry aneurysm causing subarachnoid bleeding, and a
leak of blood from a cerebral tumour, all the other fatal strokes in
our study could be correctly described as spontaneous. I have
explained that our results became so exciting that we could not resist
submitting a Preliminary Communication to The Lancetin which
journal it was immediately published (Dickinson and Thomson,
1959). Our article was accompanied by Fig. 10.1, which I have
reproduced here with the kind permission of Elsevier. Thomson and
I had identied eleven strokes with no obvious local obstructive
cause. Five strokes were infarcts, but only one could be attributed to
a visible ante-mortem clot in the artery supplying the infarcted part
of the brain. When I rst reviewed our perfusion measurements and
failed to nd the occluding clots that we had expected to nd, we
assumed that the clots had lasted long enough to cause death of
brain tissue, but had later been removed by circulating thrombolytic
agents.
Later I considered the rate at which ischaemic brain tissue
181
becomes irretrievably dead after an acute arterial obstruction. I

thought that the best chance of preventing brain death after a stroke
was to administer an intravenous thrombolytic drug as early as
possible, perhaps even before excluding bleeding by computer-aided
tomography (CT) or magnetic resonance imaging (MRI) (Dickinson, 2007). In 2009, the scales fell from my eyes. I had become
obsessed with the importance of lysing blood-clots quickly. I should
have thought again about our necropsy perfusion measurements fty
years before. Now I understand, belatedly, why early thrombolysis
has been so unsuccessful in limiting damage from established
strokes. The situation is completely dierent from the well-accepted
role for immediate thrombolysis in acute myocardial infarction. The
total blood-ow of the adult human brain is colossal. It is about four
times greater than that needed to supply blood (and energy) to the
muscles of the beating human heart of someone at rest (p 48).
The main cerebral arteries in each of us must have evolved and
grown to be the right size to carry the enormous amount of blood
that the brain needs. Why should the main cerebral arteries be much
bigger than they need to be? What could the evolutionary advantage
have been? Total cerebral blood-ow (CBF) is nearly constant over
24 h, although it diminishes slightly during deep sleep. The total
eective cerebral arterial vascular resistance of the large cerebral
arteries must, of course, be rst set by the variable congenital size of
the four main arterial trunks, but I have not seen any evidence that
their congenital size determines normal systemic arterial pressure in
humans. This possibility would be dicult but not impossible to
examine. But Julian Paton has clearly demonstrated that the
spontaneously hypertensive rat has narrow main cerebral arteries
(Chapter 8). Although Drew Thomson and I only made measurements in ninety-four cadavers, it was dicult to imagine that more
human necropsy perfusion studies would have changed our conclusionthat the summated resistances of the main cerebral arterial
trunks were closely and directly related to the previously recorded
blood pressures of each subject.
It seemed obvious that the increased ow resistance of the main
human cerebral arteries was mainly the result of the deposition of
plaques of atheroma encroaching on the arterial lumina. In human
beings this can appear in the fourth, third or even as early as the
second decade of life (e.g. in Japan). In Chapter 8, Julian Paton has
described functionally equivalent congenital narrowing of the main
182
cerebral arteries of the spontaneous hypertensive rat (SHR). He and

I suggest that when a terrestrial mammal goes to sleep, systemic
arterial pressure is programmed to fall gently until the bodys control
mechanisms in the brainstem detect the near approach or risk of
brain hypoxia, hypercapnia or acidosis. At this point, the Cushing
mechanism will take over and augment basal sympathetic vasoconstrictor activity until a new stabilised basal blood-pressure level has
been reached. If the normal fall of blood pressure during sleep is
limited by stenotic atheroma of the main cerebral arteries, by
inammatory thickening or for any other reason, basal systemic
arterial pressure cannot fall further and must stabilise at a new
higher equilibrium value.
I have tried to visualise the sequence of events when some part of
the brain nds its arterial supply becoming inadequate. Over weeks
or months before the threatened infarct becomes real, local adjustments of blood ow by neurogenic, chemical and local cytokine
activation will doubtless have ensured that cerebral arteries of every
size that were still capable of dilating will have dilated enough to
prevent death of brain tissue. So-called ischaemic preconditioning
may represent a step in the adjustment process. Because cerebral
infarcts are only seldom precipitated by the sudden development or
impaction of a blood clot in a main artery of supply, they must have
another explanation.
The human brain is supplied with blood by arteries of nite size.
As we get older, these vessels gradually lose their elasticity and
become more rigid. They often become narrowed or even closed by
atheromatous plaques. Eventually the brain needs so much blood to
stay alive that small increments of main artery resistance brought
about by stenotic atheromatous disease cannot be overcome by
further growth of collateral vessels or by any amount of downstream
arteriolar or small artery dilationalthough it was everyones condent expectation of compensatory downstream arteriolar dilation
that enabled our original necropsy perfusion studies to be ignored
and forgotten. After I had reported them to the 6th Princeton
Conference on Cerebrovascular Diseases there was a discussion
section during which my observations were noted, but deemed (by
Seymour Kety) irrevelant to the causation of essential hypertensionas the published record of that conference reveals (Kety,
1968).
After Drew Thomson and I had measured the main cerebral artery
183
resistances in our rst eighty-one cadavers, neither of us had

appreciated the high maintained level of metabolic and electrical
activity in the brain and the enormous blood ow that it needs to
stay alive. But we decided to study more people who had died with
strokes so that we might better understand what had been going on.
We therefore examined the next thirteen unselected subjects who had
died with or from strokes of various kinds. These additional results
were published in our second main paper in Clinical Science (Dickinson and Thomson, 1961, Cases 8294). This included full tables of
the new raw data in the same format that we had already used for
our rst paper (Dickinson and Thomson, 1960a, Cases 181). Fifty
years ago I had not realised that cerebral infarcts might be due
simply to not enough blood getting through the main arterial trunks
to keep all parts of the brain alive when the main cerebral arteries
were already narrowed by atheromatous plaques. It is obvious that
the lower values of blood pressure and cerebral blood-ow in sleep
must usually mark the time of greatest threat of ischaemic damage to
normal brain tissue.
To explain cerebral infarcts we do not need to incriminate either
defective arterioles or mysteriously vanishing blood clots. Neurologists are now beginning to talk about haemodynamic causes of
stroke and to use the description low ow to describe this threatening situation. Inadequate ow might be better. We need to
recognise the critical eect that plaques of atheroma in any of the
four main cerebral arteries can have after small arteries and arterioles have reached their limit of ischaemic, hypoxic or hypercapnic
dilatation during sleep. When ow becomes gradually, rather than
suddenly, inadequate, it is likely that atrophy, rather than infarction,
of the brain may ensue; but measuring the contribution of each of
the potential risk factors seems a hopeless task. It is not surprising
that a recent Dutch study of 965 people with a mean age of 58 years,
by Muller et al. (2010), identied both low and high blood pressures
as potential risk factors for brain atrophy and impaired cognitive
ability!
A survey of main cerebral artery resistances in strokes

Figure 10.2 is a copy of a gure from Dickinson and Thomson
(1961). It records on the ordinate scale (y-axis) the mean ante184
mortem blood pressures of our subjects; this ranged from 63 to

173 mmHg (i.e. between clinical readings between 90/50 and 245/
140 mmHg). These values are plotted against an abscissal x-axis scale
of summated ow-rates from all four main cerebral arteries between
21.0 and 111.9 ml/s, measured at necropsy using the standard
pressure/perfusion system I described in Chapter 4. The lowest ow
rates were those from cadavers with extensive atheromatous stenoses
of the main neck vessels. Todays readers of our two old papers
should realise that hypotensive drugs were very seldom given at all in
Fig. 10.2 Copy of gure 3 from Dickinson and Thomson (1961) showing the relation
between the ante-mortem blood pressure of all cases in the series for which adequate
blood pressures were available, and the total summated ow-rates for all four main
cerebral arteries, added together, only excluding cases of malignant hypertension.
Cadavers dead from spontaneous strokes are separately distinguished. With one
exception (see text), all the former patients with strokes had blood pressures before
death greater than 150/90 (mean blood pressure greater than 110 mmHg). This illustration, and Fig. 10.3 which follows, were both published by Dickinson and Thomson
(1961) in Clinical Science 20 334347, and are reproduced with the permission of The
Biochemical Society (website: http://www.clinsci.org).
185
London in the 1950s. That explains how we were able to identify so

many untreated severely hypertensive patients. We noticed that nonadherent ante-mortem clots were expelled as soon as we connected
our aqueous ammonia reservoir, which provided a constant pressure
of 140 mmHg. As I mentioned earlier, we only found one easily
visible arterial clot that was not expelled by the high perfusion
pressure in our system.
There had been many reports of atheromatous plaques narrowing
large cerebral arteries, but no authors before us had devised any
means of quantifying their observations and converting them into
eective ow-resistances. In our rst study, all eleven former patients
with spontaneous strokes could be separated from non-stroke
patients by a dividing line across Fig. 10.1 at about 56 ml/s ow rate
in our perfusion system. After we had extended our study by thirteen
more consecutive unselected necropsies from people who had died
with strokes, we had resistance measurements of the large cerebral
arteries in forty-seven cadavers with evident strokes, to compare
with the same measurements in forty-seven cadavers without strokes,
in terms both of maximal cervical cerebral artery uid-carrying
capacity (abscissae) and mean ante-mortem blood pressure (ordinate
scale). Figure 10.2 shows the enormous separation between subjects
with and without strokes; it could hardly have been greater. It was an
extraordinary and spectacular observation, to which I drew attention
in an annotation in the American Heart Journal (Dickinson, 1962).
Drew Thomson and I had no means of knowing whether any of
the subjects in our necropsy perfusion studies had been given constricting or other drugs immediately before death, or what neural or
chemical changes might still have remained afterwards. We were
concerned lest the smooth muscle in the walls of the arteries we were
examining might have remained randomly and unpredictably constricted after death. To avoid this possible source of confusion we
dilated each of the four main cerebral arteries with dilute ammonia
and repeated our perfusions until the maximal uid ow rate
obtainable for each artery became constant while 140 mmHg pressure was applied to the origin. It became obvious that increased main
cerebral artery resistance was the main cause of strokes, unless circulating vasoconstrictor chemicals were also present. Drew and I
envisaged that during its development the human brain would have
evolved to manage with the lowest possible blood pressure during
sleep, with all dilatable arteries as dilated as possible. Although we
186
had begun our study to nd the cause of essential hypertension, we

were soon forced to conclude that spontaneous strokes (other than
those due to sub-arachnoid bleeding) were all associated with grossly
increased resistance of the main cerebral arteries. There was no need
to invoke local arterial obstructions by clots as a common cause of
strokes.
The mysterious occurrence of massive intracerebral haemorrhage

Over a four-year period, John Stirling Meyer and his colleagues in
Detroit followed 161 previously normal subjects with an average age
of 62 years, measuring total cerebral blood-ow before and after the
development of symptoms of cerebrovascular disease (transient
ischaemic attacks or completed strokes). During the study period, 21
of their subjects developed a reduction in total cerebral blood-ow at
the same time that stroke symptoms appeared (Meyer et al., 1984).
Thus it did not surprise Thomson or me that we observed several
infarcts and recent areas of brain softening in our necropsy perfusion
study, even though we could seldom nd an acute clot obstructing an
artery leading to the damaged region of brain.
But we also saw many subjects with obvious bleeding into the
substance of the brain (intracerebral haemorrhage, ICH). Most
physicians assume that substantial intracerebral haemorrhage
appears because an unduly high systemic arterial pressure has
overstretched and ruptured previously normal small cerebral arteries. This sounds plausible, but it is not correct. Rochoux (1844) was
the rst to realise that ICH arose in an area of previous brain
softening; Globus and Strauss (1927) agreed. They regarded spontaneous intracerebral haemorrhage as the terminal phase of a
sequence of events that followed the closure of diseased arteries in a
restricted area of the brain. Rosenblath (1918) and Westphal and
Bar (1926) ascribed haemorrhage to multiple leaks from arterioles.
Lampert and Muller (1926) reported that at necropsy they could not
rupture normal human cerebral arteries of any size by increasing the
distending pressure. Arteries were usually forced o the cannula
rather than splitting, unless they were already manifestly diseased. In
his comprehensive review Schwartz (1930) reported that all the
intracerebral haemorrhages he examined were associated with, or
had been preceded by, local softening, i.e. infarction. Hicks and
187
Black (1949) and many others ascribed ICH to multiple ruptures of

previously damaged arterioles. Hicks and Warren (1951) examined
100 human cerebral infarcts and wrote: Ischemia is the cause of
virtually all cerebrovascular accidents, whether they are hemorrhagic
or non-hemorrhagic. Miller Fisher (1961) opined that ICH usually
arose from rupture of arterioles of 50200 mm internal diameter.
Neither normal arteries nor arterioles of any diameter could be
ruptured simply by increased pressure. Fisher (1965) later reported
that embolism was uncommon. He thought that some lesions that
would have been clinically diagnosed as infarcts, by their limited
extent and by the absence of associated signs or symptoms of raised
intracranial pressure, were really small encapsulated haematomas.
These might later become lacunes (Mori et al., 1985).
Observations in animals make an interesting contrast to these
human observations. Stamler (1958) confessed himself puzzled that
visible strokes of any kind simply did not occur in any of the common experimental animals then being studied, unless they had
developed the malignant phase of hypertension. Spontaneous
intracerebral haemorrhage (ICH) is often recognised in human
necropsies but was never seen in any experimental animal with
hypertension in the benign phase. I need to point out that when
Stamler made that observation, the Japanese spontaneus hypertensive rat and its stroke-prone derivatives had not yet appeared on
the scene.
Personal and other observations concerning the aetiology of the

common forms of stroke
I suggest that my necropsy studies with Drew Thomson very simply
explain the unique liability of human beings to spontaneous ICHs
and CIs. In a study entirely dierent from the cadaver-perfusion
work that I described in Chapter 4, we examined the necropsy
records of the Middlesex Hospital and reported that twenty-one
(10%) of cadavers with massive intracerebral haemorrhages also had
additional evidence of adjacent old or recent infarcts (Dickinson and
Thomson, 1960b). When Katsuki and Hirota (1966) noted the high
incidence of ICH in the Japanese, they also noted that cerebral
infarction (CI) was almost as common. In the last forty years,
innumerable observations have conrmed the relationship between
188
high blood pressure and stroke, especially that due to ICH. Populations such as the Japanese, with a high incidence of hypertension,
have also a high incidence of ICH (Goldberg and Kurland, 1962).
Can it really be that spontaneous intracerebral haemorrhage has
the same cause as spontaneous cerebral infarction? The ischaemic
origin of ICH has recently been conrmed in an interesting, unexpected but very convincing way by the extensive genetic study of the
common forms of stroke by Gretarsdottir et al. (2002). Their study
identied a stroke-susceptibility gene (STRK1) at 5q21. The
authors reported no genetic advantage (in discriminating between
the two kinds of stroke) by treating CI and ICH separately. A
commentator in The Lancet, reporting this study, regarded it as
extraordinary for what intuitively should be two distinct pathological processes (Sharma, 2004). Intuition can be unreliable, as in this
case. My old observations with Drew Thomson, and many classic
pathological studies, strongly suggest that both common forms of
stroke share the same cause, i.e. a critically restricted cerebral blood
supply. And even in the stroke-prone rat model (SHR-SP), the
incidence of ICH and of CI is much the same (Nagaoka, 1986).
Figure 10.3, from our published study, shows individually on the
ordinate scale the maximal summated ow-rates of all four main
cerebral arteries in thirty normotensive individuals who had died
with macroscopically normal brains, and whose arteries we had
examined using our standard pressure/perfusion technique. The
average maximal summated ow-rate was 89.0 ml/s. This was considerably greater than the average maximal summated ow-rate of
fteen former patients with uncomplicated essential hypertension,
without strokes: 64.2 ml/s. But that from twenty-eight cadavers with
unequivocal evidence of cerebral infarction was 48.4 ml/s and that of
sixteen cadavers with macroscopically evident intracerebral haemorrhage was 50.9 ml/s. Figure 10.3 shows that the two average total
ow rates were not signicantly dierent. Thomson and I were
forced to conclude that massive intracerebral haemorrhage must be
ischaemicthe result of unduly narrowed main cerebral arteries. This
surprising conclusion can be checked by examining the published
tables containing all our raw data. Better still, interested but sceptical clinical scientists should make some pressure/perfusion
measurements themselves, of the resistances oered by some of the
main cerebral arteries in a few cadavers with massive intracerebral
haemorrhages. All the necessary technical details were published in
189
Fig. 10.3 Comparison for forty-seven cases of stroke in separate groups (on the right),
and for forty-seven people who had died with macroscopically normal brains (on the
left), in terms of ante-mortem blood pressure and the summated uid-carrying capacity
of all four main cerebral arteries in the neck and skull base. The hypertensive groups are
divided into possibly renal hypertensive and simple essential hypertensive subject
groups. Strokes occurring with gross precipitating factors are on the extreme right side
and are discussed in the text. All other stroke cases are shown by lled circles, except
that cases of both CHs and ICHs present in the same cadaver are shown by a half-lled
circle in each group. Central horizontal lines show the means, calculated as if these
mixed stroke cases represented half the case in each group. The short thick horizontal
lines indicate 2 SEM, i.e. 95% condence limits. The thin vertical lines embrace 95%
condence limits for all observations in each group (Dickinson and Thomson, 1961).
our two main papers in Clinical Science (Dickinson and Thomson,

1960a, table II; Dickinson and Thomson, 1961, table I), and have
been republished in Chapter 4 of the present book. Since no-one has
published any comparable similar measurements, I have retained all
my original case records and am happy to show them to anyone
interested.
If we leave aside four cases of previous malignant hypertension,
and six with associated cardiovascular complications (which could
have caused an acute fall of blood pressure), we are left with similar
numbers of spontaneous ICHs and CIs, each group having comparably reduced main cerebral artery ow rates, i.e. with similarly
190
increased resistances in their main cerebral arteries (Fig. 10.3). There

was almost complete separation between the average summated
main cerebral artery ow-rates of people dying with macroscopically
normal brains and those dying either with CIs or ICHs. Two groups
of essential hypertensive and possibly renal hypertensive individuals
without strokes occupied intermediate positions.
The signicance of a raised blood pressure

Hypertension is regularly cited as the most important risk factor for
stroke. But systemic arterial hypertension should concern us not just
because it might provoke excessive myogenic constriction of small
arteries and arterioles in the brain and elsewhere. Everyone regards it
as one of the most important risk factors (i.e. predictors) of heart
disease and sudden death; it is that, of course. Treating hypertensive
individuals with drugs that lower blood pressure can prevent heart
failure and the advent of the malignant phase. But I suggest that in
adults it would be better and more accurate to think of hypertension
as a marker signifying that the total eective resistance of the cerebral arterial supply of the brain is unduly high. Thomson and I
identied only one spontaneous stroke (Case #59) in a patient whose
blood pressure on several occasions before death was only 149/
90 mmHga value that was then deemed normal. However,
although this mans blood pressure had been as low as this for three
years before his death, this former patient had died in congestive heart
failure; his heart was enlarged and weighed 482 g, and his kidneys
showed the histological changes of benign nephrosclerosis. Clearly
he must previously have had substantial essential hypertension.
After studying the literature cited in Chapter 3, I envisaged that
lowering arterial pressure (and therefore slowing blood ow) was
bound to increase the risk of local clot formation in both coronary
and cerebral arteries. Although hypotensive drugs appear to protect
against various types of clinically-evident heart failure, they have
almost no protective eect against myocardial infarction. But this is
not quite true of cerebral infarction. It is interesting that the late
Horace Smirk may have been on the right track. Hodge et al. (1961)
were probably the rst trialists to report that long-term hypotensive
treatment reduced the incidence of strokes, if only slightly. Lee et al.
(1963) reported relative freedom from strokes in adequately treated
191
hypertensive patients, though they recognised that adequate treatment may select patients with the least pre-existent cerebral arterial
disease. None the less, MacMahon et al. (1986) collated the results of
many earlier trials and reached the surprising conclusion that antihypertensive drug therapy resulted in a 40% reduction in strokes!
The (British) Medical Research Council Working Party (1985) was
less impressed. Its trial of nearly 18,000 patients recorded that antihypertensive treatment produced only a small reduction in stroke
incidence, mainly when bendrouazide was used. There was no
improvement in average life-expectancy of the treated patients.
From the late-1980s onwards, trials lowering blood pressure began
to report a small reduction in the incidence of strokes, though Klag
et al. (1989) were less certain. In some trials, the improvement in
total mortality seemed to be due entirely to a reduction in cardiac
mortality rather than to a decline in stroke mortality. Sugimoto et al.
(1999) followed the course of cerebral ischaemic damage in treated
hypertensive patients by repeated MRI examinations. They reported
that lowering raised blood pressure to normotensive levels reduced
the number of cerebral infarcts in adequately treated patients.
As I write (in 2011), some of our ideas about the protective eect
of anti-hypertensive treatment against strokes, and the stroke risk of
hypertension per se have been thrown into confusion and disarray by
the remarkable recent analysis of the Japanese longitudinal arteriosclerosis study by Yutaka Imai and his colleagues (Assayama et al.,
2009). They reported that optimally-treated hypertensive individuals had a greater stroke risk than untreated people! It will be a long
time before this contentious subject is resolved.
Is there a margin of safety in respect of human cerebral bloodow? If so, what is it?
The summated ow-rate values for all four main cerebral arteries in
our pressure/perfusion system unexpectedly provided us with more
information than Thomson and I sought. It was both interesting and
extraordinary that brain regions damaged by infarcts and haemorrhages were supplied by main arteries, which collectively, on average,
had almost exactly the same elevated maximal total ow-resistances.
But this enables me to estimate approximately the normal margin of
safety for the total eective resistance of the four main human
192
cerebral arteries in the adult human neck and base of skull. We

encountered no subjects with previously normal blood pressures
whose maximal summated cerebral arterial ow-rate measured in
our pressure/perfusion system was less than 70 ml/s. The normal
upper-limit appears to be approximately 110 ml/s (as shown by the
ordinate scale in Fig. 10.3). Subjects with uncomplicated essential
hypertension had maximal summated cerebral arterial ow rates
between 50 and 70 ml/s. Subjects with either main kinds of stroke
had average maximal summated ow-rates, which were usually less
than 50 ml/s (Fig. 10.3).
It appears that total human cerebral blood-ow can remain
adequate when the main cerebral arteries (examined at necropsy)
allow summated maximal ow-rates of at least two-thirds normal, in
our pressure/perfusion system. So-called essential hypertension
arises when summated maximal ow-rates in our study are half
normal, or less. Strokes are likely to occur when ow rates are onethird normal, or less, i.e. when total eective resistance of the main
cerebral arteries is about three times greater than its normal value.
Acute blood clots have little inuence on these estimates.
Unfortunately it is now no longer ethically possible to repeat every
part of our necropsy-perfusion study. All hypertensive patients
today have been given anti-hypertensive drugs. This makes it
impossible to determine what the true blood pressure of any
hypertensive individual would have been in the absence of drug
treatment. However, there is no reason why anyone with access to a
hospital pathology department cannot check our data and our
conclusions about the cause of spontaneous strokes, particularly that
of intracerebral haemorrhage. The time is long overdue for a proper
study, to refute, conrm or modify my observations with Drew
Thomson. They strongly reinforced the opinion of Hicks and Warren (1951): that Ischemia is the cause of virtually all cerebrovascular
accidents, whether they are hemorrhagic or non-hemorrhagic. Yet
everyone today seems to have decided that identifying bleeding is the
most important aspect of stroke management, rather than preventing or urgently treating the ischaemic brain damage that precedes the
leak of blood. The most recent edition of Stroke: practical management, edited by Warlow et al. (2008) is a massive and impressive
practical book about stroke management; but the editors and
authors are strangely reluctant to accept the absolutely overwhelming evidence that spontaneous ICH almost always arises from
193
a preceding infarct, unless some unusual brain pathology (such as

amyloid) has already weakened blood vessels. I do not understand
why they deride the evidence as old-fashioned.
I conclude this chapter by issuing a challenge to those who wish to
dispute my conclusions about the aetiology of strokes and the
overwhelming importance of atheromatous lesions in the four main
cerebral arterieseven in subjects dead from massive intracerebral
haemorrhage. Please either repeat the observations that I have
described in detail in Chapter 4, or devise and publish better
measurements of large cerebral artery resistance. Althoughat
presentthese can only be made at necropsy, no harm need be done
to any cadavers neck and face providing that care is taken to block
o the ophthalmic areries (Fig. 4.2) before any pressure-perfusion
measurements are made.
Summary
This chapter reviews the unexpected and surprising observations
made by Drew Thomson and myself when we measured the maximal
ow-rates we could obtain through the main cerebral arteries of
cadavers with strokes. We studied forty-seven cadavers dead either
from cerebral infarcts (CIs) or intracerebral haemorrhages: (ICHs),
using the pressure/perfusion system I described in Chapter 4. This
provided an inverse measure of the maximal resistance to uid ow
contributed by the complete lengths of each of the four main cerebral
arteries in parallel, in the neck and skull base. By adding the ow
rates of all four main arteries together we derived a summated owrate, which was an inverse measure of the total eective main cerebral artery resistance in each case.
Infarcts were revealed either by brain softening or by cysts formed
where dead brain tissue had been replaced by uid. All ICHs were
macroscopically obvious. We anticipated that the average summated
ow-rates of the four main cerebral arteries in our pressure/
perfusion system from former patients with CIs would be much less
than those obtained from the main cerebral arteries of cadavers with
normal brains. As we expected, the average summated maximal
ow-rates of the main cerebral arteries of subjects with previous
infarcts were only about half those from the cerebral arteries of
cadavers with macroscopically normal brains (p 190). The surprise
194
came when we perfused the four main cerebral arteries of cadavers

with evident intracerebral haemorrhages. Their average summated
maximal ow-rates were also only about half of those with normal
brains, and on average were the same as those from cadavers with
cerebral infarcts.
Our perfusion measurements made it obvious that massive intracerebral haemorrhage had nothing to do with damage from high
pressureas pathologists in the last century had consistently maintained. Bleeding came from regions of necrotic ischaemic damage to
small blood vessels. Bleeding was a late, rather than a primary,
event. Thomson and I concluded that all spontaneous strokes with
intracerebral bleeding must have resulted from preceding ischaemic
damage severe enough to cause death of brain tissue. There was an
evident and remarkable separation of patients with strokes of any
kind from people with normal brains, in terms of their summated
maximal ow-rates. It is easy to forget that the human brain needs a
tremendous amount of blood, which is supplied by four large arteries
that take twisted and convoluted paths to allow exible movements
of the neck. Total cerebral blood-ow alters very little during 24 h,
though it goes down slightly during sleep. Small rapid changes in
cortical ow occur with changes in mental activity of conscious
subjects, but they have almost no inuence on total cerebral bloodow.
Strokes occur predominantly in people with hypertension, but
hypotensive drugs give virtually no protection at all against myocardial infarcts and confer only a small (though just measurable)
protective eect against cerebral infarcts. This is not too surprising
because almost all spontaneous strokes (apart from subarachnoid
haemorrhage) are due to atheromatous stenoses distributed along
the main cerebral arterial trunks. These reduce basal cerebral perfusion and thus cause cerebral infarcts. The risk of bleeding begins
once a portion of brain is irretrievably dead, after which damaged
arterioles can start to leak.
Our original careful resistance-measurements in cadavers with
strokes have never been repeated, but have never been shown to be
wrong or misleading. Neurologists who nd our observations dicult to believe should measure the ow resistance of these large
arteries themselves.
195
11
Management and Treatment of
Cerebrovascular Hypertension
Screening
A cerebrovascular origin for high blood pressure (>140/90 mmHg)
should be suspected either in men of 2530 years or more, or in postmenopausal women, living in an urban environment of a developed
country. When nothing has been found to suggest a secondary cause,
screening for a cerebrovascular origin might be achieved by ultrasound examination of the common carotid and internal carotid
arteries in the neck. Doppler techniques might suggest the presence
of plaques of atheroma in the larger cerebral arteries. Examination
of the vertebral arteries by angiography or by other sophisticated
techniques might prove particularly interesting. My necropsy perfusions with Drew Thomson had shown that stenotic vertebral arterial
lesions were particularly closely related to previous hypertension.
Finding multiple distributed plaques of atheroma in a few major
arteries suggests an underlying cerebrovascular cause for hypertension. Conversely, the complete absence of plaques in both internal
carotid and vertebral arteries strongly suggests one of the secondary
causes for an individuals hypertension.
The presence and severity of small cerebral arterial or arteriolar
disease can be revealed by white matter hyperintensities in magnetic
resonance imaging (MRI). Inzitarii et al. (2009) surveyed 639 outpatients of average age 74 years by MRI. They reported that such
lesions strongly predicted a future risk of strokes and dementia.
Histologically, hyperintense lesions are associated with thickening of
the medial walls of small vessels. MRI is often used in clinical trials
and may eventually become part of a comprehensive health screening procedure for cognitive functional assessments. The authors
regarded hyperintense white matter lesions as risk factors. I suggest
196
MANAGEMENT AND TREATMENT OF CEREBROVASCULAR HYPERTENSION
rather that this type of small-vessel damage may be one of the

consequences of inadequate brain perfusion during sleep. It seems
likely that proximal atheromatous stenotic lesions of large arteries
may not have been severe enough in these cases to produce macroscopic infarcts. This is simply my guess, in the absence of formal
sleep studies of cerebral blood-ow. But as I pointed out in Chapter
3, essential hypertension per se does not cause hypertrophy or
thickening of the media of small cerebral arteries and arterioles.
The prevention of cerebrovascular hypertension involves preventing or minimising the deposition of atheroma in the walls of the
main cerebral arteries of the neck and skull base. This opens up an
extensive research area, in which I can only mention a few of the
current aetiological clues for atheroma of large human arteries.
Cerebrovascular hypertension is partly genetic and partly acquired.
The statin drugs have been immensely successful in reducing total
cholesterol concentrations, but it is not yet known whether they can
actually prevent deposition of plaques of atheroma or clot formation
on their vascular surfaces. I was intrigued to read a paper by
Gamliel-Lazarovitch et al. (2010) suggesting that a new aldosterone
synthase inhibitor could reduce atheroma and inammation in
apolipoprotein E-decient mice. I look forward to hearing more of
this Israel-based approach, if the initial results are conrmed.
Warfarin and aspirin (and/or clopidogrel) can be strokepreventive in patients suering from thromboembolic disease or
local platelet aggregates. Aspirin is sometimes almost sensationally
eective in preventing platelet aggregates and consequent transient
ischaemic attacks (TIAs). Warfarin, in many clinical situations, can
be protective against embolic strokes, especially if clots are coming
from a partly accid right atrium, in a patient with atrial brillation.
Unfortunately, both warfarin and aspirin bring with them an
increased risk of intracerebral bleeding. Cardiac dysrhythmias can
obviously contribute to acute strokes, but my clinical impression is
that their contribution to spontaneous completed strokes is usually
slight.
There have been many reports of the concordance of blood
pressure between unrelated people living together. There is signicant concordance between spouses in respect of blood pressure
(Speers et al., 1986), also between parents and their adopted children
(Garn et al., 1986; Mongeau et al., 1986). We still lack a comparably
accurate epidemiological knowledge of cerebral arterial atheroma
197
distribution and incidence. This is obviously much more dicult to

obtain. There is familial aggregation of blood pressure early in life,
according to Zinner et al. (1971). Slightly raised blood pressure in
children and adolescents can often be observed ten years before
frank hypertension is evident (Cruz-Coke, 1959).
All this should not be regarded as conclusive evidence of a genetic
component of hypertension manifest in childhood, because families
share the same home environment. So-called assortive mating is
another confounding factor, but studies of adopted children by
Biron et al. (1976) provide at least some evidence of an hereditary
eect operating in childhood. For that reason I am interested in
hypertension appearing in the children of hypertensive parents, who
have long been recognised to have an increased risk of being themselves hypertensive. In the study of Havlik et al. (1979), the ageadjusted correlation coecients between parents and ospring in
respect of systolic or diastolic pressures fell between 0.103 and 0.171.
Similar results have been observed for sibling relationships. An
unmodied polygenic inheritance of hypertension would predict
correlations of 0.5 in these two situations, in which about half of the
genes are shared. When the probable confounding eect of shared
environments within families is considered, the hereditary element in
essential hypertension may seem weak. However, the correlation of
blood pressure between identical twins reared apart is evidence of a
substantial hereditary eect (Hames et al., 1964). The intraclass
correlation coecients for systolic/diastolic blood pressure as
between monozygotic (0.55/0.58) and dizygotic (0.25/0.27) twins can
be mathematically expressed as a percentage of the total variance
attributable to heredity alone. This works out at about 60% (Feinleib et al., 1977). Various renements of analysis, taking account of
the possible confounding factors, have not signicantly altered these
estimates.
The large, genetic study by Hunt et al. (1986) revealed a surprisingly common association between hyperlipidaemic states and
hypertension. This was suciently striking to be given the appellation hypertensive-dyslipidaemic syndrome. Since hyperlipidaemic
states promote atheroma, this would also be compatible with an
atheromatous aetiological link. There is some evidence that a diet
containing a high proportion of polyunsaturated fats lowers blood
pressure (Puska et al., 1983; Norris et al., 1986). This might account
for some of the epidemiological evidence I reviewed in Chapter 3,
198
showing blood-pressure dierences between rural and urban populations. An atheroma-protective diet should, according to my views
about essential hypertension, act in the long term to protect against
that disease.
We know that high blood pressure from any cause is damaging.
We have all recognised families with a high prevalence of heart
attacks and strokes, but dietary changes, especially the avoidance of
high salt and animal fat, may be helpful. Many countries ban the use
of trans-fats in edible products. Sacks and Campos (2010) have
compiled a useful short review of dietary therapy in hypertension.
There is current interest in the possibility that statin drugs may not
only lower plasma cholesterol, but might also eventually reduce
cerebral artery atheroma, even though they have no benecial eects
on hypertension in the short term. Some claims have already been
made that statins can reduce blood pressure at the same time that
they reduce total cholesterol concentrations. However, if statins were
able to reduce the size of plaques of atheroma, I would not expect to
see any measurable eect on either total cerebrovascular resistance
or on blood pressure until the drugs had been used for several years.
So although Mancia et al. (2010) have failed to nd any short-term
eect, I anticipate that, as new techniques make it easier to measure
the size, distribution and severity of atheromatous plaques in the
main cerebral arteries, we may eventually nd that blood pressure
can be prevented from rising, or that it falls signicantly, if atheroma
is successfully reversed by statins or by some other eective drug
regime.
The other aspect of treatments that might lower blood pressure is
the use of arterial stents and direct surgical enlargement of the main
cerebral arterial trunks to reduce an unduly-elevated proximal
resistance created by one or more of the four main cerebral arterial
trunks. I am not aware of any large trials designed to examine this
possibility. When the carotid sinus baroreceptors are stimulated
electrically they can lower blood pressure, but they can also raise
blood pressure if they are damaged or ablated. Because a relatively
small (though variable) part of the brains blood-supply is carried by
the usually smaller vertebral arteries, surgical reconstruction and
stents of these vessels might sometimes oer the best prospect of
reducing hypertension if it is of cerebrovascular origin. I am not
aware of any attempts at direct surgical reconstruction or
endarterectomy of these vessels being aimed at minimising ow199
resistance rather than at preventing transient ischaemic attacks.

Comparisons suggest that new microvascular techniques might have
more to oer than stenting, as seems to be the case for the carotid
system (ODonnell et al., 2010). At necropsy I have seen two sizeable
vertebral arteries arising from pinhole origins in the subclavian
artery. Arterial reconstruction or stenting at this site might be easier
and more successful than high up in the neck.
The treatment of the hypertension of cerebrovascular disease

Hypertension is strongly associated with stroke (Kannel et al., 1967).
Kannel et al. (1978) clearly showed the overwhelming importance of
systolic blood pressure in stroke prediction, compared with other
possible factors that might be playing some part in aetiology.
However, Kannel et al. (1970), in their report of the Framingham
study, were not able to assign any clear causal chain to the association. They wrote: The exact mechanism of hypertension in the
occurrence of strokes is incompletely understood. Lowering blood
pressure is well known to abort the dangerous malignant phase of
hypertension. A growing body of opinion now holds that lowering
blood pressure in people with benign essential hypertension protects
against strokes and improves life-expectancy. But we need to keep
the protection against strokes and premature death in perspective.
An early estimate from New Zealand suggested that antihypertensive treatment accounted for only 10% of the reduction in
stroke deaths between 1970 and 1985 (Bonita and Beaglehole, 1986).
Undue blood-pressure reduction in severe hypertension can provoke
cerebral infarction and transient cerebral ischaemic attacks. In some
trials, reduction of total mortality was due more to a reduction in
cardiac mortality rather than to a reduction in stroke mortality,
though stroke incidence was also reduced. I share some of the views
of Strandgaard and Haunso (1987) about anti-hypertensive treatment in relation to the cerebral circulation:
There are at least three reasons why anti-hypertensive treatment
seldom causes cerebral ischaemia. First . . . there is . . . considerable scope for therapeutic reduction of blood pressure in
most patients. Thus, in an acute study, blood pressure could be
lowered by 25% before the lower limit of autoregulation was
200
reached. Secondly, some patients show adaptation of autoregulation of cerebral blood-ow during long-term antihypertensive treatment. Thirdly, below the lower limit of
autoregulation, cerebral arteriovenous oxygen extraction
increases by up to 30%, and this mechanism fails only when the
pressure is approximately halved.
The authors second point is arguable. I have explained in Chapter
5 why I remain unsure whether adaptation of autoregulation and a
change in the lower cerebral autoregulatory threshold (LCAT) take
place in essential hypertensive patients treated with hypotensive
drugs. Strandgaard and Hauso might have added that some drugs,
especially the angiotensin-converting enzyme (ACE) inhibitors and
the angiotensin receptor blockers (ARBs), are eective cerebral
artery dilators. None of these dilator mechanisms is well-developed
in the coronary circulation, which may explain why hypotensive
drug treatment does not prevent myocardial infarction and may
sometimes even precipitate it.
After the results of the rst well-controlled trial by Hamilton et al.
(1964) were published, many later trials have conrmed the
improvement in life-expectancy brought about in moderate hypertension by several dierent ways of reducing blood pressure. In all
trials, smoking emerged as a highly signicant risk factor that often
nullied the benecial eects of hypotensive drugs. In my second
monograph about essential hypertension (Dickinson, 1991), I
reviewed the trials of hypotensive drug treatment up to that time.
These all conrmed that anti-hypertensive drug therapy largely
prevented heart failure and protected the kidneys from the damaging
eects of uncontrolled hypertension. It also reversed the malignant
phase of hypertension. But it had little eect either on the incidence
or the death risk of myocardial infarction. I personally precipitated
an ischaemic stroke (as it proved) in one of my malignant hypertensive patients by lowering his blood pressure too rapidly with
intravenous diazeoxide. I also saw a presumptively ischaemic stroke
develop soon after I had given oral bethanidine (an adrenergic
neurone blocker) to a patient with modest essential hypertension.
Similar events are seldom seen today, because anti-hypertensive
treatment is begun more slowly and cautiously. We also have better
drugs, and understand better how to use them.
I am not aware of any attempt yet published to stent or to
201
reconstruct main human cerebral arteries with the sole intent of

reducing basal blood pressure. But surgical manoeuvres are often
carried out to prevent or treat transient or recurrent cerebral
ischaemic attacks (TIAs), or small strokes arising directly or indirectly from the carotid arterial territory. If my ideas about the
cause of essential hypertension are correct, such manoeuvres might
provide a way of permanently alleviating cerebrovascular hypertension without the use of drugs. Opportunities will also arise to
examine blood-pressure changes after surgical reconstruictions at the
common carotid bifurcation. Unfortunately, coincident involvement
of the carotid sinus or carotid body makes it dicult to decide
whether or to what extent reduction of internal carotid arterial
resistance, by itself, can reduce basal and casual blood pressures. An
answer will eventually come from a large number of careful clinical
observations.
Acute intravenous thrombolysis

While discussing the treatment of cerebrovascular hypertension, I
must mention intravenous thrombolysis, because this plays such an
important part in the immediate treatment of acute myocardial
infarction. Intravenous tissue plasminogen activator (tPA) or streptokinase has been given to many thousands of patients with acute
myocardial infarcts. In England, a survey ve years ago revealed that
58% of patients received intravenous thrombolytic treatment by
paramedics within 60 min of calling for professional help, and 83% of
eligible patients were given this treatment within 30 min of arriving at
hospital (Royal College of Physicians, 2006). In this context, neither
tPA nor streptokinase provoked more than 1% of intracerebral bleeds
(Rosamond et al., 1996).
Unfortunately there may be a higher incidence of bleeding than
this when tPA is given to people with (presumptive) ischaemic
strokes. If bleeding has already begun, thrombolysis will make it
worse. Thrombolytic drugs are not intentionally infused intravenously into anyone already known to be bleeding into the brain,
although they have been locally infused into established clots to
reduce their size. The best treatment of an acute ischaemic stroke
might appear to be the dissolution of the clot with intravenous tPA,
but although this drug has been directly infused into clots in the
202
main cerebral arteries, this is not usually a practical proposition.

Many studies have shown that already identied clots in main
arteries can be lysed successfully when their exact site is known (Hill
and Buchan, 2004; Wardlaw et al., 2004), but only a few acute
ischaemic stroke patients get this treatment. Clinical diagnosis of
stroke type is dicult and not very successful (Hawkins et al., 1995).
Scanning all stroke patients by computer tomography (CT) before
beginning treatment is cost-eective, but necessarily introduces
delay. A commonly accepted clinical guideline suggests that, once
bleeding has been excluded by imaging, intravenous thrombolysis is
worth giving within 3 h of a completed stroke. But if I am right that
intracerebral haemorrhage normally follows an ischaemic infarct
(for which an obstructing clot is only rarely responsible), clot
busting with IV tPA will only rarely do any good. Indeed it is likely
that when early intravenous thrombolysis appears to preserve
function after a cerebral infarcta fact that I do not disputeit
probably acts mainly at other dierent sites to prevent new clots
forming, when cerebral blood-ow is critically reduced.
In the treatment of an acute stroke in humans, immediate
thrombolysis is everywhere regarded as too dangerous to consider.
Bleeding must rst be excluded by brain imaging, but it may also
appear after giving intravenous rtPA, even when bleeding has not
been previously seen. A classic study by Brott et al. (1992) suggested
that bleeding may not often occur within the rst 90 min after a
stroke. But in 1995, the reporters of the European Cooperative
Stroke Study (of 620 patients) concluded that there were so many
haemorrhagic complications that intravenous thrombolysis with
recombinant tissue plasminogen activator could not be recommended for use in an unselected population with acute ischaemic
strokes. This gloomy verdict has since been slightly modied. In a
Cochrane review of 18 trials involving 5,727 patients, half of whom
were treated with rtPA, there was an overall small benet in
functional recovery, though there was also an increase in both early
and late deaths (van Wijngaarden et al., 2006). Getting stroke
patients quickly to imaging centres is dicult. On an event-totreatment time-scale extending to 6 h, the chance of a favourable
clinical outcome, at 3-months after a stroke, decreases as the eventto-treatment time lengthens (Kaste, 2005). A recent short review in
the British Medical Journals Uncertainties Page suggested that
patients under the age of 80 who reach strict licensing criteria, who
203
have no contraindications to rtPA and who can be treated within 3 h

should be given the drug. The available evidence suggests that signicant bleeding is unlikely to begin within the rst hour after a
cerebral infarct.
Is it ever possible to start IV thrombolysis within this time? Would
this prevent later bleeding? The available animal and clinical evidence suggests that giving IV tPA to an acute stroke patient within
60 min after the event gives a good chance of saving neural function
if the stroke is thromboembolic, and might not risk precipitating
intracerebral haemorrhage, even in patients already taking aspirin.
However, my views about early intravenous thrombolysis have
become less enthusiastic the longer I have thought back to our old
perfusion studies and to our failure to nd responsible clots in our
necropsy series of cerebral infarcts (Dickinson and Thomson, 1961).
Furthermore, a stroke may be due to a brain tumour or to subarachnoid or subdural bleeding. How serious would early thrombolysis be in such conditions? We do not know.
The clinical presentation of subarachnoid haemorrhage (SAH) is
usually dierent from that in other forms of stroke. It is curious that
anti-thrombolytic or anti-brinolytic drugs do not help patients with
SAH. A 2003 update of a Cochrane review of 9 trials involving 1,399
patients suggested that anti-brinolytic therapy for SAH had no
benecial eect on the risk of death, vegetative state or severe disability. Rebleeding was reduced, but ischaemic damage increased.
The comprehensive failure of anti-brinolysis even raises the possibility that thrombolysis itself might have little overall eect on SAH,
if the drug were to be given by mistake. We can only conclude that
the available world evidence on thrombolytic treatment is inconclusive and likely to remain so.
A recent large meta-analysis compiled by Lees et al. (2010) suggested that intravenous thrombolysis with tPA (alteplase) was benecial provided that it was given within 3 h of a stroke. Clot-busting
with alteplase may prevent new clots forming in parts of the brain
with an already poor blood-ow. However, alteplase undoubtedly
increases the risk of intracerebral haemorrhage. I know of no large
stroke units that are prepared to initiate intravenous thrombolysis
before intracerebral haemorrhage has been excluded by CT or MRI.
I have even argued that there may be a case for starting alteplase
therapy in acute stroke even before imaging (Dickinson, 2007), but
nobody is at present prepared to take the risk.
204
Once a stroke has occurred, can any drugs other than thrombolytics
lessen its ill-eects?
Many dierent drugs have been given to patients with acute strokes
in the hope of improving their recovery, but none seem to have
become part of the standard regime of acute management of strokes.
Since we know that general anaesthesia reduces cerebral blood-ow
and metabolism, general anaesthetics might theoretically (and in
practice) stabilise and improve the function of critically damaged
neurones, but I know of no formal trials of this procedure. Some
remediable measure would need to be applied during the administration of the anaesthetic. I am sure that innumerable patients with
strokes of all kinds have been administered oxygensometimes even
hyperbaric oxygenin the hope of lessening neuronal damage, but I
am not aware of any systematic attempts to assess this treatment.
A physician is often left with a feeling of helplessness when confronted by a patient who has just suered a large stroke. Much the
greater part of ischaemic damage is irreversible. I am interested that
allopurinol, a drug that inhibits the enzyme xanthine oxidase and
which is widely used to reduce gouty deposits of uric acid in joints
and elsewhere, may improve exercise tolerance in patients with
angina pectoris by increasing the local availabiliity of tissue oxygen
to heart muscle (Noman et al., 2010). The drug is cheap, orally active
and with only rare nasty allergic side-eests (Stevens-Johnson syndrome). It might be worth giving to a patient with an acute stroke,
but I am not aware of any clinical trials. Another interesting drug
that caught my eye was clusterin (apolipoprotein J), which on
intravenous administration lessens infarct size in ischaemic rat
myocardium (Van Dijk et al., 2010). If drugs of this kind can reduce
ischaemic necrosis in heart muscle, it would be interesting to nd
whether it had any comparable protective eect on brain neurones.
All the well-known dietary measures and the use of cholesterolreducing drugs like statins or brates (Jun et al., 2010) should limit
or even reduce arterial atheroma generally. This should in turn limit
or prevent basal blood pressure from rising and might also control
subsequent casual blood pressures. I look forward to long-term
studies becoming possible with the new techniques, such as resonance imaging of cervical arteries in life. These are currently mainly
research tools and are extremely expensive. Inevitably, interest is
growing in the possibility that stem cells might help to replace
205
damaged neurones but this line of possible treatment remains

experimental.
The potential inuence of our environment on atheromatous
disease is now one of the fastest-growing aspects of epidemiology.
An atheroma-inducing process might involve sodium intake, obesity,
lack of physical exercise, watching too much television, excessive
alcohol ingestion and psychosocial stresswhatever that isbut it
would be dicult to work out epidemiologically the relative contribution to hypertension of any of these factors. Most estimates
have been that two-thirds of hypertension is genetically and onethird environmentally determined. These proportions are comparable to those calculated by Cavalli-Sforza and Bodmer (1971) from
epidemiological data. It is very striking that, while blood pressure
rises steadily during childhood in all populations, more or less in
parallel with the rate of increase of height and weight, the later rise
during adult life is virtually conned to urban populations (Szklo,
1986).
Infectious and inammatory causes of atheroma

As far as I can discover, direct isolation of viruses from atheromatous plaques has not yet been accomplished. But some viruses
might be capable of setting the stage for a pathogenic process triggered by an environmental factor. Could hypercholesterolaemia be a
trigger for the development of atherosclerosis in the presence of
viruses? Is a reactivated and infectious virus the damaging agent that
initiates atherogenesis? There are many questions to be answered. It
is beyond my remit or knowledge to say more. But these observations do raise the interesting possibility that urban life could
predispose to atheroma and thus (in my view) to essential hypertension, by exposing people to one or more atheroma-provoking
virus infections. I nd this aetiological sequence more credible and
easier to examine than having to invoke psychological stress as an
important cause of atheroma and hence of hypertension.
Mattila et al. (1998) have extensively reviewed the role of infections in the development of atheroma. There are associations of
atheromatous disease prevalence with an increase in C-reactive
protein concentrations (Reynolds and Vance, 1987; Ridker et al.,
2003; Tsai et al., 2007; Pucci et al. 2008). Ridker et al. (2008) have
206
reported that if people with high C-reactive protein concentrations

are treated with a statin this may be enough to reduce the subsequent
incidence of major cardiovascular events. It is dicult to escape the
conclusion that inammatory conditions in general predispose to
atheroma. Therefore preventing them could reduce the incidence or
severity of cerebrovascular hypertension.
Many authors have suggested that specic virus infections might
predispose people to atheroma. In many cases, portions of a virus or
another infective agent has been identied as a constituent of
atheromatous plaques. These include common virus infections, e.g.
cytomegalovirus (Melnick et al., 1995; de Boer et al., 2006; Streblow
et al., 2008), hepatitis-C (Ishizaka et al., 2002), EpsteinBarr virus
(de Boer and others, 2006), and herpes simplex viruses (Raza-Ahmad
et al., 1995). Bacterial infections have also come under suspicion, e.g.
Helicobacter pylori (Kilic et al., 2006) and Chlamydophilia pneumoniae (Chui et al., 2006), Even human periodontitis has been linked
with atheroma causation (Mattila et al., 2005). There is also evidence
that immune reactions participate in the genesis and development of
atheroma (e.g. Niessner et al., 2007; Milioti et al., 2008; van der
Meer et al., 2008). If any of these common infectious or inammatory conditions can be prevented by vaccination (for example) this
might prevent acculturationthe process I mentioned in Chapter 2,
which seems to predispose people living in urban communities in
developed countries to an increased liability to develop essential
hypertension. Town-dwellers inevitably encounter many people with
infectious diseases. Because some of these seem to predispose to
atheroma, we have a potential link between atheroma and high
blood pressure.
Collateral arterial development

As I indicated in my rst chapter, for many years there was no
agreed animal model for the commonest kind of human hypertension. For more than fty years I have reviewed and marshalled the
evidence that essential hypertension, which is reaching almost epidemic proportions in most developed countries, may be due to
atheromatous stenosis of the four main cerebral arteries in the neck
and skull base. Many attempts have been made over more than a
century to capitalise on Harvey Cushings observations of the
207
neurogenic pressor eect of brainstem ischaemia in animals by

closing or narrowing the main cerebral arteries. Most of these
attempts failed because of the growth of new collateral arteries. By
contrast, most adult human beings seem to have lost the ability that
all children and young animals have to develop new collateral vessels
or to enlarge existing small channels, to neutralise the damaging
eects of increased large cerebral artery resistance brought about by
atheromatous plaques in the four main cerebral arteries.
Collateral arterial development is a fast-growing eld of interest.
A short review entitled Cardiovascular risk factors and collateral
artery formation by de Groot et al. (2009), listed the main factors
that are recognised to promote collateral arterial development. I can
envisage the possibility that collateral arterial development might
one day achieve as great a potential signicance as large artery
stents, in the treatment of cerebrovascular hypertension.
The clinical implications of recognising cerebrovascular

hypertension
Julian Paton and I suggest that when cerebrovascular hypertension is
diagnosed, and obvious secondary renal or endocrine causes of
hypertension have been ruled out, essential hypertensive patients
merit at least careful clinical and ultrasound examination of the
neck. In severely hypertensive patients, angiographic X-ray, MRI or
other more precise examinations of the four large cerebral arteries in
the neck and skull base might be worth while, in case one or two
severely stenotic lesions might be correctable. I hope that clinicians
contemplating a clinical trial will record any blood-pressure changes.
I should not expect any great hypotensive eect becaue each vertebral artery usually carries less than one-sixth of the total CBF.
Athough the proximal parts of the vertebral arteries are often narrowed by atheroma, such lesions are more often patchily distributed
along the arterial lengths. However, some opportunities will arise to
record blood-pressure changes when such lesions are surgically
corrected. This will usually be to correct minor strokes or transient
ischaemic attacks. More than a decade has passed since Piotin et al.
(2000) reported the successful stenting of the proximal vertebral
arteries in a series of patients suering from transient ischaemic
attacks or small strokes. Vertebral artery stenting has now become
208
almost a standard operative procedure in some centres, e.g. Hatano

et al. (2010), although some doubts remain (Gupta, 2010).
The advent of the spontaneous hypertensive rat (SHR)

Experiments in humans are dicult to arrange. The academic
community lacked a credible animal model for essential hypertension for many decades, until Aoki and Okamoto selectively inbred
WistarKyoto rats to develop hypertension, which might then be
described as spontaneous. The world has now accepted the SHR as
a good model for human essential hypertension. This interests me
because its neurogenic origin is not in dispute. I am also excited that
Julian Paton and his colleagues in Bristol have identied measurable
narrowing and increased resistance of the main cerebral arteries of
this animal. Paton has given an account of his work in Chapters 7
and 8, demonstrating that the cerebral blood-supply of SHR is
functionally equivalent to that of those people with essential
hypertension whose main cerebral arteries I had examined and
perfused many years before.
Summary
Hypertension is often regarded as a risk factor for stroke, but is
better looked upon as a marker for underlying stenotic atheromatous disease of the main cerebral arteries, unless there is evidence
of a recognised secondary cause for the hypertension.
Management usually involves considering the use of hypotensive
drugs, but caution is obviously needed because almost all strokes are
caused by an inadequate blood-supply to the damaged part of the
brain. Only a very few strokes are caused by an acute local clot
blocking an artery supplying the damaged area. Consequently,
although intravenous thrombolysis with drugs, such as alteplase,
may improve the eventual recovery of function if given in the
shortest possible time after the event, only a small proportion of
acute stroke patients get this treatment. In all developed countries of
the world patients with acute strokes are taken immediately to
imaging centres when these are available; but it is arguable how
useful is imaging of acute stroke patients with CT or MRIto
209
identify bleedingbecause intracerebral bleeding normally arises

from a previously infarcted region of brain. Imaging takes up valuable
potential recovery time. I have argued the case (so far unsuccessfully)
for a trial of immediate intravenous thrombolysis before imaging,
because my old necropsy/perfusion study showed that ischaemic
strokes are all potentially haemorrhagic. I suggest that those
managing acute stroke units should consider carefully the possibility
of a trial giving immediate intravenous thrombolytic treatment to
people with acute strokes, having excluded anyone with head trauma
or the sudden onset of a headache, which might suggest acute subarachnoid bleeding. Very few departments would participate, but
perhaps a cadre of well-informed patients might wish to do so. I
should be glad to join their ranks myself. Immediate thrombolysis
might not only dissolve the rare acutely occluding clot, but also
inhibit further thrombosis in other critically ischaemic areas far from
the site of immediate damage (Dickinson, 2007).
Stenting of one or more main cerebral arteries is at present only
commonly performed at the carotid bifurcation, to prevent clot
extension and embolism, rather than primarily to reduce cerebrovascular resistance, but stenting or reconstruction of the vertebral
arteries is already being carried out for patients whose vertebral
arteries can be sometimes as large as their internal carotids, and
which can be similarly narrowed by atheromatous plaques. I suggest
that surgical enlargement or stenting of the main arteries of such
patients might reduce systemic arterial pressure without the use of
drugs. This hope may be pious, but it is logical.
The future long-term management and prevention of cerebrovascular hypertension will doubtless take into account the potential
infective and inammatory nature of arterial atheroma when more is
known about its aetiology.
210
12
Epilogue: a Century of Research into
Essential Hypertension and Strokes
Why an epilogue? Is this book the end of essential hypertensionas
I hope? I have watched its excruciatingly slow demise over more than
fty years. My two monographs suggesting a credible neurogenic
cause for the disease were published in 1965 and 1991. They elicited
interest but no signicant support. Most hypertensiologists acted as
if high blood pressure was a unique primary attribute! Although my
evidence for underlying stenotic disease of the main human cerebral
arteries was not disputed, it was always deemed irrelevant because it
could be overcome by downstream dilatation of small arteries and
arterioles. Although total cerebral blood-ow could be raised to its
ceiling value by excitement or stress, this concealed the mammalian
brains enormous demands for blood and the precarious nature of its
blood supply, particularly under basal conditions.
My colleague Julian Patons comprehensive and meticulous
studies of an animal modelthe spontaneous hypertensive rat
have shown how closely this creature resembles the human adult
with essential hypertension. Its vertebral and basilar arteries are
grossly narrowed, even before its blood pressure has increased
(Chapter 8, Fig. 8.7). Julian has laid the experimental groundwork
for the thought revolution, which this subject demands.
After Seymour Kety and Carl Schmidt had devised a reliable
method of measuring total cerebral blood-ow in conscious human
beings, using nitrous oxide, a (relatively) inert gas, Kety and his
colleagues measured cerebral blood-ow in normal people, in people
with essential hypertension and in people with other hypertensive
conditions, such as pre-eclamptic toxaemia. Whenever it was
measured, total cerebral blood-ow was the same. It remained
normal even after systemic arterial presssure had been lowered
(slightly) by intravenous drugs. The apparent constancy and stability
211
of human cerebral blood-ow was the most cited and celebrated

observation in the long history of research into the cause of essential
hypertension. It is impossible to exaggerate the impact of Ketys
discovery. It was conrmed by many clinical scientists in many
countries. It seemed that there was no need for anyone to worry
about plaques of atheroma obstructing or narrowing the main
human cerebral arteries. The four large arteries to the brain would
look after all its needs for blood. Had not the famous surgeon Astley
Cooper shown, almost two centuries earlier, that his own house dog
was none the worse after he had successively ligated all its four main
cerebral arteries? The dog had simply grown new collateral vessels,
which anyone could see by inspecting the dissected animal in the
Museum of the Royal College of Surgeons in London.
In Chapter 3 I related how this huge edice of misunderstanding of
the human brains blood-supply has slowly crumbled in the last
twenty-ve years, as new atraumatic methods of measurement have
gradually revealed that total cerebral blood-ow is signicantly
reduced in essential hypertension, provided that subjects are not
unduly excited or stressed. I place a dening moment as 1984, in
which year Shaw and his colleagues showed (and many others have
conrmed since) that cerebral blood-ow in essential hypertension
diminishes as cerebral vascular resistance is increased. The academic
community of researchers into hypertension is slowly realising that
cerebral blood-ow is not the constant that everyone had believed.
Julian Paton and I hope that it will soon be accepted that a primary
increase of cerebrovascular resistance is a more plausible reason for
a uniquely human disease than some mysterious psychosocial
aberration. Our opinion is strengthened by the evidence that the
resistance of the main hindbrain arteries of SHRthe generallyaccepted rat model for essential hypertensionincreases before the
rats blood pressure has increased. This is a further blow to those
who maintain that increased cerebrovascular resistance is always the
consequence, rather than the cause of systemic arterial hypertension.
There can be no nal proof of any hypothesis. All that Julian and I
claim is that undue narrowing of the mammalian brains main
arteries can account for an elevation in basal blood pressure during
sleep. This can also lead to daytime hypertension, without transgressing any established physiological observations or principles.
Many more measurements of blood pressure and cerebral blood-ow
in sleep are obviously needed, to conrm or to reject our hypothesis
212
EPILOGUE
that the small so-called resistance arteries and arterioles are fully
relaxed and not in control of the cardiovascular system during sleep.
My personal work with Jim McCubbin in unanaesthetised dogs and
rabbits demonstrated the sensitivity and importance of the Cushing
mechanism of the mammalian brainstem (p 12). Julian Paton has
extended this work in the isolated hindbrain of rats. Neither of us is
aware of any observations that contradict our explanation for
essential hypertension. We see no reason why that common condition should not be renamed cerebrovascular hypertension, unless
someone publishes a better explanation.
Some puzzling questions

I end this book with questions, some of which still puzzle me. Why
did nobody try to repeat the careful necropsy measurements that
Drew Thomson and I made, fty years ago, of the increased vascular
resistance that the four main cerebral arteries in the human neck and
skull base must often have presented in life? What did we do wrong?
The rst problem was that almost all respected clinical investigatorsincluding Seymour Kety (p 13) and John Swales (p 79)
assumed that the increased vascular resistance of the brain was
largely made up by its small arteries and arterioles, as was the
increased vascular resistance of all other organs in people with
essential hypertension. Therefore, even if some of the four main
arteries of the brain were narrowed or occluded by atheroma or
organised blood clots, the brains small arteries and arterioles would
simply dilate appropriately. In due course new collateral blood
vessels would arise. Normal cerebral blood-ow would be restored.
This argument seemed devastating at the time, except for those
who had attended many human post-mortem examinations, but it is
fortunately no longer relevant. Total cerebral blood-ow is now
known not to be maintained in people with essential hypertension. It
diminishes with increasing age and is often less than normal, provided that subjects are at rest; but it can rise to a maximal ceiling
value during excitement or stress.
A second obvious problem was that there was already a longestablished view that essential hypertension arose from some congenital fault in the kidneys, as Arthur Guyton had persuasively
argued (p 49). Richard Johnson and his colleagues have also recently
213
and comprehensively reviewed the evidence that essential hypertension may have a renal cause (p 3), as many investigators continue to
believe today.
A third problem was that the methods used by Drew Thomson
and myself to measure large cerebral artery resistances in cadavers
were too crude. They required no sophisticated or expensive apparatus. The aetiology of essential hypertension had baed physiologists and clinical investigators for more than a century. It was absurd
for two young men to claim to have solved the problem using a na ve
pressure/perfusion technique applied to the main cerebral arteries of
ninety-four human cadavers. Drew Thomson and I had to devise a
way of measuring the eective ow-resistance of four large arteries in
parallel. The two vertebrals join to make the basilar artery, which
then joins with the two internal carotids at the Circle of Willis, from
which smaller arteries supply the brain. We envisaged that in the
course of human evolution, the small arteries and arterioles of the
brain would have been programmed to be fully relaxed during sleep,
to prevent energy and food being wasted by too high a systemic
arterial pressure at this time. We tried to simulate this imaginary but
plausible situation by rst dilating all dilatable arteries and arterioles. We cannulated each main artery separately, relaxed all postmortem spasm with ammoniated water, then measured the maximal
ow-rate we could obtain from the whole length of each main cerebral
artery, while perfusing each at a constant pressure of 140 mmHg at
the origin. All ends of the large cerebral arteries were left at atmospheric pressure during our perfusions.
I described our very simple though tedious technique in detail in
Chapter 4 because it had not been re-examined for more than fty
years. Drew Thomson and I did not see any serious logical faults in
our reasoning or technique at the time. Nor can I today, except the
obvious one that we only perfused the trunks of each of the main
cerebral arteries, while the distal pressure at the end of each artery
remained at an unrealistically low level (atmospheric). We were trying
to simulate basal conditions during sleep and conjectured that previously constricted small arteries would be fully replaced at this time.
A fourth problem arose from most peoples failure to appreciate
how enormous is the human brains need for blood. In children, in
adults and in our experimental animals, the four main arteries are
only just large enough to nourish the brain. If one or more of these
main arteries is occluded without causing an acute cerebral infarct,
214
EPILOGUE
normal cerebral blood-ow will be restored within a few days or

weeks by the growth of new collateral vessels (p 207). Although most
of us have been born with enough spare capacity to allow for temporary occlusions during neck movements or injuries, there is very
little spare capacity. This is revealed by observations on unilateral
internal carotid artery compressions during surgical operations
(p 38) and by the subnormal respiratory quotient of the brain in
essential hypertension (p 108). This indirectly reveals the problems
that the brain has been having with its blood supply. Individual
measurements suggest that there is a risk of a completed stroke if the
total cerebral artery resistance is more than twice normal, i.e. when
the total cerebral blood-ow is less than half normal. The evolution
of our species has not yet allowed for the devastating damage that
multiple atheromatous plaques can produce just by narrowing several large cerebral arteries, because most such lesions appear after
the reproductive years.
A fth problem we encountered was the intellectual diculty that
most people experience in assigning a vital role for Horace Smirks
basal blood-pressure regulation. The authors of this book place basal
blood-pressure determination at the centre of long-term blood
pressure stability. Remarkably few studies have been published of
cardiovascular controlling mechanisms during deep sleep, even
though the available evidence suggests that this is the time at which
the set-point of cardiovascular regulation is determined. Most
physiologistswe include ourselvesknow little of the sequence of
events that take place in the brainstem during the hours of sleep, but
we recognise that these mainly determine whether individuals will go
about during the next day with a low, normal or high blood pressure.
A nal problem was that many people look upon any interference
with the face, head or neck of a dead relative or loved one as
sacrilegious and disrespectful. When measuring the resistance of the
four main cerebral arteries, I had to take care to prevent watery
perfusion damage to the face and neck by obstructing the ophthalmic arteries, as I explained in Chapter 4.
I hope that a new generation of clinical scientists may be willing to
think again about the cause of essential hypertension and review
the evidence that Julian Paton and I have assembled in this book.
215
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254
Index
ACE (angiotensin converting enzyme),
inhibition 166, 168
adenosine triphosphate (ATP) metabolism
103
adrenal medulla innervation 117
aldosterone, primary excess 25, 161
synthesis inhibitor 197
allopurinol, ischaemia protection 205
ammonia, relaxing cadaver arteries 64, 75
amygdala 120
anaesthetics, general 56, 103
angiotensin-II 95, 119, 129, 130, 144, 150,
156, 163, 168
cerebral autoregulation breakthrough
95
converting enzyme (ACE) inhibitor 166,
168
hypoxia relation 136
inammation promotion 136
receptor blockade (ARB) 201
slow pressor eect 164
venoconstriction 95
arteries, see names
atheroma 10
epidemiology 35
bacterial infections 207
basilar 56
cerebral 184, 188, 189
contracture 61
epidemiology 35
femoral 74
ow resistance 10, 24, 38, 56, 70, 78, 80,
109, 177
genetics 189
inammation 148, 166, 206
internal carotid 177
occlusion 16
large, main 9, 11, 137
ligation 10, 38
lipid disorders 35
ophthalmic 78, 87
pressure/perfusion technique 11, 38
small (arterioles) 16, 69, 109.196
contracture 61
essential hypertension 11, 97
M/L ratio 57
spasm, post mortem 80, 98
subclavian 69
temporal 39
total peripheral resistance (TPR) 26
essential hypertension 16, 34.62
vertebral 33, 36, 39, 56, 73
blood ow 80
perfusions 177
pinhole origin 73
atheroma arterial 11, 33, 34
atrial baroreceptors 4, 5
natriuretic peptide 163
autoregulation of blood ow 94, 96
whole body 161
Baker, A B 34, 59
baroreceptors, arterial 8, 115, 119, 121,
122, 124, 130, 138, 139
ablation eects 8, 94, 96
denervation 35, 129
functional characteristics 138
resetting (dogs) 8
set point 125
venous 4, 5
Bayliss eect 26
blood, clots causing strokes 179, 182
blood ow, autoregulation 94
total (cardiac output) in essential
hypertension 14, 16, 34, 62
total cerebral (CBF) 94, 184, 188
measurement 41, 46, 48, 121
sleep 52, 111
total coronary 48
whole body autoregulation 94, 96, 161
255
INDEX
blood pressure,
age relation 137
anaesthesia, general 56
atrial 4
basal 5, 53, 68, 92, 157
cerebral ischaemic pressure response 3
diurnal changes 53
high, see hypertension
prognosis 92
slowly-developing pressor action of
angiotensin 164
sleep 53, 58, 111
blood vessels,
Bayliss eect (intraluminal pressure) 26
blood viscosity 84
brain, compression, hypertensive eect 3,
9
arteries, see names
foetal ketone usage 103
glucose metabolism 102
haemorrhage (intracerebral) 185, 188
Japanese 188, 189
heat production 48
hypotension, acute 179
infarction, 108, 179, 188, 189
intracerebral haemorrhage 185, 188
ischaemia, preconditioning 183
lactate metabolism 103
oxygen consumption 48
stem, central cardiovascular role 115
transient ischaemic attacks (TIAs) 170,
184, 189
uptake index (BUI ) for glucose 103
vascularity 58
white matter hyperintensities 196, 197
C1 area of medulla 119, 165
Campbell, Moran 100
cannulas, arterial pressure perfusions 72,
74, 76
carbon dioxide, brain 96, 102
cerebral, see brain
cerebrospinal uid pressure increase raises
blood pressure 6, 7, 44
chemoreceptors 120, 124, 126
Chinese, hyperlipidaemia and
hypertension 35
cholesterol, lipids 36
hypertension association 36
reducing drugs 205
Circle of Willis 39, 40, 42, 86
Cleveland Clinic 12
clots obstructing cerebral arteries 74

clots obstructing coronary arteries 182
computer-aided tomography (CT) 18
Conns syndrome (primary
hyperaldosteronism) 24 161
coronary artery blood ow 48
Crawford E S 12
Cruz-Coke 22, 23
Cushings mechanism 49, 109, 127, 143,
155
SHR and SHR-SP 109, 143, 151
CVLM (caudal ventrolateral medulla)
121
defence response 24, 129
DOCA (desoxycorticosterone acetate)
hypertension 160, 162
enkephalins (neurotransmitters) 117
eNOS (endothelial nitric oxide synthase)
147
Esler, Murray 21, 22, 170
exercise, nociceptor stimulation 130
fainting, aetiology 4, 5
Fallots tetralogy 88
Ferrario, Carlos 165
Fisher, Charles Miller 33, 34, 39, 188
foetus, brains use of ketones 103
Folkow, Bjorn 25, 27, 28, 162
GABA (gamma amino butyric acid) 121
receptors 129
RVLM (rostral ventrolateral medulla)
121
genetic factors in hypertension 23
girae, hypertension 155
glycine 119
glucose, metabolism 101, 104
brain 102, 103
glutaminergic neurones 121, 122
Goldblatt, Harry 17, 32
Grassi, Guido 21, 141
Guyton, Arthur 13, 49, 159, 251
Harrap, S B 151, 153
heart
failure 123, 163
respiratory quotient 108
output 48
pre-ganglionic motoneurones , 123
rate, essential hypertension 21, 138
256
INDEX
hypertension (systemic) 97
acculturation 24
American blacks 35
borderline 37
cerebral arterioles 56, 196
cerebrovascular 30, 69, 70, 80
epidemiology 24, 35, 54
essential, aetiology theories 158
experimental 24
genetics 189
glucose metabolism 102
haemorrhage (intracerebral) 185, 188
isolated nocturnal (INH) 52
Japanese 34, 188, 189
malignant 177, 178, 179
neurogenic 3, 130
prognosis 52, 92
renal 25, 56
aetiology 1, 25, 158, et seq, 190
sleep 52, 111
treatment 200
white-coat 22
Hutchinson, E C 13, 16
carotico-vertebral stenosis 16
hypotension, acute 179
hypothalamus 120
sodium excretion 158, 160, 162

sympathetic nerve supply 22, 128
activity raises blood pressure 170
denervation eects 160, 169
noradrenaline infusion raises blood
pressure 21
transplantation, blood pressure eects
171
Kolliker-Fuse nucleus 124
Korner, Paul 18, 23
Lambert, Gavin 110
Lassen, Niels 14, 45, 96
LCAT (lower cerebral autoregulatory
threshold) 96, 201
Lowe, Robert 87
McCubbin, Jim 12, 165, 213
Medical Research Council (British) 12
Medical Research Society (British) 177
medullipin 167, 168
metabolism, anaerobic 105
cerebral 105
Meyer, John Stirling 12, 69, 163, 186187
Middlesex Hospital 28, 100, 188
M/L (medial thickness//lumen diameter
ratio) arteriolar 57
MRI (magnetic resonance imaging) 182,
192, 196
Imai, Yutaka 53, 192

increased cerebrospinal uid pressure
eects 6, 50
intracranial pressure increase 6
pressor eect 6
ischaemic preconditioning 3, 183
cerebral 183
JAM-1 (junctional adhesion molecule)
149
Julius, Stevo 22, 25
juxta-glomerular apparatus 22
Kety, Seymour 13, 41, 44, 45, 49, 51, 67,
79, 98, 99, 101, 105, 112, 183, 211,
213
kidneys,
arterioles
medial hypertrophy in renal
hypertension 56
blood ow 17
after main artery narrowing 11,
32
ltration fraction 167
GFR (glomerular ltration rate) 167
NADH (nicotine adenine dehydrogenase)

145
natriuretic hormone, atrial 163
peptides 171
neseritide 171
nitric oxide 130, 145
noradrenaline, release from sympathetic
nerves 160
norepinephrine, see noradrenaline
NTS (nucleus of solitary tract) 58, 121,
122, 129, 131, 138, 141, 144, 145
nucleus ambiguus 123, 124
nuns, long term blood pressure constancy
23
Oxford Medical School 4
oxygen
consumption, essential hypertension
180
lack, eects 107,
angiotensin 136
257
INDEX
increased sympathetic nerve activity
143
vasoconstriction 95
oxytocin (neurotransmitter) 117
Page, Irvine 12, 163
Paton, Julian 90, 169, 115 to 156, 172, 182,
208, 209, 211, 212
Peart, Stan 22
PNMT (phenylethanolamine N-methyl
transferase) 117, 119
pneumonia, hypotension causing cerebral
infarction 179
pons 117, 118, 120
post mortem sarterial perfusion studies 9
potassium,
Conns syndrome 161
dietary, blood pressure 162
psychological factors, essential
hypertension aetiology 23
purine nucleotides (transmitters) 117
PVN (paraventricular hypothamic nuclei)
117, 150
Raab, EW 45
rabbit kidney, sodium excretion 159
rats, spontaneously hypertensive (SHR)
56, 97, 94, 138, 143, 160
stroke-prone (SHR-SP) 56, 63, 97, 183,
209
Wistar-Kyoto 56, 109
renin 26
essential hypertension 22, 167
experimental hypertension 167
release threshold 24
resistance, total peripheral (TPR) 26, 55
respiration, cardiovascular control links
120, 121, 132, 133
ventilatory eects on cerebral blood
ow 42
respiratory quotient, brain 102, 108
essential hypertension 105
Rizzoni, Damiano 57
RNA (ribose nucleic acid) 147
Rosenheim, Max 5
RVLM (rostral ventrolateral medulla)
117, 119, 120, 121, 144, 145, 154
pacemaker 120
serotonin (5-hydroxytryptamine) 117
Short, David 29, 30, 60, 61
SHR, see rats
sinus arrhythmia 120, 132, 142

sleep,
basal blood pressure 111
blood pressure regulation 68, 111, 183
cerebral blood ow 41
small cerebral arterioles and small
arteries 44
Smirk, Horace 5, 52, 92
sodium, arterial wall content 28
concentration in blood, related to renin
167
dietary 161
fast excretion in essential hypertension
162
solitary tract nucleus: nucleus tractus
solitarius (see NTS)
SPECT (single photon emission computer
tomography) 42
spinal cord, autonomic sympathetic
ischaemia eects 115
spontaneous hypertensive rat (SHR) 9,
97.143, 171, 183
Spyer, Michael 124, 125, 132, 190
Starling, Ernest 7
statins 199, 205
Strandgaard, S 97, 200, 201
strokes, see brain (cerebral), infarct (CI)
and intracerebral haemorrhage (ICH)
aetiology 178, 179, 184, 185, 189
genetics 189
subarachnoid haemorrhage 204
substance P (neurotransmitter) 117
Swales, John 16, 79, 213
sympathetic nervous system activity
(SNA) 116, 119
angiotensin eects 163
dietary chloride eects 162
essential hypertension 136
kidneys (renal) innervation 22, 69
post-ganglionic neurones 119
pre-ganglionic neurones 117, 118
renal hypertension 127, 158, 160, 161
respiratory coupling 121
spontaneously hypertensive rat (SHR)
153, 161
thirst, stimulated by angiotensin-II 166,
167
Thompson, Jon 159
Thomson, A D (Drew) 15, 16, 153, 166,
167, 177
thrombolysis, intravenous 181, 182, 202
258
INDEX
TIA (transient ischaemic [cerebral]
attacks) 197
tPA (tissue plasminogen activator) 202
TNMT (tyrosine n-methyl transferase)
117
TPR (total peripheral [arterial] resistance)
26, 138
Traube-Hering waves 134, 152
twin studies in hypertension 198
tyrosine hydroxylase (neurotransmitter)
117
University College Hospital 5
urban living 23, 24
vagus, dorsal nucleus 123
motoneurones 123, 132
VGLUT2 (vascular glutamate transporter

2) 117, 119
vasopressin (neurotransmitter) 117
viruses, atheroma relationship 207
viscosity, blood 84
Waki, H K 146, 148, 150, 154
warfarin, stroke protection/treatment 197
white matter hyperintensities (on MRI)
198
Willis, Circle of 40
Wistar-Kyoto rats 44, 56, 109
xenon (radioactive), cerebral blood ow
measurement 46, 105
Zanchetti, Alberto 169
259

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CEREBROVASCULAR HYPERTENSION

Book Guild Publishing

First published in Great Britain in 2012 by

Copyright # John Dickinson 2012

The Enigma of Essential Hypertension

A Personal Historical ReviewHarvey Cushings

The Evidence for a Neurogenic Increase of Heart Rate,

Can Essential Hypertension be Fully Explained by

Anatomy and Post-Mortem Measurements of Flow

Mechanisms of Blood-Pressure Control in Humans

Cerebral Oxidative Metabolism in Essential Hypertension 100

Neural Mechanisms for Blood-Pressure Control

Structures and Mechanisms Subserving Blood-Pressure

The Hypertensive Brainstem (by Julian F R Paton)

Secondary Causes of Hypertension and their Relation to

Stroke: the Commonest Cerebrovascular Disorder

The Cause of Strokes in Cerebrovascular Hypertension

Management and Treatment of Cerebrovascular

Epilogue: a Century of Research into Essential

But while working at the former Middlesex Hospital in London I

ow in resting subjects with essential hypertension is decreased

THE ENIGMA OF ESSENTIAL HYPERTENSION

sometimes earlier. Thereafter it becomes more common and more

A personal introduction to the neural control of the cardiovascular

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

transistors. But many years later I was able to make use of my

The challenging problem of human essential hypertension

THE ENIGMA OF ESSENTIAL HYPERTENSION

extensive literature search, mostly conducted in the dusty basement

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

of blood pressure which tends to nd a level slightly above that of the

THE ENIGMA OF ESSENTIAL HYPERTENSION

followed by Corneille Heymans (review by Heymans and Neil, 1958),

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

Jannetta et al. (1985) had devised an ingenious primate model of

Steps towards a new idea about the cause of essential hypertension

THE ENIGMA OF ESSENTIAL HYPERTENSION

medicine) and about 1980, post-mortem examinations were still

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

idea I needed a quantitative estimate of the least resistance that the

THE ENIGMA OF ESSENTIAL HYPERTENSION

A meeting with Arthur Guyton

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

(Popper, 1963), and that there is no such thing as a certain proof of

THE ENIGMA OF ESSENTIAL HYPERTENSION

control. Figure 1.1 is borrowed from Niels Lassens review. It

Almost everyone acts as if high blood pressure is the primary

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

Kety dismissed my observations with Drew Thomson because CVR

THE ENIGMA OF ESSENTIAL HYPERTENSION

the four main cerebral arteries of ninety-four cadavers, 376 large

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

THE ENIGMA OF ESSENTIAL HYPERTENSION

My second reason for suspecting that much of the increased CVR

Recent investigations into cardiovascular control by the rats

A PERSONAL HISTORICAL REVIEWHARVEY CUSHINGS EXPERIMENTS

THE ENIGMA OF ESSENTIAL HYPERTENSION

reset their sensitivity to any sustained level of blood pressure, high or

THE ENIGMA OF ESSENTIAL HYPERTENSION

cardiac blockade with atropine and propranolol (Julius et al., 1975).

THE EVIDENCE FOR A NEUROGENIC INCREASE OF HEART RATE. . .

Current explanations for increased sympathetic nervous activity in

THE ENIGMA OF ESSENTIAL HYPERTENSION

pressure elevation with age (128/79 went to 127/80 after 20 years).