Physiology 235: Lecture Timetable

Physiology 235
Lecture Timetable
Wednesday 10:00 am Simmonds Lecture Theatre

Thursday 9:00 am Simmonds Lecture Theatre
Friday 12:00 pm Simmonds Lecture Theatre
Kidney & Body Fluids (8 Lectures)

MARCH
Wednesday 1 Body fluid compartments, kidney structure Dr R. Morgan
Thursday 2 Glomerular function Dr R. Morgan
Friday 3 Tubular function I Dr R. Morgan
Wednesday 8 Tubular function II Dr R. Morgan
Thursday 9 Regulation of salt & water balance Dr R. Morgan
Friday 10 Hypertension Dr L. Beilin
Wednesday 15 Loop of Henle, collecting duct & ADH Dr R. Morgan
Thursday 16 Disorders of salt & water balance Dr R. Morgan
Friday 17 Acid-base balance Dr R. Morgan
Gastrointestinal Physiology (8 Lectures)

Wednesday 22 Co-ordinated gastrointestinal function Dr R. Morgan
Thursday 23 Gastric & pancreatic secretion Dr R. Morgan
Friday 24 Secretion of bile & hepatic function Dr R. Morgan
Wednesday 29 Digestion & absorption I Dr R. Morgan
Thursday 30 Digestion & absorption II Dr R. Morgan
Friday 31 Gastrointestinal motility Dr R. Morgan
APRIL
Wednesday 5 Gastric emptying Dr R. Morgan
Thursday 6 Malabsorption (malnutrition) Dr R. Morgan
Physiology of the Blood (6 Lectures)

Friday 7 Bone marrow function, haematopoiesis Ms D. Tomizzi
Wednesday 12 Erythrocytes & anaemia I Ms D. Tomizzi
Thursday 13 Erythrocytes & anaemia II Ms D. Tomizzi
EASTER VACATION - MID SEMESTER BREAK
Wednesday 26 Leukocytes Ms D. Tomizzi

Thursday 27 Platelets & haemostasis Ms D. Tomizzi
Friday 28 Blood groups & plasma proteins Ms D. Tomizzi
Physiology 235
Lecture Timetable
Pulmonary & Cardiovascular Physiology (8 Lectures)

MAY
Wednesday 3 PROSH
Thursday 4 Respiratory physiology - review Dr H. Mitchell
Friday 5 Causes of hypoxaemia Dr H. Mitchell
Wednesday 10 Lung pathophysiology Dr H. Mitchell
Thursday 11 Lung function tests Dr H. Mitchell
Friday 12 Normal & abnormal cardiac performance Dr R. Taylor
Wednesday 17 Electrical activity of the heart Dr R. Taylor
Thursday 18 Cardiac failure Dr R. Taylor
Endocrines (Excluding Reproduction) (8 Lectures)

Friday 19 General aspects of hormonal systems Dr T. Redgrave
Wednesday 24 Hypothalamic-hypophyseal system Dr T. Redgrave
Thursday 25 Glands controlled by adenohypophysis Dr T. Redgrave
Friday 26 Thyroid function Dr T. Redgrave
Wednesday 31 Sympathetico-adrenal system Dr T. Redgrave
JUNE
Thursday 1 Control of blood glucose Dr T. Redgrave
Friday 2 Endocrine control of mineral balance Dr T. Redgrave
(Endocrine lecture series continues in second semester)

Physiology 235
Lecture 1 - Body Fluid Compartments & Kidney Structure
Body Fluid Compartments

It has been calculated that water makes up 73.2% of the
Total Body Water
average person's lean body mass. Fat, however, contains only (TBW)
10% waster, so the more fat a person has in his or her body, 45 litres
the lower the percentage of water will be. 1/3 2/3
Extracellular Water Intracellular Water

(ECW) (ICW)
15 litres 30 litres
4/5 1/5
Interstitial Plasma
11-12 litres 3-4 litres
Note: Total blood volume is ~2x plasma volume
For a 75kg male, total body water is 60% of the total body mass, ie. 42L.
For a 60kg female, total body water is 50% of the total body mass, ie. 30L.
The above diagram outlines the distribution of total body water within a typical 75kg man of average build.
Measurement of Body Water

Calculation of volumes is achieved by a dilution technique, with the following substances:
Plasma Water - radio-iodinated serum albumin (RISA) or Evan's Blue Dye

ECW - inulin (polymer of fructose)
TBW - tritium oxide, tritriated water
ICW - calculated from TBW-ECW
Clinically, however, fat content is estimated (for example, by using callipers), can the fluid volumes are calculated
from this, using data tables.
Osmolality is most usually measured using freezing point depression.
The following table outlines the composition of the fluid compartments:
Plasma Water Interstitial Fluid Intracellular Fluid

(mmol/kg H2O) (mmol/kg H2O) (mmol/kg H2O)
Na+ 153.0 145.0 10.0
K+ 4.3 4.1 159.0
Ca2+ 2.7 2.4 ~0
Mg2+ 1.1 1.0 10.0
Total Cations 161.1 152.5 179.0
Cl- 112.0 117.0 3.0
HCO3- 25.8 27.1 7.0
Protein- 15.1 ~0 45.0
Other 8.2 8.4 124.0
Total Anions 161.1 152.5 179.0
Physiology 235
Structure & Functions of the Kidney

Each of the two kidneys weigh about 150g, combining to form 0.5% of the total body mass. 90% of the mass is
made up by nephrons, which are the basic functional unit, the remainder of which is blood vessels, nerves, etc.
There are approximately 1.5 million nephrons per kidney, each basically a modified tube, with the following
structure:
•1 Glomerulus - Glomeruli occur in the outer part of the kidney (cortex), and give a granular appearance to the
cortex in a transverse section.
•2 Proximal convoluted tubule - This is the site of most transport into and out of urine. Most sodium is
transported here, generally unregulated (atrial natriuretic factor may act here, under abnormal conditions).
•3 Loop of Henle - Short in 88% of nephrons: confined to cortex. Long in 12% of nephrons: termed
juxtamedullary. There is complex regional variation in transport and permeability, generating a 4-fold
concentration gradient across the kidney.
•4 Distal convoluted tubule - Like the proximal convoluted tubule, but less active. Sodium transport here is
regulated, by aldosterone.
•5 Collecting duct - This has a variable permeability to water, depending on the levels of antidiuretic hormone.
This is important in the generation of concentrated urine.
•6 Ureters - Conduits: no transport function.
The kidney has three distinct functions:
•1 Regulatory organ - especially maintaining body water and electrolyte homeostasis

•2 Excretory organ - waste products and toxins
•3 Hormone producer - eg. erythropoetin, vitamin D metabolites, renin.
Blood Supply
The glomerular tuft begins as a short, wide afferent arteriole, coming off a relatively large vessel, so the pressure
in this arteriole is high. The efferent arteriole is narrower.
The renal vessels are large, with a low resistance, so the renal blood flow is very high. The kidneys receive
~1200mL/min, which is 25% of the total cardiac output. There is increasing evidence that renal function can be
modulated by altering the distribution of flow to the cortex or medulla - atrial natriuretic factor may act partly in
this way.
A distinction is sometimes made between "total" renal blood/plasma flow and "effective" renal blood/plasma flow,
effective renal blood flow being only that going to glomeruli, about 90% of total flow. The usual method of
measuring renal flow, using PAH and assuming renal venous [PAH] is zero, gives effective renal plasma flow.
From the high blood flow to the kidneys, it may be deduced that these organs are metabolically very active, but the
blood supply greatly exceeds the metabolic need. The proximal convoluted tubule, the ascending limb of the loop
of Henle and the distal convoluted tubule, all sites of active sodium reabsorption, are the most metabolically active
segments, and are the segments first damaged by anoxia.
Physiology 235
There are three other important aspects of the blood flow to the kidney:
•1 afferent arterioles are richly supplied with sympathetic nerves

•2 efferent arterioles lead to capillaries around the tubule of the associated nephron
•3 the renal blood flow is strongly autoregulated, so changes in blood pressure don't greatly affect renal plasma
flow unless the blood pressure is very high or very low
Juxtaglomerular Apparatus
This is the site of renin and (indirectly) angiotensin and aldosterone production. These substances are important in
the control of blood pressure and Na+ levels. Atrial natriuretic peptide also probably has an important action
somewhere in this area.
The juxtaglomerular apparatus consists of afferent and efferent arterioles as they enter the glomerulus, with a
modified segment of distal convoluted tubule running between them (macula densa) and Goormaghtigh cells
binding all together. Renin granules are present in modified smooth muscle cells of the wall of the afferent
arteriole in the juxtaglomerular apparatus, as the afferent arteriole enters the glomerulus.
Physiology 235
Lecture 2 - Glomerular Function
Glomerular Filtration
Urine is formed in the glomerulus by ultrafiltration. This is the application of pressure on a solution on one side
of a semipermeable membrane. Water and small molecular weight substances are pushed across the membrane,
while larger molecular weight substances and proteins can't pass. The "cutoff" is the size at which substances are
held up. As water passes, concentration of protein and therefore colloidal osmotic pressure of the retained solution
rises. Eventually an equilibrium is reached, when the pressure driving the filtration equals the colloidal osmotic
pressure opposing it. There are four important points to remember about ultrafiltration:
•1 The concentration of small molecules (which pass freely across the membrane) is the same on both sides of the
membrane. In the kidney this means the concentration of small molecules in the glomerular filtrate is the
same as the plasma concentration.
•1 As the cutoff is approached, molecules pass less readily through the membrane, so their concentration in the
filtrate is lower than in the initial solution. Above the cutoff, molecules do not pass. In the kidney this means
the filtrate is essentially free of large proteins.
•1 The amount filtered depends on the driving force pushing fluid through the membrane and is opposed by the
rising colloidal osmotic pressure of the retained solution.
•1 The process is passive as far as the membrane is concerned, the energy coming from the pressure applied. In
the kidney this means from the blood pressure, ultimately from the heart and cardiovascular system. The
glomeruli are therefore relatively metabolically inactive, compared with the tubules, and the glomeruli are not
the tissues at risk initially when renal blood flow is markedly reduced in, for example, shock.
The filtration membrane consists of three layers, as basement

"feet" of podocytes
illustrated to the right. It is most probably the endothelial wall membrane
basement membrane which determines the
premeability of the whole membrane.
fenestrae
slit pores
200-1000A 35-40A 50-250A
The cutoff is approximately MW=60,000, but depends somewhat on the shape and charge of the molecule in
question (negatively charged particles may more easily pass through the negative membrane.
Forces Involved in Ultrafiltration

The driving force, tending to move fluid from the blood into the urine, is supplied by the blood pressure in the
capillary tuft (~45mmHg) plus the colloidal osmotic pressure of the fluid in the Bowman's capsule (~0mmHg).
Physiology 235
The opposing force, opposing movement of fluid into nett ultrafiltration pressure
hydrostatic pressure
urine, is supplied by the colloidal osmotic pressure of 50
in glomerular capillary
plasma, plus the pressure in the Bowman's capsule

(~10mmHg). As water and electrolytes filer off, the 40
colloidal osmotic pressure of plasma increases. The initial pressure 30

value is ~25mmHg, but by the end of the glomerular tuft, (mmHg) colloid osmotic pressure of plasma
20
it is ~35mmHg. Thus the nett force changes from its
initial value of ~10mmHg down to 0mmHg, and filtration 10
hydrostatic pressure in Bowman's capsule
ceases. 0
afferent efferent
arteriole arteriole
Measurement of Glomerular Filtration Rate

In order to measure the glomerular filtration rate, a substance must be chosen which is:
•1 freely filtered across the membrane

•2 neither absorbed nor secreted by the rest of the nephron
•3 non-toxic, easily measured, easily taken, etc.
If the substance is neither absorbed or excreted by the rest of the nephron, the amount excreted in the urine must
equal the amount filtered (although the concentration in the urine will be very different from the concentration in
the original filtrate, because 90-99% of the filtered water is reabsorbed by the nephron). If we know the
concentration of the substance in the inital filtrate we can easily calculate the volume of the initial filtrate, since:
amount filtered / minute = (concentration in filtrate) x (volume of filtrate / minute)
SO volume filtered / minute (GFR) = (amount filtered / minute) / (concentration in filtrate)
Since the substance is freely filtered across the membrane, the concentration in the filtrate is the same as the
plasma concentration.
SO GFR = (amount excreted / minute) / (plasma concentration)
A suitable substance for this purpose is inulin, but it is difficult to use clinically since it is not normally present
and has to be given intravenously, until a steady plasma concentration is reached.
The natural biochemical creatinine is almost as good as inulin. It is a natural product of protein breakdown in the
body, and is usually present in plasma at a steady concentration (~100 mML-1 ). A small amount of creatinine is
excreted in the proximal convoluted tubule, so values of GFR based on creatinine are about 10% too high, and
must be adjusted accordingly.
Physiology 235
Clearance
The final value of GFR is often called "clearance". This is because the value calculated is the volume of plasma
which has to be completely cleared of the substance in question to provide the amount excreted. This clearance can
be calculated for any substance in urine. If the substance is absorbed as it goes down the tubule, its clearance will
be less than the amount actually filtered, and the opposite can be said if the substance is excreted. Thus, if you
know the clearance of a substance you can say from the GFR value obtained whether it is absorbed or excreted in
the tubule.
There are only two clinically observed clearances: urea clearance and creatinine clearance. The urea clearance is
not of much value since it varies with urea flow rate. The creatinine clearance is of use, and is the most common
estimate of GFR. The concentration of creatinine in plasma does vary, however, as it is simply a product of protein
breakdown. This variance can be up to a factor of 2, so the final value of GFR is only an estimate.
The plasma creatinine concentration is also an important clinical value, as it allows the monitoring of patients with
renal damage. Since creatinine should be in steady state in the body, GFR x plasma concentration should be
constant. If GFR is reduced by a factor of 2, then the plasma concentration should increase two-fold, for example.
If this does not happen, renal failure has been detected.
There is one other form of clearance: free water clearance. It is really a measure of the ability to concentrate or
dilute urine. It is given by the number of millimoles of a substance (eg. glucose) per minute, divided by the plasma
osmolality.
EXAMPLE: A person excretes 900 millimoles of glucose per minute, in 1L of urine. Plasma has a normal glucose
osmolality of 300mOsm/L. Therefore normally it would be excreted in 3L of urine. The person is said to have a
free water clearance of -2L. If, however, he had excreted it in 4 litres of urine, he would have had a clearance of
+1L.
Filtration Fraction
The filtration fraction is a measure of the fraction of the plasma water which is filtered as it goes through the
kidney. It is therefore calculated by GFR/RPF, which gives a normal value of 125/625 or 0.2.
An increase in filtration fraction will lead to higher colloidal osmotic pressure of plasma perfusing that tubule and
more efficient reabsorption of fluid from that tubule. It may be altered by a change in perfusion pressure or
differential effects of drugs and hormones on afferent and efferent arterioles.
Physiology 235
Factors Affecting the Glomerular Filtration Rate
There are three groups of factors affecting the glomerular filtration rate:
•1 Haemodynamic factors
•1 The hydrostatic pressure which is pushing water through the glomerulus (arterial BP)
•2 The colloidal osmotic pressure opposing it (depends upon plasma protein concentration)
•3 Raised intracapsular pressure, for example due to a blockage in the ureter
•1 Changes in area for filtration

•1 Some drugs and hormones (especially those associated with pregnancy) may cause contraction or
relaxation of the mesangial cells, altering the area for filtration
•2 Pathological conditions may cause death of nephrons (eg. chronic nephritis)
•1 Changes in membrane permeability

•1 Most often due to nephrotic syndrome
Physiology 235
Lecture 3 - Tubular Function I
Typical Daily Absorption/Secretion

The following table outlines the most important substances excreted and absorbed in the glomeruli each day:
Substance Load Filtered/Day Load Excreted/Day Percentage Reabsorbed

(mM) (mM)
Na+ 25,000 100 >99%
Cl- 19,000 100 >99%
K+ 720 50 93%
HCO3- 4,300 2 >99%
Glucose 900 0 100%
Amino Acids 63 0 100%
Urea 1,000 400 60%
Water 180L 1.5L >99%
125mL of filtrate is produced every minute, and it is a function of the tubules to reabsorb almost all of this filtrate,
as well as adding other substances for excretion from the body. Most absorption occurs in the proximal convoluted
tubule (PCT). Some (especially sodium) occurs in the loop of Henle. The distal convoluted tubule reabsorbs
everything which is still present and requires reabsorption.
Methods of Absorption
Glomeruli absorb substances by two mechanisms:
•1 carrier-mediated transport in which there are carriers which transport the substances from the tubular lumen
into cells, and from there they diffuse out into the plasma
•1 a pump-leak system which transports sodium and calcium
If a substance is transported by a carrier, then there is a certain threshold level above which no more of the
substance can be carried, due to a limited amount of carriers. The threshold is reached gradually, and the excretion
curve is said to show "splay". This is caused by the fact that nephrons are not of uniform length.
Glucose is transported within the kidneys by two related active glucose carriers, both of which are sodium-coupled
(ie. they carry sodium as well as glucose). SGLT2, which is present in the first part of the proximal convoluted
tubule, is able to move large amounts of glucose, but due to a low affinity, leaves samples behind. The second
transporter (SGLT1) is found lower down in the PCT and has a lower capacity, but absorbs every little bit, having
a high affinity.
If glucose is not absorbed by the PCT it will be excreted. At various points along the nephron, the wall is freely
permeable to water. If large amounts of sugar are present, water will be sucked into the tubules to maintain
osmotic equilbrium. The result is an incrased volume of filtrate: a diuresis. Causes of glycosuria (glucose in urine)
are diabetes mellitus, pregnancy and an exaggerated splay.
Physiology 235
Lecture 3 - Tubular Function I
Other substances absorbed by carrier-mediated processes are amino acids and proteins. Amino acids also have
sodium-coupled carriers, and also show threshold. People sometimes have an absence of the carrier for certain
amino acids, so these amino acids are not reabsorbed in the kidney.
Not much protein appears in urine, but the concentration in the glomerular filtrate is 1/240th of that in plasma, so
about 30g of protein are lost per day. All of this is reabosorbed in the tubule, by a process with a limited capcity.
The mechanism of protein abosrption is pinocytosis into the tubular cells. Inside the cells it is digested into amino
acids, which are then returned to the body.
Physiology 235
Lecture 4 - Tubular Function II
The proximal convoluted tubule, loop of Henle and distal convoluted tubule differ in the way Na + gets into cells.
They are, however, all similar in that Na+ is pumped out using the same pump.
Proximal Convoluted Tubule (~65% of Na + Absorption)

The driving force for mechanisms of the PCT comes from the Na-K pump:
•1 Diffusion: the wall of the PCT has semipermeability to Na+. It is pumped out at the base or side of the cell.
Probably the most important mechanism for Na+ reabsorption is simple leaking.
•1 Na+/H+ antiport: Na+ moves in while H+ moves out. This is vitally important for body pH control, and
involves the presence of membrane proteins.
•1 Na+ coupled transport processes: Under conditions of high Na + concentration, glucose will bind strongly to
the carrier. The carrier then flips so it is exposed to the inner surface of the cell membrane. Both the
attached glucose and Na+ diffuse into the cell matrix.
•1 Absorption of Cl-: Cl- concentrations rise as result of other mechanisms, until they are sufficient to cause Na +
absorption as well.
When Na+ is pumped out into the interstitial space, water and other ions diffuse there also. The cells of the PCT
are permeable to water, however a concentration gradient still builds up. This water has to be taken up by nearby
capillaries, facilitated by their colloid osmotic pressure.
Blood that is perfusing around the tubule in these capillaries is from the glomerulus. Glomerulo-tubular balance
determines how much water is reabsorbed by the capillaries. If the amount of filtration in the glomerulus is high,
then the protein concentration in the plasma will be high. This will increase the colloid osmotic pressure and hence
the amount of reabsorption by the capillaries.
Loop Of Henle (~25% of Na + Absorption)

The descending limb of the loop of Henle is permeable to both Na +, Cl- and water, so no active transport is
required. As the ascending limb is approached, the water permeability disappears, but both passive movement and
active transport of Na+ and Cl- still occurs.
The movement of Na+, K+ and Cl- are coupled by a cotransport mechanism in the luminal membrane:
•1 Na+ is actively extruded across the basolateral membrane by the ATPase pump
•2 Cl- leaves the cell by chloride channels or by cotransport with K+.
•3 K+ can also exit from the cell across the luminal membrane by conductive channels.
•4 The K+ permeability of the luminal membrane gives rise to the positive luminal voltage in this region of the
nephron.
Physiology 235
Lecture 4 - Tubular Function II
Distal Convoluted Tubule (~10% of Na + Absorption)

Sodium reabsorption in the DCT is due to increased permeability of the tubular luminal membrane to Na +. This
absorption is controlled, via the hormone aldosterone. This hormone acts in three ways:
•1 it increases the permeability of the membrane to Na+

•2 it increases the energy for the Na+ pump at the base of the cell
•3 it increases the number of active pumps
Proximal Convoluted Tubule Distal Convoluted Tubule

Highly permeable to water Impermeable to water
Highly permeable to ions: no significant gradient Impermeable to ions: large gradient
Very large load can be transferred Limited transfer capacity
+ +
Na absorption is "obligatory": uncontrolled Na absorption is "facultative": by aldosterone
K+ absorbed K+ secreted (controlled by aldosterone)
Potassium Control
The importance of K+ lies in the fact that it ultimately controls the membrane potential. This is caused by the ratio
of the external and internal concentrations and the Nernst equation.
Diueritcs are drugs/treatments that produce an increased urine flow. Osmotic diuretics do this by increasing the
osmotic load and can result in a copious diuresis, but the result is essentially a pure water loss.
Potassium-Losing Diuretics
A few diuretics affect sodium reabsoprtion in the PCT, but most inhibit the reabsorption in the ascending limb of
the loop of Henle. The diuretics produce sodium and water loss from the body, but they also cause potassium loss,
and are therefore "potassium-losing" diuretics.
They act by inhibiting sodium reabsorption in the early nephron, increasing the sodium load to the distal nephron.
As a result, under the action of aldosterone in the distal nephron, more sodium is reabsorbed, and since sodium
absorption in the distal nephron is associated with potassium loss, more potassium is lost.
Potassium-Sparing Diuretics
A few diuretics act on the distal nephron and directly affect aldosterone-stimulated sodium reabsorption, leading to
increased sodium and water loss. By inhibiting sodium reabsorptioin in the distal nephron they also inhibit
potassium loss, and are therefore "potassium-sparing" diuretics.
Physiology 235
Lecture 5 - Regulation of Salt & Water Balance
Renal Plasma Flow

If the kidney is completely cleared of a substance, then the amount excreted/time is the amount carried to the
kidney. Thus:
Amt carried = blood flow x conc. AND Amt excreted/plasma conc. = blood flow
This applies to blood going to the nephron, which is completely cleared of of para-amino hippuric acid (PAH).
Not all the blood going to kidney goes to nephron - about 10% goes to the capsule. Thus measure of renal plasma
flow using PAH gives only about 90% of total RPF. This is called the effective renal plasma flow - multiply by
10/9 to gain total RPF.
625-650 mL/min is about the average value for RPF. This is about 1/4 of total cardiac output (CO).
Diffusion Trapping: Drugs can be administered to change the pH of urine to trap a drug being used. This is a
useful pharmaceutical tool.
Sodium Balance
The body has a very effective mechanism for maintaining plasma osmolality at its normal value of 200-250
mOsmL-1. If this is maintained, then any major change in salt levels in the body will result in a change in fluid
volume in the body. This is regulated by anti-diuretic hormone (ADH). This is also the reason for the following
statement:
“Sodium is the osmotic skeleton of the EC water”
It is important to regulate sodium levels as it prevents hypotension, shock, hypertension & heart failure. Many
hormones in the body help to regulate sodium levels, and thus many backup systems are available if one substance
fails. This is because of the great importance of sodium regulation.
Sodium levels are regulated by the following:
•1 Aldosterone Mechanism
•2 Haemodynamic Factors
•3 "Third Factor"
Aldosterone Mechanism
Aldosterone is a steroid hormone. It is not soluble in water, so it travels bound to albumin. It passes through
membranes and then separates from the albumin. Inside cells, it binds to intracellular receptors. Once bound, it is
translocated to the nucleus, where it binds to steroid response elements in the DNA and causes new proteins to be
formed. This mechanism takes hours to occur.
Physiology 235
Aldosterone comes from the outer part of the adrenal - the zona glomerulosa. Production is supported by the
activity of ACTH (adrenocorticotrophic hormone), produced by the pituitary, as this allows growth and function of
the adrenal (not direct stimulation of aldosterone production).
The main mechanism for aldosterone release is the renin/angiotensin system. But what controls the release of renin
from kidney? There are a number of mechanisms:
•1 decreased stretch of afferent arterioles (fall in blood pressure)

•2 sympathetic nerve activity (during fall in blood pressure or very severe exercise)
•3 reduced Na+ concentration (registered by the macula densa)
Some feedback occurs: angiotensin II production tends to inhibit renin release. ANF is also a potential inhibitor of
renin release.
Other things that stimulate aldosterone release include ACTH (limited effect) and potassium levels. A rise in
plasma potassium tends to increase aldosterone secretion directly. This increase leads to an increased sodium
reabsorption and potassium loss. This is therefore a feedback system for potassium/sodium control (particularly
potassium).
Angiotensin II also has other effects apart from aldosterone release:
•1 direct vasoconstriction
•2 vasoconstriction via the CNS and sympathetics
•3 thirst
Aldosterone has three major effects directly on the kidney:
•1 more enzymes and more energy from the pumps at the base of the cells
•2 increases the permeability of the tubular lumen of the DCT to sodium
•3 produces more pumps at the base of the cell
Aldosterone is a SLOW control.
Haemodynamic Factors
A fall in blood pressure or a change in posture or exercise, or dehydration, affect renal blood flow, causing
vasoconstriction of the afferent arterioles, and affect the colloidal osmotic presure of plasma, through reducing the
glomerular filtration. Both vasoconstriction and increased osmotic pressure in turn cause reduced GFR. This
causes the filtered load of sodium in the nephron to decrease, and effectively lowers sodium loss from the body.
The macula densa picks up this lowering of sodium filtration, initiating the slow aldosterone mechanism. This
system, however, works fast and ceases abruptly.
Physiology 235
“Third Factor”
The atrium contains cells with odd granules: these are called Atrial Natriuretic Factors (ANF). They are a family
of (at least 3) related hormones. There are several receptor types on many tissues throughout the body. With a rise
in extracellular volume, the atrium expands and the tension in the atrial wall increases. This causes the release of
the ANF. The actions of these hormones are many, but they include:
•1 stimulation of Na+ loss from the kidney (produces natriuresis & diuresis)
•2 inhibition of ADH release (augments diuresis)
•3 inhibition of aldosterone release
•4 inhibition of renin release
The glomerulus is one site which has abundant receptors for ANF, so perhaps the major effect of ANF is on
glomerular filtration rate. If affects blood flow, osmolality gradient in the kidney and reabsorption in the
collecting duct. Just how it produces the stimulation of Na loss is not known.
Addison's Disease
This is a lack of aldosterone, and is analagous to diabetes insipidus. Sufferers are very susceptible to infection, and
to starvation. Other factors of the disease are:
•1 constant Na+ loss, leading to hypotension and shock

•2 a salt hunger, requiring constant high input of salt
•3 K+ retention, leading to weakness
•4 generally precarious existence without replacement steroids
Physiology 235
Lecture 6 - Hypertension
Blood Pressure
Blood pressure is extremely variable in healthy invidivuals. This can be demonstated by monitoring arterial
pressure continuously over a 24-hour period. Pressures tend to be lower during sleep and higher during coitus and
other energetic activities. The mechanisms which damp down the changes of blood pressure levels are important.
There is an almost direct relationship between level of exercise and blood pressure. A more interesting relationship
to note is that between blood pressure and age:
•1 there is a progressive rise in blood pressure with age

•2 the systolic pressure has a steeper rise than the diastolic
•3 females have a steeper rise than males
There is also a relationship between blood pressure and life expectancy, as shown by this table:
Blood Pressure Life Expectancy

120/80 76.5
130/95 72.5
140/95 67.5
150/100 60
This is probably because people with higher blood pressures are far more prone to suffer heart attacks and other
circulatory problems.
"Essential hypertension" is due to heredity or the environment (obesity, NaCl sensitivity, alcohol, diet, low
potassium and stress).
"Secondary hypertension" is due to a physical cause.
The Circulatory System

The circulation, described in its simplest form, is as follows:
•1 heart (pump)
•2 conduit vessels
•3 resistance vessels
•4 capillaries
•5 venous pool
The arterial pressure in the system is going to be determined by both the output of the pump and the resistance of
the precapillary arterioles. Anything that narrows these vessels or increases the output of the heart will raise arterial
blood pressure. The cardiac output is determined mainly by the input of blood to the heart (more blood causes
greater contraction), but it is also mediated by vagal influences. Arterial pressure is related to the fourth power of
the radius of the vessels.
Physiology 235
Arterial pressure is normally measured in the large arteries. The biggest drop in pressure occurs in the precapillary
resistance vessels. The large conduit vessels are quite leastic. Every time the heart contracts, the aorta expands like
a balloon. This damps down any pressure changes. If it were a rigid tube, there would be a very sharp rise and fall
in pressure for every beat of the heart. As you get older, the aorta does become more rigid and fibrous, due to death
of elastic tissue, so the rises and falls become more defined. This contributes to an overall rise in pressure.
Short-Term Blood Pressure Regulation

The most important influences on blood pressure in terms of minute to minute regulation are those emanating from
the autonomic nervous system:
•1 baroreceptors
•2 sympathetic nerves
•3 parasympathetic (vagal) nerves
The baro-reflex system is driven by afferent nerves which sense the pressure in the blood vessels. A rise in arterial
pressure will cause increased discharge to the brain, which will switch off the sympathetic nervous system and
activate the vagal system. This will counter the rise in blood pressure. This baro-reflex mechanism can take effect
so quickly that it affects heart rate on every
beat.
Sympathetic nerves have a preganglionic and postganglionic component with relation to blood vessels. An
increase in sympathetic nerve activity will cause more vasoconstriction and a greater cardiac output, both rising the
blood pressure. Countering this are the vagal nerves, which will release acetylcholine in the heart and cause
slowing of the heart rate and a decrease in cardiac output.
This is then further moderated by the central nervous system's control of endocrine function through adrenal
corticotrophic hormone - ACTH, which affects cardiac contractility and tone. Noradrenalin (vasoconstrictor) is
also excreted from the adrenal medulla. Under situations of heightened emotion the blood pressure will rise due to
all of these factors.
If acute stress can raise blood pressure so much, can chronic stress cause hypertension? This question is still
unresolved, though most evidence is against the idea. Situations where this has actually been shown are following
violence, in noisy environments, or associated with sound depravation, isolation and overcrowding. Stress can only
act in man through indirect means (ie. changing alcohol consumption, etc.).
Physiology 235
Long-Term Blood Pressure Regulation

Long-term blood pressure regulation is effected by the kidney’s control of water volume (by the
renin/angiotensin/aldosterone system) and the vasodepresser systems.
Kidney disorders are often associated with high blood pressure and hypertension. If one kidney is removed for any
reason, a rise in blood pressure is more likely if the patient is exposed to any stimulus, demonstrating the
regulatory effect of the kidney. This situation is worsened by the fact that hypertension interferes with the blood
pressure regulation function of the kidney itself. Thus hypertension damages the kidney, lessening its effectiveness
in overcoming the hypertension.
Conditions of the kidney which may cause problems include:
•1 renal arterial stenosis, due to fibrous plaques in the lining of the vessel
•2 renin-producing tumours in the kidney
•3 polycystic kidneys, an inherited disorder
Renin is one of the critical hormones produced by the kidney, in the afferent arteriole. Renin is synthesised in
granules, and this synthesis is regulated by sodium levels and blood pressure.
Renin from the juxtaglomerular apparatus, acts on a substrate from the liver, splitting off angiotensin I, which is
further converted in the circulation (particularly in the lungs) to angiotensin II. This has a range of effects, all of
which tend to increase the blood pressure:
•1 it has an immediate vasoconstrictor effect

•2 it stimulates aldosterone secretion from the adrenal cortex
•3 it directly affects the kidney, increasing water and salt retention
•4 it augments sympathetic outflow
Malignant hypertension is a condition where renin secretion is not regulated by salt and water balance. This can be
due to extreme stenosis of renal arteries, or even breakdown of the arterial wall. This will cause death within a
year.
There is a lot of evidence linking salt intake and sodium balance to high blood pressure. Humans show marked
variations in their genetic sensitivity to sodium intake (the genes responsible for this are, as of yet, unknown). The
most extreme example of the effect of sodium is in someone who has a bilateral absence of kidneys.
Tumours in the adrenal gland can often cause excess sodium retention by producing too much aldosterone, and
not being regulated by renin. There is evidence to suggest that this is responsible for ~5% of hypertension cases.
The increased aldosterone production causes salt and water retention, depressing renin and angiotensin production
(which will not cause the normal decrease in aldosterone secretion). Hence the sodium retention will continue.
Physiology 235
Myogenic Tone
The third major area of regulation is the blood vessels themselves and their responses to angiotensin, noradrenalin,
and the newly discovered local factors within the wall of blood vessels allowing them to control their own tone.
The resistance arterioles are responsible, to a certain extent, for myogenic tone. If more blood flows through the
vessels, they contract to regulate flow. It is now know that the endothelium is a powerhouse of substances that
effect vascular tone. There is a biochemical pathway by which larginine is converted by nitric oxide synthetase
into nitric oxide (NO). This conversion allows NO to diffuse into the smooth muscle where it results in increased
cyclic GMP formation, causing the muscle to relax. NO can therefore be classified as an endothelial dependent
relaxing factor (EDRF). Another important action of nitric oxide is to stop platelets sticking to blood vessel walls.
Blood pressure is just the phenotypic expression of the effect of a number of environmental factors on a whole
range of physiological control mechanisms. The central nervous system, endocrines, renal system and local
vascular factors are all integrated together. It is the outcome of these interactions which determines the blood
pressure. In clinical terms it is more complicated, because genotype also to some extent determines our behaviour,
and thus genetics itself plays a role.
Physiology 235
Lecture 7 - Loop of Henle, Collecting Duct & ADH
Loop of Henle
88% of nephrones are in outer part of cortex of kidney and only have a short loop of Henle.. about 12% are
juxtamedullary - close to the medulla, with a long loop of Henle which dips down to the apex of the papillae of
kidney.
The loop of Henle is relatively passive in the thin section, but has interesting per changes to electrolytes and urea.
This leads to an effective mechanism known as countercurrent which enables concentration of urine:
•1 The descending limb of the loop of Henle is relatively impermeable to Na +, Cl- and urea but freely permeable
to water.
•2 The ascending limb of the loop of Henle is freely permeable to Na + and Cl`, moderately permeable to urea and
impermeable to water.
•3 The distal convoluted tubule is impermeable to water and urea whether or not ADH is present.
•4 The collecting duct is impermeable to water in the absence of ADH but permeable to water in the presence of
ADH.
•5 The upper part of the collecting duct is impermeable to urea and the lower part is relatively permeable to urea.
This dirrerential urea permability is affected by ADH
The thick ascending limb has a very powerful NaCl / K pump. If it results in Na + being pumped out of the
ascending limb, the concentration of electrolytes in the interstitial fluid will rise. Therefore, as urine comes down
the thin limb which is permeable to water, but impermeable to ions, it will lose water and become a little more
concentrated. This is the basic action of the countercurrent multiplier. As more urine passes down the thin
descending limb of loop of Henle, it becomes more and more concentrated. The pump in the thick ascending limb
is therefore the powerhouse for gradient formation across the kidney.
By the action of this variable permeability and the movement of urea, the concentration of electrolytes at the
bottom of loop is about 1200 mOsm/L (made up of ~600 from NaCl and ~600 from urea), compared to plasma
osmolality of about 300 mOsm/L.
In the distal convoluted tubule and the first part of the collecting duct, aldosterone is acting to promote Na+
reabsorption. By the time urine enters the duct, although the interstitial space has an osmolality of 300 mOsm/L,
the urine is only about 100mOsm/L, since NaCl has been removed.
Collecting Duct
The collecting duct runs through the large concentration gradient, from the cortex (300) to the tip of the papilla
(1200). If the collecting duct is permeable to water, water will move out and the urine concentration will also be
1200 mOsm/L by the end of the duct. If it is not permeable to water, then the urine will be at 100 mOsm/L (as
discussed above), as no movement of water will occur.Thus the concentration of urine is governed by the water
permeability of the collecting duct.
Physiology 235
Concentration Gradient
The inulin concentration in urine is a good indication of its osmolality. In the PCT, it will be about 3x as high as
plasma inulin, because about 2/3 of the water is reabsorbed in the PCT. Due to further movement of water
throughout the loop of Henle, it will rise to about 7x in the ascending limb, before it enters the collecting duct. At
this stage, the urine represents 1/7th of the GFR.
If the collecting duct was impermeable to water, then the volume of urine excreted would be 28L/day. This
happens in diabetes insipidus. But if the tubule is permeable, then the inulin concentration increases to 180x
plasma inulin, indicating excretion of 1L/day.
If there is a high rate of flow through the tubules due to diuresis, then the interstitial gradient tends to be washed
out, depressing the kidney's ability to concentrate urine. High blood flow through the vasa recta has a similar
effect: one of the effects of ANF is the increase blood flow to wash out the concentration gradient. Another factor
affecting urine concentrating ability is the amount of urea in the urine.
The minimum urine volume compatible with continued health is 500 mL/day. Without this level, possible
problems include uraemia and renal failure. Any damage to the loop of Henle leads to breakdown of the gradient.
If the DCT is damaged, then the ability to transport Na + will be affected and hence the ability to dilute the urine
will be reduced.
If loss of fluid as a result of vomiting or sweating, etc. occurs, then unless concentrated urine can be produced,
severe problems will ensue, as body fluid osmolality must be maintained. The major control of water loss is
through controlling the permeability of the DCT. This is controlled by ADH - antidiuretic hormone.
Antidiuretic Hormone (ADH)

ADH is a peptide hormone: it is water soluble, and cannot enter the cell. It therefore produces its effect by the
action of second messengers. Their major effect is enzyme regulation (as opposed to RNA production
regulation). The action of ADH is very fast, as is the destruction of unused quantities.
ADH is released from the pituitary - a little knob of tissue connected by a stalk to the hypothalamus. It is
synthesised in nuclei in the hypothalamus and transported down neurones to the synapse in the pituitary where it is
stored. When osmoreceptors in the hypothalamus are stimulated, they cause release of ADH into the bloodstream.
NOTE: Another name for ADH is Argenine Vasopressin. This is due to its vasoactive nature.
Physiology 235
The following diagram outlines the mechanisms causing release of ADH:
Emotional Stress Pain
+ +
Peripheral Chemoreceptors Stress
 pO 2  CO 2
+ CNS +
 pH
 Central Venous  Carotid Artery

Pressure Pressure
 H2O  NaCl Ethanol
Uptake - -
- +
Left Atrium Carotid & Aortic
Hypothalamus + Volume Receptors Baroreceptors
 ECF Osmolality
(Pituitary)
+ - -
Diencephalon
Central Osmoreceptors ADH
Collecting Duct
If both the osmoreceptors and baro receptors are stimulated, which one "wins"? It depends upon the strength of the
signal. One important feature of the osmoreceptors, however, is that if the blood volume is reduced, the
osmoreceptors effectively become more sensitive.
The effect of consumption of saline is variable from person to person: it generally depends upon the level of
hydration of the person before ingestion.
Physiology 235
Lecture 8 - Disorders of Salt & Water Balance
Normal Fluid Balance

The following table outlines fluid balance in a normal person:
Intake (mL/day) Output (mL/day)

Drink 1,200 Skin 500
Diet 1,100 Lungs 500
Metabolic 300 Urine 1,500
Faeces 100
(Sweat) 0
TOTAL 2,600 TOTAL 2,600
The following graph illustrates the effect of plasma volume on ADH regulation:
decreased 15%
10
plasma volume
8
increased 15%
plasma ADH 6
(pg/mL)
4
0
260 270 280 290 300
Disorders of Fluid Balance

Disorders of fluid balance can be divided into three categories:
•1 volume without composition (cardiovascular symptoms)

•2 osmolality without composition (CNS symptoms)
•3 composition
Physiology 235
Changes in ECW (Plasma) Volume

•1 Rise in ECW volume
•1 hypertension
•2 oedema
•3 heart failure (if heart damaged)
•4 a normal heart can handle such a rise
•1 Fall in ECW volume

•1 low blood pressure
•2 shock
•3 fainting
•4 a normal heart can't handle this, but compensatory mechanisms will minimise the effects
Changes In ECW (Plasma) Osmolality

•1 Rapid fall in ECW osmolality
•1 rapid rise in ICW volume
•2 raised intracranial pressure
•3 “intoxication”
•4 vomiting
•5 headache
•6 coma
•7 death (respiratory failure: brain gets pushed downwards, cutting off medullary blood sample)
•1 Rapid rise in ECW osmolality

•1 rapid fall in ICW volume
•2 hallucinations
•3 psychosis
•4 madness
Problems occur with acute changes. With chronic changes, the brain simply adapts.
Loss or Excess of Salt or Water

Pure Water Loss
•1 Symptoms
•1 disorientation, delirium, coma and sweating
•2 Causes
•1 infant on a hot day
•2 elderly, confused on a hot day
•3 feverish, disorientation
•4 diabetes insipidus (lack of ADH)
Physiology 235
Pure Water Excess

•1 Symptoms
•1 "water intoxication", confusion, medullary "coning", death
•2 Causes
•1 self induced
•2 renal failure with continued uncontrolled intake
Pure Salt Loss

•1 Symptoms
•1 shock, great thirst, sweating, cramps
•2 Causes
•1 sweating and replacing with water alone
•2 Addison's disease (lack of aldosterone)
Pure Salt Excess

•1 Symptoms
•1 hypertension, oedema, heart failure, weakness
•2 Causes
•1 "mariposa" (drinking seawater)
•2 salt tablet ingestion - accident or suicide
•3 Conn's syndrome (hyperaldosteronism)
Physiology 235
Lecture 9 - Acid-Base Balance
Weak Acids & Bases

Acids are proton (H+) donors, and bases are proton acceptors. Thus acids undergo the following dissociation
reactions in aqueous solution:
HA « A- + H+
For strong acids, the dissociation is almost complete, so at reasonable concentrations, this dissociation leads to a
high [H+]. For weak acids, the dissociation is incomplete, and an equilibrium is reached with a dissociation
constant k, where:
[A - ][H + ]
k =
[H A]
k is a measure of the tendency of the acid to dissociate and is thus a measure of the strength of the acid. For a
strong acid, [HA] is low and the product [A -][H+] is large, so k is large, whereas the opposite occurs for a weak
acid, due to its low tendency to dissociate.
Buffers
Buffers are solutions of weak acids or weak bases. In these solutions, HA « A- + H+. If H+ is added, the reaction
is driven to the left, so some of the H + disappears by being bound to A -. Similarly if H+ is removed the reaction is
driven to the right and the loss of H + is partly compensated for by dissociation of HA. Consequently, changes in H +
are minimised. Notice that as the system buffers, A - or HA is used up, so buffering capacity depends on the
concentration of the buffer system. Also, optimal buffering (in both directions) will occur when [HA] and [A -] are
equal, ie. the buffer is half ionised. At this point, pH = pK a.
When a mixture of buffers is present, they will all indiviaully tend to reduce the effect of added acid or base.
Nevertheless, the "k value" still applies for each buffer system, and from the measured pH it is possible to
calculate the relative abundance of HA and A -. A corollary of this is that if you manipulate the amount of HA
and/or A- of one of the buffer systems, the pH of the whole system will change.
Bicarbonate Buffer System

CO2 dissolves readily in water and is hydrated to H 2CO3. This then dissociates into H + and HCO3-, as shown, and
with the equilibrium constant shown:
[HCO 3 - ][H + ]
CO2 + H2O « H2CO3 « HCO + H 3
- +
k =
[H 2 CO 3 ]
If pCO2 increases, [H2CO3] increases, as do the concentrations of both ions. Thus the pH falls. Similarly if pCO 2
falls, pH rises.
Physiology 235
The Henderson-Hasselbach equation may be used to determine the pH of blood from the concentrations of CO 2
and HCO3-, as shown below:
[HCO 3 - ]
pH = 6.1 + log
[CO 2 ]
In this equation, [HCO3-] is normally 24 mmolL -1. CO2 in the body is normally 40mmHg, or 1.2mmolL -1, so the
normal plasma pH can be calculated as 7.4.
Buffers in the Body

The importance of buffer systems in the body depend on the concentration of the buffers (their capacity to absorb
H+ or OH-) and whether the buffer system can be manipulated to control [H +]. There are 4 major systems:
•1 Protein. Major buffers in the body, especially intracellular protein. Most of the rapid buffering of added acid
or base occurs through protein. Not controlled as part of acid-base balance.
•1 Phosphate. Good buffers, acting fairly near their pK, but present only in low concentrations. Important in
buffering urine when their concentration rises as urine is concentrated, allowing the excretion of increased
amounts of H+. Level controlled as part of control of calcium levels, but not as part of acid-base control. The
reaction concerned is HPO42- + H+ « H2PO4-.
•1 Bicarbonate. This is the most important system as far as the control of pH is concerned. Although the
bicarbonate system operates some distance from its pK, and the components are not present in high
concentrations, both [H2CO3] (in the lungs) and [HCO3-] (in the kidneys) can be controlled, thus manipulating
body pH.
•1 Ammonium. The kidney secretes ammonia into the tubules, reacting with excess H + to form the ammonium
ion, which is secreted in urine. This effectively raises the pH by removing H + ions.
Protection Against pH Change

Rapid protection against pH change is provided by either increased or decreased respiration, leading to reduction
or retention of CO2 and hence H2CO3. These changes are mediated through the effect of plasma (and hence CSF)
pH on respiration. However this respiratory compensation will leave the body's "buffer reserves" disturbed, since
changes in pCO2 result in changes in HCO3-.
Slow protection occurs via the kidney. It works by a change in H + secretion (through the Na+/H+ antiport in the
PCT and the H+ pump in the DCT competing with K +). The H+ in the tubules reacts with bicarbonate, forming
H2CO3. This dissociates into H 2O and CO2 via the action of carbonic anhydrase. The CO2 diffuses into cells,
reacting with water to form bicarbonate ions, and hence change the pH.
Physiology 235
Respiratory Disorders
The Davenport Diagram illustrated below may help to explain the following common respiratory disorders:
· Respiratory Acidosis: Due to hypoventilation, resulting in an increase in pCO 2 . Thus the ratio changes
(HCO3- goes up a bit because of dissociation of acid formed from the CO 2 ) and the pH falls (N to B). The
kidney eventually compensates by conserving HCO 3-. This is done by excreting H2PO4- or NH4 and reabsorbing
HCO3-. The ratio is returned to near normal and goes from (B to E).
· Respiratory Alkalosis: Can be due to hyperventilation, eg. at high altitude. There is a fall in pCO 2 thus
increasing pH (N to A). Get renal compensation by excreting more HCO 3- (A to G).
· Metabolic Acidosis: If there is accumlation of acids in the blood (eg. diabetes) the HCO 3- falls and the pH
falls (N to F). Respiratory compensation (F to G) via hyperventilation in response to the H + on
chemoreceptors.
· Metabolic Alkalosis: Loss of gastric acid increases the HCO 3- and the pH (N to C). Respiratory compensation
(C to E) by hypoventilation, increasing pCO2 .
E
plasma bicarbonate 40 C
concentration
D
30 B
N A
20
H G
F
Davenport Diagram
10
7.1 7.4 7.7

pH
Physiology 235
Lecture 10 - Co-ordinated Gastrointestinal Function
The whole function of the gastrointestinal tract tract is coordinated to produce optimal conditions for the digestion
and absorption of material.
The Mouth & Oesophagus

The function of the mouth is to grind and chop food, reducing it to a small volume which can be easily
swallowed. It is then mixed with salivary secretions. The saliva consists of a mixture of mucus (for lubrication)
and an aqueous part (dissolves out material so it may be tasted). Taste is an important part of the control
mechanism. Taste actually increases pancreatic and intestinal activity. With tasteless food, the GI tract will not be
readied for entering food.
The salivary secretions also contain a number of enzymes, the most important of which is amylase: an enzyme
which breaks down starch. It also contains lysozymes, which cause bacterial breakdown.
Food is swallowed down the oesophagus, which has striated muscle under voluntary control. Most of the control
is a question of anatomy: the way the muscles lie and the way in which nerves are activated during the swallowing
reflex.
The Stomach
The oesophagus is in the thorax, and the diaphragm, together with the muscular ring at the end of the oesophagus,
act as a shutter valve so that material entering the stomach does not come back.
The major functions of the stomach are mixing and a small degree of digestion. Most importantly, though the food
must be broken down into small particles for the duodenum to be able to digest.
The stomach secretes mucus (protecting the stomach against scratching and digestion). It also secretes pepsinogen
(activated by HCl) and intrinsic factor: responsible for digestion of Vit B12, which is vital for life.
The pyloric sphincter is important in controlling the amount of material entering the duodenum. It is controlled by
both gastric and duodenal motility.
Small Intestine
The small intestineis about 4 metres in length, made up of the following sections:
•1 Duodenum: where digestion really begins. Pancreatic and bile secretions enter just after the pylorus, through
one or two ampullas. The contents become neutralised and isotonic with the plasma, through the pancreatic
secretions and the movement of water.
•1 Jejunum: the first third to half of the small intestine after the duodenum. Effective absorption begins here:
glucose, iron, fats, proteins, water and fat soluble vitamins and electrolytes are absorbed.
Physiology 235
•1 Ileum: which performs specific absorption of a couple of substances. It can absorb anything that the jejunum
can, as well as vitamin B12 and bile salts. All the bile salts entering in the duodenum are need for the entire
length of the jejunum; hence the absorption at the end.
Colon
The caecum and appendix have no major use in humans. The ill-defined ileo-caecal valve allows emptying into
the colon after a meal. The colon has four parts: ascending, transverse, descendiing and sigmoid. This is the site of
absorption of water and salts, reducing perhaps 1.5 litres of ileal contents to 200mL of fluid in the feaces. Colonic
movement is not very exciting: mainly controlled by factors of neurophysiology or anatomy. In salt deficiency,
aldosterone acts to increase reabsorption of salt in the colon.
Structure of the Intestine

The intestine is hanging in the peritoneal cavity from mesentery, containing blood vessels, nerves (sympathetic &
parasympathetic) and lymphatic vessels. The nerves impinge upon two plexuses in the gut wall:
•1 myenteric plexus: between circular and longitudinal muscle layers

•2 submucosal plexus: between circular muscle and lumen of the gut
These two plexuses are very important in regulation of intestinal function. They are quite autonomous, making a
dense nerve plexus at both levels, and also interconnecting.
The intestinal mucosa is thrown up into folds to increase the surface area for absorption. Fingerlike projections
called villi also serve to increase surface area, and have absorptive cells which are constantly being replaced. New
cells are formed at the base of the villus, slowly migrating to the tip where they are extruded. They become mature
about halfway up the villus. It is this renewal of cells which helps to prevent cancer of the small intestine. Crypts,
or pits in the intestinal wall are the site of cell production.
Blood Supply
21% of the cardiac output is supplied to the intestine at rest. During exercise this amount decreases due to
vasodilation to skeletal muscles. All blood to the intestine drains back through the portal vein to the liver. This is
because the liver removes toxins before the blood returns to the heart, and bile salts must be reabsorbed. The liver
also gets an arterial supply: about ¼ of the blood to the liver comes from arteries.
Physiology 235
Nervous & Hormonal Control

Nervous control of the gut occurs by both intrinsic and extrinsic pathways. The extrinsic nerves are sympathetic
and parasypmethtic carried in the mesentery. The control centre for this extrinsic pathway is the vagal centre of the
hypothalamus. Three types of transmitters are used: ACh, NA and NANC.
The intrinsic nerve plexuses are more important, and can function effectively without the action of the extrinsics.
They use the same transmitters, sending sensory impulses to cells lining the intestinal wall. Acid, irritant material
and tonicity stimulate nerve endings, in addition to the stretch receptors in the wall of the gut.
Peptide hormones were first found in the gut. The gut produces 40 or 50 separate peptides involved with intestinal
function, secretin being one example. The hormone-secreting cells are scattered throughout the intestine,
concentrated in the upper section, within the crypts. They release hormones in response to external stimuli
(nervous or chemical). For the most part, their action is paracrine: acting on adjacent cells.
Physiology 235
Lecture 11 - Gastric & Pancreatic Secretion
Anatomy
The stomach is located beneath the diaphragm, and only protrudes into the thorax during a hiatus hernia, resulting
in severe heartburn. The stomach is divided into the fundus, body and antrum. Both ends are controlled by
sphincters.
The fundus of the stomach secretes alkaline mucus and has a thin muscular wall. The main role of the fundus is
storage.
The body of the stomach contains gastric glands. They contain a lot of surface mucus-secreting cells protecting
from the action of the acid, as well as the following cell types:
•1 Parietal cells secrete HCl and intrinsic factor. It has a vast number of mitochondria and vast folds of
intracellular membranes, as well as large numbers of microvilli. This is because secretion of high
concentrations of H+ ions requires both high energy and surface area. The hydrogen ions come from the
breakdown of water. The OH- from this reaction reacts with H + from carbonic acid breakdown, causing
secretion of HCO3- into the plasma.
•1 Chief cells secete pepsinogen. They are typical of enzyme secreting cells, with lots of endoplasmic reticulum,
granules and mitochondria. The enzyme is released from these granules, to the outside of the cells.
•1 ECL (enterochromaffin-like) cells secrete at least twenty different granules. They sit adjacent to the parietal
cells, and their most important secretion is histamine.
Parietal cells are not found in the pyloric antrum. A new type of cell is the G cell, which secretes gastrin. These
are typical enterochromaffin-like (dye-loving), argyrophil/argentaffin (silver-loving) cells. They respond to the
actual gastric contents. Under certain stimuli they release gastrin into the blood stream, which is carried back to the
oxyntic cells.
Gastrin and cholecystokinin can act interchangeably, being weak forms of each other. This is due to a similarity in
amino acid structure.
The Phases of Digestion

Interdigestive Phase
Very little is happening in the intestine and gut during this phase. The gut is empty, containing a small
volume of low pH juice, which turns off secretion of acid.
Cephalic Phase
This is while you are seeing, smelling, tasting or just thinking about food, and is largely controlled by
nervous (vagovagal) reflexes, coordinated in the vagus centre in the hypothalamus. Effects include salivary
secretion, gastric secretion of acid and pepsin, pancreatic secretion of enzymes and increased gut motility.
This overlaps the gastric phase, when food actually enters the stomach. The cephalic phase continues while
you are still receiving sensory input. It has been shown that the cephalic phase is only initiated by
pleasant-tasting food.
Physiology 235
Gastric Phase
Swallowing the food reinforces stimulation of gastrsic and pancreatic secretions, stimulates more motility
and inhibits tone.
Intestinal Phase
This is the period where food is in the small intestine. There are 4 major changes during this phase: gastric
secretion and motility is modulated, pancreatic, liver and gut secretion of HCO 3- is stimulated, pancreatic
secretion of enzymes is stimulated and gall bladder emptying is stimulated.
Mechanisms
Vagal activity may either go through the intraneural plexus or act directly on cells in the antrum. It stimulates the
following:
•1 HCl release from parietal cells

•2 gastrin release from G cells
•3 histamine release from ECL cells
Synergism is the theory behind activation of parietal cells. ACh and gastrin both stimulate production of histamine
from ECL cells. All three products then stimulate the parietal cells.
Acid secretion begins during the gastric phase. Vagus activity is augmented by a vagovagal reflex: local activity
from the nerve plexuses and stretch receptors in the gut wall sends messages up the vagus nerve, increasing vagal
output. All cell types are stimulated to release their respective substances by stretch and chemoreceptors. In
addition, the contents of the stomach act directly on the G cells. Ethanol and caffeine are two potent stimulants of
gastrin release.
Luminal Stimulus
+
+
- Somatostatin
- -
-
+ + Parietal
G Cell ECL
Cell
+ +
+
Vagus
Control of Gastrin Release

Somatostatin is a peptide which inhibits the action of just about anything. Somatostatin-secreting cells have many
villi which sense the contents of the gastric glands. When they are stimulated by acid, somatostatin is released,
inhibiting the release of gastrin. This is the basis for the acid secretion decreasing when the pH reaches ~3.5. These
cells are also found in the body of the stomach, responding to nervous stimuli and other hormones.
Vagal input inhibits the activity of the somatostatin cells, while the hormone secretin stimulates release of
somatostatin.
Physiology 235
Intestinal Phase
During the intestinal phase, food entering the intestine causes the release of hormones from the duodenal mucosa.
Those hormones further inhibit gastric secretion and gastric emptying. The hormones involved are:
Gastric Inhibitory Polypeptide (GIP): This is released from the wall in contact with fat and glucose, and is a
potent inhibitor of gastric motility and secretion. It also stimulates insulin release from islets of Langerhans in the
pancreas.
Secretin: This is released by the presence of acid in duodenum. It may inhibit gastrin release and may inhibit
oxyntic cells directly. It is synergistic with CCK.
Cholecystokinin (CCK): This is a competitive inhibitor of gastrin, which is synergistic with secretion.
The Exocrine Pancreas

The pancreas is an elongated structure sitting in the c-shaped bend of the duodenum. The liver sits up underneath
the right side of the diaphragm. Both organs are developed from outpouchings of the intestine during
embryogenesis. They do have some relationship in that under certain pathological conditions, parts of the pancreas
can resemble liver cells and vice versa.
The pancreas is a large acinar gland. It has a long central duct which branches repeatedly, and on the end of each
branch is a clump of acinar cells. These make up 85% of the pancreas; the ducts make up ~10% and the islets of
Langerhans ~5%.
The pancreas has two major exocrine secretions: digestive enzymes and bicarbonate ions.
Pancreatic Digestive Enzymes

Digestive enzymes are secreted from the acinar cells. The rich nerve supply of the cells can be accounted for by the
fact that the major stimulus for enzyme release is ACh secreted from the nerve endings. The acinar cells are typical
protein-producing cells in that they contain vast quantities of rough ER and granules. When they are stimulated,
the granules fuse with the lumen of the ducts and the contents diffuse out, as well as being washed out by passing
fluid.
The pancreas secretes at least 50 different digestive enzymes, including lipase, amylase and various proteolytic
enzymes. Each acinar cell has the capacity to secrete each enzyme, and all are produced in about 10 times the
required amounts. The actual composition of pancreatic secretions can change slowly over time, depending upon
the person's dietary habits.
Physiology 235
Proteolytic enzymes would destroy the pancreatic cells if activated. Thus they are secreted as inactive precursors.
They are all activated by trypsin, which splits off a small amount of the enzymes, activating them. Trypsinogen is
secreted inactively as well. It is converetd to trypsin by a very specific proteolytic enzyme made by intestinal cells:
enterokinase. Acute pancreatitis results from activated enzymes being present in the pancreas.
During the gastric and cephalic phases, ACh stimulates minor secretion of enzymes which wait in the duodenum
for the arrival of food matter. These digest the fat and protein which arrives, stimulating CCK release and hence
further secretion of enzymes from the pancreas.
Bicarbonate Ions
These ions are released by the action of secretin (and CCK, synergistically). This is released from the duodenum
in the presence of H+. The secretion of bicarbonate acts as a feedback mechanism, as it is ultimately regulated by
pH and it serves to control the pH by neutralising the acid from the stomach. It does this so that the digestive
enzymes in the duodenum can function properly.
As the pancreatic secretion travels down the ducts, the concentration of bicarbonate ions decreases, as these ions
diffuse back into the plasma and are replaced by chloride ions. Thus the final [HCO 3-] is also dependent upon flow
rate.
Physiology 235
Lecture 12 - Secretion of Bile & Hepatic Function
Bile & The Liver

Cells in the liver are arranged in hexagonal arrays. They consist of rows of cells radiating outwards from a central
vein. Blood flows from the abdomen to the liver through the portal vein. It then passes through capillaries or
sinusoids towards the central vein. These are closely associated with bile canaliculi. The bile in these very thin
spaces (1m in diameter) travels in the opposite direction to the blood through the capillaries (a countercurrent
system) towards the bile duct of the portal triad. Thus bile can either be actually produced by liver cells (and
diffuse into the canaliculi) or can be reclaimed from blood.
Hepatic Gall Bladder

Water 97% 84%
Bile Acids 1% 9%
Electrolytes 1% 1%
Lipids 0.2% 2%
Bile Pigments 0.4% 4%
Hepatic and gall bladder bile composition
Cholesterol intake is normally 0.3g from diet and 1.2g from biliary input, and output is 0.6g from bile salts and
0.9 from neutral sterols. The body pool of cholesterol is ~150g. If you can increase the amount of bile salts
produced, you increase the amount of cholesterol leaving the body.
The bile salts excreted from the liver come from two sources: bile salt synthesis and recirculated bile salts. Over
95% are recircualted.
Bile is produced by two pathways: cholesterol catabolism (de novo synthesis) and a salvage pathway. These two
processes regulate each other: if the salvage pathway is possible, it occurs and it decreases the amount of de novo
synthesis which takes place.
Bile Secretion
There are two forces at work creating flow of bile into the canaliculi in the liver:
•1 Bile acid dependent (BAD): This is the active transport of bile acids into the canaliculi via the osmotic
gradient. Water and electrolytes follow by osmosis. Flow is proportional to bile acid secretion, so if more bile
acids are present, more bile flow occurs. This is the most important cause of flow of bile into the canaliculi.
•1 Bile acid independent (BAI): Even when there is no bile acid secretion, flow still exists. This can be
separated into a canalicular and ductule component. It is firstly due to active transport of Na + in the canaliculi
by a Na+/K+ ATPase pump. Secondly it is generated is caused by HCO 3- secretion in the ductules of the liver,
caused by the presence of secretin (secreted when food enters the intestine).
Physiology 235
Lecture 12 - Secretion of Bile & Hepatic Function
Primary & Secondary Bile Salts

Primary bile acids are those synthesised by the liver, through cholesterol catabolism:
cholic acid: 3, 7, 12 trihydroxy cholanic acid

chernodeoxycholic acid:3, 7 dihydroxy cholanic acid
These are always conjugated (linked) to amino acids via peptide bond as they leave the liver, glycine (75%) and
taurine (25%).
Secondary bile acids are those modified in the gut by bacteria. Some bile acids are deconjugated and then
dehydroxylated by bacteria in terminal ileum before reabsorption.
Most treatments aiming to decrease plasma cholesterol act by increasing the excretion of bile salts. This stimulates
more production of bile salts from cholesterol.
The major determinant of the bile flow from the liver to the gallbladder is the rate of return of bile salts, rather than
through actual digestion of food, or hormonal or nervous control. The bile is stored in the gallbladder until food
enters the intestine: when this happens, CCK is released, causing contraction of the gallbladder and relaxation of
the sphincter of Oddi, releasing the bile.
The following are statistics related to the average person’s body bile content:
size of pool 2-4g

recycles 6-10 times per day
total secretion nby liver 12-40g
efficiency of reabsorption >95%
faecal loss per day 0.2-0.6g
hepatic synthesis per day 0.2-0.6g
The Gallbladder
Bile is concentrated about 10x in a normal gallbladder, by the active transport of electrolytes out of the
gallbladder, and the passive movement of water following the electrolytes.
Bile salts, lipids and bile pigments remain in the gallbladder, due to the molecules being too large or too water
insoluble. As the concentration rises, however, the cholesterol may crystallise, beginning the formation of gall
stones. Another less common effect is crystallisation of the pigments, forming pigment gall stones (as in
haemolytic anaemia).
Gallbladder removal results in more continuous flow of bile from the liver straight into the intestine. This usually
has no major side effects as the output is excessive in most people anyway.
Physiology 235
Lecture 13 - Digestion & Absorption I
Absorption
There are three major methods of absorption in the intestine:
•1 Diffusion
•1 rate proportional to concentration difference, size of molecule and solubility
•2 through water filled pores (small water-soluble particles)
•3 through lipid membrane (larger lipid-soluble particles)
•1 Carrier-mediated
•1 rate limited by carrier availability or energy levels
•2 facilitated diffusion (carrier in membrane, not energy dependent, can’t go against gradient)
•3 active transport (linked to energy source, can go against concentration gradient)
•1 Pinocytosis
•1 form of active transport across membranes
•2 very small particles
•3 not important in intestine
Digestion & Absorption of Fat

“Fat” comes in a variety of molecules, none of which are water soluble:
•1 cholesterol
•2 phospholipids
•3 triglycerides (major fat in diet)
•4 fat-soluble vitamins (essential)
Triglycerides are esters of glycerol (tri-hydroxic alcohol) and fatty acids. These fatty acids can be:
•1 long chain
•1 saturated (eg. palmitic 16, stearic 18)
•2 unsaturated (eg. oleic 18:1)
•3 polyunsaturated (eg. linoleic 18:2, linolenic 18:3, arachidonic 20:4) - essential, from plants
•2 medium & short chain
•1 almost always saturated and 12C or less
All of these are lipid soluble substances, and thus would have no problems getting into cells through simple
diffusion. Their major problem is actually getting to the membrane to be absorbed. This is the role of bile in fat
absorption: transport of the fats to the absorptive cells of the intestine.
Physiology 235
Lecture 13 - Digestion & Absorption I
The Action of Bile Salts

Bile salts are detergents, surfactants, emulsifiers, emulgates, solubilisers, amphipaths, amphiphiles and surface
active agents. They have two major functions:
•1 emulsify fat: allows faster lipolysis, improved digestion

•2 solubilise products of fat digestion (monoglycerides and fatty acids)
This micellar solubilisation:

i) clears interface for future lipolysis
ii) transports products up to mucosa
The fatty acid molecule acts as a classic detergent, aligning itself at lipid-water interfaces. The fat soluble part (16-
24 carbon chain) is in the lipid area, and the polar COO - is in the water.
Why is it important to emulsify fat? Triglycerides are not water soluble, however lipase is water soluble The only
place it can therefore act on fat is at the water-lipid interface. Thus the more interface which is present, the faster
can be the digestion. Emulsification greatly increases the lipid-water interface size. It is broken down by lactase,
acting the ester linkage. The first cleaving forms a fatty acid and a diglyceride. The second produces a
monoglyceride and another fatty acid. All products can then be solubilised by bile salts and carried to the
absorptive surface.
Lipase is present in excess, so the rate of digestion is determined by the substrate concentration and surface area
for action of the enzyme.
If you have poor digestion of fatty acids, you are not able to solubilise the fat-soluble vitamins: the only real
physiological problem of not being able to abosrb fat is the malabsorption of the vitamins.
Physiology 235
Lecture 14 - Digestion & Absorption II
Intestinal Structure
The intestinal tube is thrown up into folds with villi and absorptive cells. The villus has a fairly complicated
structure: a capillary network and a central lacteal (lymphatic duct). The capillaries are fairly impermeable, most
large substances passing into the lacteals. The lymph from these drains into the thoracic duct.
Looking closer, the intestine contains a layer of closely packed microvilli, on top of which is a glycoprotein
surface coat. And on top of this layer is a layer of “structured water”. Anything passing from the lumen to the
absorptive cells must diffuse across this unstirrable layer of water, which is anything up to 0.5mm in thickness.
Bile Salts Revisited

Bile salts solubilise fat, and diffuse it across the unstirred layer. They act as a transport vehicle for absoprtion of
lipids. They also act as normal detergents, containing both an oil loving and a water loving part, separated by
distance. Adding them to to water, they tend to accumulate at either the air/water interface or oil/water interface. In
so doing, they stretch the interace, lowering surface tension. If you keep adding detergent to the water, an you
measure the surface tension, you get the graph to the left.
surface tension
[detergent]
From this graph, it can be seen that a saturated level is eventually reached. This level is determined by the relative
sizes or strengths of the two parts of the detergent. The ones added after this level will aggregate all their
hydrophilic parts on the outside, and all the hydrophobic parts together (micelle formation). Above the critical
micellar concentration (CMC), detergents, including bile salts, form micelles:
•1 they are only a few molecules across (unlike emulsions) therefore micellar solutions are clear
•2 they form spontaneously above the CMC and are thermodynamically stable (unlike emulsions)
•3 they have lipoidal centres, where micellar solubilisation of lipids occurs
Bile salts are quite unique in being planar ampipaths: they have a hydrophilic and lipophilic face, rather than
end. Thus the micelles they form are different from the norm as well, called “hatbox micelles”. They are bilayers
of bile salts, with a few salts in the centre. They are not particularly good at solubilising non-polar detergents, but
are very good at solubilising slightly polar lipids, such as fatty acids and monoglycerides.
In fact if you don’t produce bile salts, you still get 60-70% fat absorption at intestinal pHs. Without lipase you get
40% absorption, due to the presence of some lipases in the stomach which will digest small amounts of
triglyceride.
Physiology 235
Fate of Fatty Acids

Once the bile salts have transported the fatty acids and monoglycerides across the water layer, they break down
and deliver the lipids into the lipoidal absorptive mucosa. Inside the mucosa, the lipids diffuse into the ER of the
cells, where they are converted back into triglycerides. The mixture of fatty acids and monoglycerides has been
changed during the transport process, so the triglycerides eventually formed are different from the original ones in
the diet.
These fat droplets can be seen appearing in the upper parts of the cells, coated with protein and phospholipids.
These coated droplets are called chylomicrons, and they are extruded as the base of the cells, accumulating
between cells while fat is being absorbed. They are then taken up by the lacteals and eventually into the blood
stream.
Short and medium chain triglycerides are quite readily split by by pancreatic and other lipases in the gut. Unlike
with the long chain monoglycerides, these are not protected from glycolysis, resulting in lipase forming mostly
free fatty acids and very little monoglyceride.
The shorter the chain, the more soluble it is. Adequate solubilisation occurs without the presence of bile salts, but
the lipids are not re-esterified in the intestinal absorptive cells: they are carried directly to the liver where they are
used as an energy source. Thus a patient with no bile salts must be provided with only short chain triglycerides, to
prevent severe diarrhoea.
Digestion & Absorption of Carbohydrates

Carbohydrates are consumed in the diet as large polymers which must be digested into smaller components which
may be absorbed by the intestine: glucose, galactose and fructose. The average daily diet contains ~350g of
carbohydrate:
60% starch (polymer of glucose)

30% sucrose (glucose & fructose)
10% lactose (glucose & galactose)
Glucose is very water soluble, with a MW of 180, and can be absorbed by facilitated diffusion or carrier mediated
transport: it is too large for simple diffusion. Dissacharides are much too big for diffusion and have no mediated
transport methods. Starch is similar but much bigger: 20% amylose (long chains of 20-200 glucose) and 80%
amylopectin (cross-linked chains of 5000+ glucose).
The enzyme amylase, produced by the pancreas and salivary glands, can split the 1-4 linked glucose units, but not
the branches. Thus the products of starch digestion by amylase are:
•1 maltose (2 glucose units)

•2 maltotriose (3 glucose units)
•3 limit dextrins
Dissacharidases (maltases, a-dextrinase, sucrases, lactases, etc.) lie at the digestive/absorptive surface, to break the
dissacharides into monosaccharides. These enzymes are intimately bound up with the specific monosaccharides
carriers which transport the sugars into the cells.
Physiology 235
The active transport mechanism for the monosaccharides has a high affinity for glucose (higher than for galactose
or fructose). It requires sodium, having the same carrier as in the first part of the PCT: there no localised uptake
of glucose in the intestine. It competes with amino acids (probably both systems compete for the same energy
source: Na+ transport).
Due to this coupled absorption of glucose and sodium, if promotion of sodium absorption is required, glucose
must be provided. This is especially important in treatment of diseases such as cholera.
Carbohydrates are not essential nutrients. Energy can be equally gained from other substances. Itf they are not
absorbed in the intestine, bacteria in the colon may produce gas and lactic acid, possibly causing explosive
diarrhoea. An example of a sugar not completed digested in the intestine is stachyose, found in baked beans!
Cellulose is another glucose polymer like starch, with a different type of linkage which humans can’t digest.
Some dietary fibre can be digested, eg. hemicellulose. Thus although fibre is considered good for you, it also
contains calories. The importance of fibre is that it makes you feel full and speeds up passage through the intestine,
keeping the gut relatively free of carcinogens.
Digestion & Absorption of Protein

Protein digestion begins in the stomach, through the stomach’s violent proteolytic enzymes, including pepsin, and
the denaturing action of hydrochloric acid.
In the intestine, the protein is bathed in a potent mixture of 15-20 proteolytic enzymes from the pancreas, triggered
by CCK in the stomach. All are secreted as proenzymes, and are activated by contact with the intestinal mucosa
through the enzyme enterokinase. There are two sorts of proteolytic enzymes produced by the pancreas and the
stomach:
•1 endopeptidases: These attack the protein in the middle of the peptide chain, forming shorter proteins. These
are also much more active than the other type of peptidase. Trypsin, chymotrypsin and elastase are the very
potent endopeptidases, each with specific substrates.
•1 exopeptidases: These attack the ends of the peptide chains, splitting off single amino acids. These are not very
active. The two most common examples are carboxypeptidases A and B.
The amino acids are absorbed into the absorptive intestinal cells in a similar way to glucose: by a sodium coupled
transport system. This is the same as that found in the kidney. There are, however, at least 4 separate transport
systems which all absorb different classes of amino acids.
There is huge competition for absorption of amino acids, caused predominantly by glucose. Therefore the most
important pathway for entry of amino acids into the intestinal cells is in the form of short peptides.
Physiology 235
Peptides can be absorbed by three methods:
•1 Peptidases are bound to the surface of the cells: these may digest the peptides, before which they are absorbed
as amino acids.
•1 There appears to be one active transport system for peptides, with a very wide specificity. This may or may not
be sodium-coupled. It handles peptides with up to 5 amino acids. Intracellular peptidases exist to digest the
peptides. The amino acids are then passed out of the cells.
•1 If no intracellular peptidases are present for the particular peptide, it may be passed directly out of the cell, and
eventually excreted intact as a peptide. The sort that are handled this way are those containing proline and
hydroxyproline (components of gelatine). Fortunately, they are not essential amino acids.
There is no evidence that there is significant absorption of intact proteins. This has been noticed in newborn
animals, but not in humans. Some people have allergies to certain proteins in food, suggesting that in these people
at least, there may be small absorption of intact protein, but not nutritionally significant amounts.
Physiology 235
Lecture 15 - Gastrointestinal Motility
Intestinal Structure
The following are the layers of the intestinal wall:
•1 mucosa
•2 submucosal muscle
•3 Meissner (submucosal) plexus
•4 inner circular muscle
•5 Auerbach (myenteric) plexus
•6 outer longitudinal muscle
•7 mesentery
The important controlling mechanisms are the plexuses. Interstitial cells of Cajal are strange cells that look to be
half muscle and half nerve. These actually generate the electrical activity important in controlling muscular
movement. Although the intrinsic nerves control muscle contraction, their effect is modulated by vagus and
sympathetic nerves. The gut still functions without the extrinsic input. Hirschsprung’s disease and Chaga’s disease
are cases where intrinsic nerves are destroyed.
Electrical Activity
Smooth muscle cells are about 120 microns long, and 10 wide. They contain actin and myosin fibres, responsible
for contraction. They are joined by nexuses between the cells, allowing contractual interaction. Depolarisation of
these muscle cells has some important characteristics:
•1 Resting membrane potential: unstable, resulting in basic electrical rhythm (BER)

•2 Threshold: a fall below threshold causes depolarisation
•3 Action potentials “spikes”: trigger contraction of muscle
The BER is characteristic of intestinal smooth muscle. It ranges from 10-15mV, with the following statistics:
•1 stomach: 3 waves/min, 1 cm/sec

•2 duodenum: 11 waves/min
•3 ileum: 9 waves/min, 15 cm/sec
It is thought to arise in the interstitial cells of Cajal, conduct through the longitudinal layer of muscle and spread to
the circular layer. It is also thought to be regulated by oscillatory activity of an electrogenic sodium pump or
cyclical changes in membrane permability. New pacemaker regions are located throughout the gut.
If the resting membrane potential is close enough to threshold, then one cycle of the BER will cause an action
potential, triggering muscular contraction. When one muscle cell contracts, the cells around also tend to contract
due to linking through the muscular mexuses.
Physiology 235
Lecture 15 - Gastrointestinal Motility
Altering Motility
Stretching the muscle: Through the enteric nerves, the resting potential is raised, so contraction is
more likely to be triggered with each pulse of the BER. Thus presence of food
in the gut effectively increases motility.
ACh and parasympathetics: This hypopolarises the membrane potential, increasing the rate of contractions.
Depolarisation: This will initially cause a huge contraction, but then no more contractions will
be possible, due to no K+ gradient existing.
Adrenalin or Noradrenalin: This hyperpolarises the muscle, decreasing the resting membrane potential, and
making any contraction unlikely.
The BER is always present, gut is not the same as the gut motility, as not every pulse generates a contraction.
However, the maximal rate of contraction is the rate of the BER.
Peristalsis & Segmentation

Peristalsis occurs when you get an initial contraction, and then subsequent contractions occurring smoothly and
regularly down the rest of the gut at the rate of the BER, pushing everything before it. This is the type of gut
motility found in the stomach. It causes no mixing or absorption, and would lead to copious diarrhoea if it
occurred in the small intestine.
Segmentation is the process in the small intestine. It causes very effective mixing and reduced flow rate, by
moving the food backwards and forwards: not always towards the colon. This allows exposure to bile and
digestive enzymes, and presents the contents to the absorptive surface.
Interdigestive Housekeeper
This occurs in the interdigestive period, ie. between meals. There are 4 phases every 2 hours:
Phase 1: 45-60 min no activity

Phase 2: 30-45 min rising activity
Phase 3: 5-15 min maximal activity
Phase 4: “short” back to phase 1
Peristaltic waves arise in the proximal stomach, sweep over the stomach, pass to the duodenum and all the way
down the small intestine. Unlike the usual gastric peristalsis seen after a meal, these “housekeeper” waves are
associated with an open pylorus so solid material can be swept out - this empties indigestible solids.
Physiology 235
Lecture 16 - Gastric Emptying
Introduction
Liquid, digestible solid and indigestible solid empty from the stomach at different rates. The stomach can be
divided in various ways:
•1 anatomically: cardia, fundus, body, antrum

•2 electrically: proximal, distal
Proximal Stomach
The proximal stomach has poorly delineated muscle layers. It has no basic electrical rhythm (BER), and its resting
membrane potential is very steady. Its electrical activity consists of small, slow depolarisations, without spikes.
These slow contractions last between 1 and 3 minutes.
Contractions in the fundus determine the intragastric pressure. Since the pylorus offers little resistance to
movement of liquids, the rate of emptying of a liquid meal is proportional to the intragastric pressure.
Intragastric pressure rises less than would be expected when a meal is eaten, because the stomach relaxes as food is
swallowed. This is caused by two mechanisms, both aspects of the same phenomenon:
•1 receptive relaxation: When food is swallowed, a vagal reflex causes relaxation of the proximal stomach,
decreases the rise in intragastric relax. Although a vagal reflex, this is NANC (non-adrenergic, non-
cholinergic).
•1 accommodation: When food is placed directly into the stomach, the stomach relaxes. This is probably similar
to the above relaxation, a vago-vagal reflex.
But pressure does rise when a meal is eaten, and a major factor in affecting gastric emptying of a fluid meal is the
volume (and therefore the rise in intragastric pressure) when the meal is taken.
The following gastrointestinal hormones have important effects on the proximal stomach:
•1 gastrin: causes relaxation, slows emptying

•2 CCK: causes profound inhibition of proximal stomach, important in intestinal phase
•3 motilin: increases pressure, speeds emptying, important in interdigestive housekeeper
Distal Stomach
The distal stomach has much better defined muscle layers. It has pace-setter potentials (PCP) like the small
intestine, but at a much slower rate. The PCPs arise at the junction of the proximal and distal stomach. The distal
stomach sontrols emptying of solids. The pylorus poses high resistance for movement of solids, and contraction of
the distal stomach (antrum and pylorus) determines this resistance).
Physiology 235
Lecture 16 - Gastric Emptying
Contractions in the distal stomach are related to pace-stter activity. They can also be affected by the
neurotransmitter acetylcholine:
•1 high levels increase the resting membrane potential, causing strong peristaltic contractions at the rate of the
PCP
•1 low levels decrease the resting membrane potential, causing weak contractions at a slower rate than the PCP
In the body of the stomach peristaltic waves don’t meet. They just mix fastric contents, but as the wave
approaches the antrum, opposing walls of the peristaltic ring may get close, and start to grind the gastric contents.
At the antrum, the muscle is thicker, and conducts the BER 10 times faster, so the whole antrum contracts as a
unit, squirting contents both ways. A small volume goes into the duodenum, before the pylorus closes. The volume
ejected depends on the duodenum being relaxed as the antrum contracts. With the pylorus closed, the remaining
contents in the antrum are vigorously mixed.
Increased activity of the distal stomach results in an increased rate of gastric emptying if the gastric and duodenal
motility are co-ordinated. If the activity is not co-ordinated, increased gastric motility may result in slower gastric
emptying because the pylorus is clsoed for longer periods and resistance to flow is increased.
Control of the distal stomach is achieved by:
•1 Nerves: Vagal activity increases and sympathetic activity decreases coupling between BER and contractions.
Therefore vagal activity usually speeds gastric emptying, sympathetic activity decreases it.
•2 Hormones: Gastrin increases frequency of BER coupling, but slows emptying, because gastric and duodenal
activity uncoordinated.
Indigestible solids don’t usually remain in the stomach forever. Larger indigestible solids are removed by the
Interdigestive Myoelectric Complex (IMC), or Migrating Motor Complex, or Interdigestive Housekeeper.
Physiology 235
Lecture 17 - Malabsorption
Nutrient Deficiencies
There are five possible causes of all nutrient deficiencies:
•1 inadequate intake
•2 inadquate absorption ie. malabsorption
•3 inadequate utilisation
•4 increased requirements
•5 increased excretion
Steatorrhoea
This is the presence of excess amounts of fat in the faeces (more than ~6g/day). Normally, gastric emptying will be
at such a rate that the small intestine can absorb all of the fat before it reaches the colon. The presence of
steatorrhoea is usually an indication of a defect in digestion (eg. pancreatic destruction) or absorption (intestinal
mucosal damage).
Diarrhoea is an increased water content: if more than 500mL is excreted per day, it may be diagnosed. This
condition can be produced by steatorrhoea, in that fatty acids produced in the colon can lead to increased water
secretion in colon.
The most important point to remember about steatorrhoea is that it may be associated with a deficiency in fat-
soluble vitamins.
There are two major causes of steatorrhoea:
Defect in pancreatic secretions: With a lack of digestive enzymes, you will not get adequate digestion or
absorption of nutrients from food. A component of this is that a lack of bicarbonate secreiton will cause an
inoptimal media for action of digestive enzymes.
Defect in bile secretion: Whereas a defect in pancreatic secretion will lead to complete malabsorption, this will
only lead to fat malabsorption.
Mechanical Malabsorption
This is not signalled by any pain, but by sudden disease. It may be present from birth or may suddenly appear
during adulthood. It is usually due to damage of the absorptive surface.
Coeliac disease is caused by an allergy to the protein gluten in the diet. The allergy causes damage to the surface
of the lumen, decreasing the absorptive surface area. It is not usually associated with any severe symptoms, though
there may be an attack of bacterial infection. Reduced mucosal surface area leads to general malabsorption.
Physiology 235
Tests for Malabsorption

Faecal analysis: This involves either microscopy or chemical analysis. This is usually not very effective, although
detection of undigested protein, for example, supports the diagnosis of general malabsorption.
Xylose absorption test: This is a good test for the integrity, size and ability of intestinal mucosa to absorb. It is a
non-specific test of the surface area of the intestine. Xylose, a 5-carbon sugar, can only be absorbed by simple
diffusion, so the amount of xylose absorption is measured, giving an accurate estimation of the absorptive surface
of the intestine.
Look! endoscopy: This is the most recent innovation in terms of gastrointestinal medicine: the ability to look
directly at the mucosa through a mini-telescope.
Small intestinal biopsy: This is important in terms of detection of structural damage and for confirming the
diagnosis of coeliac disease or physical damage to the intestine.
Pancreatic function tests: The most common is the ECRP: endoscopic retrograde cholangio-pancreatography).
This test samples pancreatic juice by entering a balloon thorugh the pancreatic duct and inflating it. This does,
however, cause acute pancreatitis in 1% of people.
Breath tests: This is accomplished by feeding a patient sugar and measuring hydrogen excretion by the patient.
This hydrogen is produced when the sugar is not absorbed in the intestine, and the bacteria in the colon digest it
instead. It can therefore detect malabsorption of specific sugars.
Clinical trial of gluten-free diet: This is the common method for GPs to identify coeliac disease or sprue. They
take a mucosal biospy, put them on the diet, and take another biospy, noting any changes in mucosal appearance.
Ulcer Surgery
Ulcer surgery is performed to reduce acid secretion. It was originally performed by cutting the vagus nerve, thus
decreasing vagal stimulation of the stomach. However, this may cause gastric stasis, due to loss of nervous supply
to the pylorus and antrum. Thus a drainage system is required (usually a loop of intestine is brought up and sutured
to the base of the stomach. Most ulcer surgery now, however, is achieved by removing the antrum.
Small remnant syndrome is caused by leaving behind a small section of stomach. The sufferer will only eat small
amounts at a time, and will hence lose weight. This is an effective therapy for morbid obesity: banding or stapling
part of the stomach to reduce the total volume.
Malabsorption will occur, because the gastric contents will enter the intestine further down than the bile and
pancreatic juice, and hence there will not be sufficient mixture for complete digestion. Also, secretion of bile and
pancreatic juices is caused by presence of food in the proximal intestine: the food may not even enter this region.
Physiology 235
Surgery
Stomach: Particularly if the body is removed, intrinsic factor will be dimished, leading to low absorption of
vitamin B12.
Duodenum: This is where the pancreatic juice and bile enter, and reorganisation of these channels is near-
impossible.
Jejunum: Need at least 30-50 cm of this for barely adequate absorption.
Ileum: Need terminal part for normal bile salt and vitamin B 12 absorption.
Dumping Syndrome
Dumping syndrome consists of a series of symptoms: fullness in the stomach, churning in the abdomen, weakness,
dizziness, fainting, rapid heart rate and palpitations. These are also the classic symptoms of shock. There are two
distinct forms:
Early Postprandial Dumping Syndrome

This occurs within 30 minutes of eating. Rapid gastric emptying leads to large volumes of hypertonic food
entering the jejunum and drawing fluid into the gut lumen. This leads to a fall in blood volume, and thus a fall in
BP: hypotension. There is probably also a hormonal component, as symptoms sometimes precede changes in
plasma volume.
Late Postprandial Dumping Syndrome

This occurs 1-3 hours after the meal, again with rapid emptying of the stomach. This, however, leads to rapid
absorption of glucose. This leads to excess insulin secretion, and hence reactive hypoglycaemia.
Physiology 235
Lecture 18 - Bone Marrow & Haematopoiesis
Overview of Haematopoiesis
Definition: Haemoatopoiesis is the formation of the cellular components of the blood.
Sites: In the embryo, haematopoiesis occurs in the yolk sac and then in the liver, spleen and lymph
nodes. At birth, haematopoiesis occurs in the bone marrow of all bones, while lymphocyte
production continues in the spleen and lymphoid tissue. In the adult, haematopoiesis is confined
to the marrow of the axial skeleton and lymphocyte production in the spleen and lymphoid tissue.
Cellular Processes
All blood cells are derived the same pluripotential stem cell. This is an unlimited supply, as division of these
cells includes formation of new pluripotential stem cells. The other product of division is a committed stem cell:
the beginning of a pathway giving rise to a particular type of cell. This is called differentiation.
Cell division then occurs, giving rise to precursor cells, or blast cells. These undergo many divisions, during the
proliferation stage. Eventually they reach a point where no more divisions occur, though further development
occurs. This is called maturation. The “mature” cells are then released from the bone marrow into the circulation.
A More Complicated Pathway

The first option for pluripotential stem cells is whether to become a lymphoid stem cell or not. If it decides not to
become one of these, it is called a stem cell GEMM (or colony forming unit, CFU-GEMM), which can still give
rise to four different cell types..
It then has several choices:
•1 erythroid stem cell, which has two progressive forms, BFU-E and CFU-E
•2 megakaryocyte stem cell (CFU-Meg), which forms megakaryoblasts & cytes, then platelets
•3 granulocyte-monocyte stem cell (CFU-GM), which forms monoblasts, or neutrophilic, eosinophilic or
basophilic myeloblasts
Erythropoiesis
Differentiation pluripotential stem cell
committed stem cell
Proliferation proerythroblast large, pale nucleus, blue cytoplasm (15-20m)
early erythroblast (basophilic) smaller, denser nucleus
intermediate erythroblast (polychromatophilic) streaks of orange in cytoplasm (10-14m)
Maturation late erythroblast (orthochromatic) pyknotic nucleus, orange & blue
reticulocyte no nucleus, blue patch in cytoplasm
mature erythrocyte completely orange/red (7m)
Physiology 235
Note: 1) a “normoblast” is a normal erythroblast

2) mature erythrocytes last ~120 days in the circulation
The following are the overall changes which occur during erythropoiesis:
•1 decreased cell size

•1 proerythroblasts: 15-20 um in diameter
•2 erythrocytes: 7-8 um in diameter
•1 loss of nucleus
•1 proerythroblasts: large pale nucleus
•2 late erythroblasts: small, dense, non-functional nucleus (pyknotic)
•3 reticulocytes: nucleus is extruded from cell
•1 loss of other cytoplasmic organelles

•1 mitochondria
•2 endoplasmic reticulum
•3 ribosomes
•4 etc.
•1 change in cytoplasmic colour

•1 blue colour (basophilia) due to RNA: decreases
•2 orange/red colour (eosinophilia) due to haemoglobin: increases
•1 loss of ability to take up iron

•1 iron required for haemoglobin synthesis
•2 specific membrane receptors for transferrin (iron transport protein) decreased
Measuring Erythropoiesis
Not all erythropoiesis is effective: some of the reticulocytes may be destroyed at a late stage. The system is
normally 20% ineffective - cells are removed by macrophages in the bone marrow. The following are the common
methods of measuring levels of red blood cell production in the body:
•1 Total erythropoiesis
•1 erythroid hyperplasia or hypoplasia in bone marrow
•2 plasma iron turnover - radioactive iron 59Fe
•1 Effective erythropoiesis
•1 reticulocyte count
•2 0.2 - 2.0% of RBC
•3 0.01 - 0.1x1012 total in number
•4 Reticulocyte Production Index (RPI)
•1 % incorporation of 59Fe into circulating RBC
Physiology 235
Leukopoiesis
Once the pluripotential stem cell has become the GM stem cell, it can lead to the monocyte pathway or the
granulocyte pathway.
Monocyte precursors are called monoblasts. The pathway is not very well understood, and morphological appear
insignificant. Monocytes are released into the blood for less than a day, before becoming macrophages in various
parts of the body. These macrophages may be generalised or specialised to certain areas (such as alveolar
macrophages in the lung, or Kupffer cells in the liver).
Granulocytes include neutrophils, eosinophils and basophils. Eosinophils and basophils may have their own stem
cell: this has not been confirmed. The following are the intermediates:
•1 Myeloblasts distinctive white nucleoli

•2 Promyelocytes slightly smaller
•3 Myelocytes specific granules in the cytoplasm
•4 Metamyelocytes kidney shaped nucleus
•5 Band forms released into blood (equivalent of reticulocyte)
•6 Mature granulocytes nucleus segments.
Mature granulocytes remain in the blood stream for ~8 hours, with most of their action being in fighting infections
in the tissues.
Lymphocyte Production
Once the pluripotential stem cell becomes a lymphoid stem cell, it must split into one of two pathways, as a B cell
or T cell precursor (or lymphoblast).
T cell lymphoblasts move into the thymus through the blood stream, where they become functional T
lymphocytes. They then undergo preprocessing, which involves insertion of specific receptors for antigens in the
cell membrane. They are then released into the body’s circulation of blood and lymphatics.
B cell lymphoblasts undergo similar preprocessing in the bone marrow before migrating into the blood and
circulating throughout the body.
Upon stimulation of mature lymphocytes, by appearance of specific antigen:
•1 B cells will proliferate and give rise to plasma cells, which produce antibodies
•2 T cells will proliferate to produce activated T cells, important in the immune response
Physiology 235
Platelet Production
•1 Pluripotential stem cell becomes committed stem cell, giving rise to megakaryoblasts.
•2 This undergoes nuclear and cytoplasmic replication, increasing to up to 32 times original size.
•3 Cytoplasmic fragmentation forms platelets.
•4 Megakaryocyte can give rise to up to 6000 platelets.
•5 The platelet life span is approximately 10 days.
Hormonal Regulation
The only substance in the following table which is strictly a hormone is erythropoietin, the others being cytokines.
Type of cell “Hormone”

RBC erythropoietin
platelets thrombopoeitin
granulocytes & monocytes colony-stimulating factors (CSF)
lymphocytes interleukins (Il - 1, 2, 4, 5, 6)
Interleukin 3 is required for the differentiation of pluripotential stem cells into the various forms of committed
stem cells.
Erythropoietin is produced by the cells of the kidney in response to hypoxia. It has been shown to function by the
following negative feedback loop, which is stimulated by decreased RBC, high altitude, respiratory diseases, etc.
Decreased oxygen (-ve) Increased red blood cell

delivery to tissues production in bone marrow
Decreased oxygen partial Increased erythropoetin

pressure in kidneys synthesis and release
Other hormones work directly on erythroid precursors. They include:
•1 androgens
•2 growth hormone
•3 corticosteroids
•4 oestrogen (negative effect)
Physiology 235
Lecture 19 - Erythrocytes & Anaemia I
Nutritional Requirements for Erythropoiesis

Because erythrocytes have a short life span, and because we have so many of them, the body must produce 23
billion red blood cells each day. This means that the RBC system is extremely sensitive to nutritional deficiencies:
•1 irondeficiency is a common cause of anaemia

•2 folate (folic acid) deficiency is a common cause of anaemia
•3 vitamin B12 deficiency is a common cause of anaemia
•4 amino acids deficiency leads to a protein deficiency, and hence anaemia
•5 copper essential co-factor for many enzymes (eg. cytochromes)
deficiency (rare) leads to anaemia
•1 pyridoxine (vit B6) essential for haem synthesisis
ALA synthetase requires pyridoxal-5-PO4 as a co-factor
•1 vitamin C affects iron absorption
deficiency causes scurvy, leading to anaemia
Iron Distribution
Total body iron is 3-4 grams. The following table outlines the distribution of iron in the body:
Haemoglobin 65-75%
Iron stores (RES, Liver) 15-30%
Myoglobin 4-5%
Enzymes (cytochromes, cytochrome oxidase, peroxidase, catalase) 0.5%
Transport (bound to plasma protein transferrin) 0.1%
The following diagram outlines iron movement throughout the body:
GIT
MACROPHAGES - RES
(dietary iron)
(storage)
LIVER
(storage)
BLOOD
(red blood cells)
CELLS
(enzymes)
PLASMA
MARROW
(transferrin)
(RBC precursors)
(-Hb synthesis)
LOSS LOSS
(git, skin, urinary tract) (menstrual)
1mg/day 1mg/day
Physiology 235
Factors Affecting Iron Absorption

Iron in the diet comes in two major forms: haem iron (from meat) and non-haem iron.
•1 Dietary Factors: The non-haem iron forms insoluble complexes with phytates, phosphates and oxalates,
which cannot be absorbed. This problem is solved by the presence of vitamin C, which leads to formation
of a stable, soluble complex.
•2 Lumenal Factors: At low pH, non-haem iron is more soluble.
•3 Mucosal Factors: The iron content of the mucosal cells will affect the rate of absoprtion of iron from the
lumen, as it will directly affect the concentration gradient.
•4 Internal Factors: Transferrin saturation, the availability of apotransferrin, and the rate of transferrin synthesis
will all affect iron absorption.
Iron Deficiency
With an iron deficiency, the body does not have enough iron to make haemoglobin. RBC synthesis may also
decrease, or the erythrocytes produced may be small or not contain enough haemoglobin: microcytic, hypochromic
anaemia. It can be caused by:
•1 Dietary deficiency: although this is fairly uncommon

•2 Increased blood loss: including excessive menstrual blood loss or gastrointestinal bleeding.
•3 Increased requirements: generally associated with major cell growth, such as in pregnancy, lactation, rapid
childhood growth and malignancy.
Iron Excess (haemachromatosis)

An iron excess does not affect blood cells. There will be, however, excess iron storage in the tissues, leading to
failure of the liver, heart or pancreas. It may be due to:
•1 Excessive amounts in diet, eg. medicinal overdose

•2 Genetic disorder: increased iron absorption in the gastrointestinal tract
•3 Repeated blood transfusions: thalassemia, for example is commonly treated with blood transfusions. Each
new tranfusion increases the body’s iron levels.
Physiology 235
Folate and Vitamin B12

Both folate and vitamin B 12 are required for DNA synthesis. Thus a deficiency in either or both of them will lead
to:
•1 decreased DNA synthesis
•2 decreased RBC production
•3 decreased nuclear maturation
•4 macrocytic, megaloblastic anaemia
The following table summarises the causes of folate and vitamin B 12 deficiencies:
Folate Vitamin B12

Dietary deficiency found in leafy green vegetables, found in animal products &
liver, kidney, yellow fruits & mushrooms, so can be a problem for
mushrooms, but destroyed by vegans
excessive cooking
Decreased absorption due to intestinal disease or chronic due to ileal disease or resection, or a
alcoholism lack of intrinsic factor (gastrectomy
or pernicious anaemia)
Increased requirements during periods of cell growth (lactation, pregnancy, childhood growth,
malignancy)
These two deficiencies have identical effects on the blood. The only way to distinguish between them is to look for
neural damage, associated with the B 12 deficiency (the mechanism for this is not known).
Haemoglobin and Red Cell Function

Each haemoglobin molecule consists of 4 subunits: two  subunits and two  subunits. Each subunit consists of an
iron atom Fe2+, a porphyrin ring and a polypeptide (globin) chain.
1 molecule of oxygen binds with each Fe 2+. Therefore 1 molecule of Hb binds 4 molecules of O 2. Binding is weak
and reversible. Fe2+ is not oxidised to Fe 3+. 1 gram of haemoglobin, when fully saturated, binds 1.34mL of
oxygen.
100
80
60
% saturation
40
20
0
0 20 40 60 80 100
partial pressure of oxygen (mmHg)

The sigmoid shape of the oxygen dissociation curve shown to the left is due to haem-haem interactions. At the pO 2
values found in the tissues, a small change in pO 2 will give a large release of O2 from haemoglobin.
Shift to left: increased affinity, caused by increased pH, decreased 2,3 DPG, abnormal Hb.
Shift to right: decreased affinity, caused by decreased pH, increased 2,3 DPG, abnormal Hb.
Physiology 235
Red Cell Metabolism

The red blood cell has no cellular organelles, so metabolism is very limited; only aerobic glycolysis and the
pentose phosphate shunt (hexose monophosphate pathway) provide energy. Four important metabolites are
produced in these pathways:
ATP: This is produced by anaerobic glycolysis, and is needed to make glucose available for further metabolism
(glucose ® glucose 6-phosphate) and to operate ion pumps in the membrane.
NADH: This is formed from NAD+ by aerobic glycolysis. NADH provides the reducing power necessary to
maintain the iron of Hb in its reduced (ferrous) form. Normally it is slowly oxidised to met Hb, but the enzyme
methaemoglobin reductase, using NADH as a co-factor, reverses this.
2,3 DPG: This binds to deoxygenated (reduced) Hb and affects its O 2 affinity. Metabolic alterations in cells can
change levels of 2,3 DPG causing shifts in the O 2 dissociation curve and changing O2 delivery to the tissues.
Increased production is an important compensatory mechanism in anaemia.
NADPH & glutathione: This is necessary to maintain -SH groups in red cell membrane, enzymes and Hb in their
active reduced form. This is achieved by the tripeptide glutathione (GSH). In the process of reducing -SH groups,
GSH is oxidised to G-S-S-G (oxidised glutathione). This is reduced to GSH by the enzyme glutatione reductase
which requires NADPH as a hydrogen donor. NADPH is maintained in the reduced form by the hexose
monophosphate pathway.
Red Cell Destruction

Life span: Normally red blood cells survive in the circulation for approximately 120 days. We can measure
RBC life span by tagging RBCs with radioactive labels and measuring the disappearance of tagged
cells from the circulation.
As erythrocytes age, a number of changes occur which cause the cells to become less deformable, more fragile and
have altered cell surface structure. These cells eventually become trapped or rupture in the spleen (and, to a lesser
extent, the liver and bone marrow) where they are engulfed by macrophages. This is known as extravascular lysis.
Haemoglobin
Haem Globin
Bilirubin CO Iron Amino acids

(urine & faeces) (expired) (re-used) (re-used)
Normally, less than 10% of our RBC breakdown is through intravascular lysis, however this level is raised in
some haemolytic anaemias.In this form of breakdown, haemoglobin travels to the liver bound to haptoglobin and
haemopexin, where essentially the same breakdown occurs as in the macrophages.
Physiology 235
Lecture 20 - Erythrocytes & Anaemia II
Anaemia
This is defined as a decrease in Hb concentration in the blood. The normal values are shown below:
Subject [Hb] (gL-1)

Birth 170
1 - 3 months 140
3 months - 5 years 120
6 - 10 years 120
11 - 15 years 130
Adult male 150
Adult female (pre-menopausal) 135
Pregnancy (last trimester) 120
Clinical Features
These are bacially those of oxygen lack: less Hb causes less carrying ability.
Mild Anaemia: Symptoms are generally associated with an underlyling cause. Will have symptoms of O 2
lack during exercise (excessive dyspnoea and palpitations).
Severe Anaemia: As above plus tiredness, easy fatiguability generalised muscle weakness, throbbing
headache, pounding pulse, and possibly cardiac failure due to compensatory increase in
cardiac output.
Compensatory Mechanisms
Oxygen transport is basically determined by the oxygen carrying capacity of blood. Fortunately it is also affected
by the cardiac output and the A-V oxygen difference.
Increased Cardiac Output

Decreased viscosity causes increased venous return and hence increased stroke volume. Also a drop in TPR
(induced by vasodilation from hypoxia) causes a reflex increase in cardiac output. Increased CO is responsible for
the throbbing heaches, poundpulse and cardiac failure.
Redistribution of Blood Flow

It is redistributed from low O2 consumption tissues (skin), to high O 2 consumption tissues (heart, CNS, skeletal
muscles). This accounts for the pallour associated with anaemia, and is caused by vasodilation from local hypoxia.
Incrased A-V Oxygen Difference

This is through an increase in 2,3 DPG levels, shifting the O 2 dissociation curve to the right, and increasing oxygen
delivery to the tissues.
Maintenance of Blood Volume

Total blood volume can fall during anaemia, possibly by having small erythrocytes. It can be maintained by
increasing plasma volume through short-term fluid shifts.
Physiology 235
Lecture 20 - Erythrocytes & Anaemia II
Classification of Causes of Anaemia
¯ Erythropoietin
Hyperproliferation
Marrow damage (chemicals, drugs
radiation, idiopathic, infiltration)
¯ Production
¯ DNA synthesis (B12 / folate deficiency)

Maturation
¯ Hb synthesis (Fe deficiency, globin /
porphyrin defect)
Anaemia
Intrinsic (membrane / metabolic / Hb defect)

Haemolytic
Extrinsic (antibodies, chemicals, drugs, toxins
IV clotting, burns, hypertension)
Loss/Destruction
Acute Blood Loss
Thalassemias involve a defect in the alpha or beta globin chains. With less productive globin, there will be less
haemoglobin.
Sideroblastic anaemias involve the erythroblasts containing a ring of large iron granules encircling the nucleus.
Polycythaemia
This is usually defined in terms of the PCV, but can be defined as abnormally high haemoglobin concentration in
the blood:
Males Hb > 180g/L PCV > 0.54

Females Hb > 160g/L PCV > 0.49
Clinical features
Inadequate O2 supplies due to increased viscosity of the blood. This causes malaise, fatigue, headaches, etc. It may
also cause congestive heart failure and thrombotic disorders. Treatment is dependent upon the underlying
condition, but may include phlebotomy (removal of blood).
Classifications
Relative: due to dehydration (decreased plasma volume)
Absolute: primary increased erythropoeitin (from renal tumour)

stem cell malignancy (polycythaemia vera)
secondary physiological response to chronic tissue hypoxia (from high altitude, pulmonary
disease, abnormal haemoglobin, decreased 2,3DPG or renal artery stenosis)
Physiology 235
Lecture 21 - Leukocytes
Leukocytes
Total circulating white cell count: 4-10´109 cells/L
Leukocytes % in circulating blood

Neutrophils 40-75
Eosinophils 1-6
Basophils <1
Monocytes 2-10
Lymphocytes (T&B) 20-50
General Properties of Granulocytes & Macrophages

•1 Ameboid motion: the capability to move through the tissues, by extending cytoplasmic protrusions which
attach to tissues, and then dragging the rest of the cell behind.
•1 Diapedesis: the ability of the cells to squeeze through small pores in capillaries.
•1 Chemotaxis: the motion of cells toward a source of infection, aided by an increase in capillary permeability.
Chemotactic substances include bacterial toxins, cell breakdown products, complement factors, and substances
released by other WBC. The steps involved are margination, diapedesis and ameboid motion along
concentration gradients (low to high).
•1 Phagocytosis: the engulfing of particles by cells. First the cells attach themselves to the particle, then they
encircle the particle with pseudopodia. The pseudopodia fuse together, forming a phagosome containing the
particle, which then fuses with lysosomes and granules containing digestive enzymes and bacteria to break
down the particle.
Specific Functions of WBC

Neutrophils
These are phagocytic cells which can ingest small particles of cell debris: up to ~20 bacteria each. They are very
sensitive to chemotactic substances, are highly mobile, and are present in blood in large numbers. They are
therefore the first WBCs to sites of infection in effective amounts.
Eosinophils
These are weakly phagocytic cells, whose main roles are external attacks in parasitic infections, and limiting of
inflammatory and allergic reactions. They are attracted to such sites by eosinophilic chemotactic factor, released
from basophils and mast cells. On arrival, they detoxify substances which induce inflammation, and they also
destroy allergen-antibody complexes, preventing spread of the inflammation.
Physiology 235
Basophils
These are functionally (but not morphologically) the same as mast cells. They are responsible for initiation of the
inflammatory response, by release of their granules, which contain histamine, serotonin, bradykinin, heparin (an
anti-coagulant) and eosinophilic chemotactic factor. They also increase capillary permeability, allowing more
WBCs, antibodies, and clotting factors to the site of infection.
They also initiate the allergic response. IgE antibodies bind to the surface of basophils. When the allergen binds to
this antibody, the basophil ruptures, releasing:
•1 histamine
•2 serotonin increased vasodilation &
•3 bradykinin capillary permeability
•4 heparin
•5 lysosomal enzymes tissue damage
•6 slow reacting substances of anaphylaxis smooth muscle spasms
•7 eosinophilic chemotactic factor
Examples of allergic responses include:
Skin: urticaria (hives)

Eyes: itchiness from histamine
Bronchi: asthma attack from smooth muscle spasms
Circulation: anaphylactic shock
Monocytes
These are only active once they become mobile macrophages in the tissues (after 8 hours). These are powerful
phagocytes, able to absorb ~100 bacteria each, or larger particles, and can detoxify harmful chemicals. They are
also responsible from antigen modification and presentation to lymphocytes. Some of the cytokines (hormone-like
substances) they release include:
Cytokine Increased production of...

Interleukin I lymphocytes
G-CSF granulocytes
M-CSF monocytes
GM-CSF granulocytes & monocytes
Lymphocytes
There are two types of lymphocytes: B cells and T cells. These are morphologically identical, but functionally
quite different.
B cells: humoral immunity (antibody production and complement activation)

T cells: cell-mediated immunity
Preprocessing occurs in the thymus or the bone marrow. This makes the lymphocytes functional or
“immunocompetent”. Specific receptors for foreign antigens are inserted into the membranes.
Physiology 235
B Lymphocyte Response to Specific Antigen

Before 1st Exposure 1st Exposure
(days)
a few B cells specific proliferation many plasma
for antigen cells
antibodies
2nd Exposure
(hours)
many memory cells many more
specific for antigen plasma cells “memory” B cells
specific for antigen
more antibodies
more memory cells
The second exposure to the antigen results in a faster and stronger response (more antibodies).
Effects of Antibodies
Binding of antibodies to antigens causes the following:
•1 agglutination (aids phagocytosis)

•2 precipitation (aids phagocytosis)
•3 neutralisation (antibodies cover toxic sites)
•4 cell lysis (rarely)
•5 activation of the complement system (proteolytic enzyme cascade)
This proteolytic enzyme cascade need not be known in detail. Activation is brought about by either an antigen-
antibody complex (which takes hours to days) or by some micro-organisms binding to factors B & D, starting the
cascade at C3.
If started at the beginning, however, C1 is the first enzyme, leading to C2, etc. The final product is C5b6789,
which lyses foreign cells. Along the cascade, the number of factors produced gradually increases.
Other useful by-products include:
C3b, which causes opsonisation of bacteria (immune adherence)

inflammation factors, acting directly or through basophil activation
C5a, which is chemotactic for all leukocytes
other factors which can directly cause viral neutralisation and agglutination
Physiology 235
T Lymphocytes
The response of T cells to specific antigens is identical to that of B cells, however the products, rather than plasma
cells and antibodies, are activated T cells. There are three main types of activated T cells:
•1 Helper T Cells: These secrete lymphokines, with the following effects:

•1 stimulate production of other T cells (including other helpers)
•2 stimulate production and function of B cells
•3 stimulate production of neutrophils and macrophages (GM-CSF)
•4 activate macrophages
•5 inhibit viral replication and infection - interferon
Hence these stimulate virtually all aspects of the immune response. Without helper T cell activity, the
body’s defenses are severely limited (eg. AIDS).
•1 Cytotoxic (Killer) T Cells: These bind to foreign cells (micro-organisms, transplant cells, etc.) or altered cells
(virally infected cells, cancer cells, etc.) and secrete cytolytic substances to destroy them.
•1 Suppressor T Cells: These secrete lymphokines which inhibit other T and B cells.
Physiology 235
Lecture 22 - Platelets & Haemostasis
Haemostasis
Haemostasis is the set of processes which maintain vascular integrity, arrest bleeding and initiate repair when
blood vessels are damaged. The stages involved are:
•1 vasoconstriction
•2 platelet activation: platelet plug formation
•3 coagulation: formation of fibrin clot
•4 fibrinolysis: removal of clot, allowing repair
Vasoconstriction
This is initially myogenic and possibly neurogenic constriction of damaged vessels and supplying arteries and
arterioles. Secondary vasoconstriction follows the release of vasoconstrictors from platelets and damaged tissues:
•1 thromboxane A2 (a prostaglandin-type molecule)

•2 ADP
•3 serotonin (can cause vasoconstriction or vasodilation)
Vasoconstriction is generally short-lived, not contributing much to the process of haemostasis.
Platelet Activation
The platelet membrane has three important properties:
•1 it contains receptors for activating agents

•2 it contains a specific phospholipid which is required for coagulation reactions
•3 it acts as a storage site for arachidonic acid (for synthesis of thromboxane A 2
The platelet response can be described as follows:
•1 Adhesion to exposed collagen
•1 Aggregation, initially induced by collagen nd ADP released from damaged cells. Further aggregation occurs
after release of substances from activated platelets, eg. thromboxane A 2
•1 Activation involves:
•1 shape change
•2 exposure o f the pro-coagulant phospholipid on membrane surface
•3 synthesis and release of thromboxane A2
•4 release of granular contents
•5 increased intracellular Ca++
Physiology 235
The platelet plug stays intact for 2-3 minutes, before being broken down by lysosomal enzymes. It must therefore
be reinforced by fibrin. This binds the platelet plug with neighbouring red cells forming a solid clot. Note: PDGF
is “Platelet-derived growth factor”, which stimulates the division of vascular endothelial cells of smooth muscle
cell and of fibroblasts.
Coagulation
Coagulation is an enzyme cascade: inactivated clotting factors are sequentially activated, becoming proteolytic
enzymes and continuing the chain. The end product is fibrin.
Intrinsic activation Extrinsic activation

(foreign surface) (tissue factor / factor III)
Prothrombin activator complex
Prothrombin Thrombin XIII
Fibrinogen Fibrin
(soluble monomers) (insol. monomers)
XIIIa
X-linked fibrin
(covalently bonded)
Vitamin K Dependent Coagulation Factors

Factors II, VII, IX and X require post-translational modifications to become effective. This involves a -carboxy
group addition, and requires the presence of Vitamin K. Other Vitamin K dependent proteins have recently been
found in the plasma: proteins C & S.
Fibrinolysis
Plasminogen activators
These reactions occur on or within the fibrin clot.
Plasminogen Plasmin
Fibrin Fibrin degradiation products

Physiology 235
Regulation of Haemostasis
•1 Intact healthy vessels
These secrete prostacyclin, which inhibits platelet aggregation. Pathological changes to the blood vessel
walls leads to activation of platelets and coagulation factors, causing thrombosis.
•1 Surface localisation of reactions

Platelets aggregate at haemostatic sites, providing the surface for coagulation reactions. Complexes are
held together by Ca2+. Fibrinolysis reactions occur on the fibrin slot surface.
•1 Inhibitors
Coagulation: antithrombin III (inhibits Xa, IXa & IIa), protein C & S (inhibit VIIIa & Va), fibrin
degradation products (inhibit fibrin polymerisation).
Fibrinolysis: 2 antiplasmin (inhibits plasmin).
General Protease Inhibitors: 2 macroglobulin, 1 antitrypsin, C1 esterase inhibitor.
•1 Balance between systems

There must be equilibrium between the two opposing systems: coagulation and fibrinolysis.
•1 Removal of factors
Macrophages remove excess activated factors in the liver, spleen, etc.
Disorders of Haemostasis
Haemorrhagic
Acquired: liver disease

vitamin K deficiency (malabsorption, treated with long-term oral antibiotics)
thrombocytopenia
Genetic: haemophila A (factor VIII deficiency)

haemophilia B (factor IX deficiency)
Thrombotic
Acquired: damage to vessel walls (atherosclerosis)

increased platelet activity
reduced blood flow / increased tissue factor (post-operative thrombosis)
Genetic: rare, such as decreased antithrombin III

Physiology 235
Therapeutic Agents
Anticoagulants are used to prevent excessive coagulation. They are divided into three groups:
•1 Heparin: an immediate-acting anticoagulant given by IV injection. It binds to the naturally occurring

thrombin inhibitor, antithrombin III (AT III), altering its conformation so that the reactive site is more
available to the serine centre of thrombin. This accelerates the inhibition of thrombin. Heparin-AT III also
inhibits Xa and IXa.
•1 Vitamin K antagonists: eg. warfarin (oral anticoagulant). Vitamin K is a necessary cofactor for post-
translational modification of factors II, VII, IX and X, adding on an extra -carboxy group. Vitamin K
anatagonists prevent this -carboxylation, giving rise to coagulation factors which fail to bind Ca 2+ and
therefore do not function normally. As these anticoagulants act on coagulation factor synthesis they take
several days to become effective.
•1 Anti-platelet drugs: these are a fairly recent addition to the anticoagulant drugs. They function by inhibiting
prostaglandin synthesis. In the absence of thromboxane A 2 paltelet aggregation is greatly reduced. The
most common of these drugs is acetylsalicylic acid (aspirin).
Thrombolytic agents are used to lyse intravascular thrombi: the most commonly used is Tissue Plasminogen
Activator (TPA), which is the plasminogen activator produced by damaged tissues. It is most effective when
applied directly to the sites of the thrombus via a catheter. TPA activates plasminogen in the thrombus to form
plasmin which lyses the thrombus. It is currently used to treat myocardial infarctions. If given within one hour
there is minimal damage to the heart muscle.
Physiology 235
Lecture 23 - Blood Groups & Plasma Proteins
Blood groups are genetically determined antigenic characteristics of blood components. In the broadest sense this
applies to antigens on red cells, white cells, platelets and plasma proteins; in common usage term refers to red cell
antigens, the most important of which are those of the ABO and Rhesus systems.
ABO Blood Groups

Blood Group Antigen on RBC Possible Genotypes
A A AA, AO
B B BB, BO
O neither OO
AB A&B AB
There are 3 allelic genes on chromosome 9: A, B and O. The A and B genes are co-dominant, allowing the
presence of an AB blood group. The O gene is recessive to both, hence for a blood group of O, the subject must be
homozygous for that gene.
The genes code for enzymes which act on a precursor carbohydrate chain on the red cell membrane, ending in -
galactose. The H gene is necessary as the enzyme it produces adds -fucose to the precursor carbohydrate chain,
giving rise to the H antigen. The enzymes produced by the A and B genes then act on the H antigen, adding -N-
acetylgalactosamine or -D-galactose respectively to produce the A and B antigens. Group O people have only the
H antigen on their red cells.
People without the H gene (a rare condition, where they must be homozygous hh), will always turn up as group O,
even though they may have the A or B genes. This happens because the precursors will be left on the RBCs, rather
than A or B antigens. These people are classified as O(hh) or “Bombay” type blood.
ABO Subtypes
The most common subtypes include:
A1: 810,000 - 1,170,000 Ag/Cell

A2: 240,000 - 290,000 Ag/Cell (weaker reaction)
There are also A3, A4, A5, A6, AM, AD, and AZ, which have decreasing Ag/Cell and weaker reactions. B subgroups
also exist, but are very rare. The following outliens the frequencies of the ABO blood groups in Australia:
O 46.1%
A 39.0% (A1: 29.7%, A2 9.3%)
B 11.4%
AB 3.5% (A1B: 2.3%, A2B: 1.2%)
Physiology 235
Naturally Occurring ABO Antibodies
These antibodies are produced during the first 6 months of life, and present in plasma from then on:
Blood Groups Antigens on RBC Antibodies in Plasma

A A Anti-B
B B Anti-A
O neither Anti-A & Anti-B
AB A&B neither
With ABO incompatible blood transfusions, the antibodies to incompatible cells are already present and in
relatively high concentrations, so there is an immediate, strong response. The antibodies are of the IgM class, with
the following properties:
•1 they cause intravascular lysis of incompatible red cells

•1 cell breakdown products ® anaphylactic shock
•2 free Hb ® renal damage
•3 tissue factor release ® intravascular coagulation
•4 DEATH
•2 they cannot cross the placenta
Rhesus Blood Groups

The rhesus blood group system is dependent upon 5 antigens, controlled by 3 sets of allelic genes at 3 linked loci
on chromosome 1:
•1 C/c
•2 D/d
•3 E/e
Note: the “d” gene is silent, so there is no d antigen.
Rhesus antigens are integral membrane proteins coded for directly by the rhesus genes. All of the genes are co-
dominant (except d). D is the most antigenic gene, and therefore clinically most important:
Blood Group Frequency (%) Antigen on RBC Genotypes

Rh(D) +ve 83.5 D DD, Dd
Rh(D) -ve 16.5 - dd
Rhesus antibodies are not naturally-occurring. They are stimulated by incompatible transfusion or chil-birth. These
IgG antibodies have the follow characteristics:
•1 they cause extravascular lysis

•2 they can cross the placenta
•1 antibodies in the maternal circulation can destroy fetal RBC
•2 this causes HDNB
Physiology 235
Haemolytic Disease of the Newborn (HDNB)
In the past this was most commonly caused by antibodies to the Rhesus D antigen. If a D-ve mother gives birth to
a D+ve child, she is exposed to the child’s D+ve cells at delivery and produced an IgG anti-D antibody. If a
subsequent fetus is also D+ve, its red cells will be destroyed by the maternal anti-D which can cross the placenta.
Prevention of Rh(D) HDNB is possible by passive immunisation of the D-ve mother with anti-D within 72 hours
of delivery of a D+ve child. HDNB cases are now therefore less severe and caused by other antibodies (eg. Rhesus
C).
Plasma Proteins
Separation and classification
separation by molecular weight, electric charge, immulogical reactions
classification: albumin, 1, 2, , and  globulins
Synthesis
most are synthesised in the liver
immunoglobulins are synthesised by B lymphocytes and plasma cells
Catabolism
different rates and probably different mechanisms for different proteins
albumin: catabolism by pinocytosis and intracellular digestion
Distribution
present in plasma and interstitial fluid (concentration much lower in interstitial fluid)
Plasma proteins have three general functions:
•1 Colloid osmotic pressure (oncotic pressure)

•1 ~ 28 mmHg
•2 important in balancing fluid movements across capillary walls
•2 Cell nutrition: source of amino acids
•3 Blood buffers: amphoteric
•1 at normal blood pH (7.35-7.45) proteins exist as weak bases, binding excess H +
•2 contribute about 1/6 of total buffering capacity of blood
Albumin (45gL-1)
45 g/L, 60% of total plasma protein.
contributes 75-80% of colloid OP.
contributes most to buffering and as a source of amino acids.
transport protein for free fatty acids, bilirubin, some hormones (eg. thyroxine), and many drugs.
Immunoglobulins (antibodies)
IgG, IgM, IgA (and small amounts of IgD, IgE).
Antibodies bind to foreign particles and aid in phagocytosis, also activating the complement system.
Physiology 235
Carrier Proteins
transferrin (3g/L) : iron apolipoproteins : lipids
haptoglobin : plasma Hb ceruloplasmin : copper
transcortin : cortisol transcobalamine I & II : vitamin B12
Fibrinogen (2-6gL-1)
When acted on by enzymes of blood coagulation, soluble fibrinogen is converted to insoluble polymers of fibrin
(blood clot).
Proteolytic Enzyme Systems

Blood coagulation system: activated by damage to blood vessels or exposure of blood to foreign surfaces.
Fibrinolytic system: brings about digestion of fibrin clot, allowing healing and restoration of
function in blood vessels.
Complement system: activated by antibodies binding to foreign particles. Produces substances which
aid in phagocytosis, enhance the inflammatory response and cause lysis of
foreign cells.
Kinin system: Activated by inflammation and injury, producing bradykinin (powerful
vasodilator) and enhancing inflammation
Protelyic Enzyme Inhibitors

Inhibit and control the proteolytic enzyme systems of the blood, eg. 1-protease inhibitor (formerly 1-antitrypsin)
and 2-macroglobulin.
Acute Phase Proteins

When tissue injury or infection occur, synthesis of a number of plasma proteins is increased. These are know as
acute phase proteins, and they include:
•1 fibrinogen - stops blood loss and spread of infection

•2 coagulation factors - stop blood loss and spread of infection
•3 complement factors - aid fighting of infection
•4 proteolytic enzyme inhibitors - to control the excess enzymes
•5 haptoglobin - to remove excess free Hb
•6 C-reactive protein - seems to be involved in complement activation
Physiology 235
Lecture 24 - Respiratory Physiology - Review
Important Lung Volumes

Inspiratory Reserve Volume (IRV): maximum volume of inspiration after a normal inspiration
Tidal Volume (TV): normal volume of inspiration or expiration
Expiratory Reserve Volume (ERV): maximum volume of expiration after a normal expiration
Residual Volume (RV): volume left in the lungs after maximum expiration
Inspiratory Capacity (IC): maximum volume of inspiration after a normal expiration

Functional Residual Capacity (FRC): volume left in the lungs after a normal expiration
Vital Capacity (VC): maximum volume of expiration from the lungs after maximum inhalation
Residual Volume (RV): volume left in the lungs after maximum expiration
Total Lung Capacity (TLC): volume in the lungs after maximum inspiration
TLC = VC + RV = IC + FRC = IRV + TV + ERV + RV
Pressures in the Lung

In order to draw air through the conducting part of the respiratory system, sufficient pressure must be generated to
overcome two major forces:
•1 resistance to air flow through the tubes

•2 elastance of the lung alveoli
P Presist + Pelast
Ptotal = Presist + Pelast AND R= SO Rtotal = 
F V
P r esist P V
Raw = V (cmH2O L s )
-1 -1
AND Elast = ela st OR Compliance =
V P ela st
The following graph outlines compliance in the lungs:
Lung Volume (L)

3
0 -1 -2
Intrapleural Pressure (cm Water)
The inner lines are called the “static compliance”: measuring compliance without air flow. The darker lines are
called the “dynamic compliance”: measuring compliance during air flow. The difference between the two paired
curves is due to the presence of resistive forces.
Physiology 235
Elastic Recoil Pressure

The elastic recoil pressure in the lungs determines the maximum air flow. When you exhale, positive pressure is
generated in the alveoli, caused by the value of the elastic recoil pressure. The following graph outlines this
pressure:
Maximum
Expiratory
Flow (Ls-1)
0 4 8 12
Elastic Recoil Pressure (cm H2O)
The broad gray region indicates the function of a normal lung. If elastic recoil is low, such as in emphysema, the
curve will be shorter than normal. If the lung has increased resistance, it will be wider and lower than normal.
Airways Resistance
Clearly the airways resistance is strongly influenced by the diameter of the airways. Thus most of the airways
resistance is created by the large segmental bronchi (diameter 3-5mm). A disease of the small airways will have
little effect, due to their combined small diameter.
The value of airways resistance varies thorughout the breathing cycle: it is a function of lung volume. During
inspiration, the lung exapnds, placing a pressure on the airways, causing dilation.
4 4
3 3
Resistance Conductance
(cmH2O L-1 s-1) 2 2 (L s-1 cmH2O-1)
1 1
0 0
0 2 4 6 8
Lung Volume (L)
As can be seen from the above graph, resistance is inversely proportional to lung volume. Since conductance (G) is
the inverse of resistance, it is directly proportional to volume (as illustrated by the straight line above. However, an
even more useful quantity is the specific conductance:
sGaw = Gaw / V
This value allows comparison between different conditions, and even comparison between different individuals.
Physiology 235
Low airways resistance allows high PEF (peak expiratory flow). However, it is also partly dependent upon effort.
Changing the effort has no effect on the flow rate at the mid to lwo lung low volume: this region is said to be
“efort independent”.
The Breathing Cycle

Pre-Inspiration
•1 no flow of air
•2 no pressure gradient through airways
•3 intrapleural pressure of -5cm H2O
During Inspiration
•1 inspiring because of intrapleural pressure of -7cm H2O
•2 alveolar pressure is -2cm H2O because of elastic recoil
•3 a gradient is developed throughout the airways
End-Respiration
•1 the thorax is expanded
•2 intrapleural pressure is -8cm H2O
•3 there is no flow of air, as the elastic recoil is 8cm H2O
•4 pressure is uniform throughout the system
Forced Expiration
•1 a positive intrapleural pressure of 30cm H2O is created by effort
•2 this adds to the elastic recoil pressure of the lung (8cm H 2O)
•3 the pressure at the mouth is 0 (as always), so there is a pressure drop along the airways
•4 the pressure between the inside (x) and outside (30) will cause “dynamic compression”
•5 as x increases, the dynamic compression increases
It is due to this “dynamic compression”, which is proportional to the original effort that extra effort cannnot raise
the flow rate towards the end of expiration.
Physiology 235
Lecture 25 - Causes of Hypoxaemia
Hypoxaemia & Anaemia

The consequence of many respiratory problems is reduced availability of O 2 in the blood. Reduced O2 content, or
concentration, in arterial blood (ie. <200mL per litre of blood) can occur either because of a reduced O 2 input (ie.
paO2) or because there is a reduced O2 carrying capacity: anaemia.
Anaemia, or reduced O2 carrying capacity, can be caused by two major factors:
•1 reduced [Hb]
•1 reduced Hb synthesis
•2 blood loss
•3 iron deficiency
•1 reduced O2 binding capacity

•1 CO poisoning
•2 deletions / substitutions or globin chains - thalassaemia, sickle cell anaemia
The other cause of hypoxaemia, namely reduced paO2 can be caused by:
•1 alveolar hypoventilation ( V
 A)
•2 ventilation / perfusion mismatch
•3 reduced alveolar-capillary diffusion
•4 anatomical shunt
These four factors will now be discussed in more detail.
Alveolar Hypoventilation
Cardinal features are reduced paO2 and increased paCO2. Generally caused by airway obstruction and/or respiratory
muscle failure.
Airway obstructions
asthma: excessive airway narrowing due to airway wall thickening, oedema, mucous, smooth muscle
contraction - results from airway inflammation/allergy
emphysema: alveolar breakdown reduces adventitial support (radial traction) to the airway wall so the airway
narrows “passively”
bronchitis: excessive mucous production caused by mucosal inflammation

Physiology 235
Lecture 25 - Causes of Hypoxaemia
Respiratory muscle failure
Reduced nerve signal to respiratory muscles:
•1 CNS depression (eg. drug-induced)

•2 dislocation of cervical cord (C3, 4, 5)
•3 duschene muscular dystrophy (genetic mutations for “dystrophin” - deterioration of skeletal muscle strength
and mass
•4 snake bite (alph bungarotoxin toxins contain neuromuscular blockers)
•5 myasthenia gravis (autoimmune disease of nicotinic ACh receptors)
Ventilation / Perfusion Mismatch

Overall the V  A / Q ratio is 0.8, but there are regional differences. If the ratio is reduced (eg. in obstructive
disease), paO2 falls and paCO2 rises. Normally, matching is helped by hypoxic vasoconstriction in underventilated
regions.
Mismatch is a common problem in asthma. It is also associated with Adult Respiratory Distress Syndrome
(ARDS) in which there is excessive hypoxic vasoconstriction. ARDS occurs as a consequence of massive sepsis.
This results in generalised pulmonary vasoconstriction, hypertension, and oedema. Modern treatments are with
Ca2+ channel blockers and inhaled NO.
Reduced Alveolar-Capillary Diffusion

Diffusion  surface area/thickness
From this equation, it can be deduced that reduced alveolar-capillary diffusion can be caused by:
•1 decreased surface area (emphysema)

•2 increased membrane thickness (fibrosing alveolitis)
Anatomical Shunt
A right to left shunt, bypassing the alveoli, results in deoxygenation of arterial blood. There is normally a 2%
shunt bia the bronchial circulation. Causes include:
•1 congenital septal defects in atria or ventricles (“blue babies”: cyanosis)

•2 patent ductus arteriosus in which the duct fails to close at birth
Physiology 235
Lecture 26 - Lung Pathophysiology
Classification of Diseases
It is convenient to divide respiratory problems into obstructive or restrictive disorders. This is not all
encompassing and it does not include many common problems such as hay-fever, respiratory tract infections, etc.
“obstructive” “restrictive”
reversible - COPD - fibrosing - pneumothorax

- asthma - emphysema alveolitis - arthritic diseases of thorax
- bronchitis - pleurisy
Asthma
Airways in the lung are surrounded by mucus glands and smooth muscle with a circular orientation. The asthmatic
airway has a very folded, convoluted wall. This is because the wall has become thicker, and the smooth muscle is
in a state of constant contraction, pushing the mucosa inward and hence causing folding.
allergen lymphocytes
pollen IgE antibodies lipid mediators
house dust mites’ excrement acute muscle
mast cells
flakes of skin or fur from animals (eg. histamine) contraction
cytokines
eosinophils chronic
inflammation
Emphysema
This is a condition causing breakdown of the interstitial septa to break down, resulting in fewer, larger alveoli:
smoke macrophages
or pollution elastase
interstitial
breakdown
a 1 - antitrypsin
Fibrosis
This is also known as fibrosing alveolitis, and is a condition causing thickening of the alveolar walls and
interstitium, due to laying down of excess collagen and elastin.
Physiology 235
Lecture 27 - Lung Function Tests
Lung Function Tests

A preliminary “diagnosis” can be made from patterns of lung function. For this a battery of tests are performed. In
the case of obstructive disease a further classification of reversible vs. chronic is made on the basis of reversibility
by a bronchodilator drug such as Ventolin (salbutamol: beta agonist). Chronic obstructive pulmonary disease
(COPD) is thought to be a mixture of asthma, emphysema and bronchitis.
Flows & Lung Volumes

A flow-volume curve is used to determine peak expiratory flow (PEF). Flow is measured by expiring through a
pneumotachograph from TLC to RV. The volume is measured simultaneously by integrating the flow signal.
Three patterns are seen:
Obstructives typically have a high RV and

FRC but a reduced PEF and MEF.
normal
8 Restrictives have a low FRC and RV and
reduced PEF because of low lung volume.
6
obstructive 4 restrictive
9 8 7 6 5 4 3 2 1 0
Lung volume (L)
Measuring FEV1
Flow is very dependent on lung volumes (eg. VC). Therefore FEV 1 is also important, and is expressed as a % of
the forced VC.
Normal Obstructive Restrictive

FEV 4.0 1.3 2.8
FVC 5.0 3.1 3.1
FEV1 80% 42% 90%
Obstructive: airways are narrowed because of smooth muscle contraction (asthma) or loss of radial traction
(emphysema)
Restrictive: airways wide open because of increased radial traction
Physiology 235
Lung Volume
FRC (or intrathoracic gas volume) is measured by He dilution or by whole body “plethysmography”.
Plethysmography
The subject sits in a fixed volume plethysmograph and breaths normally through a mouthpiece from which mouth
(ie. lung) pressure is recorded when the shutter is closed. The subject pants against the closed shutter. During
panting, lung pressure and lung volume change.
Boyle’s Law is applied twice during calculations:
1) To determine change in lung volume, V, during the pant, from changes in box pressure:
P1V1 = P2 (V1-V)
V = P1V1/P2
2) To determine FRC from changes in lung pressure during panting:
P3V3 = P4(V3 + V)

V3 = (P4V/P3-P4)
In practice, the relationship between box pressure and lung pressure is plotted, and the slope represents the lung
volume.
Airways Resistance
Measurement of airways resistance is also carried out in the whole body plethysmograph during normal breathing:
P - Pa lveoli
R a w = m out h
V
Air flow can be measured at the mouth using a pneumotachograph. Alveolar pressure cannot be recorded directly,
but is proportional to the change in box pressure during breathing. Therefore the box pressure should be plotted
against air flow, and the resulting slope is the R aw. This is normally partitioned into inspiratory and expiratory
values, as the slopes are often significantly different.
Obstructive disease: high slope (representing higher airways resistance)

Restrictive disease: normal slope
Single Breath Nitrogen Test

This test is divided into two parts:
•1 test for uneven ventilation

•2 airway closing test for small airway stability
Physiology 235
Uneven Ventilation
This tests whether a single breath-in of oxygen is distributed evenly throughout all the alveoli, or whether more of
it goes to one region than another (ie. it is unevenly distributed). Uneven ventilation occurs if certain bronchi are
more obstructued than others - this is very typical of asthma, but it would also occur with physical obstructions or
tumours. The procedure is as follows:
•1 exhale
•2 slowly inhale 100% O2 to TLC
•3 slowly exhale though a mouthpiece connected to a N2 analyser
•4 record the % N2 in the exhaled gas at the mouth
TLC RV At the end of expiration, all alveoli contain gas which is

50 about 80% N2. On inspiration, the 100% O2 will go fairly
1 2 3 4
evenly throughout the lung. Depending on your lung
40 volumes the N2 in the lung will have become diluted, eg.
to 40%.
30
% nitrogen
20
10
6 5 4 3 2 1 0
Lung volume (L)
On exhalation the first few hundred mLs of gas will have been in the dead space and will therefore contain 100%
O2 and 0% N2. This is “phase 1” on the recording to the left.
Then alveolar gas will begin to appear at the mouth, during “phase 2”. After about 750 mLs, pure alveolar gas will
appear at the mouth. This should contain about 40% N 2 and should remain close this level (within 2%) whilst most
of the remaining alveolar air is blown out (“phase 3”).
In the event that the inhaled gas was evenly distributed then some regions of the lung would contain gas containing
less O2 and correspondingly a higher % N2. On exhalation, this gas would be gradually delivered to the mouth, and
so there would by a greater proprtion of N2 in “phase 3”, ie. >2% increase in N2.
Closing Volume
At very low lung volumes (near RV) some of the small airways at the base of the lung close-off. Diseased airways
are more likely to close than healthy ones. This test establishes the lung volume at which small airway closure
occurs.
This test is performed with the above test for uneven ventilation, except the subject exhales to RV. Near this
volume, the % N2 in the expired air suddenly rises, marking the “closing volume”, and this is usually <600 mLs
from the RV.
Alveoli at the base of the lung are normally smaller (less inflated) than alveoli at the apex. This is because the
pressure around the lung base is higher than around the apex - so the alveoli at the base and apex are at different
starting positions on their respective pressure-volume curves.
Physiology 235
100%
apex of lung
volume
50%
base of lung
+10 0 -10 -20 -30
intrapleural pressure (cm water)

Consequently, on inspiration of the 100% O2, a greater proportion of O2 goes to expanding the lower alveoli and a
lesser proportion of O2 goes to the upper alveoli.
On expiration, as the lung volume approaches RV, the pressure around the base of the lung is ~0 (ie. atmospheric),
and so the little airways and alveoli at the base start to close off. Accordingly, the only air now being delivered to
the mouth is air that is coming from the upper regions of the lung - and these contained less O 2, so more N2.
At the point of airway closure, the % N 2 suddenly rises: the “closing volume”. In a normal lung, the closing
volume is <600 mLs from RV - in small airway disease it is >600 mLs from RV.
Measurement of Gas Diffusion


V 
V
ga s CO
Diffu sion Ca pa cit y = CO Diffu sion Ca pa cit y =
P1 - P2 PACO
The rate of diffusion of gas from the alveolar air to the pulmonary capillary blood is dependent on:
•1 surface area of the alveoli

•2 thickness of the “membrane”
•3 diffusing pressure (pp of gas in air vs. blood)
•4 blood flow through the lung
It might be sensible to measure diffusion of O2 or CO2, but this is hard because you have to do arterial puncture for
estimating either partial pressure in pulmonary capillary blood. Instead CO is used, because it combines so readily
with Hb that ‘none’ is left in physical solution in the blood and so the pCO is practically zero, and it can be
ignored. The following is an outline of the procedure of this test:
•1 rest subject (remember, diffusion partly depends on cardiac output)

•2 inhale gas mixture containing 0.3% CO and 10% He (allowing lung volume to be measured)
•3 record inspired volume and so calculate the CO amount in mLs delivered to the lung
•4 hold breath for 10 seconds (to allow some of the CO to diffuse into the blood)
•5 exhale and measure % CO and pCO in alveolar air
•6 calculate the amount of CO left after diffusion
•7 calculate the difference between input and remaining CO: diffusion in mLs/mmHg/min
This is the diffusing capacity, or transfer factor. It is normally about 30 mLs/mmHg/min. Several disease states
reduce this rate of diffusion (eg. emphysema, fibrosing alveolitis). It is increased in exercise.
Physiology 235
Lecture 28 - Normal & Abnormal Cardiac Performance
Muscle Mechanics Revision

When muscle contracts, depending upon the conditions imposed on the muscle, its length may be held fixed and it
may be made to develop force without shortening - isometric contraction; or it may be allowed to shorten against
zero resistance - isotonic contraction; or something in between.
Muscle in the intact heart displays a combination of the two, ie. muscle in the left ventricular wall develops tension
which is transmitted to the cavity to generate intracavitary pressure. When the pressure in the left ventricle reaches
aortic diastolic pressure, the aortic valve opens. Muscle shortening proceeds against aortic pressure, reducing the
size of the ventricular cavity and resulting in ejection of blood through the aortic valve.
During ejection, 1/2 to 2/3 of the end-diastolic volume (EDV) is ejected as stroke volume (SV) and the ratio of
SV:EDV is called the ejection fraction. Greater resistance to ejection (greater arterial systolic pressure,
necessitating greater ventricular systolic pressure and more left ventricular wall tension) will reduce the amount of
muscle shortening and hence reduce stroke volume and ejection fraction. Increase in end-diastolic muscle fibre
length and by the Frank Starling mechanism, this results in greater shortening (ie. greater stroke volume) during
systole.
Increase in contractility or inotropic state of the left ventricle results in greater muscle shortening (and stroke
volume) if end-diastolic volume (fibre length) and resistance to shortening (wall tension and hence arterial
pressure) remain constant. Note: increase in contractility also implies more rapid shortening and sometimes this is
the main expression of increased contractility.
Valves
There are four valves associated with the heart:
•1 atrioventricular valves: tricuspid and mitral atria to ventricles

•2 semilunar valves: pulmonary and aortic ventricles to arteries
The valves normally allow free forward flow of blood when open, having orifcies suffieicntly large to allow flow
with essentially no pressure difference being required to drive blood across the valve. Stenosis of the valves
necessitates pressure differences in this way. If any blood leaks backwards through a valve, it is said to be
incompetent and to allow regurgitation.
Ventricular Pressure & Heart Sounds

Pressure begins low and rises slowly as diastole proceeds and blood flows freely from left atrium to ventricle
through the mitral valve. Just before ventricular contraction, the atrium contracts. This increases the rate of flow
across the mitral valve, and produces a further “kick” in pressure (the “a wave”) in the left ventricle and atrium.
The atrium starts to relax and the ventricular pressure is momentarily above atrial pressure. The mitral flaps begin
to float together.
Physiology 235
The left ventricle begins to contract, and a pressure rise occurs, which completes the closure of the mitral valve.
This is accompanied by the 1st heart sound, which therefore marks the beginning of ventricular contraction.
Isovolumic ventricular contraction proceeds, with a rapid rise in wall tension and intracavitary pressure, until the
ventricular pressure reaches the aortic pressure, when the aortic valve opens.
The ventricular muscle shortens, ejecting the stroke volume against aortic presure. As the ventricle relaxes, the
pressure drops, closing the aortic valve, and causing the 2nd heart sound. Isovolumic relaxation proceeds, until the
ventricular pressure falls below atrial pressure, when the mitral valve re-opens, and blood is allowed to flow in the
ventricle. This flow sometimes causes a 3rd heart sound in normal young people.
If atrial contraction is very powerful, it also may set up audible ventricular vibrations, called the 4th heart sound,
but this is not normal.
Atrial Pressure
Atrial pressure is low throughout the cardiac cycle but shows phasic changes in wave form. As the atrium
contracts, blood is forced into the ventricle, but pressure rises in both atrium and ventricle: the “a wave”. The
atrium then relaxes and ventricular contraction pulls down the A-V ring: the “x descent”. Throughout the later part
of ventricular contraction blood banks up in the atrium behind the closed mitral valve, giving a rise in pressure: the
“v wave”. As the ventricle relaxes, and the mitral valve opens, the pressure falls: the “y descent”. From here the
pressure rises, but only slightly, throughout diastole, as blood flows freely from atrium to ventricle.
Right vs. Left Heart

Events on the right and left sides of the heart are almost synchronous. Mitral and tricuspid closure are usually so
close that only one component of the 1 st heart sound is heard. However, right ventricular ejection normally
continues longer than left, especially during inspiration and pulmonary valve closure occurs after aortic closure.
The 2nd heart sound is therefore commonly heard to be split into two components (“A2, P2”) during inspiration,
while the components come together and are heard singly in expiration.
Opening of the mitral valve (or aortic valve) cannot normally be heard, but if the mitral valve is stenotic with high
pressure in the left atrium, the pressure level at which the mitral valve opens is high, and as ventricular pressure
falls a large pressure differential between atrium and ventricle is rapidly established; the mitral valve “bangs
open”.
Valve Dysfunction
Forward flow of blood across valves does not usually produce audible sound, but with a stenotic valve the velocity
of flow across the narrowing increases, the pattern of flow is distorted, turbulence is set up, and a heart murmur is
produced. Similarly, regurgitation produces murmurs.
Physiology 235
Valve incompetence produces regurgitation of blood and “volume overload”. Valve stenosis requires a higher
pressure in the chamber proximal to the stenosis to drive blood across the valve - pressure overload. The heart may
compensate acutely (tachycardia, dilatation involving the Frank Starling mechanism, increased contractility) or
chronically (structural changfes of dilatation and/or hypertrophy).
Volume overload is compensated for primarily by dilatation (and secondarily hypertrophy). Pressure overload
requires more muscle - hypertrophy; but not a greater cavity volume - no initial dilatation.
Mitral Regurgitation
Normally the mitral cusps approximate towards the end of diastole and ventricular contraction completes closure
of the valve. The two cusps are held by their chordae and the co-ordinated function of the papillary muscles, no
flow occurring from LV to LA. The pathophysiology of a leak, or regurgitation, at the mitral valve depends upon:
•1 the volume of regurgitation (and hence arterial pressure level)

•2 the rapidity of its development
•3 the size and compliance of the left atrium
•4 the contractile state of the LV myocardium
•5 the cardiac rhythm
For example, severe mitral regurgitation may develop acutely with rupture of a papillary muscle or of a chord, or
with perforation of a cusp by infection. The left atrium is normal sized; it is not adapted to accommodate the
regurgitated blood and pressure rises markedly in the LA during ventricular systole. Other possible changes could
include:
•1 greatly increased mean LA pressure

•2 elevation of LV diastolic pressure
•3 fluid retention and other compensatory changes
Clinical Recognition of Mitral Regurgitation
The major finding leading to the diagnosis is an apical systolic murmur. Characteristically, the murmur is:
•1 long systolic or pansystolic
•2 blowing and high pitched, but can be harsh
•3 maximal at the apex radiating to the axilla
Other auscultatory findings may be:

•1 short diastolic murmur due to high early diastolic mitral flow
•2 3rd sound at the end of rapid flow into dilated LV
•3 1st sound may be diminished
Supportive evidence is obtained by:

•1 evidence of LA enlargement: x-ray, ECG, echocardiogram
•2 evidence of LV enlargement: examination, x-ray, ECG, echocardiogram
Physiology 235
Mitral Stenosis
Mitral stenosis results when the mitral orifice (normally ~6cm 2) is narrowed; nearly all cases follow clinical or
sub-clinical rheumatic fever, significant stenosis developing 6 months to years later.
Obstruction to mitral flow leads to increases in LA, pulmonary and right heart pressures. With significant stenosis
this increase necessarily occurs because a pressure gradient is necessary to drive blood across the valve during
diastole. The diastolic valve area, presure gradient and diastolic flow rate are related by Gorlin’s formula:
CO
Va lve a r ea =
(H R  dia st olic t ime)
With severe stenosis, the gradient decreases during diastole until atrial contraction increases it towards the end of
ventricular diastole. With mild stenosis, the gradient may be present only in early diastole, at time of rapid filling,
and during atrial contraction. The gradient is measured from simultaneous LA and LV pressures.
The 1st heart sound is particularly loud in MS because the valve is open at the beginning of ventricular contraction;
the normal floating together of the leaflets of the mitral valve does not occur, since the left atrial pressure is raised.
Diagnosis
This diagnosis is made primarily on clinical examination and identification of the typical apical, low pitched mid
diastolic murmur, and the loud 1st heart sound. Evidence of pulmonary venous congestion, pulmonary
hypertension, right ventricular hypertropohy or congestive cardiac failure may be additional findings. History (of
rheumatic fever, symptoms), ECG (LA enlargement, right axis deviation, rarely voltage evidence of RVH), chest
x-ray (LA enlargement, mitral calcification, pulmonary vasculature changes) help in the assessment and are usually
carried out.
Aortic Regurgitation
Chronic aortic regurgitation places a volume load on the left ventricle, leading to structural changes of dilatation
and hypertrophy with normal left ventricular end-diastolic pressure until myocardial failure occurs. SV is increased
to compensate for regurgitation. Myocardial ischaemia is caused by:
•1 large mass of myocardium to be perfused and greater distance for perfusion into hypertrophied myocardial
cells
•2 low aortic diastolic pressure and hence diastolic coronary perfusion pressure
•3 (later) elevated left ventricular diastolic pressure
•4 co-existent coronary artery disease
Symptoms include angina, episodic ischaemic cardiac pain, symptoms of left and/or right heart failure, syncope,
palpitations and sudden death. Signs include early diastolic murmur, aortic systolic murmur, and high pulse
pressure.
Physiology 235
Aortic Stenosis
This is most commonly aortic valve stenosis, but must be differentiated from subvalve stenosis. If the aortic valve
is narrowed to less than ~1.5cm 2, then a gradient is required to eject blood. A decrease in the rate of ejection
through the valve leads to small volume and a slow rising arterial pulse. Myocardial ischaemia may occur for
similar reasons to that in aortic regurgitation. Syncope may occur on exertion or at other times.
Symptoms are angina, syncope, symptoms of pulmonary congestion and sudden death, while the warning signs
include aortic systolic or mid-systolic murmur, soft or absent A 2 sound, evidence of left ventricular hypertrophy
and a slow rising pulse.
Tricuspid Valve Disease

Tricuspid regurgitation is usually ‘functional’ and is much more common than stenosis which is organic and
usually rheumatic. Tricuspid murmurs typically increase with inspiration due to greater venous return to the right
heart.
Tricuspid Regurgitation
This occurs in severe right heart failure of any cause due to RV and tricuspid ring dilatation. Signs include a long
systolic murmur, large V wave in jugular venous pulse and pulsatile hepatomegaly.
Tricuspid Stenosis
This is uncommon and usually rheumatic. Signs are auscultation like MS, and an increase in jugular venous
pressure.
Atrial Fibrillation in Valvular Heart Disease

Atrial fibrillation occurs late and uncommonly in aortic valve disease, but commonly in mitral valve disease. It
occurs particularly in:
•1 moderate to severe valvular disease & myocardial disease

•2 large left atrium
•3 older patient
Atrial fibrillation
•1 increases risk of thromboembolism; all patients should receive long term anticoagulation.
•2 leads to deterioration of cardiac function
A decrease of cardiac function will initially cause depressed cardiac output and blood pressure, but may be
compensated for in the long term, at the expense of a rise in end-diastolic pressure.
Physiology 235
Arrhythmias
These occur when normal ‘sinus rhythm’ is disturbed by abnormality of electrical impulse generation or
conduction, an arrhythmia or dysrhythmia is present. Arrhythmias may be:
•1 bradyarrhythmias, ie. abnormally slow rhythms

•2 tachyarrhythmias, ie. abnormally fast rhythms
They may be intermittent or persistent. They may be transient or permanent. Their significance depends not only
upon the nature of the arrhythmia, but the setting in which it occurs.
Bradyarrhythmias
These may be associated with depression of impulse generation:
•1 sinus bradycardia: inappropriately slow rhythm which originates in the SA node
•2 slow AV nodal rhythm: SA node function is so depressed that the AV node takes over
They may alternatively be caused by a block in impulse conduction:

•1 within the SA node (uncommon)
•2 within the AV node
•3 in the ventricular conducting system (most common)
AV Block is often due to disease of the ventricular conducting system, rather than the AV node itself. It may be:
•1 1st Degree: Delay between atrial and ventricular depolarisation with prolonged PR interval, and hence this in
itself does not produce bradycardia.
•1 2nd Degree: Some atrial depolarisations do not get through to the ventricles, but others do. This may be a fixed
ratio, or variable.
•1 3rd Degree: Also known as ‘complete heart block’. The atria and ventricles depolarise completely
independently; there is no conduction between them, so P waves and QRS complexes are independent. The
symptoms will be those of low cardiac output or congestion, since the rate of ventricular depolarisation will be
slower than normal.
Tachyarrhythmias
Increase in impulse generation produces tachyarrhythmia, which may originate in the ventricles, the AV node or
the atria. The mechanisms vary with the particular arrhythmia, but the generalisation can be made that there may
be an ectopic focus mechanism or a “re-entry” mechanism. In the latter there may be a well defined ‘circus’
pathway around which a ‘re-entering’ depolarisation wave travels, which may be large or small. However, in atrial
and ventricular fibrillation, there is totally chaotic ‘re-entry’.
Physiology 235
Supraventricular and Ventricular ‘Ectopic Beats’

An impulse arising in the ventricles or above the ventricles, depolarises the tissue before the next impulse from the
SA node has a chance to do so. These depolarisations are then premature and are called premature beats. When
they occur repeatedly, they usually have a constant ‘coupling interval’ with the preceding normal complex. Ectopic
beats are common in the heart in the absence of organic heart disease, with no major importance.
On ECG, ventricular ectopics are associated with a QRS of abnormal shape and prlonged duration, since the
ventricles are not depolarised through the conducting system in a normal sequence. They are not preceded by atrial
depolarisation, ie, a P wave. Supraventricular ectopics will have a normal QRS, preceded by an abnormal
(sometimes inverted) P wave.
Supraventricular Tachycardia
This may be due to an ectopic focus mechanism in the atria, but is more often associated with a re-entry
mechanism. While it usually depends upon a large or small circus pathway, it is common in otherwise normal
patients, and is common with organic heart disease. It is characterised by a regular tachycardia with normal QRS
complexes. P waves may be obvious on ECG but are often buried in other wave forms.
Atrial Flutter
Similar to atrial fibrillation, in that it usually occurs with obvious heart disease. There is, however, a regular circus
movement pathway in the atria, resulting in rapid regular atrial activity at about 200-300/min. The ECG shows a
regularly recurring atrial depolarisation pattern of flutter waves.
Atrial Fibrillation
Depolarisation waves travel randomly and irregularly throughout the atria, resulting in no effective contractions.
The ECG shows absence of any regular P wave, and irregular, fast, QRS complexes. This is a common problem in
organic heart disease.
Ventricular Tachycardia
Almost always associated with organic heart disease. May lead to ventricular fibrillation and death. The
tachycardia originates in the ventricles and hence QRS complexes are of abnormal shape and duration.
Ventricular Fibrillation
There is totally chaotic depolarisation of ventricles and hence no effective ventricular contraction. Unless relieved,
this results in clinical cardiac arrest, cessation of the circulation, and death. It may be reverted by a large electric
shock aimed at depolarising all ventricular myocardium simultaneously.
Physiology 235
Lecture 29 - Electric Activity of the Heart
Physiology 235
Lecture 30 - Cardiac Failure
Circulatory Failure & Cardiac Failure

“Circulatory failure” may be defined as failure of the circulation to maintain adequate tissue blood flow and/or
normal intravascular pressures. When defective cardiac function is responsible, the term “cardiac failure” may be
use.
Circulatory failure: - peripheral circulatory failure

- depletion of intravascular volume
Cardiac failure - cardiogenic shock

- increased cardiac filling pressures
Mechanisms of Cardiac Failure

The following are the mechanisms leading to the syndrome of “cardiac failure”:
•1 inability of the ventricular muscle to meet demands placed upon it by circulatory requirements
•1 loss of functioning muscle and/or depressed contractility of muscle
•2 overwhelming load in the presence of relatively normal muscle
•2 obstruction to blood flow (ie. valve stenosis)
•3 increased impedance to cardiac filling (eg. constriction by constrictive pericarditis)
•1 aggravation of one or other of the above by arrhythmia, commonly atrial fibrilation

•1 removes atrial contribution to ventricular filling
•2 removes normal mechanism for AV valve closure, aggravating mitral/tricuspid regurgitation
•3 associated with rapid irregular ventricular response
•1 a combination of the above (most commonly the case)
And the following are the mechanisms by which the heart and circulation attempt to compensate for a cardiac
pumping defect:
•1 cardiac mechanisms, either acute (tachycardia, increased contractility and the Frank Starling mechanism) or
chronic (dilatation and/or hypertrophy)
•2 adaptation of vascular system: arteriolar constriction, venoconstriction
•3 expansion of circulatory blood volume by salt and water retention (reduced GFR, increased ADH), which may
also cause oedema
Syndromes
The precise syndrome (ie. group of signs and symptoms) which results in any case of “cardiac failure” depends not
only upon the nature of the cardiac mechanisms, but upon compensatory mechanisms and their time relations, ie.
acute damage to heart muscle by myocardial infarction may result in cardiac shock. If time for chronic
compensatory changes is allowed, the manifestations of salt and water retention may become the dominant
features.
Physiology 235
Acute cardiogenic shock syndrome

•1 low cardiac output and organ blood flows
•2 low arterial pressure, despite tachycardia & arteriolar and venoconstriction
•3 possible raised cardiac filling pressures
Congestive syndromes
•1 increased pulmonary or systemic venous pressures
•2 renal retention of salt & water
•1 expansion of intravascular volume
•2 increased capillary pressure
•3 accumulation of interstitial fluid
•3 low cardiac output
•4 normal arterial blood pressure
Left Heart Failure: elevation of left atrial & pulmonary venous pressures
pulmonary venous congestion & increase in pulmonary blood volume
high capillary pressure leading to pulmonary oedema
breathlessness (dyspnoea)
cough & sputum
haemoptysis
Right Heart Failure: “congestive cardiac failure”

elevation of systemic central venous pressure
evidence of congested organs (hepatomegaly, splenomegaly, peripheral)
oedema of lower limbs & sacrum
generally follows left heart failure
The reason for congestive heart failure following left heart failure is linked to renal retention of salt and water. The
fluid which is retained is distributed in the body according to the relative elevation of pulmonary and systemic
venous pressures. Hence even a small elevation of systemic venous pressure will tend to localise fluid in the
systemic tissues if fluid is being retained.
This elevation can be caused by:
•1 pulmonary hypertension, and subsequent increased load on the right ventricle

•1 dilatation and increased filling pressure
•2 hypertrophy with decreased distensibility of the ventricle
•3 “functional” tricuspid regurgition
•2 depression of right ventricular contractility?
•3 the Berheim effect (ie. hypertrophied and/or dilated left ventricle pushing over the interventricular septum and
interfering with the filling of the right ventricle
•4 arrhythmias, leading to impairment of left and right ventricular function
Physiology 235
Exercise
The breathlessness of left heart failure may be severe at rest, or may only become apparent on exertion. The terms
“compensated” or “incipient” heart failure, or “limited cardiac reserve” are sometimes used if symptoms and signs
only then become apparent. That is, pulmonary venous pressure is normal at rest, but increases abnormally with
exercise, and/or cardiac output is normal at rest but fails to increase normally with exercise.
Myocardial Failure
The ventricle is working on a flat part of its function curve. SV and rate of ejection are minimally increased despite
increased ventricular filling and high diastolic pressure. Additionally, if due to ischaemic heart disease, increasing
ischaemia is associated with further depression of myocardial function.
Mitral Stenosis
There is a fixed obstruction; an incrase in flow rate across the valve necessarily requires a greater pressure gradient
and higher left atrial pressure. If MS is significant, pulmonary venous pressure increases and/or CO fails to
increase normally. Additionally, especially if rhythm is atrial fibrillation, excessive increase in ventricular rate may
occur and further encroach on diastole and time for mitral diastolic flow, etc.
Pulmonary Vascular Disease

When significant pulmonary vascular disease and elevation of pulmonary vascular resistance occur, the symptoms
of left heart failure may not continue to increase in severity because “right heart” failure limits the increase in
return to the left heart. If marked limitation of cardiac output or exertion is the most prominent aspect of “heart
failure”, then lethargy, ease of tiring, tends to be the most prominent symptom.
Physiology 235
Lecture 31 - General Aspects of Hormonal Systems
Introduction
The endocrine system is a very important control system for the body, allowing us to react to different external
events. For example, it sllow the cardiovascular system to respond to changes in posture and/or exercise, and co-
ordinates secretion and motility in the gastrointestinal tract.
Some hormones are present to keep our body in general good health, such as secretions from the adrenal glands.
Others need to be present for fine-tuning of metabolic responses, such as insulin from the pancreas in response to
increased blood glucose.
It is useful when discussing the endocrine system, to compare its function with that of the nervous system. Several
comparisons may be made:
Proximity: The chemical mediator of the nervous system (ACh) is secreted in close proximity to the target
cell, with nerves stretching most of the distance. With hormones, the secretion may travel a long
distance through the blood to reach its target cell.
Specificity: In the case of neural transmission, specificity is achieved through the close proximity of the
proximal nerve to the target cell. With blood-borne hormones, specificity is achieved by the nature
of the hormone-receptor interaction and the chemical structure of the particular hormone.
Classification
When talking about hormones, we are considering the control of activity of cells by the secretions of other cells.
This is actually a very diverse process, and can be broken down into three systems depending upon the proximity
and range of the effects:
Paracrine: histamine, 5-HT, prostaglandins, GABA, growth factors, NO, endothelin
Endocrine
peptide hormones: hypothalamic releasing factors, ADH, oxytocin, thyroid hormones, adrenaline,
angiotensin, etc.
protein hormones: insulin, glucagon, gastrin, secretin, parathormone, calcitonin, GH, TSH, LH, FSH, ACTH,
MSH, prolactin, renin, chorionic gonadotrophin, placnetal lacrogen, etc.
steroid hormones: adrenal cortical hormones, sex hormones, vitamin D, etc.
Neuronal: acetylcholine, noradrenaline, GABA, DOPA, CCK, somatostatin, enkephalins, endorphins, etc.
Physiology 235
Characteristics of Endocrine Systems

Low concentrations of hormone
In most cases, the concentrations of hormones (paricularly those secreted in the blood) is extremely low. In fact,
levels were so low that until recently, blood assays were not sensitive enough to even detect the presence of some
hormones.
Specificity
This is a feature of the interaction between the chemical structure of the hormone and the nature of the receptor
process in the target cell. It is essentially a “lock & key” situation, where variations in hormone structure may
affect the ability of the receptor to function and vice versa.
Feed-back control
Several different mechanisms exist to provide feed-back which will ultimately control the level of secretion of the
initiating hormone in any response. The usual mediating substance is another hormone, released by the terminal
targey cell of the process.
End Organ Specificity

The specificity of a hormonal response depends upon:
1. Hormone chemistry
The chemical nature of the hormone determines which cells are going to be affected. There are exceptions, for
example thyroid stimulating hormone will cause production of thyroid hormones, but whether T 3 or T4 is
produced depends upon levels of enzymes in the gland. Another example is testosterone; some cells contain
enzymes which can convert this to dihydroxytestosterone, which has a much more vigorous effect than the
original hormone.
2. Hormone local concentration

In certain situations, the distribution of blood to various target cells is altered, to adjust the concentrations of
hormones present. For example, cells in the pituitary are exposed to higher than normal levels of neurohormone
releasing factors, due to abnormal blood supply.
3. Hormone-protein binding and catabolism

Many hormones bind strongly to proteins in the blood. Since only free hormones are able to interact with target
cells, the rate of dissociation from carrier proteins is important. An example is some of the growth hormones,
and of particular interest are the smaller hormones, which would otherwise be excreted through the kidney.
4. Cell receptor mechanisms

Hormones cannot affect cells which do not possess receptor mechanisms. The predominant class is membrane
receptors, interacting mostly with peptide and protein hormones which are unable to cross the plasma
membrane. In general, steroid hormones are able to diffuse through the membrane, hence reacting with
cytoplasmic receptors. Oestrogen and thyroid hormones diffuse right through the cells and interact with nuclear
receptors.
Physiology 235
Another point to remember is that one hormone may have different effects in different tissues, eg:
adrenaline: cardiac muscle: stimulatory effect

smooth muscle of intestine: inhibitory effect
The receptor mechanisms are actually as important as the hormones themselves. Many deficiencies exist in this
area, with one example including dwarfism, where receptors for various growth hormones are impaired or
deficient.
What is a Receptor?
A specific molecule or macro-molecular complex able to recognise and interact with hormones.
Properties of Receptors
•1 High affinity at physiological concentrations of hormone
•2 Saturation of a (variable) finite number of receptors
•3 Time relationship with hormone action
•4 Tissue specificity of receptors consistent with hormone action
Types of Receptors
•1 Membrane
•2 Cytosolic
•3 Nuclear
Desensitisation occurs when a target cell is exposed to a constant high level of a hormone. When hormone is
detected, the number of receptors on the cell surface will decrease, due to some being internalised. Thus if the level
remains high, the numbers of receptors will remain low, and the response will hence be lowered, compared to if
high and low levels were alternated.
Messages are transmitted into cells by the action of second messengers such as adenylate cyclase, leading to
cAMP, etc. Examples of these second messenger substances include:
•1 cAMP
•2 Ca2+
•3 cGMP
•4 protein kinases (phosphorylations)
•5 inositol trisphosphate & diacylglycerols
•6 arachidonic acid metabolites
Cell Surface Receptors

1. Channel-linked (transmitters)
2. Catalytic (receptor kinases)
3. G-protein linked (linked to cAMP, Ca 2+, etc.)
Physiology 235
G-proteins are substances which act as intermediaries between hormones and receptors. They provide a few of the
large number of possible pathways of varying complexity which can lead to increases of concentrations of second
messengers within target cells.
Calcium: intracellular 10-7 M

extracellular 2 - 3´10-7 M
The concentration of calcium within cells is maintained at very low levels because it is tightly bound to proteins
such as calsequestrin. Specific calcium pumps may become activated to monitor levels. The messages may be
conveyed from the surface membrane to storage organelles by IP 3.
receptor ligand
¯
G-protein Gs/GI
¯
adenylate cyclase
¯
cAMP
¯
A-kinase
¯
phosphorylations
This process allows for both amplification and specificity of the response. Another possible aspect of protein
hormone and receptor interaction: mitogenic effects.
Epidermal growth factor is a hormone. When it binds to its receptor, the receptor itself becomes phosphorylated.
This activates a whole range of things (including oncogenes) by processes involving a cascade of kinases and
calcium, and ultimately causes cell division
Physiology 235
Lecture 32 - Hypothalamic-Hypophyseal System
Other Types of Receptors

Through the activation of certain enzymes, called oncogene products, messages can be transmitted into the
nucleus. Thus signals received at the cell membrane can mediate cell division: the mitogenic effect of hormones.
Examples include insulin and other peptide hormones.
One particular class of membrane receptors is “seven-membrane-spanning proteins”. These have their protein
chain folding backwards and forwards through the lipid bilayer, therefore containing two distinct sections:
•1 an external section, able to interact with specific hormones unable to cross the membrane, and the nature of
which is determined by amino acid sequences
•1 an internal section, with tyrosine residues that may become phosphorylated as part of the hormonal interaction,
causing other intracellular changes
Examples include adrenaline receptors, and rhodopsin. This contains a molecule of vitamin A which is stimulated
by visible light. Also in this class are -adrenergic receptors and muscarinic receptors for acetylcholine.
Cytoplasmic Receptors
Specific intracellular proteins for steroid hormones. The complex then binds to nuclear chromatin. Transcription of
specific mRNA’s is modulated.
Nuclear Receptors
Binding of T3 (& T4) to nuclear receptor-chromatin complexes. Modulates synthesis of specific mRNA’s.
Feedback
Negative Feedback
The action of the hormone leads to either decreased need for the hormone or inhibition of secretion:
•1 Insulin is secreted from pancreatic islets in response to an increase in blood glucose. It then acts to cause
movement of glucose out of the plasma, decreasing levels and hence removing the initial stimulus. This serves
to decrease secretion of insulin: negative feedback.
•1 Antidiuretic hormone is secreted in response to an increase in plasma osmolarity. It causes the kidney to
retain water and hence decrease the osmolarity, removing the stimulus.
•1 The pituitary gland is stimulated to secrete hormones by adjacent brain tissue. Neurones in the hypothalamus
secrete releasing factors that stimulate cells in the pituitary to secrete. The pituitary hormones then cause their
effect on their respective end-organs, which in turn secrete other hormones which provide negative feedback to
either the pituitary or the hypothalamus. Examples of pituitary hormones include thyroid hormone,
testosterone, cortisol, ACTH and growth hormone.
Physiology 235
Positive Feedback
This form of feedback is only in effect for one hormone: estradiol. LHRH, a hypothalamic releasing factor,
stimulates the pituitary to secrete LH, which in turn stimulates cells in the ovarian follicles to secrete estradiol,
leading to production of oestrogen. This occurs just prior to release of the developing ovum, at a time when
oestrogen levels are high. Rather than inhibiting the activity of the hypothalamus and pituitary, it increases their
effectiveness, by increasing synthesis and expression of oestrogen receptors. There is a rapid boost of secretion of
estradiol and oestrogen, which only comes to a conclusion when the ovum is released, and progesterone inhibits
the process.
End-Organ Feedback
When insulin receptors interact with insulin, they become internalised. This is “down-regulation” of receptor
expression, sometimes called heterologous desensitisation: if a hormone is present continuously, a cell will
become less responsive to that hormone. This can be through internalisation of receptors, or some conformational
change decreasing affinity for the hormone.
The Pituitary Gland

Embryologically, the pituitary gland is derived from two sources:
•1 anterior pituitary (adenohypophysis): upbudding from oropharynx

•2 posterior pituitary (neurohypophysis): downward budding from hypothalamus itself
Thus the two sections are functionally and anatomically different. Neurones from the brain pass down to terminate
in the posterior pituitary gland, having direct effects. However, secretions from the neurones in the hypothalamus
also regulate activity of the anterior part of the pituitary gland. This is achieved through the arrangement of
capillaries between the two sections.
The anterior pituitary has a pivotal role in the control of endocrine function in humans and other mammals. Its
functions include control of the following:
•1 activity of the adrenal gland, through secretion of ACTH

•2 growth, through growth hormone, which mediates release of somatomedins from liver
•3 secretion of thyroid hormone from thyroid gland through TSH
•4 reproductive endocrinology (oestrogen, progesterone, testosterone) by secretion of FSH and LH
•5 production of milk, through secretion of prolactin
Hypothalamic Releasing Factors

Hormone No. of Residues Target Cell
CRH 41 corticotrope ® ACTH
TRH 3 thyrotrope ® TSH
GRH 40 somatotrope ® GH
LHRH (GnRH) 10 gonadotrope ® LH, FSH
Somatostatin (SS) 14 (inhibits LH, FSH)
Dopamine (DA) 1 (inhibits prolactin)
Physiology 235
Knowledge of these connections helps us to understand the following two problems:
Why do LHRH neurones have cilia?

This can be explained by the developmental link between the oropharynx and the base of the brain. Respiratory
epithelium is ciliated, so there must be residual expression on some of the neurones in the pituitary gland, such
as LHRH neurones.
Why are some men with anosmia also infertile?

A rare condition, called Kallman’s syndrome results in anosmia (inability to smell). These men are also
infertile; it has been found that they have an abnormality in LHRH, so production of gonadotrophins is not
properly regulated. It has been established that certain cells which originate in the placode region of the
primitive pharynx migrate up to interact with cells in the hypothalamus. These cells eventually reach the pre-
optic area, which is also the location of neurones which secrete hypothalamic releasing hormones associated
with LHRH.
Another important characteristic of the releasing factors is that their release is pulsatile. This is particularly
important in relation to reproductive endocrinology, with the best example being LHRH. If this is infused
continuously, it actually has an inhibitory effect on secretion. This discovery has led to the development of
“chemical castration”, whereby an LHRH analogue is constantly released from a pump in the body.
ADH & Oxytocin

Antidiuretic hormone (ADH) or argenine vasopressin, is secreted from neurones which travel from the brain into
the neurohypophysis. The ADH itself is only a small part of a large precursor molecule, the principle part of which
is neurophysin. It is spliced by peptidases during secretion to produce the final peptide product.
ADH acts by affecting the permeability of the collecting duct of the kidney, altering the reabsorption of water from
the glomerular filtrate. It has the capacity to vary the ratio of urine osmolarity compared with plasma from 1/4 to 4
(a factor of 16).
There is a direct relationship between the amount of ADH in plasma and the concentration ability of the kidney.
There is also a relationship between plasma volume and levels of ADH in the plasma.
Oxytocin, the other hormone secreted from the neurohypophysis, has a similar structure to ADH, differing only in
two amino acids. They are the same in their secretion and response to stimuli; the most important stimuli for
oxytocin are suckling and parturition. The following table outlines the plasma content of experimental rats:
ADH Oxytocin
Control 1.8 2.2
2% NaCl 4.0 9.6
Thirsty 3.2 8.3
Physiology 235
ADH
Stimuli: increased plasma osmolarity, decreased blood volume, pain, stress, nausea & exercise
Inhibitors: alcohol, cortisol
Effects: increases permeability of the collecting ducts, contracts smooth muscle (to increase BP), lowers
portal venous pressure & stimulates hepatic gluconeogenesis
Oxytocin
Stimuli: suckling, psychogenic factors, mechanical stimulation of the uterine cervix
Effects: contracts myoepithelial cells in the ducts of the breast & contracts smooth muscle of the pregnant
uterus
Diabetes insipidus is a nephrogenic condition causing decreased ADH. It can be caused by trauma, antibodies, and
enzyme-mediated causes.
Physiology 235
Lecture 33 - Glands Controlled by Adenohypophysis
Introduction
After infancy, growth is mediated by the pituitary, through the secretion of growth hormone (GH). This is secreted
from specific cells in the adenohypophysis, which are stimulated by GHRH, one of the larger releasing factors
secreted by the neurones in the hypothalamus.
Often prolactin and GH are considered together, since they clearly evolve from a common precursor. They are also
both large glycoprotein hormones with MW of around 20,000. GH is now available from recombinant techniques,
and is used to treat people would otherwise be dwarfed. It is also used in some aspects of the food industry.
The receptor for GHRH is a member of the seven-helix transmembrane protein family.
GHRH is secreted in a pulsatile fashion. The majority of GH is secreted during the early phase of sleep (deep
sleep), although there are other, lesser bursts throughout the day.
Effects of GH
Indirectly causes growth, through metabolic effects:
•1 stimulates protein synthesis

•2 increases blood glucose
•3 stimulates TAG lipolysis in adipose
•1 direct effects
•2 short-lasting
•3 insulin receptor mediated?
Giantism: if excess GH before epiphyseal closure

Acromegaly: if excess GH after closure
Pituitary Dwarfism: decreased growth of bone, decreased numbers of muscle cells
Growth hormone does not interact directly with the bones to produce growth. It is not localised around the
growing ends of bones, but rather in soft tissues such as the liver and kidney.
It continues to be secreted in the adult, though in gradually declining amounts. Therefore it may play a part in
maintaining normal health into maturity. Older people may be treated with GH to prevent osteoporosis and other
age-related conditions.
Physiology 235
Regulation of GH Synthesis & Secretion

Stimulators Inhibitors
Neurohormone: GHRH somatostatin
somatomedins (IGF)
Central Effects: decreased blood glucose increased blood glucose
plasma aa’s (arginine, lysine, leucine) plasma free fatty acids
deep sleep
Hormones: TH progesterone
cortisol cortisol (high dose)
adrenergic agonists -adrenergic agonists
dopamine
serotonin
enkephalins
How Does GH Work?

GH binds to specific transmembrane receptor proteins in the liver. In response, IGF is secreted from the liver. This
presents us with another mechanism which can fail and cause growth problems.
Bone and other soft tissues have receptors for IGF, which stimulates them to grow. Since the IGFs are inhibitory
for secretion of GH from the pituitary, a negative feedback obviously exists. Metabolic effects, such as changes in
amino acid levels will also have indirect feedback mechanisms.
IGFs are also responsible for some forms of dwarfism, such as in toy poodles. They may have normal levels or
even elevated levels of GH, but since they have low levels of IGFs, growth is slow.
Somatomedins
There are many other terms for “somatomedin”:
IGF, sulphation factor (SF), non-suppressible insulin-like activity (NSILA)
They are produced mainly in the liver, and have a similar structure to insulin. Levels are:
•1 increased in puberty
•2 increased in late pregnancy
•3 increased in acromegaly
•4 decreased in dwarfism (GH may be normal: lorain dwarf)
•5 decreased in diabetes
•6 decreased in protein malnutrition
Lorain dwarfs:IGF decreased, normal GH

Pigmies: normal GH & IGF, lack of receptors for IGF
Physiology 235
How does IGF make us grow?
It binds to receptors which are similar to the insulin receptor. When they bind, specific residues (mainly tyrosines),
become phosphorylated, and we see the activation of all these phosphorylation pathways. Some products get into
nucleus and affect cell division (mitogenic response). This in turn leaves to tissue growth.
Other Growth Factors

Epidermal growth factors (EGF): 53 residues, single chain, MW 6,045
Nerve growth factor (NGF): dimeric, MW 26,500
Somatomedin (IGF): single chain, MW 7,000
Platelet derived growth factor (PDGF): two chains, MW 30,000
Fibroblast growth factor
Frequent sequence homology with insulin

Receptors have tyrosine kinase activity
Prolactin
Prolactin is clinically important, mainly when secreted in excess in adult life. The cells that secrete it constitute
most of the bulk of cells in the pituitary gland.
•1 Dopamine is the major (inhibitory) regulator

•2 TSH and oestrogens are stimulatory
•3 There is a diurnal peak of secretion in the basal state during sleep
•4 Receptors for PRL are found in the breast, liver, kidney, etc
•5 The role in males and in other tissues is unknown
•6 Increased PRL is associated with infertility in both sexes (inhibits LH & FSH)
Physiology 235
Lecture 34 - Thyroid Function
Introduction
This pathway begins with the hypothalamus secreting TRF, a small releasing factor containing only 3 residues.
Under the stimulus of this hormone, thyrotropes secrete TSH, which is carried in the blood to the thyroid gland, on
the anterior part of the neck. This is stimulated to secrete the thyroid hormones:
T4 thyroxine
T3 tri-iodo-thyromine
A negative feedback is exerted by the thyroid hormones upon the thyroid gland, through reduction of expression of
receptors on the follicle cells. There is also negative feedback on the pituitary itself, through induction of a TRH-
degrading enzyme in the anterior pituitary.
Thyroid Stimulating Hormone

TSH is a large glycoprotein hormone, MW 30,000. It is made up of two polypeptide chains linked together. The 
chain is identical to that of LH and FSH, so specificity is achieved through the polypeptide sequence of the 
chains. It acts on receptors to activate adenylate cyclase (and hence cAMP). When it acts on the thyroid gland, it
stimulates all aspects of cell activity.
For thyroid hormone to be manufactured by the follicle cells, the gland must have a supply of iodine (from the
diet). The mechanism for this uptake involves active transport. Nutritional iodine deficiency will result in goitre
(enlargement of the thyroid gland). Thyroid hormones cannot be produced, diminishing the feedback mechanisms,
and hence increasing production of TRF and TSH, stimulating thyroid tissue to grow.
The follicles actually synthesis thyroglobulin, on which the thyroid hormones are made. The thyroid hormones
themselves are unusual in their structure. They are modified iodine residues with tyrosines stuck on them. T 3
contains three iodines, while T4 has four.
After iodine the oxidised (by peroxidases, etc.), it is incorporated into the tyrosine structure, with each tyrosine
residue containing 1 or 2 iodines: mono- or di-iodotyrosine. The protein then folds, bringing pairs of tyrosines
together, which are linked, forming the final hormones.
The tissue surrounding the acini of the thyroid gland is a rich protein-containing tissue called colloid. It mainly
comprises thyroglobulin, a large protein containing a few molecules of T 3 and T4. When the gland is stimulated to
secrete thyroid hormone, it engulfs some of the colloid, by a process of endocytosis. The protein is degraded by
lysosomes, and T3 and T4 are released, to be secreted from the gland. Some of the MIT and DIT are not used, but
are recycled. Hypothyroidism can occur if the recycling is defective.
The ratio between T3 and T4 secreted from the thyroid gland varies depending upon the body’s metabolic needs. A
normal ratio is 10 T4 : 1 T3. The two are interconverted to change the ratio, by an enzyme described on the next
page.
Physiology 235
Peripheral Metabolism of Thyroid Hormone

The de-iosinase enzymes which convert T 4 to T3 are present in the follicle cells, and also in preipheral tissues, such
as liver and BAT (brown adipose tissue). T 3 lacks the iodine from the 5’ position, so the conversion requires 5’ de-
iodinase.
The same tissues also contain 5 de-iodinase, which forms the inactive rT 3. The final fate of all thyroid hormones is
removal of another iodine, forming inactive T2.
T4 T3
Binding efficiency 99.96% 99.6%
Free concentration 2-6 ng/dL 0.1-0.6 ng/dL
Thyroid-binding globulin 75% 50%
Circulation half-life 5-6 days 1-3 days
Increases in binding proteins can cause an increase in plasma T 4, but no hyperthyroid state.
Pre-albumin and albumin have a greater capacity for binding thyroid hormone, though they also have a
significantly lower affinity, cancelling out this effect.
Actions of Thyroid Hormones

•1 increases metabolic rate
•2 increases gene expression
•3 activates ATPases
•4 induces -adrenergic receptors
•5 increases metabolism of protein, carbohydrates, lipids, vitamins, drugs
•6 development of CNS: required for arborization and myelination
•7 induces growth directly on bones and indirectly through GH and IGF
Thyroid deficiency in infancy is a serious problem. If it is undiagnosed at birth, the child will be severely mentally
handicapped. This condition is called cretinism, and is an avoidable cause of mental deficiency. Bone growth and
height can be restored, but mental development cannot, hence the need for immediate treatment.
Thyroid Hormone Receptors

•1 molecular weight of 54,000
•2 binding sites for thyroid hormone and DNA
•3 15,000 receptors in each cell nucleus
•4 half life of 4.5 hours
•5 rate of biosynthesis is 2000/hour
•6 at least two different receptors, products of different genes
•7 all are members of the thyroid-steroid receptors “super-family”
Physiology 235
Thyroid hormone exerts its effects by regulation of mRNA synthesis
Stimulation of: growth hormone mRNA

malic enzyme mRNA
-myosin heavy chain in myocardium
many unknown proteins
Inhibition of: thyrotropin

-myosin heavy chain in myocardium
It is essential for expression of uncoupling protein -> thermogenesis in brown adipose tissue (BAT). This, and the
general increase in metabolic rate in most organs, is responsible for temperature homeostasis in the body.
Problems
Hyperthyroidism
Features are: tachycardia, hypermetabolism, fever, tremors, exopthalmos
Hypothyroidism
Infancy: 1 in 4000 cretinism
Adult: 40% of normal metabolic rate, bradycardia, constipation, increased plasma cholesterol
cold intolerance, dry skin and hair, myxoedema, mucopolysaccharides, drug toxicities
Goitre
Iodine lack ® impaired hormone synthesis ® excessive TSH secretion ® thyroid hypertrophy
Physiology 235
Lecture 35 - Sympathetico-Adrenal System
The Adrenal Glands

Secretions of the adrenal cortex are essential for life. Also, many people are under treatment with cortisone-type
drugs, for common conditions, such as asthma, arthritis, bowel disease, and general treatment after transplants.
The adrenal glands are characterised by the “fight or flight” mechanism, created by Hans Selye to describe
corticosterods and adrenaline. They are small organs sitting above the kidneys, often called the suprarenal glands.
90% of the mass is from the cortex, although secretions of the medulla are equally important (especially
adrenaline).
Three zones can be recognised in the adrenal cortex:
•1 zona glomerulosa (ZG)

•2 zona fasciculata (ZF)
•3 zona reticularis (ZR)
Blood flows in through small vessels which penetrate from the outside, so the highest oxygen tension is in the
outermost layer, the zona glomerulosa. Secretions are collected in the blood, and distributed to all cells in the
body, to react with their specific target receptors.
Regulatory Mechanisms
The adrenal cortex is primarily under the control of the pituitary gland. Under certain stimuli such as stress, nerve
cells in the hypothalamus secrete corticotropins, which stimulates corticotropes in the adenohypophysis to secrete
POMC (pro opio melanocortin). This molecule contains:
•1 ACTH (adrenocorticotrophic hormone)

•2 MSH (melanocyte stimulating hormone)
•3 Endorphins (control moods)
•4 CLIPs (corticotropin-like intermediate products)
•5 -LPH (lipotropic hormone)
•6 -END (beta endorphin)
ACTH, which is carried in the blood, interacts with specific membrane receptors in the adrenal cortex, activating
adenylate cyclase and cAMP. In response, the cells release their hormones:
ZG: aldosterone
ZF: glucocorticoids (eg. cortisol): negative feedback on POMC
ZR: androgenic hormones (eg. dehydroepiandrosterone / DHEA)
Tuberculosis is a condition which renders the adrenal cortex inactive, so no cortisol is present, and no negative
feedback occurs to inhibit POMC secretion. Thus there will be high levels of ACTH, MSH and endorphins. The
high MSH leads to pigmentation.
Physiology 235
There is evidence that stimulus such as heavy exercise will increase adrenal secretions:
•1 during rest, the concentrations of both cortisol and ACTH are higher in fitter subjects
•2 in response to exercise, all subjects show increases in concentrations of both cortisol and ACTH
The secretions of the cortex are not constant during the day; the main peak is associated with getting up in the
morning. Other bursts will occur during the day, with levels falling away during the evening.
Steroid Hormones
Steroid hormones are small, lipid-soluble molecules which are derived from cholesterol. The great majority of
them are associated with transporting proteins in the blood. Only free hormones, however, are able to diffuse into
tissues and exert negative feedback on the anterior pituitary.
Pathway of Formation
Steroid hormones are all derived from cholesterol, with its four-membered ring structure. This cholesterol is
normally taken from LDL’s, predominantly in esterified form.
There are a number of specific enzymatic steps during the formation process. In certain genetic conditions, some of
these enzymes may be absent. This means that cortisol cannot be produced, and hence ACTH is not inhibited, and
adrenal hypertrophy occurs. This also leads to huge production of other hormones.
DHEA: secreted by ZR side-chain is completely removed ketone group added

cortisol: secreted by ZF A & B rings very modified double bonds shifted
aldosterone: secreted by ZG most highly oxidised ketones & alcohols added
Mechanism of Action
Being lipid-soluble, steroid hormones can bind to cytoplasmic protein receptors. The complex which is formed can
cross the nuclear membrane and bind to specific sites on DNA within the nucleus, where the transcription is
regulated.
The only difference between steroid hormone action and thyroid hormone action is that all thyroid hormone
receptors are found in the nucleus. Steroid receptors may be present in the nucleus or the cytoplasm.
They all, however, come from a family of related proteins. Within the structure of the receptor proteins is a region
which binds individual hormones with precise specificity. Similar structures bind derivatives of vitamin A
(retinoids) and derivatives of vitamin D.
Binding of the hormone causes a conformational change in the receptor, increasing its affinity to specific DNA
sequences. This then allows the mitogenic response.
Physiology 235
Effects of Glucocorticoids
In response to stress, glucocorticoids...
•1 increase blood glucose: gluconeogenesis, diminished utilisation

•2 increase plasma free fatty acids: lipolysis
•3 maintain blood pressure: adrenal medulla, arteriolar response
•4 induce anti-inflammatory response: decreased lymphocytes, increased PMN
•5 suppress ACTH: atrophy of adrenal cortex
•6 stimulate GH synthesis
•7 cause diuresis: increased GFR, decreased ADH
•8 induce general catabolic effect: muscle wasting, bone demineralisation
Over 90% of cortisol in the plasma is carried by the plasma protein corticosteroid-binding-globulin, which is
normally less than 50% saturated.
Cushing’s Disease: obesity and high blood pressure

Adrenal Insufficiency: low blood pressure and pigmentation
While ACTH doesn't regulate the secretion of aldosterone, it is necessary because of its trophic effect on the
cortex; if the cortex fails, so will production of aldosterone.
Adrenaline
Through several enzymatic steps, noradrenaline is produced from tyrosine. An enzyme called phenylethanolamine-
N-methyltransferase (PNMT) then removes a methyl group from the terminal nitrogen on noradrenaline to convert
it to adrenaline. This enzyme requires the presence of cortisol. Note: Nor stands for “nitrogen ohne radikal”
(nitrogen without radical).
Adrenaline is then stored in chromaffin granules in the adrenal medulla. Under appropriate stimulus (usually input
from preganglionic fibres of the sympathetic nervous system) these granules, containing 80% adrenaline and 20%
noradrenaline, are released into the blood stream. Other stimuli include pain, fear, cold, exercise & fall in blood
glucose. The following table outlines the effects of the two hormones:
Adrenaline Noradrenaline
increases heart rate decreases
increases blood pressure increases
decreases peripheral resistance increases
constricts arterioles constricts
increases muscle blood flow decreases
dilates bronchi -
increases metabolic rate -
increases blood glucose -
decreases renal blood flow decreases
increases sweating -
increases piloerection -
increases lipolysis -
Physiology 235
Lecture 36 - Control of Blood Glucose
Insulin
The most common endocrine disorders are related to insulin, eg. diabetes. Insulin is the hormone concerned with
regulation of plasma glucose. Glucose levels are generally maintained between 3.5 and 5.5 mmolL -1.
brain
6g/hour
liver intestine
4g/hour
Fed State muscle &

adipose
brain
20-50
liver g/hour intestine
Fasting State muscle &

adipose
History of Pancreas & Blood Glucose

1869: Langerhans cells in pancreas (now called islet cells)
1889: pancreatectomized dogs polyuric (osmotic diuresis) and glycosuric
1900: acinar, but not islet degeneration after ligation of pancreatic duct
1920: successful extraction of a hypoglycaemic agent from dogs with ligated pancreatic ducts
1926: obtained crystalline Zn-insulin
1950’s: primary structure of insulin identified, radio immunoassay achieved
1960’s: total synthesis
1980’s: gene isolated, bacterial synthesis
1985: insulin receptor DNA isolated, structure revealed
1988: glucose transporter sequences identified
1991... intracellular events?
Islets Of Langerhans
The 0.5-1.5´106 pancreatic islets comprise 1-2% of the tissue. Each one is ~0.1mm in diameter. There are four
different types of cells in pancreatic islets, each with its own secretion.
Physiology 235
A cells: secrete glucagon (increases plasma glucose levels)

B cells: secrete insulin
D cells: secrete somatostatin (role in regulation of insulin secretion)
F cells: secrete pancreatic polypeptide
B cells make up 70-80% of the total mass of pancreatic islets.
Regulation of Insulin Secretion

Stimulation Inhibition
glucose somatostatin
amino acids (esp. alanine) sympathetics (-adrenergic)
GIP
glucagon
Insulin is derived from pre-pro-insulin, and undergoes several cleavage processes and folding, before being bound
by disulfide bridges. It is stored as a complex with Zn 2+. The liver takes up and degrades about half the insulin
secreted. The capacity for fine control is quite precise.
The extracellular concentration of glucose is primarily responsible for insulin secretion, although intracellular
concentrations also have an effect.
A negative feedback system is present, where insulin stimulates uptake of glucose into target cells, decreasing
plasma concentration and removing the initial stimulus.
Insulin Receptors
These are integral membrane proteins. They are tetrameric, with 2  subunits and 2  subunits, which are all
linked by disulfide bonds. It is formed from a 1370 residue precursor.
Insulin binds to the  subunits; although two can be bound by each receptors, affinity for the second binding is
lowered by the first. Binding of insulin to the  subunit leads to auto-phosphorylation of tyrosine residues on the 
subunit, and phosphorylation of other proteins. The insulin receptors are:
•1 inducible
•2 suppressible
•3 present in most tissues
•4 accessible to antibodies
The following six glucose transporters have a MW of ~50-60,000 and have considerable homology:
GLUT1 Erythrocyte (many tissues)

GLUT2 Liver, beta-cell, intestine and kidney
GLUT3 Brain (many tissues)
GLUT4 Muscle-Fat
GLUT5 Intestine, (Kidney,muscle-fat)
GLUT6 All tissues
Physiology 235
Effects of Insulin on Target Tissues

Effect Tissue
Rapid effects glucose uptake muscle, adipose

amino acid uptake muscle, adipose, liver
Intermediate Effects
i) carbohydrate metabolism glycogen synthesis muscle, liver
¯ glycogenolysis muscle, liver
glycolysis muscle, liver, adipose
¯ gluconeogenesis liver
ii) lipid metabolism lipogenesis liver, adipose

¯ lipolysis adipose
¯ ketogenesis liver
iii) protein metabolism synthesis muscle, liver, adipose

¯ proteolysis muscle, liver
Long Term Effects cell growth

cell division
DNA & RNA synthesis
Diabetes
This is caused by decreased insulin or decreased effectiveness of either receptors or transporters. The resultant
increased glucose levels lead to polyphagia (apetite), polyuria, polydipsia (thirst), glycosuria and glycosylation of
proteins. It also causes increases FFA, leading to increased triglycerides, and also diabetic keto-acidosis. Excess
glucose caused by increased decreased insulin has nowhere to go, and so is excreted in the urine. Excess insulin
(eg. through over-injection) causes insulinoma, iatrogenic effects.
brain
6g/hour
14g/hour intestine
liver
urine
1g/hour
Diabetes muscle &

adipose
Glucagon
Glucagon is derived from prohormone, which is secreted from the A cells in pancreatic islets. Secretion is
stimulated by decreased glucose, decreasd amino acids and exercise. The final product contains 29 residues, and is
a single chain in a random coil.
The biological effects of glucagon include increase in glucose through hepatic glycogenolysis and
gluconeogenesis. Glucagon receptors have been cloned; they are in the same family as receptors for secretin,
calcitonin, PTH and VIP.
Physiology 235
Lecture 37 - Endocrine Control of Mineral Balance
Calcium
Plasma ionised Ca2+ must be regulated within a small range. The actions of calcium include:
1. Regulation of plasma membrane permeability to Na +

2. Trigger for release of acetylcholine at neuromuscular junctions
3. Excitation-contraction coupling in muscle
4. Intracellular messenger
5. Required by some enzymes
6. Required for blood clotting
7. Required for protein secretion
8. Required for mineralisation of bone
99% of calcium is found in bone in the form of hydroxyapatite.

1% is found in soft tissues and ECF.
Plasma [Ca2+]: 2.5mM/L

50% ionised
50% complexed, mostly with albumin
Parathyroid Hormone (PTH)

This hormone is secreted by the 4 small parathyroid glands, embedded in the posterior aspect of the thyroid gland.
PTH is a polypeptide, with MW 9,500. It exists in several forms in plasma, most of the activity being in an 84-
residue fragment. It is broken down quickly in blood, so in order to maintain concentrations at physiological
levels, it needs to secreted continually.
When calcium falls below its normal concentration of 1.3mM, secretion of PTH is stimulated. Negative feedback
occurs so that when calcium is restored to normal, PTH synthesis stops. PTH acts to increase the concentration of
plasma calcium by two methods:
•1 release of calcium from bone mineral, by stimulation of osteoclasts (by cAMP)

•2 increase in reabsorption of calcium in the proximal tubule
PTH simultaneously increases phosphate excretion in the urine.
Renal Handling of Calcium

The 50% of the calcium in the plasma which is not bound to albumin, is freely filtered. Of what is filtered, 50% is
immediately reabsorbed by an unregulated active transport process in the proximal tubule. Another 40% is
passively absorbed through the loop of Henle.
9% is then normally reabsorbed by a different active transport process present in the distal tubule. If plasma
calcium decreases, more PTH is secreted, and this may cause complete reabsorption.
Physiology 235
Hypercalcaemia
Due to parathyroid tumour or secondary renal disease
Increased PTH leads to increased calcium levels
•1 decreased neuromuscular excitability: lethargy, muscle weakness, anorexia
•2 renal calculi: in the bladder or ureters, due to overloading of calcium in kidneys
•3 peptic ulceration
•4 bone weakness & irregularity: due to demineralisation
Hypocalcaemia
Due to parathyroid disease or damage during thyroid surgery
Decreased PTH leads to decreased calcium levels
•1 increased neuromuscular excitability: tetany, convulsions, laryngeal spasms
Treatment: 1,25(OH)2-D3 (calcium supplements)
Vitamin D
Vitamin D is obtained from two sources; diet, particularly dairy products, and through the action of sunlight on
cholesterol in the skin. Vitamin D 3 is produced in the skin reaction, but this is not the active form. The liver
modifies this to form 25-OH-D3. Then another enzyme, this time in the kidney, forms 1,25-(OH) 2-D3.
The receptor for this hormone is in the same class of cytopoasmic nuclear receptors that bind steroid hormones.
The activity of the kidney enzyme decreases with age, and the effectiveness of the final form of vitamin D also
decreases with age, leading to osteoporosis.
Effects
Vitamin D works mainly on the intestine, unlike PTH. It promotes reabosprtion of calcium, and also increases
absorption of phosphate, and stimulates osteoblasts in the bone. It works in conjunction to maintain and increase
plasma calcium:
•1 PTH stimulates activity of the kidney’s enzyme which forms active vitamin D 3
•2 vitamin D feeds back on PTH to decrease its synthesis
Vitamin D - Cell Biology

Vitamin D is transported in association with a specific plasma globulin protein. Receptors for the hormone have
been found in just about every cell of the body:
•1 intestinal mucosal cells
•2 osteoblasts
•3 kidney (distal tubule)
•4 parathyroid
•5 pancreatic islet cells
•6 skin keratinocytes
•7 of cancer cell lines
•8 brain, muscle, salivary gland, etc.
Physiology 235
Vitamin D works through affecting transcription; it alters the production of mRNA and hence the formation of a
number of important proteins. One example is a specific calcium transport protein in the intestine. The expression
of the receptors and the protein is under genetic control. Variation in the genetic mechanism accounts for
expression of osteoporosis.
A deficiency in vitamin D will require both a dietary deficiency and lack of exposure to sunlight. Such a deficiency
can be responsible for rickets (children) and osteomalacia (adults).
Osteoporosis
•1 affects up to 60% of women, also occurs in men
•2 bone mass is determined by genes
•3 the vitamin D receptor gene accounts for 75% of variation in bone mass
•4 bone loss increases with age
•5 an important determining factor is calcium level during late teen years
Effect of Calcium in Diet

Extra calcium in the diet causes an initial increase in calcium levels, but the regulatory mechanisms are so efficient
and fast-acting, that balance is achieved almost instantly. This is due to the following changes:
•1 increased active vitamin D

•2 decreased PTH
•3 increased cAMP in urine
•4 increased calcitonin
Calcitonin
PTH alone is unable to account for total calcium control. Calcitonin is also a simply polypeptide chain, containing
just 32 amino acids. It’s structure is folded and held by a disulfide bridge. It generally has the opposite effects to
PTH.
Calcitonin is secreted by C cells (parafollicular cells) located within the thyroid gland and other tissues. The only
stimulus for secretion is an increase in plasma calcium.
Its major effects include turning off the mobilisation of calcium from bone, and hence mineral deposition in the
bone. It also promotes the excretion of calcium and phosphate from the renal tubules. It has other unknown effects,
possibly playing a role in osteoporosis and Paget’s disease.
Physiology 235
Calcium: Summary Table

PTH CT 1,25(OH)2-D3
Plasma Ca2+ ¯
Plasma PO43- ¯ ¯
Reabsorption of Ca2+ in Kidney ¯
Reabsorption of PO43- in Kidney ¯ ¯
1--hydroxylase activity - -
bone resorption ¯ promotes PTH
intestinal absorption promotes 1,25 -

Physiology 235: Lecture Timetable

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Physiology 235: Lecture Timetable

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Physiology 235

Wednesday 10:00 am Simmonds Lecture Theatre

Kidney & Body Fluids (8 Lectures)

Gastrointestinal Physiology (8 Lectures)

Physiology of the Blood (6 Lectures)

EASTER VACATION - MID SEMESTER BREAK

Wednesday 26 Leukocytes Ms D. Tomizzi

Pulmonary & Cardiovascular Physiology (8 Lectures)

Endocrines (Excluding Reproduction) (8 Lectures)

(Endocrine lecture series continues in second semester)

Body Fluid Compartments

Extracellular Water Intracellular Water

Note: Total blood volume is ~2x plasma volume

Measurement of Body Water

Plasma Water - radio-iodinated serum albumin (RISA) or Evan's Blue Dye

Osmolality is most usually measured using freezing point depression.

The following table outlines the composition of the fluid compartments:

Plasma Water Interstitial Fluid Intracellular Fluid

Structure & Functions of the Kidney

The kidney has three distinct functions:

•1 Regulatory organ - especially maintaining body water and electrolyte homeostasis

•1 afferent arterioles are richly supplied with sympathetic nerves

The filtration membrane consists of three layers, as basement

200-1000A 35-40A 50-250A

Forces Involved in Ultrafiltration

plasma, plus the pressure in the Bowman's capsule

colloidal osmotic pressure of plasma increases. The initial pressure 30

Measurement of Glomerular Filtration Rate

•1 freely filtered across the membrane

amount filtered / minute = (concentration in filtrate) x (volume of filtrate / minute)

SO volume filtered / minute (GFR) = (amount filtered / minute) / (concentration in filtrate)

SO GFR = (amount excreted / minute) / (plasma concentration)

Factors Affecting the Glomerular Filtration Rate

•1 Changes in area for filtration

•1 Changes in membrane permeability

Typical Daily Absorption/Secretion

Substance Load Filtered/Day Load Excreted/Day Percentage Reabsorbed

•1 a pump-leak system which transports sodium and calcium

Proximal Convoluted Tubule (~65% of Na + Absorption)

Loop Of Henle (~25% of Na + Absorption)

Distal Convoluted Tubule (~10% of Na + Absorption)

•1 it increases the permeability of the membrane to Na+

Proximal Convoluted Tubule Distal Convoluted Tubule

Renal Plasma Flow

“Sodium is the osmotic skeleton of the EC water”

Sodium levels are regulated by the following:

•1 decreased stretch of afferent arterioles (fall in blood pressure)

Angiotensin II also has other effects apart from aldosterone release:

Aldosterone has three major effects directly on the kidney:

Aldosterone is a SLOW control.

•1 constant Na+ loss, leading to hypotension and shock

•1 there is a progressive rise in blood pressure with age

Blood Pressure Life Expectancy

"Secondary hypertension" is due to a physical cause.

The Circulatory System

Short-Term Blood Pressure Regulation

Long-Term Blood Pressure Regulation

Conditions of the kidney which may cause problems include:

•1 it has an immediate vasoconstrictor effect

Antidiuretic Hormone (ADH)

The following diagram outlines the mechanisms causing release of ADH:

Emotional Stress Pain