Physiol Rev 90: 675–754, 2010;

doi:10.1152/physrev.00012.2009.

The Ventilatory Response to Hypoxia in Mammals:

Mechanisms, Measurement, and Analysis

LUC J. TEPPEMA AND ALBERT DAHAN

Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

I. Introduction 676
II. The Hypoxic Ventilatory Response in Fetal and Neonatal Mammals 677
A. Fetal breathing movements 677
B. Hypoxia inhibits fetal breathing movements 677
C. Maturation of the HVR in neonatal animals 679
D. Developmental plasticity of the HVR 681
E. The HVR in term and preterm babies 684
III. Peripheral and Central Mechanisms Mediating the Hypoxic Ventilatory Response in Adult Mammals 685
A. Carotid body mechanisms in oxygen sensing 685
B. Hypoxia activates the transcription factor hypoxia-inducible factor-1 690
C. Central effects of hypoxia 692
D. Hypoxic ventilatory decline in the adult mammal 698
IV. Genetic Influence on the Ventilatory Response to Hypoxia 703
A. The genome and HVR 703
B. Mutations and HVR 704
V. Pathophysiological Influences on the Hypoxic Ventilatory Response 705
A. Biological variability 705
B. Ageing 706
C. Gender and pregnancy 706
D. Influence of CO2 on the HVR: O2-CO2 interaction 707
E. Carotid body resection and the HVR 710
F. Chronic hypoxia and the HVR 711
G. Chronic intermittent hypoxia and the HVR 720
VI. Measuring, Expressing, and Modeling the Hypoxic Ventilatory Response 725
A. Measuring the HVR 725
B. Expressing the steady-state HVR 731
C. Modeling the HVR 731
VII. Comments and Future Challenges 732

Teppema LJ, Dahan A. The Ventilatory Response to Hypoxia in Mammals: Mechanisms, Measurement, and
Analysis. Physiol Rev 90: 675–754, 2010; doi:10.1152/physrev.00012.2009.—The respiratory response to hypoxia
in mammals develops from an inhibition of breathing movements in utero into a sustained increase in
ventilation in the adult. This ventilatory response to hypoxia (HVR) in mammals is the subject of this review.
The period immediately after birth contains a critical time window in which environmental factors can cause
long-term changes in the structural and functional properties of the respiratory system, resulting in an altered
HVR phenotype. Both neonatal chronic and chronic intermittent hypoxia, but also chronic hyperoxia, can
induce such plastic changes, the nature of which depends on the time pattern and duration of the exposure
(acute or chronic, episodic or not, etc.). At adult age, exposure to chronic hypoxic paradigms induces
adjustments in the HVR that seem reversible when the respiratory system is fully matured. These changes are
orchestrated by transcription factors of which hypoxia-inducible factor 1 has been identified as the master
regulator. We discuss the mechanisms underlying the HVR and its adaptations to chronic changes in ambient
oxygen concentration, with emphasis on the carotid bodies that contain oxygen sensors and initiate the
response, and on the contribution of central neurotransmitters and brain stem regions. We also briefly
summarize the techniques used in small animals and in humans to measure the HVR and discuss the specific
difficulties encountered in its measurement and analysis.

www.prv.org 0031-9333/10 $18.00 Copyright © 2010 the American Physiological Society 675
676 LUC J. TEPPEMA AND ALBERT DAHAN
I. INTRODUCTION
The independent discovery of oxygen by the Swedish
apothecary Carl Wilhelm Sheele in 1772 and the English
scientist Joseph Priestley in 1774 is considered one of the
greatest scientific discoveries (for a historical overview,
see Ref. 698). To date, 235 years later, it is a well estab-
lished fact that aerobic metabolism in mammals relies on
sufficient oxygen availability in the mitochondria where
its reduction to water is coupled to the generation of ATP
molecules. To be completed, this process of oxidative
phosphorylation requires efficient transport of electrons
between five major protein complexes (mitochondrial
electron transport chain, attached to the inner mitochon-
drial membrane). The total amount of oxygen in the body
is low (⬃1.5 liter in total, ⬃50 ml of which is stored in the
tissues), so an undisturbed and complete oxidative phos-
phorylation requires a continuous fresh supply of oxygen
from the environment. Thus an insufficient supply of ox-
ygen may compromise the electron transport chain result-
ing not only in a decrease in ATP production but also in an
increased generation of reactive oxygen species (ROS),
such as superoxide anion. ROS can cause structural dam-
age to nucleic acids, proteins, and lipids. At the same
time, cytoplasmic signaling-transduction cascades can di-
rectly be influenced by ROS. Mobilization of antioxidant
defense mechanisms, such as superoxide dismutase that
catalyzes the conversion of superoxide anion into hydro-
gen peroxide and catalase that accelerates the conversion
of H2O2 into water and oxygen, helps to restore the cel-
lular redox balance.
Apart from cellular antioxidant enzymes, the body
has several means to compensate for an acute decrease in
oxygen availability (acute hypoxia). Animals relying on
pulmonary ventilation for their oxygen supply increase
their ventilation to improve the uptake of oxygen. This
ventilatory response to hypoxia (HVR) in mammals, i.e.,
the increase in pulmonary ventilation that results from a
decrease in the partial pressure of oxygen in the arterial
blood (PaO2) is the subject of this review. Another means
that mammals can utilize to preserve oxygen homeostasis
in acute hypoxia is to optimize and decrease the rate of
aerobic metabolism, thus reducing oxygen demand and at
the same time increasing ATP production from anaerobic
metabolism (glycolysis).
Neonatal and adult animals use the options of chang-
ing ventilation and/or metabolism in a different way.
Apart from an initial fast and transient rise in ventilation,
neonates, when exposed to acute hypoxia lasting 20 –30
min, display only a minor increase in ventilation but an
appreciable reduction in metabolism, thereby optimizing
the ratio ventilation over oxygen consumption. During
maturation into adulthood, this composite response grad-
ually develops into one with a predominant and sustained
increase in ventilation (while the biphasic character of the
Physiol Rev • VOL
response is maintained) but without a(n) (appreciable)
decrease in metabolism.
Fetal animals respond differently to hypoxia. They
display breathing movements in utero that can be de-
tected in an early stage of gestation (for example, ⬃40
days in lambs with a term duration of ⬃147 days and ⬃10
wk in humans). When the fetus is exposed to a low
maternal PaO2 or umbilical cord occlusion, breathing
movements are reduced in frequency and can be com-
pletely abolished (54, 137, 170). This review describes the
mechanisms underlying both the fetal and neonatal
breathing responses to hypoxia and summarizes how the
neonatal response gradually matures into the adult phe-
notype. The influence of the genotype on the HVR is also
briefly discussed.
Both in neonates and in the adult, the initial increase
in ventilation in hypoxia is initiated by the carotid bodies,
located at the carotid bifurcations and containing oxygen-
sensitive cells that increase their activity in hypoxia (278,
280). The carotid bodies send their afferent input to the
brain stem where further processing by the respiratory
centers takes place. During the last two decades, consid-
erable progression has been made in elucidating the
mechanism of oxygen sensing in the carotid bodies, the
factors that modulate it, and the way in which the brain
stem processes the afferent traffic from the carotid bod-
ies, and in this review we present a state of the art of
these areas.
Studying the mechanisms underlying respiratory ad-
justments (rise in ventilation, increase in the HVR) to
chronic hypoxia and chronic intermittent hypoxia in ani-
mals (mainly rats) has revealed a fascinating picture of
numerous plastic morphological, biochemical, and func-
tional changes in the carotid bodies and brain stem that
are initiated and maintained by transcription factors that
regulate the expression of many genes. Both during neo-
natal development and in adulthood, the respiratory sys-
tems of rats and other species display plasticity, i.e., the
ability to learn from previous experience and to alter the
phenotype of several reflex responses. One developmen-
tal period is of particular interest: immediately after birth,
within the period of postnatal maturation, there is a crit-
ical period (“critical time window”) during which environ-
mental factors can modulate structural and functional
properties of the respiratory system. These plastic
changes can be permanent and may be irreversible in
adulthood and possibly even in adolescence (115). An
example is chronic exposure to hyperoxia during this
period: it leads to degenerative changes in the carotid
bodies and to a reduced HVR that may persist until
adulthood (189, 220, 838). Adaptations of the HVR to
(intermittent) chronic hypoxic paradigms in this criti-
cal neonatal time window will be compared with those
in adulthood and placed in the context of plastic
changes in the carotid bodies and brain stem that result
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
from changes in gene expression. Of critical impor-
tance in interpreting these studies is to take into ac-
count the specific methods that are used to measure the
HVR, the environmental and physiological context in
which they are preformed, and the analytical methods
that are applied to quantify and compare data. We
briefly summarize the techniques used in small animals
and in humans and discuss the specific difficulties that
are encountered in measurement and analysis.
II. THE HYPOXIC VENTILATORY RESPONSE IN
FETAL AND NEONATAL MAMMALS
A. Fetal Breathing Movements
Fetal breathing movements (FBM) are coordinated
rhythmical contractions of respiratory muscles that inter-
mittently reduce intrathoracic pressure and cause amni-
otic fluid movements within the trachea (302). FBM are
crucial for fetal lung growth and maturation and are ob-
served in all mammalian species studied thus far (49, 85,
302, 357, 391, 651, 725, 814). The most commonly ob-
served FBM are rapid irregular movements and can be
detected in sheep (mean term duration 147 days) from
⬃40 days gestation and in humans from ⬃10 wk (88, 137,
170, 302). Early in gestation, until about day 115, fetal
lambs show continuous FBM that are sometimes inter-
rupted by apneas; in the third semester, EEG activity
starts to differentiate between states of low- and high-
voltage cortical activity associated with rapid eye move-
ments (active sleep) and active movements of neck and
limb muscles, respectively. From this developmental stage un-
til term, FBM are limited to active sleep (low voltage
cortical activity; reviewed in Refs. 85, 170, 302, 317, 357,
625, 814). This association of FBM and electrocortical
activity is disrupted after brain transection rostral from
the caudal hypothalamus; when this transection is per-
formed at upper pontine level, i.e., a region close to the
inferior colliculus in the vicinity of the principal sensory
and motor nuclei of the trigeminal nerve, FBM become
almost continuous (170, 171, 271, 363, 396, 523, 814, 815).
Sleep state should be considered as a factor modulating
fetal breathing rather than providing a primary inducing
role: in fetal lambs, periodic FBM precede the electrocor-
tical differentiation by ⬃1 wk, while at term the animal
starts to breathe continuously without changes in EEG
pattern (651).
B. Hypoxia Inhibits Fetal Breathing Movements
In fetal sheep, hypoxia caused by (gradually) expos-
ing ewes to a hypoxic gas mixture (mostly with CO2
added to maintain isocapnia) to achieve fetal saturation
Physiol Rev • VOL
677
levels of ⬃30% leads to adaptations such as spinal inhibi-
tion, a reduction in rapid eye movements, facilitation of
high-voltage electrocortical electroencephalogram (EEG)
activity, inhibition of FBM, a fall in metabolic rate, and a
rise in cerebral blood flow (CBF) (85, 88, 137, 170, 317,
408, 588). In the lamb, FBM account for ⬃30% of overall
oxygen consumption (670). Anemia, reduced uterine
blood flow, and/or umbilical cord occlusion also lead to
FBM inhibition (74, 87, 328, 830). Hypoxic inhibition of
FBM also occurs in fetal rat (391), rhesus monkeys (488),
and given the relative low FBM incidence in growth-
retarded fetuses, presumably also in humans (54, 251).
The mechanism of hypoxic inhibition of FBM is complex
and may be causally related to one or more of the above
adaptations. Below we discuss some major factors influ-
encing hypoxic inhibition of FBM with emphasis on those
that may still contribute to shaping the HVR in newborns
and even adults.
1. CBF and metabolism and hypoxic inhibition
of FBM
The fetal brain exhibits a relatively large rate of
oxygen consumption that is tightly linked to oxygen de-
livery (588). In the fetus, hypoxia not only leads to de-
creases in neuronal activity and metabolic rate, but also
to a rise in CBF, and both these responses have been
linked to the inhibition of FBM (588).
2. Pontine and thalamic areas and hypoxic inhibition
of FBM
In fetal lambs, brain stem transection at the (mid)
collicular level or electrolytic lesions somewhat more
caudally in the upper lateral pons in the vicinity of the
trigeminal sensory nuclei involving parts of the medial
parabrachial and Kölliker Fuse nuclei has two important
consequences: 1) it leads to continuous breathing in nor-
moxia and to a dissociation between EEG activity and
breathing, and 2) it converts the inhibitory response to
hypoxia in the intact condition into a stimulatory one
after transection (170, 171, 271, 363, 396, 523, 814, 815).
Transection more rostrally through the caudal hypothal-
amus did not affect hypoxia-induced inhibition of FBM,
indicating that an area caudally from it is able to elicit this
response independently from higher centers (170).
In fetal lambs, hypoxia facilitates a high-voltage elec-
trocortical EEG pattern (80). FBM and low-voltage elec-
trocortical activity are closely linked, so brain areas in-
fluencing behavioral state may modulate hypoxic inhibi-
tion of FBM. One such area is the parafascicular nucleus
of the thalamus. Lesions in this area abolish hypoxia-in-
duced inhibition of FBM while local electrical stimulation
effectively decreases respiratory frequency (397–399).
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678 LUC J. TEPPEMA AND ALBERT DAHAN
3. Peripheral chemoreceptors and hypoxic inhibition
of FBM
In fetal sheep, the carotid bodies are active and
respond to hypoxia with excitation (79). Thus the ques-
tion arises whether they may have a counteractive role
in hypoxia or, alternatively, stimulate brain regions that
are directly involved in inhibiting FBM. Carotid sinus
nerve and aortic transection do not prevent hypoxic
inhibition of FBM but delay the onset of the response,
suggesting a supportive but not indispensable influence
of the peripheral chemoreceptors (406). After midcol-
licular transection, hypoxia induced an increase in
FBM in fetal lambs, and this response still existed after
subsequent carotid body denervation (171). After ca-
rotid sinus nerve transection, some fetal sheep showed
continuous breathing in normoxia and even FBM in
hypoxia; peripheral chemodenervation alone neither
changed the incidence of FBM in normoxia nor the
hypoxia-induced inhibition of breathing (523). In an-
other study, hypoxic stimulation of FBM after transec-
tion depended on carotid sinus nerve integrity, suggest-
ing that in the intact condition (i.e., without any lesion)
a stimulatory influence of the carotid bodies may be
overridden (363, 396). In general, the emerging picture
is that at least in fetal lambs intact carotid bodies are
not required to produce hypoxic inhibition of FBM,
while their role in stimulating breathing in hypoxia
after brain stem transection is somewhat controversial.
4. Placental factors and hypoxic inhibition of FBM
By itself, the fact that umbilical cord occlusion
leads to hypoxia in the fetus and decreases the inci-
dence of FBM (328, 830) does not exclude placental
factors as the source of FBM inhibition during maternal
hypoxemia. Theoretically, a reduced release by the pla-
centa of stimulatory agents could contribute to the
reduction of FBM, but to date, such factors have not
been identified. The placenta produces inhibitory sub-
stances such as prostaglandin E2 (PGE2), adenosine,
and several peptides (16, 704, 815), while indomethacin
and adenosine antagonists induce continuous breathing
and reverse hypoxic inhibition of FBM, respectively
(125, 170, 403, 404, 407). After prolonged reductions in
uterine blood flow, plasma PGE2 concentration in fetal
lambs and the decrease in incidence of FBM showed
parallel time courses (328). However, because sub-
stances released from the placenta during maternal
hypoxemia did not reduce FBM when the fetal PO2 was
kept normoxic (413), we suggest that in this condition
hypoxic FBM inhibition is caused by local factors in the
hypoxic fetal brain that also inhibit respiratory move-
ments during reduced uterine blood flow/umbilical cord
occlusion.
Physiol Rev • VOL
5. Neuromodulators and receptors in hypoxic
inhibition of FBM
A) ADRENERGIC MECHANISMS. Hypoxia-induced inhibition
of FBM may be mediated via adrenergic receptors. In fetal
sheep, hypoxia activates catecholaminergic neurons in
subcoeruleus- and Kölliker-Fuse regions in the dorsolat-
eral pons, some of which appear to have direct connec-
tions with the phrenic motoneuron pool in the cervical
cord (551). In both intact and brain stem transected fetal
lambs, systemic clonidine reduced the incidence of FBM,
and this effect was blocked by an ␣2-adrenergic antago-
nist (32). Prolonged reduction in uterine blood flow in-
creased plasma norepinephrine concentration in fetal
lambs (328), while ventricular administration of clonidine
reduced the incidence of breathing and a specific ␣2-
adrenergic receptor antagonist abolished hypoxic inhibi-
tion of FBM (31). Systemic administration of both ␣1- and
␣2-adrenergic antagonists had similar effects (270).
B) ADENOSINE A1 AND A2 RECEPTORS. An important mole-
cule in the coupling of cerebral blood flow to metabolism
is adenosine. Via adenosine A2 receptors, this molecule
induces ⬃50% of the hypoxia-induced rise in CBF, while
A1 receptors mediate hypoxic depression of cerebral me-
tabolism (83, 479, 588).
Experimental evidence indicates that adenosine is an
important player in the hypoxia-induced reduction in
FBM incidence. In fetal lambs, systemic adenosine caused
a decrease in FBM incidence similar to hypoxia, while
adenosine receptor antagonists had the reverse effects
(76, 125, 405). The posteromedial thalamus displays in-
creased adenosine production during hypoxia and con-
tains a high density of adenosine A2A receptors that me-
diate FBM inhibition (402, 404, 830, 862). Intra-arterial
infusion of a specific A2A but not A1 receptor antagonist
abolished both the hypoxic inhibition of rapid eye and
breathing movements, while A1 antagonism only elimi-
nated the FBM response (403). Anemic hypoxia upregu-
lates pontine adenosine A1 receptors in the brain stem of
fetal lambs, while the same receptor type in the rostroven-
trolateral medulla is also involved in the hypoxic FBM
response (76, 396), possibly by directly depressing local
metabolism (84, 479).
The way in which adenosine causes hypoxic inhibi-
tion of FBM may be quite complex. Following lesion of
the upper lateral pons in the vicinity of the trigeminal
sensory nucleus (see above), normoxic respiratory fre-
quency substantially decreases (363). Thus this region
may exert a tonic excitatory effect on ventrolateral med-
ullary respiratory neurons in normoxia, possibly by hy-
perpolarizing postinspiratory neurons. If during hypoxia
adenosine, by a presynaptic action, inhibits these pontine
neurons, postinspiratory neurons may now depolarize,
thus inhibiting respiratory motor output. This would be
consistent with in vitro data from neonatal rat and mice
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
showing hypoxia-induced depolarization of postinspira-
tory neurons (see references in Ref. 73).
In summary, ample evidence thus far indicates in-
volvement of adrenergic and purinergic, adenosine A1 as
well as A2A mechanisms in the hypoxic inhibition of FBM,
but further studies are necessary to further characterize
and localize other transmitters and receptor subtypes
involved.
6. Some further considerations on hypoxia and
fetal breathing
In most of the above studies, hypoxia was tested in
fetal lambs in the last gestational semester. In midgesta-
tion, hypoxic inhibition of FBM is milder if not absent,
indicating that it develops over the second half of preg-
nancy (496).
Does the low fetal arterial PO2 (⬃25 Torr) imply a
tonic reduction of FBM? This seems unlikely, since nei-
ther fetal lambs (125–130 days gestation) nor normal hu-
man fetuses show significant increases in the incidence of
FBM during maternal hyperoxia (54, 78, 88, 654 and ref-
erences therein), although at least in the lamb it cannot be
excluded that after ⬎130 days of gestation a response of
continuous breathing to hyperoxia starts to develop (24).
In humans, it is only in growth-retarded fetuses that hy-
peroxia results in a higher FBM frequency (54, 251).
In fetal lambs, prolonged hypoxia (⬎12 h) initially
leads to a reduction in FBM frequency, but after a period
of 12–20 h it returns to normal (86, 328, 401, 496, 831).
How this reversal occurs is unknown, but it has been
related to a downregulation of adenosine receptors and
plasma glucose levels, respectively (328, 405).
Several alternative mechanisms to explain the hy-
poxic inhibition of FBM have been suggested, of which
acidemia (647), increased blood flow through the ductus
venosus (217), and decreased mitochondrial ATP produc-
tion (407) warrant further investigation. The cellular basis
of the response is unknown.
C. Maturation of the HVR in Neonatal Animals
1. Measuring the HVR in small animals
The most frequently used techniques to study breath-
ing in awake mice and rats are modifications of body
plethysmography described by Drorbaugh and Fenn (193).
Their barometric method is based on the principle that
when an animal in a closed chamber inhales a tidal vol-
ume, this volume is warmed to body temperature, satu-
rated with water vapor giving rise to pressure changes in
the chamber. As discussed by others, both closed and
open systems are subject to limitations (e.g., related to
pressure changes due to warming, humidification, and air
leaks) and particularly in neonatal animals the pressure
Physiol Rev • VOL
679
signal may be contaminated by airway resistance effects
that may lead to erroneous estimation of tidal volume
(218, 219, 356, 477, 751).
The absence of blood gas data (in most cases) com-
bined with the impossibility to control end-tidal gases
renders a reliable comparison of HVRs between treat-
ments difficult. By sheer necessity, the ambient O2 frac-
tion is often taken as the independent variable, but its
relationship with the actual stimulus is uncertain and may
vary. If in a chronic paradigm normoxic ventilation in-
creases, arterial PO2 will be higher and PCO2 lower for any
inspired PO2 level resulting in less carotid body stimula-
tion; thus, in such cases, it is inaccurate to quantify the
HVR as the magnitude of the change in ventilation per
given decrease in ambient PO2. In addition, a lower initial
PCO2 may tend to further reduce at least the early phase of
the HVR, owing to O2-CO2 interaction in the carotid bod-
ies (see sect. V). Without addition of CO2, hypoxic tests
may be poikilocapnic depending on changes in ventilation
and/or metabolism. In the ideal case, preferably three or
four measurement points well within the curvilinear part
of the exponential ventilation-PO2 relationship should be
chosen, avoiding levels at which maximal ventilation is
reached (39). A further point concerns the influence of the
vigilance state on the HVR (421, 472, 729). Particularly in
neonates, EEG recordings are challenging and often not
performed, so vigilance state-dependent changes in sen-
sitivity cannot be accounted for. On the other hand, the
influence of the latter factor may be limited because
sleep-wake cycles are not clearly defined in early life.
Balbir et al. (29) proposed a noninvasive method for
sleep-wake assessment in neonatal mice, providing a po-
tential means to account for (changes in) brain state. These
authors found a sound correlation between high electromyo-
gram (EMG) activity (associated with the awake state) and
coordinated limb/head movements and suggested that this
behavioral index could be useful in avoiding the stress re-
lated to EMG instrumentation in newborn animals (29).
These are only a few of the considerations to take into
account when comparing HVRs between treatments.
2. Maturation of the HVR in neonatal animals
In neonatal animals, the HVR appears as a biphasic
response consisting of a short initial rise in ventilation
(augmentation phase) rapidly followed by a secondary
roll-off mostly to a level below control (depressing phase;
Ref. 73). Postnatal maturation of the HVR was already
described in older studies and in various species such as
lambs (e.g., Ref. 102), cats (89, 90, 301, 487, 653), piglets
(212), and rats (208, 453, 454). In all species, the relative
magnitudes of both phases are subject to maturation.
Generally, shortly after birth, the initial rise in ventilation
is (much) smaller than the secondary roll-off, rapidly
resulting in a lower baseline ventilation compared with
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680 LUC J. TEPPEMA AND ALBERT DAHAN
normoxia. However, when maturation proceeds, the ini-
tial rise becomes larger, the secondary depression be-
comes smaller, and eventually a sustained rise in ventila-
tion remains. Age-matched comparisons between species
are complicated by the different stimulus paradigms em-
ployed. For example, deeper hypoxia may result in a
greater initial increase and a larger decrease in ventilation
in the depressing phase (see Ref. 73 in which data from
humans, rat, cat, monkey, and sheep are shown). In ad-
dition, relatively mature species at birth have a better
sustained neonatal HVR than those born less mature, e.g.,
sheep (mean term duration 147 days) are more mature
than rat (term duration 18 –23 days) and cat (term dura-
tion 58 – 64 days; Refs. 73, 529). In 2- to 17-day-old piglets
(term duration 112–120 days), the secondary roll-off
seems to be limited to the phrenic motoneuron pool, since
upper airways muscle EMGs showed a sustained increase
in activity in the presence of a biphasic response of the
diaphragm (490).
In most neonates, a vital component of the hypoxic
response is a decrease in metabolism (hypoxic hypome-
tabolism; Refs. 90, 529, 531, 532). Newborns of many
species demonstrate a drop in oxygen consumption (V̇O2)
that in relatively mature species tends to be smaller. All
species investigated show an increase in the ratio expired
ventilation (V̇E)/V̇O2 (i.e., the ratio expired ventilation over
O2 consumption), indicating a hyperventilatory response,
and this occurs irrespective of the magnitude of the HVR
(529, 531, 532). Thus ventilation may decrease in hypoxia,
but still the outcome will be hyperventilation because of
a larger drop in V̇O2. The fall in metabolism is due to a
reduction in nonshivering thermogenesis by brown adi-
pose tissue, rather than to the hypoxia-induced (limited)
decrease in body temperature (526, 529, 531, 532). Resting
metabolism is an important determinant of the hypoxic
drop in V̇O2. Generally, animals with higher metabolic rate
(e.g., small animals) demonstrate larger decreases in V̇O2,
but there are exceptions (243, 526, 531). In a cold envi-
ronment, requiring more thermogenesis to generate heat,
a given animal will show much larger hypoxia-induced
decreases in V̇O2 and ventilation (or smaller rise in venti-
lation) than at an ambient temperature close to thermo-
neutrality (526, 531). Consequently, measurements of the
HVR per se are more meaningful when combined with V̇O2
measurements and supplemented with end-tidal CO2 val-
ues. Furthermore, comparisons between treatments
should preferably be made at equal ambient temperature
(526, 531).
When maturation proceeds towards the adult stage,
hyperpnea replaces hypometabolism as the predominant
feature of the hypoxic response, but in many adult spe-
cies, depending on the ambient temperature, the drop in
metabolism can remain an important element of it (243,
260, 482, 526, 531, 675). The magnitude of the fall in
metabolism is inversely related to resting V̇O2 relative to
Physiol Rev • VOL
body weight and therefore could be limited or absent in
adults of larger species (243, 531). The processes under-
lying maturation of the HVR are briefly reviewed below by
considering the augmentation and depressing phases sep-
arately. In section IIIC, we briefly discuss a potential neu-
ronal circuit that may be involved in the thermogenic
component of the HVR.
A) AUGMENTATION PHASE OF THE HVR. In newborn lambs,
piglets, and rats, the relatively rapid initial rise in ventila-
tion in acute hypoxia, designated as the augmentation
phase (73), is abolished or greatly attenuated after carotid
sinus nerve transection, indicating that the carotid bodies
mediate the augmentation phase (103, 166, 249, 473, 474,
533, 740). Shortly after birth, in newborn lambs, the PaO2
threshold for hypoxic activation of the carotid body is
reset from the low fetal PO2 (25 Torr) to ⬃55 Torr (79, 82).
This is followed by a gradual increase in hypoxic sensi-
tivity of the carotid sinus nerve, a shift of the hyperbolic
response curve to higher PO2 values, a gradual appearance
of O2-CO2 interaction, and an improved ability to maintain
elevated discharge levels during prolonged hypoxia (116,
188, 487, 533, 601). The time course of these developmen-
tal changes (a few days to 3– 4 wk) varies between spe-
cies, and the relative maturity at birth determines the time
point at which adultlike responses are reached (33, 103,
208, 487, 601, 826). Processes underlying maturation of
the augmentation phase appear to be a complex fine
tuning between afferent nerve innervation of the carotid
bodies involving trophic factors such as brain-derived
neuorotrophic factor and all elements of the of hypoxic
stimulus-transduction cascade including membrane chan-
nels, neurotransmitters, receptors, and enzymes (see sect.
III) and are reviewed elsewhere (26, 94, 191, 258, 611).
These maturational processes must keep pace with
developmental changes in the central nervous system, for
example, in the nuclei of the solitary tracts (NTS), the first
relay station of incoming carotid body afferent input.
These processes involve changes in the activity of tran-
scription factors, formation of anatomical connections
within the neuronal respiratory circuitry, and alterations
in neurotransmitter contents and receptor densities to set
the balance between excitatory and inhibitory neuro-
transmission. For example, during maturation, the density
and expression of the glutamate receptor ionotropic N-
methyl-D-aspartate 1 (NR1) subunit of the NMDA (N-methyl-
D-aspartic acid) receptor in the rat NTS increases, which
leads to the upregulation of transcription factors and
other proteins that are involved in the hypoxic response
(564, 702). Another example of a developmental change in
the NTS is the downregulation of platelet-derived growth
factor (PDGF) during early maturation (702; PDGF exerts
an inhibitory influence on ion currents through NMDA
receptors, see also sect. IIID). Also in the rat, Wong-Riley
and Liu (847) have shown shifts in the expression of
GABA receptor subunits in the NTS and Pre-Bötzinger
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
complex around postnatal day 12 (P12) that were paral-
leled by ventilatory adjustments at the end of the second
postnatal week. Between P12 and P16, the HVR showed a
sharp decline to reach a minimum at P13, whereafter it
gradually increased to a final magnitude on P20 –P21.
Body temperature during hypoxia gradually rose during
the first three postnatal weeks to also reach the normoxic
value at P20 –P21 (847), consistent with a lesser contribu-
tion of the thermogenic component to the hypoxic re-
sponse at older age (see sect. IIC2). Maturation of the
mammalian respiratory network is reviewed in Refer-
ences 115, 186, 846.
3. Depressing phase of the HVR
The secondary roll-off in neonates may be associated
with pulmonary mechanics, a time-dependent decrease in
carotid body activity or sensitivity, impaired central inte-
gration of afferent carotid sinus nerve input, decreased
metabolism, increased CBF and, similar to the inhibition
of FBM, active inhibition by pontine and mesencephalic
structures involving inhibitory neurotransmitters (re-
viewed in Ref. 73). Muscle fatigue is unlikely to play a
significant role, since the phrenic nerve response in anes-
thetized neonatal animals does also show a biphasic pat-
tern, indicating that the secondary roll-off is a neurogenic
mechanism (121, 249, 522).
In 5- to 10-day-old rabbit pups, brain stem transection
at the midbrain-pontine junction converted the hypoxia-
induced depression in controls into sustained stimulation
in test animals (491). Focal cooling in the locus coeruleus
reversibly abolished the hypoxia-induced depression in 3-
to 8-day-old anesthetized lambs (522).
Available evidence also points to a role of the carotid
bodies in the depressing phase. The temporal response of
the sinus nerve discharge in kittens differed among stud-
ies, declining in some (116, 487) but sustained in others
(81). In 2- to 3-day-old lambs, a sudden hyperoxic stimulus
during a hypoxic exposure had a larger effect after 3 min
than after 15 min, suggesting waning peripheral chemore-
ceptor activity or impaired central integration (117). Ca-
rotid body denervation attenuated but not completely
abolished most of the secondary roll-off in 0- to 13-day-old
rats (249), and in newborn lambs the subcoeruleus area
showed increased activation in hypoxia after carotid body
denervation only (95).
In neonates, adenosine, serotonin, prostaglandin,
GABA, opioids, catecholamines acting at ␣2-receptors,
and other neuromodulators may all be involved in the
depressing phase (e.g., Refs. 212, 340, 400, 462, 740; see
further references in Refs. 73, 285, 702). The strongest
case was made for adenosine, which, similar to the fetus,
in neonatal sheep reduces hypoxic ventilation both via
adenosine A1A, but mainly adenosine A2A receptors (400).
In newborn lambs showing a biphasic phrenic hypoxic
Physiol Rev • VOL
681
response, focal cooling of regions in the locus coeruleus
prevented the (secondary) fall in respiratory motor out-
put induced by adenosine and hypoxia, respectively (522).
In 3-day-old piglets, the hypoxia-induced increase in tidal
volume waned between the second and fifth minute of
hypoxia, but this gradual waning could be prevented by
the adenosine antagonist 8-phenyltheophylline; 3-wk-old
animals, however, did not show this secondary decrease
in tidal volume, whilst the adenosine antagonist did not
have any influence on the sustained rise in ventilation
(212). In piglets 2–7 days of age, aminophylline prevented
the secondary decrease in phrenic activity during hypoxia
(121). In summary, the secondary roll-off in neonates may
be partly a manifestation of similar mechanisms that in-
duce hypoxic inhibition of FBM in the fetus on which a
postnatal influence of the peripheral chemoreceptors is
superimposed. Note, however, that in many of the above
neonatal studies, the end-tidal PCO2 was uncontrolled. If in
small animals the HVR is measured at temperatures below
thermoneutrality (which is often the case), a fall in me-
tabolism could well contribute to the secondary roll-off.
In these cases, measurements of metabolism and body
temperature would be very helpful (260). Other factors
such as the vigilance state, the severity of the hypoxic
stimulus, and other experimental conditions will also in-
fluence the magnitude of the depressing phase in the
neonatal period.
D. Developmental Plasticity of the HVR
A definition of developmental plasticity of respira-
tory control was provided by Carroll (115) as “long-term
alterations in the structure or function of the respiratory
control neural network caused by experience during pre-
or postnatal formation of the respiratory control system.”
Overwhelming evidence has identified the neonatal
environmental PO2 as a major factor influencing normal
HVR development. Hypoxia and/or hyperoxia around the
time of birth and the first few weeks thereafter can dis-
turb normal development of the HVR that may persist
until adulthood. The effects of perinatal chronic or inter-
mittent hypercapnia were less frequently studied; in the
rat, neither the neonatal nor the adult HVR seems to be
affected by neonatal hypercapnic exposures (43, 646).
1. Effects of neonatal chronic intermittent hypoxia
Term and preterm infants in particular are repeatedly
exposed to hypoxia due to their irregular breathing pat-
tern with many apneas. Animal studies have now made
clear that within a critical time window of neonatal de-
velopmental plasticity, chronic intermittent hypoxia can
induce life-long alterations in the control of breathing
with potential pathophysiological consequences (617,
633, 827). In this context, the critical time window of
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682 LUC J. TEPPEMA AND ALBERT DAHAN
neonatal plasticity was defined as a period within the
developmental stage in which the organism is uniquely
sensitive to environmental perturbations that may alter
the ultimate configuration of the neuronal network and
associated functions (115, 632). In terms of respiratory
control, it may imply that exposure to low or abnormally
high oxygen (or CO2) tensions within this window can
lead to life-long perturbations in respiratory control.
The effects of repeated exposures to hypoxia can be
quite complex and critically depend on the total duration
of an intermittent stimulus, its frequency, the overall num-
ber of cycles, and postnatal age which all appear to inter-
act (633, 827). One reason for this interaction is that the
HVR is build up of a series of sequential events with
different lags, time constants, gains, and recovery times.
For example, hypoxia augments carotid body activity,
increases the discharge frequency in the carotid sinus
nerve that results in the release of neurotransmitters in
the NTS, in turn leading to the release of neurotransmit-
ters in the ventrolateral medulla etc., eventually causing a
time-dependent recruitment of motoneurons. When a new
stimulus is offered while one of the processes initiated by
the previous stimulus is still in its recovery time or even
(partly or fully) active, it is conceivable that the effects of
both stimuli on motor output will differ (827).
To investigate the effect of chronic intermittent hyp-
oxia on developmental plasticity of the HVR, a variety of
paradigms with different stimulus magnitude, length, and
total duration and number of exposures were used in
several species such as mice (197), rabbits (789), piglets
(828), and rats (reviewed in Ref. 286). In the rat studies,
the age of the animals varied from 0 to as many as 30 days
and more, well beyond the critical time window for de-
velopmental plasticity (115, 286). The results of these
studies in different species are equivocal, varying from a
reduced (45, 497, 633, 635, 828 and references therein),
unaltered (197, 676) to an enhanced (367, 585, 598) HVR
and/or carotid body sensitivity. In the rat, blunting of the
HVR was reported to persist at 1 mo after cessation of the
stimulus paradigm (635). As shown in neonatal piglets,
the background PCO2 during the hypoxic episodes may
have an important influence: a poikilocapnic paradigm
(10% O2) blunted the HVR, but hypercapnic chronic inter-
mittent hypoxia (6% CO2, 10% O2) caused an increase
(828, 829). In instrumented anesthetized piglets, 11 peri-
ods of recurrent hypoxia blunted the phrenic nerve re-
sponse to acute hypoxia in young (2–10 days) but not
older (2–3 and 8 –10 wk) animals (509; note however that
in all recovery periods, these animals breathed 100% O2
which may have an effect by itself, see below). In most
(but not all) studies, normoxic ventilation increased (599,
631– 633) and, depending on the animal’s age at the onset
of the hypoxic stimulus, this effect was permanent (the
first two postnatal weeks were most efficient in this re-
spect; Refs. 632, 633, reviewed in Ref. 45).
Physiol Rev • VOL
These distinct effects of various specific neonatal
chronic intermittent hypoxia protocols on the augmenta-
tion phase of the HVR and mechanisms underlying neo-
natal respiratory plasticity are reviewed elsewhere (45,
115, 515, 631, 632, 827). The effects on the depressing
phase have not been studied extensively, but at least in
the rat, the secondary roll-off seems to be attenuated and
related to increased nitric oxide synthesis in the caudal
brain stem (286).
We attribute the above divergence in study outcomes
to the considerable variations in the applied stimulus
level, cycle length, the amount of hypoxic episodes, and
the number of exposure days. Differences in methodology
(e.g., plethysmography vs. pneumotachography) and de-
velopmental critical time windows between species will
also play a role (115). Interpretation problems due to
chronic intermittent hypoxia-induced changes in nor-
moxic ventilation and the employment of different meth-
ods to normalize data are illustrated by the work of Ling
et al. (449) and Reeves et al. (633) in adult and neonatal
animals, respectively. The poikilocapnic nature of the
experiments is also a confounding factor. As shown in
infants, kittens, and dogs, hypoxic hypometabolism can
be accompanied by a (sustained) fall in PaCO2 in the
depressing phase despite the decrease in ventilation (93,
489, 528, 648, 652).
The problem of measuring in a closed loop configu-
ration can be overcome by working with anesthetized
animals or ex vivo carotid body preparations. Rat pups
subjected to chronic intermittent hypoxia soon after birth
(15 s in 5% O2 followed by 5 min in 21%, 9 episodes/h
during 16 h) showed an augmented ex vivo hypoxic ca-
rotid body sensitivity that persisted until adulthood and
was associated with hyperplasia of glomus cells (585).
Carotid bodies from neonates are much more sensitive to
chronic intermittent hypoxia than those of adult animals
and the effects in neonatal animals are permanent (585).
Recently, Pawar et al. (586) showed that in neonatal rats
chronic intermittent hypoxia induced an augmented basal
release of endothelin-1 (ET-1) in normoxia, upregulation
of ETA receptor mRNA, and an enhanced carotid body
sensitivity to ET-1. In another study, a chronic intermit-
tent paradigm led to decreases in both the HVR and
isocapnic hypoxic phrenic response (635), which would
be more in line with the effect of chronic hypoxia. The
paradigm consisted of alternating room air with 10% O2
every 90 s (12 h/day, during 30 days), raising the question
whether after a short period of low oxygen, 90 s is suffi-
cient to completely restore tissue oxygenation to normal,
possibly resulting in chronic hypoxia rather than chronic
intermittent hypoxia.
In conclusion, recent data from ex vivo carotid bod-
ies indicate an increase in sensitivity by neonatal chronic
intermittent hypoxia. Technical limitations and method-
ological differences are probably responsible for the fact
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
that as yet these important results could not be consis-
tently confirmed at the level of minute ventilation. Stan-
dardizing protocols, uniform quantification of HVR data
(combined with metabolic data), and blood gas measure-
ments may help to reach consensus on the effects of
neonatal chronic intermittent hypoxia. Intermittent expo-
sures in which hypoxic episodes follow each other so
closely in time that episodic reoxygenation is incomplete
or does not occur at all may be interpreted as chronic (see
also ref 827).
2. Effects of neonatal chronic hypoxia
Cats, sheep, and rats subjected to hypoxia (10 –15%
O2) from birth until 24 h before they were tested at ages
varying from 5 days to 10 wk showed a markedly reduced
HVR, mainly caused by a depression of the augmentation
phase (39, 42, 42, 45, 207, 567, 703 and references therein).
In rats and sheep exposed to neonatal hypoxia for 1–2
wk, blunting of the HVR persisted for at least 5–12 wk (39,
476, 567, 703), which in the rat was sex specific (only ob-
served in males; Refs. 42, 476). The effect of neonatal hyp-
oxia on normoxic ventilation is variable: in some studies, a
long-lasting increase was observed (527, 566, 567) while it
was absent in others (42, 476, 703). At the age of 12 wk, both
male and female rats displayed an impaired ventilatory ac-
climatization to chronic hypoxia (2 wk in 10% O2) when they
were raised in hypoxia until postnatal day 10 (476).
Initially, in the first weeks of maturation the blunted
HVR in chronically hypoxic neonates may be due to a
delayed carotid body resetting and/or to an attenuation of
the maturation of the O2-CO2 interaction (301, 303, 437,
730, 826; further references in Ref. 115). Single fibers of
the carotid sinus nerve from rat puppies that were raised
in 9% O2 from the first or second postnatal day until 3– 4
wk later, showed a 50% lower peak response to severe
hypoxia than controls (186). Both at the ages of 3 and 8
wk, rats exposed to hypoxia for 6 days in their neonatal
period had increased carotid body dopamine and norepi-
nephrine levels (721). Glomus cells from neonatal rats
reared in 12% O2 during 1–3 wk demonstrated a reduced
rise in intracellular [Ca2⫹] in hypoxia compared with cells
from normoxic aged-matched controls, and this impaired
maturation partially recovered 1 wk upon return to nor-
moxia (731). Rat puppies born and raised in 10% O2 for
9 –14 days had a substantially reduced HVR and possessed
type I cells that displayed a reduced expression of maxi-K
channels and failed to depolarize in hypoxia (854). In
neonatal and juvenile type I cells from rats cultured in 6%
O2 for 12 days, maxi-K channels were downregulated
(354). These studies suggest that the neonatal chronic
hypoxia-induced HVR reduction is at least partly due to an
impaired carotid body function. Not all data, however,
support this because changes in sodium and potassium
Physiol Rev • VOL
683
currents that would tend to increase the excitability of
type I cells were also reported (315, 316, 726, 727).
Neonatal chronic hypoxia will also affect or delay
normal maturation of the central respiratory neuronal
network. For example, exposing newborn rat pups to 6
days of chronic hypoxia resulted in a decreased norepi-
nephrine turnover in the caudal part of the noradrenergic
A2 region in the NTS (an important projection area of
carotid body afferents) at the age of 8 wk, suggesting
long-term effects of the neonatal challenge (721). NMDA
receptors in pons and caudal medulla of rats raised in 10%
for 4 –5 wk from birth were downregulated (248). After
they were raised in 13–15% O2 from birth to 5–10 wk
postnatally, anesthetized rats showed normal (i.e., similar
to age-matched normoxic controls) isocapnic hypoxic si-
nus nerve responses, but their HVR remained blunted
(207). Adult anesthetized rats, kept in 10% O2 during their
first postnatal week, had a normal phrenic response to
isocapnic hypoxia, but their HVR was reduced (43). The
authors of the latter two studies suggested that the sus-
tained reduction in HVR after neonatal CH may originate
downstream from the phrenic motoneuron pool. Abnor-
mal and/or retarded lung growth may then provide a
potential explanation (493). Normal maturation of the
HVR is also associated with an age-dependent attenuation
of the, centrally governed, depressing phase (see above).
In rat puppies, chronic hypoxia from birth delays this
decrease (207). Other adaptations observed after neonatal
chronic hypoxia in rats are an increase in hematocrit,
decrease in metabolism, and an enlarged alveolar gas
exchange surface perhaps tending to compensate for a
reduced HVR (527, 531 and references therein). Exposing
newborn piglets to hypobaric hypoxia during 3 days
caused pulmonary hypertension and prevented the rapid
remodeling of the cytoskeleton of pulmonary arterial smooth
muscle cells that normally contributes to the postnatal de-
crease in pulmonary vascular resistance (298).
Taken together, neonatal chronic hypoxia-induced blunt-
ing of the HVR has multifactorial causes involving plastic
changes in the carotid bodies, the central nervous system,
and possibly also lung mechanics and pulmonary vessels.
3. Effects of postnatal chronic hyperoxia
Earlier experiments in fetal sheep suggested that
brief prenatal hyperoxia would hasten resetting of the
carotid bodies explaining the reported increased carotid
body O2 sensitivity in these animals (82). This contrasts
with many studies showing a reduced HVR after chronic
neonatal hyperoxia. For example, kittens breathing 30%
O2 during their first 13 days showed a reduced early-phase
HVR right away after this exposure (301). In recent years,
much attention was focused on the effects of immediate
postnatal chronic hyperoxia on the HVR on the longer
term, extending to the adult age (reviewed in Refs. 39, 45,
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684 LUC J. TEPPEMA AND ALBERT DAHAN
115). Here we will briefly highlight some main findings.
The effect of neonatal hyperoxia on adult normoxic base-
line ventilation appears variable, with some studies show-
ing an increase and others reporting no change (refer-
ences in Ref. 45). The consequences for the HVR and
hypoxic responses of the phrenic and carotid sinus nerves
at the adult age can be summarized as follows: 1) chronic
neonatal hyperoxia causes a decrease in hypoxic sensi-
tivity at all these three integration levels that persists into
adulthood (71, 246, 449). 2) The critical time window to
induce this effect, which is dose dependent and can al-
ready be induced by 30% O2, lies within the first 2 wk;
longer exposures cause no additional depression (40, 41,
71). 3) The attenuation of the HVR can be limited by
alternating the chronic hyperoxia with periodic hypercap-
nia or by replacing chronic by intermittent hyperoxia,
suggesting that intermittently increasing carotid body ac-
tivity reduces the effect (43). 4) Central (carotid sinus to
phrenic nerve) integration remains unimpaired, suggest-
ing that the depressing effect originates from the carotid
bodies (450). 5) The carotid bodies show degeneration,
hypoplasia, changes in membrane properties, and a re-
duced number of unmyelinated fibers that altogether lead
to reduced O2 sensitivity of glomus cells and the carotid
body in vitro (189, 220, 622, 838). 6) Petrosal ganglion
neurons also show degenerative changes (loss of tyrosine
hydroxylase expression; Ref. 220).
A recent study focused on the time course of alter-
ations in hypoxic responses of glomus cells and carotid
sinus nerve afferents from rats exposed to chronic hyper-
oxia starting on postnatal day 7 and lasting for 1, 3, 5, 8,
and 14 days, respectively. On postnatal day 8 (so after 1
day of hyperoxia), the secretory response of glomus cells
and the nerve response to hypoxia were increased, but
beyond exposure days 3–5, both responses were reduced,
and this reduced sensitivity persisted until at least 1 wk
after exposure (187). Are these effects reversible once
animals have reached the adult age? Bisgard et al. (72)
reported that sustained hypoxia at adult age (3–5 mo)
only sensitized the carotid sinus nerve when the chronic
neonatal hyperoxia did not outlast 2 wk. However, an-
other study showed recovery from the deleterious effects
of chronic hyperoxia during the first month after birth at
the age of 4 mo (247). An antioxidant rich diet during the
neonatal hyperoxia did not prevent an impaired HVR at
adult age (44), not supporting ROS-mediated toxicity. Fu-
ture studies are warranted to further examine the influ-
ence of dose and duration of neonatal chronic hyperoxia
and how an impaired HVR at adult age might be restored.
E. The HVR in Term and Preterm Babies
In most cases, the HVR in young babies is measured
by exposing them to 15% O2, seldom with addition of CO2.
Physiol Rev • VOL
Most recordings are from quiet sleep when breathing is
predominantly under metabolic control and somewhat
less unstable than in active sleep, with less frequent
arousals. Control of end-tidal gases is unusual so that the
magnitude of the HVR reflects the closed-loop properties
of the respiratory system.
With the exception of very small premature infants
showing a sustained “fetal-like” decrease in ventilation
(15), most term and preterm infants exhibit a biphasic
HVR upon exposure to 15% O2 during 5 min, much similar
to that in neonatal animals. The secondary fall appears to
be due mainly to a fall in frequency while in most cases
tidal volume shows a sustained increase, sometimes after
an initial overshoot (138, 139, 489, 552, 637, 648, 651, 652).
With some exceptions (e.g., Refs. 139, 723) early in devel-
opment the depressing phase of the HVR is associated
with a sustained decrease in end-tidal PCO2 (489, 637, 648),
similar to neonatal animals, and this is possibly related to
a fall in metabolism (147, 332). During maturation, the
decrease in frequency gradually becomes less dramatic,
and with advancing age, tidal volume tends to remain
elevated (489, 648, 651).
The normal developmental time course of the HVR in
humans appears difficult to determine. Breathing in term
and especially preterm infants is characterized by irregu-
larities and apneas (625) that have been related to imma-
ture brain stem function and connections (318) and also
to a relatively low PaO2 leading to brisk hypoxic respon-
ses, hypocapnia, and central apneas (552). Consequently,
when occurring within the critical developmental time
window, both the resulting chronic and intermittent hyp-
oxia or a combination may hinder a normal development
of the HVR. Despite the quite different term durations in
rodents and humans, the animal data raise the question as
to whether oxygen therapy in the neonatal period may
have unwanted side effects with regard to the develop-
ment of normal O2 and CO2 reflex sensitivities. By itself,
preterm birth exposes the newborn to an environment
that is hyperoxic relative to postconceptional age.
Whether this is related to the lower HVR of preterm
infants compared with age-matched controls remains to
be investigated. The higher prevalence of the sudden
infant death syndrome (SIDS) in preterm compared with
term babies has been related to relative immaturity of the
cardiorespiratory neuronal circuitry resulting in failure of
ventilatory and arousal responses (518).
Of practical interest when studying the HVR in both
neonatal animals and infants is its dependency on the
vigilance state (317, 319, 472, 648, 651, 729). Most HVR
data were collected in quiet sleep, but potential influences
of arousal are not always taken into consideration (648).
In a longitudinal study in healthy term infants, the HVR
was reported to mature between 2–5 wk and 5– 6 mo of
age in quiet but not active sleep, especially in children
that did not arouse by the stimulus (15% O2 during 5 min
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 685

or 85% SpO2, see Fig. 1). Even at the age of 5– 6 mo,
ventilation did not exceed prehypoxic control after a
5-min hypoxic challenge, and this was considered an im-
mature HVR. However, taking into account that the pro-
tocol was clearly poikilocapnic and that the HVR was
identical to that after 2–3 mo and very similar to the
poikilocapnic HVR in adult humans (cf. Fig. 1) leads us to
suggest that maturation of the HVR in term infants may be
complete at ⬃2 mo. Direct assessments of carotid body
sensitivity with brief exposures to 100% O2 (Dejours test;
Ref. 13) or by offering alternating breaths containing
room air and 16% O2 (108, 843) pointed to full maturation
of the peripheral chemoreflex within the first few weeks
and possibly even the first 48 h after birth (13; note,
however, that data obtained with Dejours tests should be
interpreted with caution because the peripheral chemo-
receptors may still display considerable activity in hyper-
oxia). That in term infants the O2-CO2 interaction has
been reported to emerge at an age somewhere between
day 2 and week 8 (no testing after ⬃2 wk) is not incon-
sistent with this picture (723).
III. PERIPHERAL AND CENTRAL MECHANISMS
MEDIATING THE HYPOXIC VENTILATORY
RESPONSE IN ADULT MAMMALS
A. Carotid Body Mechanisms in Oxygen Sensing
The ventilatory response to hypoxia is initiated by
the carotid bodies, with the aortic bodies playing only a
secondary role, perhaps with the exception of conditions
wherein the carotid bodies are functionally eliminated
(278). The carotid bodies, bilaterally located in the carotid
bifurcations at the port of the brain circulation, have the
V
highest blood flow-to-metabolism ratio in the body and,
both anatomically and biochemically, are extremely com-
plex organs (278, 280 and references therein). Not only do
they possess cells specialized in oxygen sensing, but in
fact, they appear to be polymodal and sensitive to a
variety of stimuli such as pressure, hypercapnia, acidosis,
hyperkalemia, hyposmolality, circulating hormones, hy-
perthermia, hypoglycemia, and numerous pharmacologi-
cal agents (reviewed in Refs. 416, 558).
The two main cell types in the carotid bodies are
glomus (type I) cells, having many similarities with sen-
sory neurons and thought to be oxygen sensitive and
sustentacular (type II) cells with a glialike appearance
(278). Sensory neurons with cell bodies in the petrosal
ganglia send peripheral axons to the carotid bodies that
run with the carotid sinus nerve, a side-branch of the
glossopharyngeal nerve, and have nerve endings closely
oriented to type I cells. Central axons of these sensory
neurons enter the brain stem with the glossopharyngeal
nerve and terminate in caudal subnuclei of the NTS that
have extensive connections with the brain stem respira-
tory network (references in Refs. 232, 335).
Hypoxia is followed by release of neurotransmitters
by type I cells that act on the afferent endings of the
carotid sinus nerve to increase impulse traffic to the brain
stem (278). Neurotransmitter release is the result of a rise
in intracellular [Ca2⫹] following depolarization of the
membrane potential of type I cells. The mechanisms un-
derlying the entire signal-transduction cascade in type I
cells from hypoxia to the release of neurotransmitters
have been the focus of numerous studies over the last two
decades. This has resulted in the acceptance, albeit not
without controversies, of a framework in which hypoxia
leads to inhibition of ion currents through potassium
channels in the cell membrane resulting in membrane

*
.
V

** *
**

FIG. 1. Poikilocapnic hypoxic ventilatory responses in young babies and adults. A: maturation of the ventilatory response to 15% O2 in 15 term
infants between the ages of 2–3 wk (■), 2–3 mo (E), and 5– 6 mo (Œ). *Significantly different with levels after 2–3 mo. **Significantly different when
compared with 5– 6 mo. Measurements were performed in quiet sleep, and the children did not arouse from the stimulus. B: poikilocapnic hypoxic
ventilatory responses in 10 healthy young adults upon a step decrease to and end-tidal PO2 of ⬃44 Torr. Note that both after 2 and 5 mo the
poikilocapnic responses are qualitatively similar to the adult. [Adapted from Richardson et al. (648) and Steinback and Poulin (728).]

Physiol Rev • VOL 90 • APRIL 2010 • www.prv.org

686 LUC J. TEPPEMA AND ALBERT DAHAN
depolarization, influx of extracellular Ca2⫹ via voltage-
gated (mainly L and P/Q type) Ca2⫹ channels, and release
of neurotransmitters (278, 465, 467, 469, 662, 835, see Fig. 2).
Overall, the main focuses of attention were the following:
1) the element(s) that initiate(s) the cascade, in other
words the identity of the intrinsic O2 sensor(s); 2) the
cause(s) by which the resting membrane potential chan-
ges, the identity of potassium channels involved in this,
and the link of these channels with the intrinsic O2 sen-
sor(s); and 3) the identity of the neurotransmitters that
are released by type I cells and excite afferent nerve
endings. With regard to the identity of the contributing
potassium channels and excitatory neurotransmitters,
there seems to be a reasonable consensus, although some
aspects remain controversial. These issues are covered by
several recent reviews and are briefly referred to below
but not discussed in detail. Recent studies on the identity
of the O2 sensor(s), and their link with potassium chan-
nels, to be discussed below in more detail, have improved
FIG. 2. Stimulus transduction cascade in oxygen-sensitive cells in
the carotid body in hypoxia. A decrease in oxygen tension in oxygen-
sensitive carotid body type I cells is detected by primary oxygen sensors
that rapidly communicate with potassium channels (mitochondria could
also sense changes in PO2 and communicate with potassium channels).
This leads to closure of these channels, which results in membrane
depolarization, influx of Ca2⫹ via voltage-dependent Ca2⫹ channels, and
subsequently to a release of neurotransmitters, whereby acetylcholine
and ATP are thought to excite the afferent nerve endings of fibers that
run in the carotid sinus nerve. NTS, nucleus of the solitary tract.
Physiol Rev • VOL 90 • APRIL 2010 •
our insight into the way type I cells couple changes in
PaO2 to alterations in potassium channel activity.
1. Hypoxia decreases the open probability of
potassium channels
It is now widely accepted that hypoxia decreases the
open probability of potassium channels. A first report in
1998 showing hypoxic inhibition of voltage-gated potas-
sium channels in rabbit type I cells (466) was followed by
numerous other studies, but here we only highlight major
findings. Three main categories of O2-sensitive potassium
channels in type I cells have been described. 1) Channels
that produce voltage-gated K⫹ currents (Kv channels), of
which several isoforms have been suggested to be O2
sensitive (reviewed in Ref. 470). 2) Large-conductance K⫹
channels that are activated by both voltage and intracel-
lular Ca2⫹ (KCa2⫹, maxi-K, or BK channels; reviewed in
Ref. 594). 3) Voltage-independent two-pore domain back-
ground (K2P) channels that contribute to the resting mem-
brane potential and of which several isoforms are de-
tected in glomus cells (861): K2P3.1 (TASK-1), K2P4.1
(TRAAK), K2P5.1 (TASK-2), and K2P9.1 (TASK-3 ). TASK-1
(TWIK-1-related acid-sensitive K⫹ channel; TWIK channel,
tandem pore domain weak inward rectifying potassium
channel) is the most likely candidate to operate as O2-
sensitive background K⫹ channel (reviewed in Refs. 98,
196, 788). Different species appear to have distinct types
of oxygen-sensitive potassium channels. For example, in
rabbits, Kv isoforms are the predominant types, but in the
rat carotid body, significant roles of both maxi-K and
TASK-1 have been demonstrated (98, 278, 594 for further
references).
2. Carotid body neurotransmitters
The carotid bodies contain a variety of neurotrans-
mitters that are either stored in vesicles or appear as
by-products of enzymatic processes in the cytosol where
they can influence the signal-transduction cascade (426,
558). The first category comprises the biogenic amines
acetylcholine, dopamine, norepinephrine, serotonin, and
histamine; (neuro)peptides such as substance P, endothe-
lins, and angiotensin II; and amino acids such as GABA
and the purine ATP (see Refs. 394 and 438 for histamine
and Ref. 426 for further references). Nitric oxide (NO) and
carbon monoxide (CO) are important representatives of
the second category, synthesized with the aid of the
heme-containing enzymes NO synthase and heme oxygen-
ase, respectively. For an extensive discussion of the role
of all these neurotransmitters and modulators, the reader
is referred to several excellent reviews (425, 426, 558, 621,
701, 868). With regard to the overall stimulus-transduction
cascade, there seems to be consensus, albeit not without
controversy, that hypoxia induces the release of acetyl-
choline and ATP and that these neurotransmitters are
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 687

responsible for the excitation of the afferent nerve end- hibited by low PO2 (593, 853). In carotid body cells iso-
ings (350, 559, 644, 645, 799; see Refs. 558 and 868 for lated from neonatal (8 –11 day) rats, substrates of HO-2
further references). (heme and NADPH) activated native maxi-K channels.
Since increased HO-2 activity generates CO, that by itself
3. O2 sensing in the carotid bodies activates maxi-K channels, it was suggested that the en-
zyme acts as an O2 sensor (844). How CO specifically
Over the last decades two main hypothesis of O2
interacts with maxi-K channels is unknown.
sensing have been at the foreground: 1) ion channels, and
At an age ⬍3 mo, mice deficient in HO-2 (HO-2⫺/⫺)
potassium channels in particular, as the initiators of the
show a carotid body phenotype typical for oxidative
transduction cascade, referred to as the “membrane hy-
stress with enlargement of the organ and downregulation
pothesis”; and 2) heme proteins as oxygen sensors, re-
of maxi-K channels and a marked upregulation of tyrosine
ferred to as the “metabolic” or “mitochondrial” hypothesis
hydroxylase, suggesting that HO-2 could be a potential O2
(278, 279, 430, 620).
sensor (574, 854). Type I cells isolated from HO-2⫺/⫺ mice
The role of potassium channels in type I cell mem-
have a normal catecholamine secretory response to hyp-
brane depolarization is now well established (see above).
oxia, which may suggest that HO-2 is not a key O2 sensor
In excised membrane patches, this hypoxia-induced de-
and maxi-K channels are not required for a normal secre-
polarization is still present, but in the course of time a
tory response to occur (574). Carotid sinus nerve record-
significant rundown occurs, indicating that O2 sensing
ings were not performed in this study, so it remains to be
may be a membrane-delimited process requiring cytosolic
seen whether a normal secretory response also predicts a
factors to be preserved for longer time periods (800, 842).
normal nerve response. Although at the level of type I
Whether or not potassium channels possess structural
cells the release of catecholamines is considered a mea-
components required for direct oxygen sensing, many of
sure of type I cell activation (e.g., Ref. 574), changes in
them appear to be redox sensitive (392, 409, 468, 603), but
their release do not always mirror alterations of carotid
it is unlikely that hypoxia inhibits the current through
sinus nerve activity (100, 185, 350, 351 and references
these channels by oxidizing or reducing functional chan-
therein). It is interesting that HO-2⫺/⫺ mice showed a
nel protein components (reviewed in Ref. 282). Generally,
reduced poikilocapnic HVR despite the fact that, com-
reductants and oxidants decrease and increase, respec-
pared with wild types, they were challenged with a much
tively, the open probability of rapidly inactivating O2-
more severe hypoxic stimulus because of their lower
sensitive potassium channels in particular, but the effects on
initial arterial PO2 (4). So it seems reasonable to conclude
maxi-K channels are more variable (references in Ref. 282).
that to date the identity of HO-2 as an oxygen sensor
For several decades, mitochondrial cytochromes
remains unsettled. Finally, concerning the participation of
were considered potential O2 sensors providing the link
maxi-K channels in oxygen sensing, it is worth noting that
between type I cell metabolism and afferent nerve activ-
these channels tend to be activated at a membrane poten-
ity, but to date, their exact role is still a subject of discus-
tial more positive than that seen in type I cells. Therefore,
sion (recently reviewed in Refs. 122, 295, 296, 415, 465,
in order for the maxi-K channel to be the initial sensor, it
837). Generally, with a few exceptions, inhibitors of mi-
would have to be open at or near the glomus cell resting
tochondrial complex proteins inhibit currents through
membrane potential.
potassium channels, depolarize type I cells, and can oc-
clude the hypoxic response (references below). However,
inhibition of the cytosolic heme-containing enzymes 2. NADPH oxidase
NADPH oxidase, heme oxygenase 2, and NO synthase
Acker and co-workers (2, 3) suggested a role of the
may also have these effects and may thus also serve as
membrane-bound extra-mitochondrial enzyme complex
candidate O2 sensors.
NADPH oxidase using NADPH as an electron donor that
produces O⫺ 2 in proportion to PO2 and proposed that ROS
1. Heme oxygenase 2
would activate nearby potassium channels in normoxia
After demonstrating the presence of heme oxygenase but less so in hypoxia when NADPH oxidase activity
2 (HO-2) in rat and cat carotid bodies, Prabhakar et al. would be reduced (reviewed in Ref. 3). Several NADPH
616) showed that blockade of HO-2 increased afferent oxidase isoforms were identified in carotid body cells
carotid sinus nerve discharge in the cat that was revers- including those containing the subunits gp91phox and
ible with CO. Recently, Kemp, Peers, and co-workers p47phox (references in Ref. 3). Later, NADPH oxidase 4
(844) showed that HO-2 coimmunoprecipitated with het- was identified as one of these isoforms in glomus cells
erologously expressed maxi-K channels in human embry- (184, 276). Diphenyliodonium (DPI), an unspecific NADPH
onic kidney cells and that blocking the enzyme with small oxidase inhibitor, increased basal carotid sinus nerve activ-
interference RNA abolished channel inhibition by low PO2 ity in the rat and inhibited the hypoxia-induced increase in
(844). In rat carotid body cells, maxi-K channels are in- nerve activity (146). In an in vitro perfused carotid body

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688 LUC J. TEPPEMA AND ALBERT DAHAN
preparation from the rat, hypoxia reduced a cytochrome
b558 isoform whilst the specific NADPH oxidase inhibitor
4-(-2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) increased
carotid sinus nerve activity and occluded the hypoxic
response (424). Transfection of TASK-1 channels in hu-
man embryonic kidney (HEK) cells endogenously ex-
pressing NADPH oxidase 4 resulted in colocalization of
both in the plasma membrane; overexpression of the
enzyme enhanced the hypoxia-induced TASK-1 current
inhibition in these cells, but eliminating the enzyme abol-
ished the hypoxic response (439).
In the HEK cell model, the concept of ROS-mediated
TASK-1 activation was recently challenged because it ap-
peared to be determined by O2 binding to the heme moi-
ety of the enzyme rather than by the production of ROS
(582). Other evidence did not support a crucial role for
NADPH oxidase. For example, in both rat and rabbit
carotid body cells, specific inhibitors of the enzyme did
not affect catcholamine release in normoxia or its in-
crease in hypoxia; in addition, DPI seemed to have effects
independent from NADPH oxidase inhibition (561). Com-
pared with wild types, adult mice deficient in gp91phox do
not show altered responses of ventilation, carotid sinus
nerve activity, potassium currents, or intracellular [Ca2⫹]
to hypoxia (306, 310, 667). Very interesting results were
obtained from p47phox⫺/⫺ mice: 1) type I cells from
knockout mice did not show the hypoxia-induced in-
crease in [ROS] that was observed in cells from wild
types, but displayed an enhanced depression of potassium
currents and a substantial greater rise intracellular
[Ca2⫹]; and 2) both the HVR and hypoxic carotid sinus
nerve responses in knockout mice were substantially
greater than in wild types (184, 310, 678). From these
observations it was concluded that hypoxia induces a rise
in [ROS] in type I cells with NADPH oxidase as their
source and that these ROS modulate (increase) the open
probability of (Kv) potassium channels, rather than being
directly involved in oxygen sensing.
3. NO synthase
At least two NO synthase (NOS) isoforms have been
identified in the carotid bodies: 1) NOS-1 (neuronal NOS)
located in sensory and autonomic nerve fibers innervating
vessels and lobules of glomus cells and 2) endothelial
NOS (NOS-3; references in Refs. 109, 426). Aspecific NOS
inhibition increases basal carotid sinus nerve discharge
and enhances hypoxic carotid body sensitivity and the
HVR, whilst NO donors do the opposite (290, 619 for
further references). Whether NOS is activated or inhibited
during hypoxia is controversial (references in Ref. 426).
NOS-1⫺/⫺ mice show an enhanced hypoxic carotid body
sensitivity and HVR, supporting an inhibitory role of NO
(389). NO may modulate carotid body sensitivity by alter-
Physiol Rev • VOL
ing blood flow and/or exerting direct effects on type I cells
(references in Refs. 109, 426, 619).
4. Mitochondrial complex proteins and
complex-derived ROS
The role of ROS in oxygen sensing is the subject of a
long debate with many controversial data and different
views. Partly, the lack of consensus is caused by the
difficulty of measuring ROS, by local differences in their
production in various microdomains of the cell (cell mem-
brane, cytosol, nucleus, mitochondria), and by differ-
ences between cell types (see Refs. 276, 282 for refer-
ences).
Generally, inhibitors and uncouplers of the electron
transport chain inhibit background potassium channels
and cause membrane depolarization, voltage-gated Ca2⫹
entry, and neurosecretion. They also stimulate the carotid
bodies and, provided the inhibition of electron flux is
complete, occlude the hypoxic response (851). Originally
it was thought that hypoxia would reduce cytochrome c
activity of complex IV of the electron transport chain,
which then would cause mitochondrial depolarization
and Ca2⫹ release (194). Later the rise in intracellular
[Ca2⫹] appeared to depend on extracellular Ca2⫹, and the
role of mitochondria as oxygen sensors lost support (99,
465, 802). In addition, several blockers of the electron
transport chain (rotenone in particular) have nonspecific
effects on potassium channels (573).
A modulating role of mitochondrial ROS, and in this
context the influence of cellular redox state on oxygen
sensing was investigated by Gonzalez et al. (281). The
cellular redox state was assessed by measuring the ratios
of reduced (GSH) to oxidized glutathione (GSSG), from
which the redox potential (EGSH) can be calculated. EGSH
is considered the main cellular buffer of ROS and repre-
sentative for the general redox environment of cells (281).
Briefly, Gonzalez et al. (281) found the following. 1) In
calf and rabbit carotid body cells, hypoxia did not reduce
EGSH. 2) The antioxidant and GSH precursor N-acetylcys-
teine increased EGSH in normoxia in these cells without
eliciting an increased catecholamine release. 3) N-acetyl-
cysteine also did not alter the enhanced neurotransmitter
release induced by hypoxia and high extracellular [K⫹].
4) In rat carotid body cells, specific inhibition of mito-
chondrial complexes I, II, III, and IV all reduced EGSH,
and, with the exception of the irreversible complex II
inhibitor 3-nitropropionate, decreased cellular ATP levels
and increased catecholamine release. N-acetylcysteine pre-
vented these changes in redox state without influencing
the effects on [ATP] and neurosecretion. 5) The mito-
chondrial uncoupler dinitrophenole activated rat carotid
body cells without affecting [ATP] and EGSH (275, 281,
282, 679).
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
The conclusion from these studies by Gonzalez et al.
(281) is that oxygen sensing in carotid body cells occurs
independently from changes in cellular redox state. In
fact, this was supported at the level of afferent nerve
discharges in superfused rat carotid bodies (666). How-
ever, given the fact that N-acetylcysteine restores the
redox state but does not prevent ROS production per se,
the question now arises whether mitochondrial ROS may
play any (indirect) role, for example, by influencing ATP
production. As explained in insightful reviews by Gonza-
lez and co-workers (276, 282), there is much controversy
as to whether hypoxia decreases or increases mitochon-
drial [ROS]. Briefly, these authors provided reasonable
arguments why, unlike some other cell lines, type I cells
most likely do not increase mitochondrial ROS produc-
tion in acute hypoxia and why the limited observed rise in
cellular [ROS] in type I cells is most likely due to in-
creased NADPH activity (310). Yamamoto et al. (860) also
observed an increase in [ROS]. Maintenance of the redox
state in the face of increased ROS production via this
pathway would occur by an increased production of
NADPH (reducing equivalent) along the hexose mono-
phosphate pathway (276, 310). Mitochondrial inhibitors
with divergent effects on local ROS production all had
stimulating effects on type I cells and occluded the hyp-
oxic response to hypoxia, suggesting no crucial role of
mitochondrial ROS on O2 sensing (851).
An absence of a direct involvement of ROS and the
cellular redox state in oxygen sensing does not preclude
a modulating effect of oxidants and reductants. In the
model proposed by He et al. (310) and Dinger et al. (184),
ROS, generated by NADPH oxidase activity, facilitates
potassium channels. In rat type I cells, inhibition of the
cytochrome P-450 enzyme system using NAD(P)H as elec-
tron donor prevents hypoxia-induced inhibition of potas-
sium channels (304). As suggested by Kline et al. (389), a
rise in [ROS] could decrease the bioavailability of NO,
increasing hypoxic sensitivity. Mice deficient in neuronal
NOS have an augmented HVR (389).
5. Individual mitochondrial complexes
To date, the identification of one single mitochon-
drial complex protein as the oxygen sensor in type I cells
has been elusive. Light absorption photometry has iden-
tified a cytochrome, a592, as a unique component of ca-
rotid body cytochrome-c oxidase (complex IV) with a
redox sensitivity that depends on the PO2 in a nonlinear
fashion (3, 733). By inducing a shortcut of electron flow
within complex IV, this low O2 affinity cytochrome would
contribute to mitochondrial depolarization and intracel-
lular Ca2⫹ regulation. However, the intracellular [Ca2⫹]
response to hypoxia depends on extracellular, not intra-
cellular, calcium stores (99, 465, 802), whilst the ATP
synthase inhibitor oligomycin, despite causing mitochon-
Physiol Rev • VOL
689
drial hypopolarization (194), has a similar stimulatory
effect on type I cells as mitochondrial complex inhibitors
and uncouplers which cause mitochondrial depolariza-
tion (851). Despite this, the idea of heme-containing oxy-
gen sensors with different O2 affinities in distinct mi-
crodomains of the cell, enabling it to adapt to changes in
cellular PO2 profile (“oxygen redirection”), is interesting
(837 for references).
In rat PC12 cells, hypoxia produced a selective and
fast downregulation of complex I mRNA. This suggested
that, apart from being involved in the flow of electrons
through the electron transport chain and as such may
indirectly contribute to rapid changes in [ATP], complex I
may play an important role in adapting mitochondrial
respiration to prolonged periods of hypoxia (606). In
chronic intermittent hypoxia, carotid body complex I ac-
tivity also appeared to be reduced (596).
Mice heterozygous for succinate dehydrogenase sub-
unit D (SDHD⫹/⫺), one of the anchoring proteins of com-
plex II (607), show mild carotid body hypertrophy and
hyperplasia and an enhanced catecholamine release by
type I cells in normoxia. These features are associated
with a decrease in K⫹ conductance (due to a a decreased
Ca2⫹ sensitivity of maxi-K channels) and a persistent
2⫹
Ca influx; the hypoxia-induced CA release was enhanced
in these animals, but not significantly (607). Thus these
mice do not seem to support a crucial role of complex II
in O2 sensing, and this may fit the finding that the irre-
versible complex II inhibitor 3-nitropropionate did not
alter the catecholamine release and ATP content of rat
carotid body cells (275). However, carotid body-sinus
nerve preparations from SDHD⫹/⫺ mice were not studied.
Human carriers of a missense mutation within the SDHD
gene show an altitude-related phenotype (20). Thus it
remains to be seen whether there may exist a relation
between complex II activity and oxygen sensing (for fur-
ther discussion and references, see sect. IV).
6. Mitochondria and the link between metabolism and
potassium channel activity
Failure to show an indispensable role of mitochon-
drial ROS in O2 sensing, and the fact that it has been
elusive to identify one of the electron transport chain
complexes as the O2 sensor that initiates the entire trans-
duction cascade, does not preclude a mitochondrial role
because O2 sensing could be a direct or indirect function
of mitochondrial energy metabolism and ATP synthesis
(851). Mitochondrial complex inhibitors and uncouplers
have variable effects on [ROS], but two effects that they
have in common are that they decrease ATP levels and
activate type I cells (276, 851), perhaps with the exception
of specific complex II blockers (275).
Recently, cellular energy status was linked to cell
activity in type I cells via AMP-activated protein kinase
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690 LUC J. TEPPEMA AND ALBERT DAHAN
(AMPK), which is considered the master regulator of
glucose and fatty acid metabolism (417 and 786 for refer-
ences). AMPK is a cellular energy sensor and sensitive to
the cellular AMP-to-ATP ratio. Metabolic stress including
hypoxia increases this ratio and activates AMPK, with the
result that catabolic processes are upregulated and ana-
bolic processes inhibited (417, 786). Recently, Evans et al.
(223) proposed an AMPK-mediated mechanism of O2
sensing in type I cells, and they provided substantial
experimental evidence to support their model. Their main
findings were as follows. 1) In rat type I cells, they iden-
tified an AMPK isoform that is located close enough to the
cell membrane to participate in a “membrane delimited” pro-
cess. 2) In type I cells, the AMPK mimetic agent AICAR
(5-aminoimmidazole-4-carboxamide riboside) inhibited
TASK-1 and maxi-K channels and caused depolarization
and increased Ca2⫹ influx whilst also increasing sensory
afferent discharge from an isolated carotid body prepara-
tion. 3) These effects could be inhibited by the AMPK
antagonist compound C that also reduced the effect of
hypoxia on type I cells (223, 852, 855). This model is
attractive not only because it provides a link between
cellular metabolism and potassium channel inhibition but
also because it may reconcile the “membrane” and “mito-
chondrial” hypotheses of O2 sensing (852).
Other, more direct, links between metabolism and
TASK-1 channel inhibition are also possible. In rat type I
cells, MgATP and other Mg nucleotides have a powerful
stimulatory action on background potassium channels
(800). Mitochondrial complex inhibitors cause a rise in
[Mg]i reflecting a fall in [MgATP]i, and the channels were
suggested to be coupled to (or possess) a low-affinity Mg
nucleotide sensor (800). A direct, depolarizing effect of
adenosine via A2A receptors resulting in a rise in [Ca2⫹] in
type I cells has also been reported (856). Depletion of
MgATP reflects increased production of AMP, providing
pathways to increase [adenosine] and activate AMPK,
respectively (800).
The idea of carotid bodies as metabolic sensors is not
new. For example, in an in vitro preparation, the cat
carotid body is excited by inhibition of glycolysis (560).
Recent studies have identified type I cells in isolation,
both in coculture with petrosal ganglion neurons and in
fresh carotid body slices, as direct glucose sensors that
depolarize and release neurotransmitters upon lowering
of glucose levels (254, 580, 870). However, a direct effect
of glucose on type I cells is not uncontroversial because in
the rat, low glucose increased spontaneous ventilation, an
effect that depended on the integrity of the carotid sinus
nerve, while in isolated carotid body-sinus nerve prepara-
tions it failed to have any effect on nerve discharge and
the release of catecholamines and ATP, respectively (64,
141). Several studies have clearly established the role of
the carotid bodies in glucose homeostasis, which can be
modulated by GABAergic mechanisms in the NTS (see
Physiol Rev • VOL
Refs. 440, 870 and references cited therein). Interestingly,
in humans, low plasma glucose was reported to double
the HVR, but this could be indirectly mediated by coun-
terregulatory hormones (825).
In summary, various heme proteins, such as NADPH
oxidase, HO-2, NOS, and mitochondrial complex proteins
may operate in parallel or sequentially as oxygen sensors.
The oxygen sensing machinery is already operative in
mild hypoxia, in a PO2 range in which mitochondrial com-
plex proteins, due to their low P50, will not yet be com-
promised (427, 621). This suggests that more than one O2
sensor must be operative (380, 621, 800). Across (but also
within) animal species, various classes of potassium
channels play a crucial role in the membrane depolariza-
tion of type I cells in hypoxia by reducing their current.
There are multiple ways in which these channels can be
inhibited. One of these, changes in the cellular AMP/ATP
ratio, has recently been identified as a very sensitive
manner to couple cell metabolism to potassium channel
activity and appears to operate already well before mito-
chondrial complex proteins are compromised (415). Type
I cells have an extremely complex biochemical content
and release numerous substances during hypoxia, of
which ACh and ATP are thought to be the principle excita-
tory neurotransmitters acting at the afferent endings of
petrosal ganglion neurons that innervate the carotid bodies.
B. Hypoxia Activates the Transcription Factor
Hypoxia-Inducible Factor-1
Chronic hypoxia induces expression of genes encod-
ing factors that 1) promote tissue oxygenation (e.g., an-
giogenesis); 2) sensitize oxygen-sensing mechanisms and
facilitate central processing, thus augmenting the HVR;
3) increase the blood O2 transport capacity (erythropoie-
tin production); and 4) adapt cellular metabolism by fa-
cilitating glucose uptake (upregulation of glucose trans-
porters) and promoting anaerobic metabolism whilst re-
pressing but also optimizing oxidative phosphorylation.
This altered expression of these and many other genes is
initiated by increased activity of numerous transcription
factors (reviewed in Refs. 101, 133, 149, 381, 661, 693), one
of which appears to orchestrate this master plan of gene
expression: hypoxia-inducible factor-1 (HIF-1), discov-
ered by Semenza and co-workers (see Ref. 689).
HIF-1 is a heterodimer consisting of the constitu-
tively expressed nuclear subunits HIF-1␤ and HIF-1␣. The
latter subunit, HIF-1␣, undergoes (cytoplasmic) posttran-
scriptional modification under the influence of the PO2
(Fig. 3; Ref. 690). HIF-1 induces many target genes encod-
ing proteins that influence O2 supply, metabolism, tran-
scription factors, and apoptotic and enzymatic processes
(101, 133, 371, 693). In euoxic conditions, HIF-1␣ is both
synthesized and rapidly degraded, but in hypoxia it is
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 691

FIG. 3. Influence of prolyl hydroxylases on hypoxia inducible factor (HIF) stability. In normoxia, with sufficient oxygen availability, prolyl
hydroxylases [PHD; PHD2 is the isoform that is considered the primary HIF prolyl hydroxylase in normoxia and utilizes iron and ascorbic acid (asc)
as co-factors] hydroxylate crucial proline residues in the degradation domain of HIF-1␣. This enables the von Hippel-Lindau protein (pVHL) to bind
to these residues and ubiquitylate (ubi) the protein for proteasomal degradation. As a consequence, the nucleus contains low levels of HIF-1␣ and
thus also of HIF-1, the heterodimer of HIF-1␣ and HIF-1␤. In hypoxia, PHD2 activity is limited by low PO2. Functional activity of HIF-1␣ is regulated
by factor inhibiting HIF (FIH) which, in an oxygen-dependent way, hydroxylates a crucial asparagine residue in the COOH-terminal domain (not
shown). In hypoxia, HIF-1␣ is stabilized, activated, and translocated to the nucleus. An important additional step in HIF activation in hypoxia,
correlated with the induction of target genes, is the activation of the coactivators p300 and cAMP response element binding protein (CREB) which
combine with the heterodimer. This complex binds to the hypoxia response element (HRE) of target genes while additional coactivators are also
recruited. ␣KG, ␣-ketoglutarate; succ, succinate; ROS, reactive oxygen species.

rescued from proteasomal degradation enabling it to
translocate to the nucleus where it dimerizes with the
constitutively expressed HIF-1␤ to form the transcription
factor HIF-1. The dimer binds to the hypoxia response
elements of target genes where it recruits coactivator
proteins to promote transcription. Structure and proper-
ties of HIF-1 and its subunits can be found in References
689 – 691. HIF-1␣ has two paralogs: 1) HIF-2␣, which is
also regulated by O2, and, when dimerized with HIF-1␤,
promotes the transcription of both overlapping and dis-
tinct target genes (references in Ref. 694); and 2) HIF-3␣
with a largely unexplored function (369, 694). In many if
not all body cells, HIF-1 is upregulated during hypoxia.
There are many pathways of posttranscriptional modifica-
tion of HIF-1␣ (reviewed in Refs. 133, 369, 692, 694). Here we
only briefly discuss the controversial role of ROS.
1. HIF-1␣ stabilization via increased [ROS]
HIF-1␣ contains an oxygen-dependent degradation
domain with highly conserved specific proline residues
(Pro402 and Pro563 in mice, Pro402 and Pro564 in humans)
that are hydroxylated in normoxic conditions. This hy-
droxylation is catalyzed by enzymes containing a prolyl
hydroxylase domain (PHD). Currently three PHD family
members are known, PHD1, PHD2, and PHD3, of which
PHD2 is considered the primary HIF prolyl hydroxylase in
normoxia (63, further references in Ref. 369). PHD2 is a
dioxygenase that uses molecular oxygen and ␣-ketogluta-
rate as substrates, generates CO2 and succinate as by-
products, and utilizes Fe2⫹ and ascorbic acid as cofactors.
Prolyl hydroxylation of HIF 1-␣ is required for binding of
the von Hippel-Lindau tumor suppression protein pVHL
which targets the complex for ubiquitin-mediated degra-
dation by interacting with a multiprotein ubiquitin ligase
complex thus creating a recognition site for proteasomal
degradation (Fig. 3; Refs. 352, 353, 499). The current view
is that during hypoxia the activity of PHD2 is reduced by
a combined effect of substrate (oxygen) limitation and
inhibition of the Fe2⫹ catalytic center by ROS possibly
produced by complex III of the mitochondrial electron
transport chain (55, 122, 123).
2. HIF-1 stabilization via decreased [ROS]
An opposite role of ROS in HIF-1 stabilization was
proposed by Huang et al. (341; see Ref. 276 for further
references). In human Hela cells, they showed increased
stability of the HIF-1␣ subunit in hypoxia and a rapid
breakdown in normoxia. In hepatoma 3B (Hep3B) cells,
hypoxia also induced HIF-1␣ stabilization and an in-
creased expression of erythropoietin mRNA, and both
effects were dose-dependently blocked by preexposure to
hydrogen peroxide. Oxidizing HIF-1␣ inhibited HIF-1

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692 LUC J. TEPPEMA AND ALBERT DAHAN
DNA binding, and this could be reversed by reducing
agents, possibly indicating that hypoxia stabilizes HIF-1␣
by reducing specific cysteine sulfhydryls in the molecule,
whilst hypoxia and hydrogen peroxide would reverse this
(341 and references therein).
What is the scenario in glomus cells? In carotid bodies
from rats exposed to chronic intermittent hypoxia, HIF-1␣
was upregulated and complex I activity was reduced, whilst
[ROS] and hypoxic carotid body sensitivity were increased
(597, 600). HIF⫹/⫺ mice did not display these adaptations,
and together these findings would suggest stabilization of
HIF-1␣ by increased [ROS] resulting in the augmented HVR
(600; see also sect. VG). However, with the assumption of
enhanced ROS production by mitochondrial complex inhib-
itors, the finding that in type I cells from rat, complex
inhibitors significantly reduced HIF-1␣ upregulation induced
by superfusion with a hypoxic solution for ⬃45 min, would
rather support the notion of HIF stabilization with reduced
[ROS] (22). This model could also provide a potential expla-
nation for the increase in HVR in humans after chronic
treatment with antioxidants (321, 608). Notably, the antiox-
idant N-acetylcysteine not only augmented the HVR in young
subjects but also increased the production of erythropoietin,
indicating upregulation of HIF-1 (321). Reduction of the
isocapnic HVR by low-dose anesthetics or the carbonic an-
hydrase inhibitor acetazolamide could be reversed by an
antioxidant cocktail consisting of ␣-tocopherol and ascorbic
acid (777, 780, 781). This reversal occurred in the setting of
an acute experiment, so presumably it was unlikely to be
mediated via increased stabilization of HIF-1␣. It was spec-
ulated that the reversal could be due to independent, inhib-
iting effects of the antioxidants on potassium channels, al-
though other explanations are possible (777, 780, 781). The
stimulating effect of chronic ascorbic acid on the HVR is
hard to reconcile with a single role of this antioxidant as
cofactor of PHD2. An effort to eliminate the other cofactor
of PHD2, Fe2⫹, by infusing the iron chelator desferrioxam-
ine (DFO) for 8 h did not alter the HVR in humans (639). This
could be due to failure of DFO to penetrate into type I cells,
and this is supported by data from in vitro perfused carotid
body from the rat (168). Finally, in humans, iron infusion did
not influence the augmentation of the HVR that is normally
observed after chronic hypoxia (see sect. VF), and this could be
due to the inability of iron to reach the interior of type I cells
(711).
C. Central Effects of Hypoxia
1. General effects of central nervous system hypoxia
on breathing
In the central nervous system (CNS), moderate hyp-
oxia causes a generalized reduction in neuronal excitabil-
ity and decrease in intracellular [ATP]. Depending on the
duration and severity an initial transient alkalosis, an
Physiol Rev • VOL
increase in potassium conductance and hyperpolarization
may ensue acting to conserve energy. Some neurons,
however, depolarize in hypoxia and if some other condi-
tions are also met may be classified as central O2 sensors
(see sect. IIIC2). Severe, permanent hypoxia is generally
followed by intracellular acidosis, influx of Ca2⫹ and Na⫹,
efflux of K⫹, persisting depolarization, further decreases
in intracellular [ATP], and eventually cell death (435).
Hypoxia in the brain (central hypoxia) affects breathing in
a way that depends on the integrity and activity of the
carotid bodies. In addition, several brain regions are
claimed to contain oxygen sensors that may play a role in
the HVR in some circumstances.
Shortly after carotid body denervation, cats anesthe-
tized with chloralose (urethane) show decreases in ven-
tilation and phrenic nerve activity with both hypoxemic
and CO hypoxia (314, 361, 507). With severe hypoxia, the
phrenic neurogram displays a gasplike pattern (507). An-
imals anesthetized with thiamylal, however, failed to
show ventilatory depression immediately after carotid
body excision, even with severe hypoxia (710). Carotid
body-denervated rats anesthetized with urethane do also
show a clear-cut hypoxia-induced decrease in respiratory
motor activity (436). A depressant response of CNS hyp-
oxia is also manifest in chloralose-urethane anesthetized
cats subjected to isolated brain stem perfusion with hyp-
oxic blood, even when the PCO2 of the peripheral blood is
kept hypercapnic (794, 823). In anesthetized cats sub-
jected to carotid body denervation or artificial brain stem
perfusion, hypoxic ventilatory depression may be caused
by both a fall in medullary PCO2, the metabolic stress of
lactic acidosis and/or decrease in [ATP], as well as inhib-
itory neurotransmitters (62, 436, 540, 543). The absence of
a depression in thiamylal-anesthetized animals (710)
might suggest involvement of a GABAergic mechanism.
Artificial brain stem perfusion via one vertebral artery in
the cat supplies the pons, medulla, and cerebellum with
“central blood” (59) so central hypoxic depression in this
preparation must originate from one or more of these
regions, presumably pons and/or medulla.
At least in cat and rat, the effect of (severe) CNS
hypoxia on breathing differs between the anesthetized
and awake states. Awake carotid body denervated cats
respond to mild hypoxia (FIO2 ⬃14%) with mild to mod-
erate hypoventilation (237, 261, 510) or virtually no
change (464). Severe hypoxia, however, results in a pro-
nounced tachypnea and decrease in tidal volume resulting
in either a reported decrease (261) or increase (510),
respectively, in alveolar PCO2. In unanesthetized animals,
a transition into unconsciousness during severe hypoxia
did not result in any change in breathing pattern, suggest-
ing the diencephalon as the source of the tachypnea (510).
Immediately after carotid body denervation, the awake
rat may show some hypoxic respiratory depression (492),
but the most common response is a limited rise in venti-
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
lation (570, 664, 665), raising the question whether the
carotid body-denervated rat is a suitable model to study
the isolated effect of central hypoxia. This is illustrated by
the fact that acute hyperoxia leads to an increase in
ventilation in this model, indicating a depressant effect of
central hypoxia (570). With prolonged central hypoxia,
awake goats and dogs undergoing selective carotid body
perfusion with normocapnic-normoxic blood showed an
increase in ventilation (165, 836) and an absence of respi-
ratory depression (706), respectively. Sleeping dogs in-
creased their ventilation with central hypoxia, but after
carotid body denervation there was no response (151).
Soon after carotid body denervation, ponies showed no
hypoxic ventilatory depression; however, this does not
preclude an inhibitory effect of low central PO2 during
chronic hypoxia because acute hyperoxia induced hyper-
ventilation in these animals (239).
Finally, note that the depressant effect of central
hypoxia in anesthetized cats with denervated carotid bod-
ies is different mechanistically from HVD in intact cats,
with the latter being initiated by the carotid bodies (see
also section VC).
A) CENTRAL O2 SENSORS AND HVR. Before a neuron that
depolarizes in hypoxia can be classified as intrinsically
sensitive to O2, at least four criteria must be met. 1) The
depolarization should occur independently from synaptic
events. 2) Activation of these neurons is independent
from input from the arterial chemoreceptors. 3) Within
the range of physiological O2 levels, the sensitivity of
these neurons should be much greater than that of other
neurons. 4) At least under certain physiological condi-
tions, stimulation by low oxygen of these neurons should
be able to elicit an appropriate (cardio)respiratory re-
sponse. Below we summarize which regions belonging to
the respiratory neuronal network are claimed to possess
neurons that are intrinsically sensitive to oxygen.
I) Location of central O2 sensors. Exposing anesthe-
tized cats to 10% O2 excited ⬃20% of neurons studied in
the caudal hypothalamus, independently from carotid si-
nus nerve integrity (183). Ninety percent of these cells
had a cardiovascular and/or respiratory rhythm, even af-
ter carotid body denervation (183). In brain slice prepa-
rations, ⬃80% of caudal hypothalamic neurons responded
to hypoxia independently from synaptic blockade (182,
329). O2-sensitive neurons in the caudal hypothalamus
were also found in the rat (330, 671). Oxygen-sensitive
cells in the hypothalamus may also reside rostrally in
parvocellular cells of the paraventricular nucleus (385).
Located in an area from which O2-sensitive neurons
in the caudal hypothalamus can be antidromically acti-
vated, the pontine periaqueductal gray (PAG) contains
many neurons intrinsically sensitive to O2 (410, 671). De-
pending on the stimulus location, PAG activation elicits
cardiovascular responses that are mediated via the ros-
troventrolateral medulla (RVLM; references in Ref. 410).
Physiol Rev • VOL
693
In slice preparations, the locus coeruleus in the dorsolat-
eral pons contains many neurons that are inhibited by
hypoxia and a smaller percentage that is depolarized, but
it is uncertain whether this represents intrinsic O2 sensi-
tivity (545, 864).
Both stimulation of the carotid bodies and central
hypoxia activates neurons in the RVLM, and in the latter
case, this activation is resistant to local glutamate recep-
tor antagonism and denervation of the carotid bodies. So
these cells may be intrinsically O2 sensitive, and this no-
tion was corroborated by the finding that in slice prepa-
rations RVLM neurons retained their depolarizing re-
sponse to hypoxia or cyanide even with synaptic block-
ade (741, 742, 744, 745). Nolan and Waldrop (553)
reported activation of ⬃64% of neurons studied in the
same RVLM area when exposing anesthetized spontane-
ously breathing rats to hypoxia. Many of these neurons
displayed a temporal discharge pattern related to the
cardiac and/or respiratory cycle; a similar percentage was
activated after bilateral transection of both the vagus and
carotid sinus nerves and cervical sympathetic and aortic
depressor nerves (553). Brain slices including this RVLM
area and from a region projecting to the spinal cord
contained neurons the majority (⬃70 – 80%) of which was
excited by low PO2 even after synaptic blockade; however,
a substantial amount (⬃20%) was inhibited (553). O2 sen-
sitivity in the RVLM is not a unique property of spinally
projecting barosensitive neurons because it seems to be
widely distributed in this area with many neurons either
excited or inhibited by hypoxia (378). Taken together, the
caudal hypothalamus, PAG, and RVLM might act as an
accessory circuit to amplify ventilatory and cardiovascu-
lar responses to hypoxia (410).
Located just rostral to the C1 region of the RVLM, the
pre-Bötzinger complex contains oxygen-sensitive cells.
Local application of NaCN into this area augmented in-
spiratory output including gasping in the phrenic neuro-
gram (718). Dissociated cell cultures with neurons from
both the C1 region and pre-Bötzinger complex contained
cells of which ⬃60% responded to NaCN with membrane
depolarization and an increase in firing frequency, but
⬃40% with inhibition, and these responses were resistant
to synaptic blockade (500). Both RVLM regions express
HO-2 (501), an enzyme that in the carotid bodies may be
involved in oxygen sensing (844; see also sect. IIIC1). The
expression of HO-2 in these regions is limited to oxygen-
sensitive neurons; blocking enzyme activity abolishes the re-
sponse of these neurons to hypoxic hypoxia and NaCN (153).
Oxygen-sensitive cells were also found in the NTS. In
coronal slices from the level of the obex, 75% of the
neurons tested responded to hypoxia with hyperpolariza-
tion, decreased input resistance, and decreased activity,
while 25% showed increased activity (583). Hypoxia in
these slices also decreased postsynaptic potentials elic-
ited by electric stimulation of afferents in the solitary
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Physiol Rev • VOL 90 • APRIL 2010 • www.prv.org

 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 695

tract, suggesting hypoxic gating of incoming afferent in-
put (583). O2-sensitive neurons in the NTS were also
found by Nolan and Waldrop (553).
Finally, the hypoglosssal nucleus also contains neu-
rons that depolarize upon exposure to hypoxia (297).
The mechanism of oxygen sensing in brain stem and
hypothalamic neurons is largely unknown. Does a uni-
form O2 sensor operate that would facilitate identification
and localization of these neurons? Some authors have
proposed a lack or paucity of ATP-sensitive potassium
channels as a potential basis of oxygen sensing (e.g., Ref.
864), which could make sense because hypoxia decreases
intracellular [ATP] in the brain (435, 436). Also, several
other potassium channel species have been suggested to
be involved in central oxygen sensing, as well as various
calcium and sodium channels (329, 745, 864; reviewed in
Ref. 544). Recently, D’Agostino et al. (153) reported that
excitation by hypoxia of neurons in the C1 region and
pre-Bötzinger complex of rats critically depended on the
activity of HO-2.
2. Role of central O2 sensors in the HVR?
The contribution of central oxygen sensors to the
HVR is unknown. Does the absence of an increase in
ventilation shortly after carotid body denervation as ob-
served in cats and dogs imply a trivial contribution of
central O2 chemoreceptors to the HVR of an intact organ-
ism? Taking into account that the carotid body may pro-
vide oxygen-sensitive neurons in the RVLM with a tonic
excitatory input (741, 744), a preparation with denervated
carotid bodies would not be the most suitable model to
get more insight into this issue. Could the increase in
ventilation with isolated central hypoxia in goats and
dogs with intact, separately perfused carotid bodies be
due to a facilitating peripheral chemoreceptor input, ex-
plaining, for example, the elimination of the response in
dogs after carotid body denervation (151)? Selectively
perfusing the carotid bodies with either hypoxic or hyper-
oxic blood to subsequently measure the effects of central
hypoxia could give some clue. In anesthetized cats and
awake goats, the reverse paradigm, i.e., varying the pe-
ripheral PO2 while keeping central PO2 constant at differ-
ent levels, did not reveal an influence of brain stem PO2 on
the ventilatory response induced by carotid body hypoxia
(i.e., no peripheral-central O2 interaction; Refs. 165, 794).
In cats, ponies, and rats, the respiratory system dis-
plays a remarkable plasticity in restoring the HVR after
denervation of the carotid bodies (70, 492, 664, 710). Rats
displayed a complete recovery of the HVR 90 days after
carotid body denervation which was temporally related to
changes in tyrosine hydroxylase expression in various
brain stem areas containing central O2 sensors, e.g., the
A2/C2 region in the caudal NTS and the A1/C1 region in
the RVLM (665, 665). Complete HVR recovery on a com-
parable time scale was also observed in rats after lesion-
ing glutamate receptor-containing neurons in the NTS,
initially resulting in a 70% reduction of the response (130).
It is tempting to speculate that tyrosine hydroxylase-con-
taining central O2 sensors could serve as a “back-up”
mechanism to detect low oxygen levels in cases where
peripheral chemoreceptors are functionally eliminated,
but further studies are necessary to confirm this.
Diencephalic structures play a role in the severe
hypoxia-induced tachypnea in awake cats with dener-
vated carotid bodies (510). Disinhibition of cortical-hypo-
thalamic interactions by low PO2 contribute to this phe-
nomenon. Because the caudal hypothalamus contains
neurons excited by O2 independently from the carotid
bodies and provide the RVLM with an excitatory input,
these O2 sensors could contribute to it (331, 813). Direct
stimulation of the caudal hypothalamus increases respi-
ratory frequency (813).
3. CNS neurotransmitters and HVR
A) GLUTAMATE, GABA, GLYCINE, ADENOSINE, AND ATP. The
entire respiratory network participates in the HVR, so it is
not surprising that it can be influenced by numerous
neurotransmitters/modulators and receptor agonists/an-
tagonists. Respiratory midbrain and brain stem regions,
each with a separate contribution to the HVR, contain a
variety of neurotransmitters (recently reviewed in Ref.
732). In Figure 4, the major medullary and pontine regions
are shown that participate in the HVR. Classical media-
tors of the HVR are GABA, glutamate, and adenosine, and
their temporal profiles and roles were reviewed previ-
ously (104, 327, 379, 502, 540, 649, 752). Generally, gluta-
mate is considered an excitatory neurotransmitter in the
HVR, while GABA, glycine, and adenosine are inhibitory
(18, 104, 327, 379, 565). This is probably an oversimplifi-
cation, because one particular transmitter or modulator

FIG. 4. Major brain stem regions involved in the ventilatory response to hypoxia. Major cell groups involved in the ventilatory response to
hypoxia are shown in coronal sections between rostrocaudal levels of the rat brain stem from Bregma ⫺9.16 to ⫺14.60 mm. 1, A1 noradrenergic
region; 2, caudal ventral respiratory group; 3, A2 noradrenergic region; 4, raphe pallidus; 5, raphe obscurus; 6, medial subnucleus of the nucleus of
the solitary tract; 7, commissural subnucleus of the nucleus of the solitary tract; 8, rostral ventral respiratory group; 9, C1/A1 adrenergic/
noradrenergic region; 10, C2 adrenergic region; 11, C1 adrenergic region; 12, pre-Bötzinger complex; 13, Bötzinger complex; 14, raphe magnus; 15,
retrotrapezoid nucleus; 16, A5 noradrenergic region; 17, locus coeruleus; 18, parabrachial nucleus, medial part; 19, Kölliker-Fuse nucleus. Py,
pyramidal tract; scp, superior cerebellar peduncle; Sol, nucleus of the solitary tract; V, motor nucleus of the trigeminal nerve; VII, facial nucleus.
[Sections redrawn from Paxinos and Watson (587).]

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696 LUC J. TEPPEMA AND ALBERT DAHAN
can have distinct effects on the HVR, depending on the
dose, route of administration, and site of application in
the CNS. For example, in rats, at an ambient temperature
of 30°C, the GABA agonist muscimol reduces the HVR
when microdialyzed into the NTS but augments it when
applied in raphe magnus (539, 772). Recently, a modula-
tory (facilitatory) role for ATP has been described, in
which it is released in ventral medullary surface areas in
the secondary phase of the HVR and possibly acts in the
Pre-Bötzinger complex to increase respiratory frequency
via activation of metabotropic (P2Y) receptors (284, 471).
Below we summarize the most relevant data, mainly col-
lected over the last decade, concerning the important role
of monoamines (with emphasis on serotonin) and NO in
the HVR. Figure 4 can be used as a reference to envisage
the different brain stem regions where these transmitters
exert their action.
B) MONOAMINES AND THE HVR. The absence of a signifi-
cant effect of catecholamine depletion on the HVR may
suggest that norepinephrine and/or dopamine do not
function as primary neurotransmitters in hypoxia (503).
However, monoamines are widely distributed in the brain
and as such may be expected to contribute in a complex
way. Mice lacking the gene for the dopamine transporter
(DAT⫺/⫺) show a reduced poikilocapnic HVR (805), but
data from these mice are difficult to interpret because
both carotid body and central dopamine levels will be
increased. The same problem is encountered in those
studies using dopaminergic blockers that act both periph-
erally and centrally. As is also the case for serotonin (see
below), the influence of central dopamine on the HVR is
not limited to the ventilatory component of the response
but also concerns the hypometabolic/hypothermic part of
it. For example, infusion of haloperidol in the third cere-
bral ventricle of rats (aimed at exerting effects in the
hypothalamus) reduced the drop in hypoxia-induced body
temperature without affecting the ventilatory component
(35). Dopamine 1 receptors in the anteroventral preoptic
region of the hypothalamus in particular seem to be in-
volved in this response (36).
Several regions belonging to the central neuronal
respiratory network contain noradrenergic/adrenergic
neurons, notably the A2 noradrenergic cell group in the
caudal NTS where carotid body afferents terminate, the A5
noradrenergic cell group in the ventrolateral pons, the A6
group in the locus coeruleus in the dorsolateral pons, and
the A1/C1 noradrenergic cell groups in the ventrolateral
medulla (255, 803). All these regions may contribute to the
magnitude and/or shaping of the HVR. For example, Coles
et al. (140) reported that lesions in the A5 group reduce or
abolish the reduction of respiratory frequency following
hypoxia. The A2 group, containing neurons responsive to
dopamine, is considered to play a modulatory role in the
ventilatory acclimatization to chronic hypoxia; the in-
crease in CNS gain (CNS gain is defined in sect. VF4) in
Physiol Rev • VOL
chronic hypoxia may be related to (temporal) upregula-
tion of local tyrosine hydroxylase (references in sect. VD).
In the caudal NTS, norepinephrine can influence both
gluatamatergic and GABAergic transmission via presyn-
aptic receptors and may thus have variable effects on the
HVR (873 and references cited therein). Neurons in the A1
and C1 groups are activated in acute hypoxia but do not
seem to have an altered catecholamine turnover in
chronic hypoxia (221, 722, 782). The contribution of A6
neurons will be discussed in the subsection below on the
role of central NO.
Serotonergic neurons in the brain stem are mainly
concentrated in medullary, pontine, and mesencephalic
raphe nuclei (references in Ref. 322) and may be of spe-
cial interest for the HVR for several reasons. First, they
have connections with respiratory motoneurons and are
able to increase their excitability (322, and references
cited therein). Second, they are crucial for homeostatic
thermoregulation. About 50% of 5-HT neurons in raphe
pallidus/obscurus increase their activity upon environ-
mental and/or hypothalamic cooling, and there is growing
evidence that raphe neurons modulate the hypothermic
component of the HVR (323, 324). Third, they mediate
episodic hypoxia-induced long-term facilitation (LTF) of
breathing by causing an enhanced release of 5-HT into the
phrenic motor nucleus (230, 481; for a discussion on LTF,
see sect. VG; note that LTF can also be evoked by electri-
cal simulation of raphe obscurus neurons, Ref. 512). And
finally, many raphe neurons also possess intrinsic CO2
sensitivity (322), so at least in the secondary phase of
poikilocapnic hypoxia they will certainly have an influ-
ence on ventilatory output.
Activation of neurons in the nucleus raphe magnus
attenuated the processing of afferent input from the ca-
rotid bodies by the NTS in anesthetized rats (602). Micro-
dialysis of the GABA receptor agonist muscimol into ra-
phe magnus of conscious rats augmented the poikilocap-
nic HVR measured at an environmental temperature of
30°C (within in the thermoneutral zone for rats) but re-
duced it at 24.5–26.5°C; muscimol reduced body temper-
ature at 24.5–26.5°C and increased the anapyrexic com-
ponent of the HVR without influencing these parameters
at 30°C (772). In the same species, lesions of raphe mag-
nus neurons with ibotenic acid (unspecific for serotonergic
neurons) increased the hypoxia-induced rise in ventilation
measured at an ambient temperature of 25°C without
affecting the anapyrexic response (256). However, micro-
injection of a specific 5-HT1A receptor antagonist into
raphe magnus decreased the poikilocapnic HVR (557).
Unless it is speculated that the applied antagonist (WAY-
100635) acted on presynaptic inhibitory receptors (auto-
receptors) on serotonergic neurons, the latter finding
seems difficult to reconcile with the stimulatory effects of
local lesions and muscimol application on the ventilatory
component of the HVR.
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
To address the role of central serotonin in respiratory
and thermoregulatory control, Richerson and co-workers
(324) utilized conditional knockout mice almost entirely
devoid of central 5-HT neurons, designated as Lmxlbf/f/p.
These mice are deficient in the capacity to generate heat,
resulting in a rapid lowering of body temperature when
placed in a cold environment; ventilatory CO2 sensitivity
is also greatly reduced in these animals (324). Although
they had the expected temperature-dependent hypoxia-
induced changes in ventilation and metabolism (i.e., lowering
the environmental temperature decreased the ventilatory
component of the HVR but increased the anapyrexic re-
sponse), these animals had a reduced ventilatory and
V̇E/V̇O2 response compared with wild types when the HVR
was measured at 25°C. At an ambient temperature of
30°C, no difference in HVR between both genotypes was
visible, whilst intracerebroventricular administration of
serotonin restored the impaired ventilatory response to
CO2 but did not alter the (normal) HVR (323). Whether
Lmxlbf/f/pmice would fail to show episodic hypoxia-in-
duced LTF of breathing (see sect. v) remains to be exam-
ined. Hodges and co-workers (323, 324) suggested that
serotonergic neurons are not directly involved in the HVR
per se but may be critically important to thermogenesis.
Mice showing overwhelming amounts of serotonin in
brain extracellular fluid are represented by a genotype
lacking expression of the serotonin transporter (5-HTT).
5-HTT knockout mice showed a reduced activity of brain
serotonergic neurons and decreased 5-HT1A receptor
binding (444). At room temperature, these animals had a
larger ventilation and higher metabolism but normal body
temperature. When challenged with 10% O2, they re-
sponded with a greater increase in ventilation and larger
fall in metabolism than wild types, but the change in the
V̇E/V̇O2 ratio was equal in both genotypes (444).
A role of serotonergic neurons in medullary raphe in
thermoregulation is consistent with the finding that dis-
inhibition of raphe pallidus neurons (by means of local
injection of the GABA antagonist bicuculline) increased
brown adipose sympathetic nerve activity, responsible for
thermogenesis in cold stress (482). In the rat, an increased
activity of brown adipose sympathetic nerve activity
(thought to underlie the anapyrexic response to hypoxia)
can be induced in several ways: cold stress (i.e., skin
cooling), activation of neurons in preoptic thalamic re-
gions, and disinhibition of raphe pallidus neurons and
also of neurons in the commissural subnucleus of the NTS
(482). Interestingly, carotid body activation with NaCN or
hypoxia completely inhibits the increase in sympathetic
outflow to brown adipose tissue by these interventions.
This suggests that the carotid body not only plays a pivotal
role in the hypoxia-induced rise in ventilation but also in the
anapyrexic response (further references in Ref. 482).
From all of the above data, it is not easy to distill a
clear and detailed picture of the role of central serotoner-
Physiol Rev • VOL
697
gic neurons in the HVR. A few general conclusions, how-
ever, seem justified. First, in rodents, serotonergic neu-
rons in medullary raphe are crucial for the homeostatic
control of body temperature and participate in both the
ventilatory and hypometabolic/anapyretic components of
the HVR. Second, serotonergic neurons in raphe nuclei
possessing connections with respiratory (premotor) neu-
rons are activated in hypoxia. Third, activation of seroto-
nergic neurons in raphe magnus tend to dampen the rise
in ventilation and to augment the fall in body temperature,
but the magnitude of these effects depends on the ambi-
ent temperature. And, finally, the role of raphe serotoner-
gic neurons in hypoxia-induced LTF of breathing is well
established (discussed in sect. VG1).
C) CENTRAL NO AND HVR. I) NTS. Carotid body stimula-
tion in hypoxia is followed by release of glutamate and
production of NO in the caudal (commissural) NTS. When
injected in the NTS, the NO donor sodium nitroprusside
augments the HVR while the nonselective NOS inhibitor
NG-monomethyl-L-arginine (L-NMMA) reduces it. These
observations in unanesthetized rats, together with the
finding that the increased production of NO is inhibited by
NMDA receptor antagonism, led to the suggestion that NO
and glutamate operate in the NTS in a positive feedback
cycle to increase the HVR (562; see also Ref. 257). Gluta-
mate augments the HVR by activating NMDA receptors in
projection areas of carotid body afferents in the NTS that
are rich in NO (130, 286, 288, 446; reviewed in Ref. 287). In
the conscious rat, injection of both the nonselective NOS
inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and
the selective neuronal inhibitor of the enzyme Nw-propyl-
L-arginine in the caudal NTS reduced the increase in re-
spiratory frequency induced by carotid body stimulation
with KCN (291).
Lipton et al. (451) proposed an involvement of NO in
the HVR via endogenous production of S-nitrothiosols
within the NTS. Hemoglobin desaturation goes along with
formation of S-nitrothiosols from gluthathione and cys-
teine and Hb-bound NO producing S-nitroso-gluthathione
(GSNO) and S-nitroso-L-cysteine (L-CSNO), respectively.
GSNO is converted into CGSNO (S-nitroso-cysteinyl gly-
cine), and this requires the enzyme ␥-glutamylpeptidase
(␥-GT; Ref. 451 and references therein). Local injection of
all three nitrothiosols into the NTS mimicked the HVR in
conscious rats including its recovery phase (short-term
potentiation) after removal of the hypoxic stimulus, and
the same was observed after injection of plasma from
deoxygenated but not oxygenated blood (451). The effect
of CGSNO was inhibited by pretreatment with a blocker
of ␥-GT, suggesting that conversion of GSNO into CGSNO
is an essential step in producing the effect of the former.
L-CSNO is less stable in vivo, and thus Lipton et al. (451)
hypothesized that ␥-GT would be required for a normal
HVR to occur and found the short-term potentiation to be
abolished in ␥-GT-deficient mice. Apparently, however,
90 • APRIL 2010 • www.prv.org
698 LUC J. TEPPEMA AND ALBERT DAHAN
the hypoxia-induced rise in ventilation was not eliminated
in ␥-GT⫺/⫺ mice, but their report did not show the mag-
nitude of this initial increase (451). From the fact that in
the rat denervation of the carotid bodies reduces the HVR
with at least 70% and virtually eliminates it in other spe-
cies, the quantitative contribution of S-nitrothiosols can
be estimated to be small or negligible unless carotid body-
activated NOS within the NTS would play a major role in
producing these molecules during hypoxia. On the other
hand, the reported increase of the HVR in humans by
N-acetylcysteine (321) could be related to generation of
S-nitrothiosols with the aid of Hb-bound NO (578), rather
than to the antioxidant properties of this molecule.
II) Pons and locus coeruleus. In the pontine reticular
formation, NO promotes the release of acetylcholine
which induces sleep associated with rapid eye move-
ments and respiratory depression (442). The dorsolateral
pons uses NO to promote the termination of inspiration
during lung inflation (pneumotaxic mechanism). In awake
rats, electrolytic bilateral lesions in the locus coeruleus
substantially augmented the HVR (224). In addition,
whereas acute intracerebroventricular administration of
the nonselective NOS inhibitor L-NAME almost com-
pletely inhibited the HVR in control animals, it did so by
only ⬃50% in those with the bilateral lesions, suggesting a
substantial contribution of the locus coeruleus to the
inhibition in intact animals (224). The locus coeruleus
contains the A6 cell group that is considered the major
noradrenergic cell group in the brain stem (references in
Ref. 803). Microinjection of L-NAME in the locus coer-
uleus had an impressive inhibitory effect on the HVR,
indicating that the “permissive” effect of NO may be due
to inhibition of, presumably noradrenergic, neurons in
this area (225). It is unclear why in another study in rats
chronic injection (7 days) of small amounts of L-NAME
into the right cerebral ventricle did not modify the HVR
unless it is hypothesized that chronic NO shortage may be
compensated by upregulation of NOS (688). Notwithstand-
ing this latter study, all data taken together clearly identify
the locus coeruleus as an important inhibitory modulator of
the HVR, possibly analogous to an active inhibitory role of
lateral pontine regions in the hypoxic inhibition of breathing
in newborn lambs (522; see also sect. II).
III) Other regions. Microinjection of the nonselective
NOS inhibitor L-NMMA into the RVLM reduced the HVR in
rats but not the hypothermic response (173). The same
inhibitor had a similar effect when injected into the nu-
cleus raphe magnus (556). A possible role of brain stem
NO in the acclimatization to chronic hypoxia has been
briefly mentioned in section VF.
In humans, the acute ventilatory response to hypoxia
does not seem to be influenced by systemic administra-
tion of L-NMMA (347). The intravenous dose applied in
this study (⬃62 ␮g/kg), however, was much smaller than
that mostly used for NOS inhibitors in animal studies
Physiol Rev • VOL
(including those applying ventricular administrations), so
perhaps inhibitor concentrations at target sites within the
brain were too small to produce significant effects (al-
though blood pressure clearly increased; Ref. 347).
D. Hypoxic Ventilatory Decline in the
Adult Mammal
In adult mammals, the ventilatory response to sus-
tained (15–30 min) hypoxia (end-tidal PO2 50 –55 Torr and
SaO2 ⬃80%) is biphasic (Figs. 5 and 6; Refs. 162, 204, 370,
383, 464, 752, 806). During moderate isocapnic hypoxia
(i.e., arterial PO2 ⬃50 Torr) lasting ⬎3–5 min, ventilation
shows a slow decline from its peak (75–150% above nor-
moxic resting values) to reach a new steady-state level
(25– 40% of normoxic values) within 15–20 min (162, 204,
236, 383). The slow decline was formerly known as “hyp-
oxic ventilatory depression”; current names include hyp-
oxic ventilatory decline (HVD), hypoxic ventilatory roll-
off, and secondary roll-off of the HVR.
Although consistently found across mammalian spe-
cies, dogs and goats are the exception with little or no
HVD during exposure to moderate hypoxia (113, 151,
546). However, HVD is dependent on various factors, such
as age, sex, CNS arousal state, (type of) anesthesia,
breathing route, and hypoxic test (12, 111, 498, 677, 773).
For example, HVD is most pronounced under isocapnic
experimental conditions, while the poikilocapnic HVD is
much smaller in magnitude (12).
In the awake state, the ventilatory response to sus-
tained isocapnic hypoxia has specific characteristics.
1) The magnitude of HVD is proportionally related to the
size of the initial hyperventilatory response to acute hyp-
oxia (162, 263, 266, 383). 2) Bilateral carotid body resec-
tion or chemodenervation results in the loss of the V̇I
(inspired ventilation) response to acute hypoxia and ab-
sence of HVD (Fig. 5; Refs. 383, 464). 3) HVD persists
beyond the initial period of hypoxic exposure. The V̇I
response to acute hypoxia following 20 min of moderate
isocapnic hypoxia and 5 min of air breathing is depressed
by ⬎50%. This delayed recovery persists for up to 1 h (162,
205). 4) Suppression of the peripheral drive with low-dose
dopamine yields no HVD during 20-min hypoxia. And,
despite the presence of initial central hypoxia, a subse-
quent V̇I response to acute hypoxia develops fully (Fig. 6;
Ref. 162). 5) The magnitude of the fall in ventilation upon
the relief of hypoxia is smaller than the V̇I response gener-
ated at the onset of hypoxia (204, 382). 6) Awake humans
and awake cats display similar response characteristics with
respect to characteristics 1–3 and 5 (Fig. 5; Refs. 204, 464).
These observations (most importantly characteristic
4) suggest that in conscious mammals the peripheral
chemoreceptors play a pivotal role in the development of
HVD. The issue remains whether HVD is due to adapta-
90 • APRIL 2010 • www.prv.org
 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 699

FIG. 5. Ventilatory effects of hypoxia in cats and humans. A: ventilatory responses to sustained (25–30 min) isocapnic hypoxia in the awake
cat (mean response of 7 cats) [adapted from Long et al. (461)] and awake chemodenervated cat. B: mean response of 3 cats. [Adapted from Long
et al. (464).] C: isocapnic (open symbols) and poikilocapnic (closed symbols) hypoxic ventilatory response (HVR) in 10 young subjects. [Adapted
from Steinback and Poulin (728).] D: isocapnic HVR in awake humans after bilateral carotid body resection (mean of 7 subjects). The data are
derived from otherwise healthy patients that underwent a bilateral carotid body resection after development of familial carotid body tumors. As
reported in Reference 227, the hypercapnic response in these subjects could be adequately described by a single slow (central) component,
indicating a minor or no significant contribution of a fast (peripheral) component to the response.

tion of the peripheral chemoreceptors (i.e., an exclusive
peripheral mechanism) or to the way the afferent input
from the carotid bodies is processed by the CNS (657).
The hypothesis that HVD is related to peripheral chemo-
receptor adaptation is supported by characteristics 1, 2,
and 5 and is further corroborated by the observation that
hypoxic sensitivity declines during the development of
HVD (37). However, in the anesthetized cat, the periph-
eral chemoreceptors do not adapt during hypoxic expo-
sure in terms of ventilation and afferent nerve activity,
indicating that an exclusive peripheral mechanism is un-
likely (17, 58, 807). Furthermore, characteristics 3 and 4
indicate an effect of HVD on HVR beyond hypoxic expo-
sure when peripheral chemoreceptor activity in terms of
the V̇I response to CO2 has normalized (57, 267, 461). The
current hypothesis is that, at least in the awake mammal,
a large part of HVD is due to modulation of glutamatergic
excitatory activity within the NTS (arising from afferent
carotid body input) shifting the excitatory/inhibitory bal-
ance towards a net inhibitory effect on V̇I (162, 266, 810).
At the termination of hypoxia, changes in neurotransmit-
ter turnover are not immediate and, therefore, the depres-
sant effects of hypoxia wane slowly. In the awake state, a
small part of HVD is related to an increase in brain blood
flow and the resultant washout of acid metabolites/H⫹
from the brain. Suzuki et al. (746) showed a decrease in
the gradient between jugular venous and arterial PCO2 of
⬃2 Torr during 15 min of moderate isocapnic hypoxia.
Assuming that jugular venous PCO2 approximates brain
tissue PCO2, ⬃10 –20% of measured HVD is related to an
increase in brain blood flow in the adult awake human.
Finally, at deeper levels of hypoxia, substrate insuffi-
ciency and depressed cellular metabolism may become
the major origin of HVD (435, 540).
Various mechanisms could explain the decrease in
excitatory neuronal output during sustained hypoxia. For
example, as suggested by Kazemi and Hoop (379), periph-
eral chemoreceptor afferents cause the enhancement of

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700 LUC J. TEPPEMA AND ALBERT DAHAN
FIG. 6. Dopamine and hypoxic ventilatory decline (HVD) in hu-
mans. Ventilatory response to 20-min isocapnic hypoxia (SpO2 ⫽ 80%),
5-min normoxia and subsequently a second hypoxic episode (SpO2 ⫽
80%, lasting 5 min). Closed circles, control response showing the HVD
from early to late hypoxia and a marked reduced response to a second
hypoxic exposure; open circles, low-dose dopamine infusion (gray bar:
3 ␮g 䡠 kg⫺1 䡠 min⫺1) during sustained hypoxia blunts the initial hyperven-
tilatory response and prevents development of HVD. The ventilatory
response to the second hypoxic exposure develops fully. Data are the
means of 16 subjects. [Adapted from Dahan et al. (162).]
glutamatergic excitation in areas of the brain stem in-
volved in hypoxic ventilatory control. Glutamate serves as
the precursor of GABA, and conversion of glutamate into
GABA may enhance GABAergic activity with conse-
quently a net inhibitory effect on V̇I. In the awake rat,
Tabata et al. (752) measured an increased GABA concen-
tration in the extracellular fluid in the NTS during HVD
development, which was absent in animals after bilateral
carotid body resection. Both the reduction in O2 availabil-
ity and intracellular acidosis increase GABA levels in the
brain with kinetics that are fast enough to account for
HVD (increased synthesis from glutamate through the
enzyme glutamic acid decarboxylase and decreased
breakdown by the enzyme GABA-␣-oxyglutarate transam-
inase; references in Ref. 540). Via this pathway, the NTS
itself could be the source of increased GABA during hyp-
oxia (540, 752). However, other sources of GABA are also
possible because the NTS contains many terminals immu-
noreactive to GABA that may inhibit glutamatergic inputs
(e.g., Ref. 673 and references therein). GABAergic neu-
rons in the NTS send inhibitory efferents to the caudal
ventrolateral medulla and also to the locus coeruleus,
providing other possible pathways involved in HVD (7,
795). Other regions such as the hypothalamus may also
participate in HVD via a GABAergic mechanism. For ex-
ample, Lemus et al. (440) depicted an interesting circuitry
participating in the glycemic response of carotid body
stimulation involving antidiuretic hormone (ADH)-secret-
ing neurons in the supraoptic nucleus and ADH receptors
on the membrane of GABAergic neurons in the NTS that
Physiol Rev • VOL
may originate from the paraventricular nucleus (PVN) of
the hypothalamus. It is known that arginine vasopressin-
containing neurons in the PVN and supraoptic nucleus are
stimulated by hypoxia (709 and references therein), but it
remains to be seen whether NTS neurons could be di-
rectly inhibited during hypoxia via this pathway.
Other inhibitory modulators possibly involved in
HVD include dopamine, adenosine, serotonin, endogenous opi-
oid peptides, lactic acid, NO, and Ca2⫹ (Tables 1 and 2 for
references). A relatively new observation is that of Gozal et al.
(289) who examined the role of the platelet-derived growth
factor (PDGF) isoforms PDGF-AA (with two A chains and
acting on the PDGF-␣ receptor) and PDGF-BB (with two B
chains and acting on the PDGF-␤ receptor) in the NTS during
hypoxia. The NTS and other brain stem respiratory nuclei show
an abundant expression of the PDGF-␤ but not PDGF-␣ recep-
tor. In contrast to PDGF-AA, the isoform containing two B
chains and its receptor PDGF-␤ appeared to play a functional
role in the development of HVD. Awake mice with a heterozy-
gous mutation of the PDGF-␤ receptor had an intact V̇I re-
sponse to acute hypoxia but a diminished HVD, an effect which
was unaffected by the injection of a PDGF-␤ receptor antago-
nist. However, wild-type animals showed a reduced HVD after
the antagonist. Many NTS neurons in wild-type mice (and in
rats) showed increased expression of PDGF-B chain mRNA
and protein (release) in hypoxia. These data suggest an inhib-
itory role for PDGF-BB and its receptor on ventilation during
sustained hypoxia, possibly by inhibiting NMDA receptors
within the NTS (289).
There is strong evidence that HVD development dur-
ing anesthesia is uncoupled from peripheral chemorecep-
tor activity (657). For example, in anesthetized cats sub-
jected to artificial brain stem perfusion, central hypoxia
with the carotid bodies kept normoxic results in a decline
in ventilation with dynamics similar to that observed after
central changes in PCO2 (823). Comparable observations
are made in carotid body perfusion experiments and anes-
thetized chemodenervated animals (361, 538, 543; Table 2).
Similarly, in humans exposed to halothane, the initial
hyperventilatory response is greatly reduced while the
absolute magnitude of the HVD is similar to that observed
in the awake state (160). Furthermore, the ventilatory
response to a step out of sustained hypoxia (the off-
response) shows a marked undershoot and is similar in
magnitude to the initial hyperventilatory response (the
on-response). These symmetric on- and off-responses in
humans exposed to halothane indicate that in this condi-
tion peripheral sensitivity, although reduced under of low-
dose halothane, remains unchanged during HVD. Similar
observations were made in humans injected with the
intravenous anesthetic propofol (549). These data sharply
contrast with data in awake humans and animals that do
not show HVD development after carotid body resection or
when the peripheral drive is reduced by dopamine (Fig. 6;
Refs. 162, 383, 464).
90 • APRIL 2010 • www.prv.org
 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 701

TABLE 1. Effect of pharmacological interventions on the development of HVD in adult humans

Reference
Target Agent Arousal State Effect Comments Nos.

␣2-Adrenergic receptor Clonidine Sedated AHR⫽ HVD⫽ In line with the observation that 236
the magnitude of HVD is
related to AHR
Adenosine receptor Aminophylline (adenosine Awake AHR⫽ HVD2 Data suggest a role for 203
antagonist) adenosine in the development
of HVD
265
Dipyridamole (adenosine Awake AHR1 HVD1 Pretreatment with aminophylline 859
reuptake inhibitor) abolished the dipyridamole
effect; data indicate a role for
adenosine in HVD
development
Calcium channel Verapamil (Ca2⫹ channel Awake AHR⫽ HVD⫽ Data suggest no involvement of 459
blocker) calcium ions in HVD
development
D2 receptor Low-dose dopamine Awake AHR2 HVD2 Dopamine acts peripherally at 162
this dose; the reduced HVD
prevents depression of a
subsequent V̇I response to
acute hypoxia
Awake AHR2 HVD⫽ 38
Awake AHR2 HVD2 821
Haloperidol (central and Awake AHR1 HVD⫽ Effect contrasts findings in 589
peripheral D2 antagonist) awake cats (see Refs. 769 and
460)
Domperidone (peripheral D2 Awake AHR1 HVD⫽ 38, 235
antagonist)
Lactic acid Dichloroacetate (blocks Awake AHR⫽ HVD⫽ Data suggest that brain lactic 264
lactate production) acidosis is unlikely involved in
HVD development
Opioid receptor Naloxone (opioid receptor Awake AHR⫽ HVD⫽ Data suggest no involvement of 370
antagonist) endogenous opioid system in
HVD development
Alfentanil (␮-opioid receptor Awake AHR2 HVD⫽ Data suggest that exogenous 120
agonist) opioids potentiate HVD
Morphine (␮-opioid receptor Awake AHR2 HVD⫽ 680
agonist)
Intrathecal morphine Awake AHR2 HVD⫽ 25
5-HT receptor Methysergide (5-HT receptor Awake AHR⫽ HVD⫽ Data suggest no involvement of 459
antagonist) serotonin in HVD development
Somatostatin receptor Somatostatin Awake AHR2 HVD2 Effect possibly via disinhibition 231
of GABAergic inhibitory
system
Carotid body Almitrine Awake AHR1 HVD1 In line with the observation that 266
the magnitude of HVD is
related to AHR
Central nervous system Low-dose inhalational Lightly anesthetized AHR2 HVD⫽ Data suggest that the link 798
anesthetics (halothane, between AHR and HVD is lost
isoflurane, enflurane) during anesthesia
535
235
Propofol (intravenous Lightly anesthetized AHR2 HVD1 Propofol may have increased 549
anesthetic) HVD via its action at the
GABA receptor complex;
propofol had no effect on
intermittent hypoxic
ventilation

AHR, acute hypoxic ventilatory response; HVD, hypoxic ventilatory decline; V̇I, inspired ventilation.

During anesthesia, when the peripheral drive is either
absent or severely reduced, it seems appropriate to as-
cribe the development of HVD to an effect arising selec-
tively from within the CNS. One possibility is that while
CBF-induced HVD plays only a minor role in the awake
state, it becomes the major contributor during anesthesia.
In the anesthetized cat, brain blood flow-related HVD
does explain the similarities in ventilatory time constants
of central CO2 steps and hypoxic steps, respectively, re-
stricted to the brain stem (823). It would also explain the

Physiol Rev • VOL 90 • APRIL 2010 • www.prv.org

 TABLE 2. Effect of pharmacological interventions on the development of HVD in awake and anesthetized adult animals 702
Reference
Target Agent Animal Arousal State Effect Comments Nos.

Adenosine receptor Aminophylline (adenosine Cat Anesthetized (chloralose- HVD2 The carotid sinus nerves and vagi 361
antagonist) urethane) of the animals were bilaterally
denervated
Theophylline iv and icv Cat Anesthetized (sodium pentothal) iv: AHR1 Data from these interventions 866
(adenosine antagonist) suggest involvement of
adenosine in development of
HVD
iv: HVD2
icv: AHR⫽
icv: HVD2
D2 receptor Haloperidol (central and Cat Awake AHR⫽ HVD2 HVD was abolished by 769
peripheral D2 antagonist) haloperidol
460
463
Cat Anesthetized (chloralose- AHR⫽ HVD2 Identical results as in the awake 769
urethane) cat; carotid sinus nerve activity
remained constant during HVD
development
Domperidone (peripheral D2 Cat Awake AHR⫽ HVD⫽ Data from these interventions 769
antagonist) suggest that central but not
peripheral dopaminergic

Physiol Rev • VOL

GABA receptor Bicuculline (GABA antagonist)
microinjected in the NTS
mechanisms are directly
involved in HVD
Rat Awake HVD2 GABA antagonists reduced HVD 752
in intact animals only; in
carotid body denervated
animals, no HVD was present

90 • APRIL 2010 •
and no HVD developed upon
injection of GABA antagonists
during hypoxia
Bicuculline iv (GABA antagonist) Cat Anesthetized (chloralose) HVD2 Animals were glomectomized; 508
phrenic nerve response to
LUC J. TEPPEMA AND ALBERT DAHAN

www.prv.org
progressive CO was measured
Lactic acid Dichloroacetate (prevents lactate Cat Anesthetized (chloralose) HVD2 Animals were peripherally 543
production) chemodenervated; progressive
hypoxia induced by inhalation
of CO; data suggest a role for
lactic acid in HVD generation
Nitric oxide NG-nitro-L-Arginine (a nonspecific Rat Awake HVD1 Control animals did not display 290
synthase (NOS) NOS blocker) HVD
S-methyl-L-thiocitrtrulline (a
selective neural NOS inhibitor)
Opioid receptor Naloxone (opioid receptor Cat Anesthetized (chloralose) HVD2 Animals were peripherally 541
antagonist) chemodenervated; ventilatory
response to progressive CO
was measured
Morphine (␮-opioid receptor Cat Anesthetzied (chloralose- HVD2 Steady-state response to 61
agonist) urethane) sustained hypoxia remained
unaltered by morphine,
suggesting a reduced HVD
possibly by reducing brain
blood flow response to hypoxia
 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 703

D2 receptor, dopamine 2 receptor; PB-KF, Parabrachial/Kölliker fuse complex; AHR, acute hypoxic ventilatory response; HVD, hypoxic ventilatory decline; HVR, hypoxic ventilatory
Reference symmetry in on- and off-responses observed in halothane-
Nos.

289

289
exposed humans. Manipulating brain blood flow either
92
hemodynamically (for example, by aortic balloon infla-
tion), pharmacologically (for example, by infusion of pa-
No distinction between AHR and

while after microinjection into

paverine to blood perfusing the brain stem), or by expo-

the PB-KF AHR is maintained

suggest a role for PDGF-␤ in

animals compared with their
HVD is made; data suggest a

enhancement of HVD after

sure to central hypoxia produce a similar decrease in V̇I

Control experiments show a

reduced HVD in knockout
systemic MK801 injection,

wild-type littermates; data

that is consistent with washout of central CO2 (60, 293,
reduction in AHR with

while HVD is reduced

542, 823). Finally, we cannot exclude an effect of modu-
Comments

HVD development
lators accumulating during hypoxia in the anesthetized
mammal. Indeed, some enhancement of GABAergic inhi-
bition of V̇I during hypoxia is expected, especially from
anesthetics that have agonistic activity at the GABA re-
ceptor. However, at PO2 values ⬎50 Torr, these effects are
probably small with regard to the reduced tissue PCO2 by
changes in BBF (794).
HVD2 in wild-type
microinjection:

animals only
AHR2 HVD2

IV. GENETIC INFLUENCE ON THE

Effect

VENTILATORY RESPONSE TO HYPOXIA

iv: HVR2

HVR⫽

A. The Genome and HVR

The genotype plays an important role in the magni-

tude of the HVR and consequently explains part of the
Anesthetized (halothane-

large intersubject response variability (734). Measure-

Arousal State

ments of the HVR in humans show that normal healthy

volunteers may vary a factor of 20 in the magnitude of
their response. This range is much larger than expected
urethane)

from just normal physiological variability and technical,

environmental, and/or emotional factors. Furthermore,
Awake

Awake

data from high-altitude residents indicate that genotype

may not only influence the immediate response to hyp-
oxia but possibly also the ventilatory response to sus-
Heterozygous

knockout

tained hypoxia and ventilatory adaptation to high altitude

Animal

PDGF-␤
Rat

Rat

(519).
mice

1. Human studies
PDGF-␤ antagonist microinjected

In humans, evidence for a genetic effect on HVR

response; iv, intravenous; icv, intracerebroventricular.

comes primarily from family and population studies.

PDGF-␤ antagonist (given

First-degree healthy family members of patients with pul-

microinjected in PB-KF
MK801 (NMDA receptor

monary disease associated with hypoventilation and CO2

antagonist) iv and
Agent

intraperitoneally)

retention and nonathletic parents and siblings of endur-

ance athletes show a familial clustering of HVR magni-
in the NTS

tudes at the low end of the spectrum (see Ref. 832 and
references cited therein). Similar observations were made
in families with a history of SIDS and obstructive sleep
2. —Continued

apnea (734). Twin studies show greater similarities in the

magnitude of HVR among homozygotic twins compared
with heterozygotic twins (see Ref. 734 and references
growth factor
NMDA receptor

Platelet-derived

cited therein). Most but not all interpopulation compari-

Target

sons indicate the existence of heritable HVR phenotypes

(PDGF)-␤
receptor

linked to specific populations (96, 97, 152, 783). Strong

TABLE

evidence for a hereditary component comes from studies

in Asians and South Americans. Children from Tibetan

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704 LUC J. TEPPEMA AND ALBERT DAHAN
and Han (Chinese) parents tend to be in the range ob-
served in the Han population (152). With the use of an-
cestry-informative genetic markers, an evolutionary ori-
gin was found for the low HVR in Andean high-altitude
natives of Quechua origin (97).
2. Animal studies
There is ample proof that the divergence in ventila-
tory behavior between different inbred strains of the same
species reflects genetic influences more than effects from
body mass, age, or sex. This also applies to the ventilatory
response to moderate hypoxia and the survival response
to severe hypoxia (874). In rats, most studies show an
effect of strain on the magnitude of HVR (50, 274, 736, 739,
834). Some strains are difficult to compare as underlying
disease may affect carotid body function. For example,
New Zealand hypertensive rats suffer from sclerotic dam-
age to the carotid artery and its branches (50). Strains
may differ in the magnitude of the HVR by up to a factor
of seven (834). The differences are not only related to the
carotid body response to hypoxia but also to central
neural processing during and immediately after exposure
to short episodes of hypoxia (274, 739). As stated by
Golder et al. (274), the choice of rat strain can (critically)
influence conclusions concerning the control of breath-
ing. This is also true for drug studies. For example, in rat,
the peripheral dopamine D2 receptor antagonist domperi-
done and the NOS inhibitor L-NAME differentially affect
ventilation and the HVR depending on the genetic back-
ground (737, 738).
To pinpoint the HVR phenotype to a specific rat
chromosome, Forster et al. (240) used the technique of
chromosomal substitution in which an entire chromo-
some from one inbred rat strain is introgressed into the
genetic background of another to create a consomic rat.
Initially, five chromosomes were studied. HVR was not
determined by any of the genes on these chromosomes,
although genes on chromosomes 9 and 18 did contribute
to HVD and/or a reduced metabolic rate during hypoxia.
The results of a second study indicate that there are
complex gene-gender interactions on HVR (199).
Like rats, inbred mice strains vary significantly in the
magnitude of their HVR. Tankersley et al. (760) examined
the HVR in eight inbred strains. The DBA/2J strain had the
greatest HVR, while the A/J strain displayed the lowest
response. Tankersley et al. (760) did not take the brain
state of the animals into account, and in this this regard,
it is interesting that A/J mice are more prone to sleep than
DBA/2J mice and have a higher arousal threshold in hyp-
oxia (669). So possibly the ventilatory response could be
the reflection of a stress response. However, the differ-
ence in frequency of hypoxic events during sleep (larger
in the A/J strain) was inversely related to the hypoxic
ventilatory sensitivity, whilst the arousal threshold upon
Physiol Rev • VOL
tactile/auditory stimuli was not different between both
strains (669). The difference in HVR was associated with
structural and functional changes in the carotid bodies
(858). Compared with the A/J strain, the carotid bodies of
the DBA/2J strain were larger, and acetylcholine in-
creased intracellular Ca2⫹ in more cells. These morpho-
logical and functional differences are accompanied by
differences in gene expression (30). There were differ-
ences in expression of genes related to neurotransmitter
metabolism, synaptic vesicles, and neural crest cell mi-
gration/development with less expression in A/J mice. An
important difference was the reduced expression of the
␤-subunit of maxi-K channels in A/J mice. Further studies
from Tankersley and co-workers (758, 759, 761) aimed to
uncover the genes involved in the HVR phenotype. Data
from an intercross study between C3H/3J and C57BL/6J
mice suggest that HVR in terms of respiratory timing is
dependent on only a handful of genes (759). A putative
quantitative trait locus on chromosome 9 could be iden-
tified with a significant association with several hypoxic
ventilatory variables (758), while another locus on chro-
mosome 3 was significantly associated with hypoxic in-
spiratory drive. Both loci explained 26 –30% of the pheno-
typic variation among F2 offspring. The interaction be-
tween hypoxia and hypercapnia on breathing was linked
to two different loci on chromosomes 1 and 5 (761). The
simplicity of this genetic model is appealing and is much
less complex than in the rat. It is doubtful whether such a
restricted model also applies to the human HVR phenotype.
B. Mutations and HVR
Examples of targeted gene deletions in mice to study
the process of oxygen sensing at the carotid bodies and/or
to understand the peripheral and central processing of the
carotid body response to hypoxia are discussed in section
III. Here we briefly discuss mouse strains developed to
study specific diseases and that show altered ventilatory
responses to hypoxia. We further discuss two human
conditions in which one specific mutation is linked to an
altered HVR.
Various mouse strains have been engineered to study
the Congenital Central Hypoventilation Syndrome (CCHS),
some of which have recently been reviewed (see Ref.
259). Particularly genes of the endothelin and c-ret path-
way have been the focus of interest, for example, endo-
thelin converting enzyme (ECE1), endothelin-1 (EDN1),
endothelin-3 (EDN3), endothelin receptor A (Ednra), en-
dothelin receptor B (Ednrb), Mash-1, c-ret, Phox2a, Phox2b,
brain-derived neurotrophic factor (Bdnf), and orphan ho-
meobox (Rnx) genes (169, 259, 849). Knockouts at these
genes display a variable respiratory phenotype with reduced
hypercapnic response and/or HVR in ECE1⫹/⫺, EDN1⫺/⫺,
Ednra⫺/⫺ and Mash-1⫹/⫺ newborn mice; however, with the
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
exception of EDN1⫺/⫺ mice, these genotypes did not display
abnormalities as adults. This is an important limitation for a
disease that in humans persists throughout life (259). There
are other mice models associated with CCHS such as the
Nurr1 mutant mouse and the microphtalmia-associated tran-
scription factor (Mitf) mutant mouse (555, 754). Nurr1 mu-
tant mice show complete agenesis of midbrain dopamine
cells. Newborn Nurr1 knockout mice have a severely dis-
turbed pattern of breathing with a blunted HVR (555). Mitf
plays an essential role in the differentiation of neural crest-
derived melanocytes. Mitf mutant mice display an increased
HVR. The authors relate this to a reduction of melanocyte-
derived opioids within the CNS (754). This suggests an in-
hibitory role of endogenous opioids on the central ventila-
tory network and is in agreement with observations in ␮-opi-
oid receptor gene knockout mice (158).
A mouse model associated with the Rett syndrome is
represented by a genotype with a ubiquitous deletion of
one allele of the X-linked Mecp2 gene, encoding the DNA-
binding protein methyl CpG (Mecp2) involved in gene
silencing. Female Mecp2⫹/⫺ mice have a respiratory phe-
notype resembling that of the Rett syndrome and that is
characterized by episodes of hyperventilation and respi-
ratory depression (75). The (isocapnic) HVR in heterozy-
gous females is larger than in wild types; mice with a
selective deletion of the protein in neurons do also display
an enhanced HVR but do not show the typical episodes of
respiratory depression (75). It is interesting to note that
different respiratory phenotypes also exist between dif-
ferent mouse strains with the gene deletion (references in
Ref. 563).
In humans, carotid body tumors are rare and often
associated with chronic hypoxia from altitude, cyanotic
heart disease, and pulmonary disease. One hereditary
form of carotid body tumor (as part of the hereditary
familiar paraganglioma syndrome) is due to a missense
mutation within the gene that encodes succinate dehydro-
genase D (SDHD; Refs. 48, 154, 213). SDHD is an essential
enzyme of the tricarboxylic acid cycle and part of cyto-
chrome b588 of the mitochondrial respiratory chain com-
plex II. All patients are heterozygous: animal studies in-
dicate that homozygotes do not survive and die in utero
(607). We measured the isocapnic HVR and hypercapnic
ventilatory responses in normoxia and hypoxia in 12 tu-
mor-free carriers of the mutation (as tested by MRI; au-
thor’s unpublished observation). There were three main
observations: 1) hypercapnic ventilatory responses were
not different from age-matched healthy controls, 2) the
magnitude of the isocapnic HVR was at the low end of
“normal” (mean value 0.3 versus 1.2 l 䡠min⫺1 䡠%⫺1 in con-
trols), and 3) in contrast to controls, none of the tested
carriers of the SDHD gene showed any O2-CO2 interaction
on the HCVR. These data may link the SDHD gene to
carotid body oxygen sensing and/or to the well-described
multiplicative action of CO2 on the HVR (see sect. VD).
Physiol Rev • VOL
705
Robbins and co-workers (712) studied the effect of a
mutation in the von Hippel-Lindau tumor suppressor pro-
tein (VHL) gene. A homozygous missense mutation that
impairs but does not ablate VHL function causes Chuvash
polycythemia (47, 213). The disease is endemic to the
Chuvash population of Russia. In patients with Chuvash
polycythemia, binding of VHL to HIF-1␣ is diminished and
hence normal degradation reduced causing the accumu-
lation of HIF (in normoxia) and consequent upregulation
of certain target genes such as the erythropoietin gene.
The three patients studied showed several abnormalities
in respiratory and pulmonary vascular regulation. Most
importantly, the isocapnic HVR and pulmonary artery
pressure responses to hypoxia were increased compared
with healthy and polycythemia control subjects (712). In
other words, cardiorespiratory responses to hypoxia were
upregulated in patients with increased HIF levels and up-
regulated HIF target genes. These data are in agreement
with animal studies showing downregulated cardiopulmo-
nary responses in HIF-1␣⫹/⫺ mice and attenuated adaptive
responses to chronic intermittent hypoxia (see sect. V).
In conclusion, the above examples of the influence of
single gene defects (and their inheritance) on the HVR are
clear illustrations of a genetic influence. Strain differ-
ences in animals and differences in HVR between low-
landers and high-altitude natives illustrate the influence of
genomic factors, i.e., the interaction between different
genes on the one hand and that between genes and the
environment on the other hand. Both respiratory and
nonrespiratory stimuli are able to affect the development
of the HVR (developmental plasticity) causing alterations
in response that may persist throughout adulthood. In
section II we discussed the influence of changes in oxygen
tension in the neonatal period. One clear example of a
nonrespiratory stimulus leading to plastic changes is
stress from neonatal maternal separation that leads to a
permanently augmented HVR of male but not female rats
(262). Brain stem areas involved in ventilatory control of the
neonate have strong plastic capacities depending on specific
environmental stimuli and genetic background (735).
V. PATHOPHYSIOLOGICAL INFLUENCES ON
THE HYPOXIC VENTILATORY RESPONSE
A. Biological Variability
Apart from a between-subject variability, one has to
consider the appreciable within-subject variation in the
magnitude of the HVR. The coefficient of variation of
repeated HVRs obtained over a 2-h period ranges from 10
to 60% among subjects (mean 20%; Ref. 674). Between-day
variability is 20 –50% greater than within-day variability.
The cause of the large between-subject variability may lie
in differences in genetic make-up and race of the different
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706 LUC J. TEPPEMA AND ALBERT DAHAN
subjects tested. However, this explains just part of the
variability (see sect. IV). Other causes are related to phys-
iological factors (such as age, metabolism, body temper-
ature, the circadian rhythm, hormonal status, and preg-
nancy), psychological factors (anxiety, full bladder),
pathophysiological factors, the use of pharmacological
agents that may affect HVR, and environmental factors
(previous exposure to hypoxia, altitude). To reduce within- and
between-subject variability, it is important to perform
hypoxic experiments in subjects that feel comfortable with the
setup, protocol, and laboratory surroundings and have no
apparent urges that may influence their responses (e.g., a
full bladder). Also the investigator should do everything
not to influence the subject (for example, whispering may
have a negative influence on the subject).
B. Ageing
Breathing is affected by ageing due to a decline in
function at multiple levels of the neuromechanical link
between chemosensors, brain stem, and ventilatory pump,
causing a reduced ability to maintain blood gas homeosta-
sis (360). Morphometric studies of rat carotid bodies in-
dicate the occurrence of degenerative changes in old age
(142, 179, 610). The carotid bodies of aged rats (⬎23 mo)
show an increase in extracellular matrix, a reduction in
the number and volume of type I cells, and the presence
of necrotic cells (142, 179, 610). In the remaining func-
tional type I cells, mitochondrial volumes and neurose-
cretory fill-up of vesicles are reduced (610). Carotid body
catecholamine content and turnover time is reduced with
age, as is the catecholamine response to hypoxic stimu-
lation (142). Conde et al. (142) measured afferent carotid
sinus nerve activity during hypoxic and CO2/acidotic stim-
ulation in young (3 mo) and old (18 mo) rats. While no age
effect was observed in the nerve response to CO2/
acidosis, in old animals a ⬎50% reduction was observed in
the response to hypoxia. Degenerative changes such as
fibrosis and loss of glomus tissue have been observed in
the human carotid body (311). In 15–30% of humans in
their eighth and ninth decade, there may be signs of
chronic carotid glomitis with infiltration of T-cell lympho-
cytes (311). These data collectively indicate important
age-dependent morphological and functional changes of
the carotid bodies.
A minority of human studies observed a reduced HVR
in older persons (age range 64 –79 yr; Refs. 412, 604).
However, the majority of studies observed no differences
in HVR between young (20 –30 yr) and old (60 –79 yr) (6,
609, 610, 714), while one study observed an increase in
HVR (124). The overall picture that emerges from the
human literature is that HVR is marginally affected at old
age and hence suggests that carotid body function re-
mains unaltered. This stands in sharp contrast to the
Physiol Rev • VOL
morphometric and functional studies in carotid bodies of
aged rats (see above). However, it may well be that the
human studies were performed at the older end of normal
adult function when no functional decline in carotid body
function is yet apparent (714). Another possible cause for
the difference between morphological appearance of the
carotid body and its function may be found in the exis-
tence of redundancy in carotid body-mediated processes.
A reduced number of type I cells may be able to sustain
the functional tasks of the carotid bodies (610). Finally, a
failing carotid body function in old age may result in
plastic changes in brain stem areas involved in the pro-
cessing of its afferent output, causing the (partial) resto-
ration of the HVR (610).
C. Gender and Pregnancy
Sex hormones (progesterone and the combination
progesterone/estrogen as well as testosterone) have a
stimulatory effect on breathing and HVR. Progesterone
stimulates breathing via hypothalamic sites through es-
trogen-dependent receptors (46). The role of progester-
one in causing an increase in HVR is twofold: it increases
carotid body sensitivity to hypoxia, and in combination
with estrogen, it has a central modulatory effect on its
afferent output (299). Testosterone increases breathing
and the HVR probably through an increase in metabolic
rate and central modulatory effects (766, 841).
The majority of human studies could not find a dif-
ference in HVR between men and women (157, 362, 364,
418, 677, 680, 681). However, most of the studies involved
did not control for the phase of the menstrual cycle or
tested women in just one phase (often the follicular
phase). The number of animal studies on gender effect on
HVR is limited, but all, in contrast to the human data,
point toward a greater carotid body response to hypoxia
in female animals (366, 530, 765). Only part of these sex
differences is related to the acute effects of sex steroids.
Castration of the adult animals does lead to a reduced
HVR in males and females, but the sex differences persist
(767). This is not surprising taking into account the long-
term developmental and organizational effects of sex ste-
roids on neuronal systems that occur in prenatal and early
postnatal life. In this light, the absence of clear sex dif-
ferences in the human population seems remarkable.
An effect of the menstrual cycle on the HVR is small
and ranges from an increased HVR in the luteal phase by
10 –20% compared with the follicular phase (157, 840).
Pregnancy is associated with hyperventilation due to an
increase in metabolic rate and the stimulatory effects of
progesterone (636). Also, the HVR is increased during
pregnancy, an effect that is already apparent at 20 wk and
reaches a maximum at 36 wk (521). More than 60% of the
increase in HVR is related to sex hormones, the rest to the
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
increase in metabolic rate (521, 636). A more extensive
overview of the effect of sex steroids on ventilatory con-
trol during development and in adult life has been pub-
lished recently (52).
D. Influence of CO2 on the HVR:
O2-CO2 Interaction
In both humans and animals, there is ample evidence
for a multiplicative effect of O2 and CO2 on the HVR (12,
150, 178, 156, 195, 494, 517, 777). It is uncertain if quanti-
tatively this O2-CO2 synergism observed at the ventilation
level is entirely due to a multiplicative interaction in the
carotid bodies (423; further references in Ref. 178).
However, CO2 does not always act as a multiplier of
the HVR. In conscious cats, O2-CO2 synergism does not
seem to exist, due to a negative interactive effect on tidal
volume (575, 576). When anesthetized, however, this spe-
cies demonstrates interaction at both carotid body and
ventilation levels (234, 423). Although displaying multipli-
cative interaction in the carotid bodies (601), the anesthe-
tized rat only seems to display a positive synergistic hy-
percapnic-hypoxic action at the level of ventilation at
hypocapnic arterial PCO2 values (145, 613). Earlier studies
showed that in other species O2-CO2 interaction may be
hypoadditive or at best additive (references in Ref. 145;
more recent studies are discussed below).
A modulating effect of CO2 on the HVR could origi-
nate from three sources: the carotid bodies, a central-
peripheral interaction, and/or central O2-CO2 interaction.
While a multiplicative interaction in the carotid bodies is
evident, the brief overview below shows that there is no
consensus as to the modality of the peripheral-central
interaction: hyperadditive, simply additive, or hypoaddi-
tive. There is no evidence for central O2-CO2 interaction.
1. Carotid sinus nerve recording: properties of
type I cells
A relatively simple method to study O2-CO2 interac-
tion in the carotid bodies is with carotid sinus nerve
recording. Anesthetized cats, rats, lambs, and rabbits
demonstrate O2-CO2 interaction in the carotid sinus nerve
(116, 118, 119, 234, 333, 386, 423, 601, 660; further refer-
ences in Ref. 233) that most likely can be reduced to the
properties of type I cells. The few studies that have been
performed in type I cells may indeed suggest an interac-
tion between acid/high CO2 and low O2 on intracellular
[Ca2⫹] (167, 668). As outlined by Peers (592), a thorough
quantitative analysis of the relation between neurotrans-
mitter release and intracellular [Ca2⫹] is required to shed
more light on the mechanism of stimulus interaction in
type I cells. Other neurotransmitters than dopamine alone
should be implicated in such analysis because the in-
crease in afferent carotid sinus nerve activity by hyper-
Physiol Rev • VOL
707
capnia and hypoxia is not tightly coupled to dopamine
release (100, 351, 743). The O2 sensor may behave like a
hemoglobin molecule and, analogous to the Bohr shift, O2
binding may be competitively inhibited by CO2/H⫹, ex-
plaining the finding that the maximal effect of a very high
PCO2 (⬃270 Torr) was the same regardless of the PO2 (180
and references therein).
2. Separate perfusion of peripheral and
central chemoreceptors
A) DOGS. In a majority of early studies utilizing selec-
tive perfusion of the carotid bodies, hypoadditive effects
on ventilation of peripheral and central stimuli were re-
ported (references in Ref. 5). Multiplicative O2-CO2 inter-
action at the level of minute integrated phrenic nerve
activity was also reported (132). More recently, Smith et
al. (707) showed a clear multiplicative action of periph-
eral O2 and CO2 on ventilation but also a much larger
inhibiting effect on the HVR of systemic hypocapnia than
of carotid body hypocapnia alone, thus not supporting a
hypoadditive peripheral-central interaction. In the same
animal model, it was recently shown that isolated carotid
body perfusion with hyperoxic hypocapnic blood led to a
substantial decrease in ventilation despite a considerable
rise in PCO2, not only suggesting an important role of the
carotid body in euoxic/normocapnic ventilation but also a
hyperadditive peripheral-central interaction (77).
B) GOATS. Awake goats subjected to selective carotid
body perfusion showed O2-CO2 multiplication at the level
of both carotid bodies and ventilation without any periph-
eral-central interaction other than simply additive (163
164, 165). In awake goats instrumented for ventriculocis-
ternal perfusion, carotid body stimulation with NaCN in-
creased ventilation more at a relatively alkaline perfusate
pH, possibly suggesting negative peripheral-central inter-
action. However, in this study an alkaline cerebrospinal
fluid pH was associated with much higher PaCO2 levels
(708), thus almost inevitably leading to more intense cen-
tral stimulation and potentially to simple additive central
effects consistent with the findings in goats subjected to
selective carotid body perfusion (163, 164, 165).
C) CATS. Anesthetized cats subjected to artificial brain
stem perfusion did not show any central-peripheral inter-
action other than simply additive (314, 793). As in awake
goats and dogs (163, 707), selective manipulation of pe-
ripheral gas tensions showed a multiplicative O2-CO2 ef-
fect on ventilation (314, 793). These findings might not
entirely be compatible with those in the anesthetized cat
showing that, with a constant level of hypoxia and a linear
CO2 response of the carotid sinus nerve, CO2 had a
smaller effect on ventilation below the eucapnic PCO2 than
above it, suggesting some form of hyperadditive periph-
eral-central interaction (422). The disparity between the
findings in anesthetized and awake cats (awake animals
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708 LUC J. TEPPEMA AND ALBERT DAHAN
showing a negative peripheral-central interaction of tidal
volume; Refs. 575, 576) cannot be explained by other than
unidentified influences of anesthesia and/or arousal ef-
fects of hypoxia during wakefulness.
D) RATS. Utilizing an in situ dual perfusion system in
the rat to separately perfuse peripheral and central che-
moreceptors, Day and Wilson (172) found a hypoadditive
effect of the central PCO2 on the hypoxic phrenic ampli-
tude response. Perhaps this may explain the large HVR in
this species at hypocapnic but not hypercapnic PaCO2
levels (145).
3. Dynamic end-tidal forcing
In both animals and humans, peripheral-central inter-
action can be studied using end-tidal forcing (DEF), en-
abling one to estimate separate gains of the central (Gc)
and peripheral (Gp) chemoreflex loops, respectively (175,
747; see sect. VI). In the cat, Gc and Gp (assessed with
both DEF and artificial brain stem perfusion) are indepen-
dent, indicating no central-peripheral interaction other
than additive (175, 314, 793). In addition, in the cat, O2-
CO2 interaction takes place at the level of the carotid
sinus nerve (234, 423), so the increase in ventilatory CO2
sensitivity with hypoxia in this species seems entirely due
to a peripheral O2-CO2 interaction, compatible with an
increased Gp but unaltered Gc in overall hypoxia (e.g.,
Refs. 779, 793). In young piglets, hypoxia increased Gp but
did not alter Gc (845). In humans, an unchanged Gc with
hypoxia was not always observed, with some studies
showing a small but significant rise (226, 227) but others
reporting no significant change (56, 156, 591). When Gp
was lowered by inhalation of subanesthetic concentra-
tions of volatile anesthetics, Gc did not change, not sup-
porting an other-than-additive central-peripheral interac-
tion (161, 796, 797).
4. Dynamic end-tidal forcing in carotid body
resected subjects
Bellville (56) reported an ⬃50% lower central chemo-
sensitivity in carotid body-resected subjects compared
with healthy controls, indicating that a peripheral-central
interaction other than simply additive cannot be ex-
cluded. One to 26 six years after bilateral removal of the
carotid bodies due to paraganglioma, subjects displayed a
lower central CO2 sensitivity than an age- and sex-
matched control group (227). Three days after carotid
body resection (due to hereditary paraganglioma), three
patients showed a substantially reduced central CO2 sen-
sitivity that gradually recovered in the following 1–3 years
(154). In the anesthetized cat, carotid sinus nerve transec-
tion did not reduce central CO2 sensitivity in an acute
setting (314). Thus removal of a tonic input from the
carotid bodies could lead to a resetting of central CO2
sensitivity that needs time to develop. Whether such a
Physiol Rev • VOL
relatively slow process may also be responsible for the
lower CO2 sensitivity and higher resting arterial PCO2 after
carotid body denervation in goats and dogs remains to be
established (579, 663).
5. Other approaches used in humans
In earlier studies, so-called withdrawal tests were
performed, suddenly removing a central or peripheral
stimulus keeping the background peripheral or central
gas tensions, respectively, at constant levels (reviewed in
Ref. 150). Underlying assumptions such as lack of activity
and absence of undershoots in carotid sinus nerve dis-
charge in (mild) hyperoxia make these studies difficult to
interpret (e.g., Ref. 325). Other workers compared tran-
sient and steady stimuli assuming that responses to the
former originate at the peripheral chemoreceptors and
those to the latter at both peripheral and central sites (see
Ref. 206 for earlier references). The role of HVD could not
always be taken into account, as well as the possible
existence of an interaction component with a fast time
constant (e.g., Ref. 656).
One way to study peripheral-central interaction is to
expose subjects to peripheral stimuli at different central
PCO2 levels. Robbins (656) compared the effects of a step
decrease in end-tidal O2 performed just 30 s after impos-
ing a step decrease in end-tidal CO2 with those performed
at constant steady-state end-tidal CO2. In two of three
subjects, the response was larger under the former con-
dition, suggesting a more-than-additive central-peripheral
interaction (alternative explanations were left open; Ref.
656). However, St Croix et al. (724) could not reproduce
this. Clement et al. (136) found no evidence for different
responses to isocapnic changes in arterial pH induced by
infusion of acid and bicarbonate performed at quite dif-
ferent background PCO2 levels. With the assumption that
with acid-base changes the peripheral chemoreceptors
respond uniquely to changes in arterial [H⫹] (190, 292,
334, 687), these findings provided no evidence for an
interaction other than simply additive (136).
Recently, we measured hypoxic sensitivity in hu-
mans, defined as the ratio ⌬V̇I/⌬log PaO2, at three different
levels of constant end-tidal CO2. The rationale of using the
ratio ⌬V̇I/⌬log PaO2 rather than the conventional ratio
⌬V̇I/⌬SpO2 is explained in section VIB (see also Ref. 775).
As also demonstrated in the cat (650), humans display a
steep and sound linear relationship between hypoxic sen-
sitivity and arterial [H⫹], representing a powerful O2-CO2
interaction (Fig. 7; Ref. 775). But is hypoxic sensitivity a
unique function of arterial [H⫹]? This seems unlikely be-
cause it would imply an almost infinitely high sensitivity
in a metabolic acidosis with a pH of ⬃7.3 ([H⫹] ⬃50 nM)
which, for example, can be induced by the carbonic an-
hydrase inhibitor acetazolamide (775, 778). To investigate
this further, bicarbonate was infused isocapnically, and
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
FIG. 7. Relationship between hypoxic ventilatory response and
arterial H⫹ concentration in humans. Hypoxic sensitivity, defined as
⌬V̇I/⌬log PaO2 as a function of arterial [H⫹]. The right line represents the
condition with normal arterial bicarbonate concentration in the arterial
blood. The acute hypoxic response (i.e., the response 3 min after a step
decrease in end-tidal O2) is measured at three constant levels of arterial
PCO2 (numbers are arterial PCO2 values). There is a sound linear rela-
tionship between hypoxic sensitivity and arterial H⫹ concentration in-
dicating a powerful O2/CO2-H⫹ interaction at ventilation level. When
subjects are given intravenous bicarbonate (left line), the line shifts to
lower values of arterial [H⫹] in an approximately parallel way. Thus
apparently hypoxic sensitivity is not a unique function of the arterial
[H⫹]. Points a and f are virtually isohydric points, and the lower hypoxic
sensitivity in point a is presumably due to the lower PCO2 in the carotid
bodies. See text for further explanation. Data are means ⫾ SE from 8
young healthy volunteers. [Adapted from Teppema et al. (775).]
this yielded two isocapnic and two virtually isohydric
situations with different hypoxic sensitivities as shown in
Figure 7. From these data (775), we can draw several
conclusions. First, O2 sensitivity increases with an isocap-
nic rise in arterial [H⫹], and this is presumably due to
interaction at the carotid bodies (cf. points c and f and b
and d in Fig. 7). Second, although with acid-base alter-
ations extracellular H⫹ may be the adequate stimulus to
the carotid bodies, there is no unique relationship be-
tween hypoxic sensitivity and arterial [H⫹] (cf. points f
and a in Fig. 7). Thus, in this regard, our data do not
support earlier conclusions (e.g., Refs. 250, 349), but nei-
ther do they provide conclusive evidence for the carotid
bodies as the exclusive site of the O2-CO2/H⫹ interaction.
The lower hypoxic sensitivity in point a compared with f
in Figure 7 could be due to the lower carotid body PCO2
(peripheral O2-CO2 interaction) combined with a dimin-
ished efficacy of afferent carotid body input to increase
ventilation due to the also lower central PCO2. Perhaps a
more likely explanation is that it is the intracellular envi-
ronment (pH?) of carotid body cells that, together with
the extracellular pH, determines O2 sensitivity.
Roberts et al. (660) subjected humans to mechanical
ventilation to produce apnea at different end-tidal CO2
levels varying from 2.5 Torr above to 7.5 Torr below
eucapnia. The background end-tidal CO2 dose-depen-
dently influenced the magnitude of the EMG response to
a “standard” peripheral chemoreceptor stimulus that was
completely absent at an end-tidal CO2 ⬃7.5 Torr below
Physiol Rev • VOL 90 • APRIL 2010 •
709
eucapnia (the stimulus consisted of a rapid desaturation
within 30 s with the end-tidal CO2 briefly adjusted to the
subject’s eucapnic value). These data may suggest that an
augmented carotid body output is translated into an in-
crease in respiratory motor output only at sufficiently
high central chemoreceptor PCO2 levels. Corne et al. (144)
used volume cycle-assisted ventilation to produce steady-
state mild and moderate hypocapnia while maintaining
stable spontaneous breathing. At arterial PCO2 values 5–10
Torr below eucapnia, but not in mild hypocapnia or eu-
capnia, a ventilatory response to hypoxia was totally ab-
sent. Although clearly of clinical significance, a clear pic-
ture of peripheral-central interaction cannot be deduced
from this approach because a separation with O2-CO2
interaction at the carotid bodies cannot be made. In ad-
dition, an influence of developing HVD in these subjects
cannot be excluded even though the hypoxic tests did not
outlast 5 min: at the end of the hypoxic test in moderate
hypocapnia (in the absence of an HVR), subjects venti-
lated less than in the prehypoxic period suggesting HVD
(144).
Yang et al. (863) introduced a method for estimating
the dynamic response to simultaneous changes in PCO2
and PO2 in humans, and their data could be well described
with a two compartment model, one comprising the slow
CO2 and the other the fast O2-CO2 interaction component.
The interaction could be entirely modeled by the fast
component attributed to the peripheral chemoreceptors,
thus not supporting a significant central O2-CO2 interac-
tion and/or more than simply additive peripheral and
central effects.
Agents not crossing the blood-brain barrier and not
influencing central CO2 sensitivity could be used to
investigate possible selective effects on the carotid
bodies. Acetazolamide, a moderately permeable car-
bonic anhydrase inhibitor, will not have penetrated into
the brain in significant amounts 1 h after administration
of a low dose. About 1 h after infusion of 4 mg/kg, the
O2-CO2 interaction in healthy subjects was completely
abolished, and this was reversible with antioxidants
(Fig. 8; Ref. 777). Infusion of 500 mg in humans did not
change hyperoxic CO2 sensitivity, indicating an unal-
tered central ventilatory CO2 sensitivity (750). With the
assumption of no central effects of acetazolamide,
these findings suggest that in humans, the O2-CO2 in-
teraction entirely resides in the carotid bodies. A usual
clinical oral dose of acetazolamide does not affect the
interaction, indicating that its effect depends on the
dose and route of administration (750, 775). Animal
data suggest that analogous to its effect on hypoxic
pulmonary vasoconstriction (749), the inhibitory action
of acetazolamide on the HVR may occur independently
from carbonic anhydrase inhibition (776).
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710 LUC J. TEPPEMA AND ALBERT DAHAN

FIG. 8. Effect of acetazolamide on O2-CO2 interaction in humans. Left: intravenous low-dose (4 mg/kg) acetazolamide (ACTZ) lowers the acute
hypoxic response in normocapnia (N) but also abolishes the increase in its magnitude in hypercapnia (H). Thus this agent, which at the applied dose
is unlikely to have direct effects on the central nervous system, is able to abolish the O2-CO2 interaction by a peripheral action most likely located
in the carotid bodies. An antioxidant cocktail (AOX; ␣-tocopherol and ascorbic acid) reversed the effects of ACTZ. Right: control study in which
after the ACTZ, subjects received placebo (PLCB) instead of AOX. See text for further explanation. [From Teppema et al. (777).]

6. Conclusion ment of local tumors and/or hyperplasia that, for example,

In all species investigated, O2 and CO2 have multipli-
cative actions on carotid body output both when awake
and anesthetized, but the interaction site within type I
cells has not yet been established. The existence of a
multiplicative O2-CO2 interaction on ventilation depends
on the species, state of consciousness, and the peripheral-
central interaction mode. Generally, humans show O2-
CO2 multiplication, but it appears difficult to characterize
the mode of peripheral-central interaction, although there
is no conclusive evidence for hypoadditive central and
peripheral effects. Direct anatomical connections be-
tween the first relay station of the peripheral chemore-
ceptors in the NTS and central chemoreceptors in the
retrotrapezoid nucleus (RTN) as described for the rat
(753), may render a clear separation of central and pe-
ripheral contributions elusive. In addition, a subset of CO2
chemoreceptors in the RTN receives an inhibitory input
from (mainly slowly adapting) pulmonary stretch recep-
tors (525), providing another complicating factor in the
interpretation of data from intact as well as vagotomized
animals.
E. Carotid Body Resection and the HVR
Resection of the human carotid bodies was per-
formed for a variety of reasons. Both unilateral and bilat-
eral resections were carried out in patients with severe
bronchial asthma and chronic obstructive pulmonary dis-
ease. Although the main goal for resection in these pa-
tients was often achieved (that is, the alleviation of
breathlessness), the therapy is controversial and cur-
rently not practiced on a wide scale (326, 475, 812). An-
other reason for carotid body resection is the develop-
may arise from genetic defects (see sect. IV) and from
chronic hypoxemia related to cyanotic heart disease, pul-
monary disease, and high altitude (154, 312). Inadvertent
loss of carotid body function may arise from surgical
procedures in the neck region, such as carotid endarteri-
ectomy and neck dissection as part of the treatment of
head and neck cancer (524, 812).
Both animal and human studies show immediate hy-
poventilation, respiratory acidosis, and loss of the hyp-
oxic drive in response to bilateral carotid body resection
(Fig. 5; Refs. 154, 473, 474, 492, 570, 664). In a small
human population tested before and after bilateral re-
moval of the carotid bodies for tumors due to a mutation
in the SDHD gene, end-tidal PCO2 increased by ⬎8 Torr
within the first day after resection (154). Similar observa-
tions were made in awake rats over a 75-day period after
carotid body excision (570). These data indicate that the
carotid bodies are essential in maintaining normal venti-
lation during air breathing. Especially in the neonatal
period, elimination of the carotid bodies can have pro-
found effects on the control of breathing, depending on
the denervation technique used and the developmental
period in which it is performed (238 and references cited
therein). Partial restoration of the hypoxic drive is ob-
served in some species (rat, goat, cat, pony, piglet) and is
most likely in neonatal animals (69, 473, 474, 492, 710).
The rate of recovery is species dependent and ranges
from weeks (piglet, rat) to months (goat) to years (pony).
The compensatory mechanisms of the partial recovery of
the hypoxic drive in these animal studies remain un-
known. Potential mechanisms include reinforcement of
aortic bodies, activation of medullary oxygen-sensing
neurons, chemosensory input from secondary glomus tis-
sue in the head/neck region (such as the vagal body in the

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
neck), regeneration of sensory terminals of the sinus
nerve, and/or plastic changes in the central respiratory
neuronal network. In humans, we were unable to observe
any recovery in the HVR over a period of 4 years after
bilateral removal of the carotid bodies (154). Similar ob-
servations were reported by Wade et al. (812) in patients
up to 8 years postsurgery. Honda et al. (326) did show
some restoration of the HVR in patients two decades after
bilateral carotid body resection, although this effect was
dependent on the specific hypoxic test employed.
F. Chronic Hypoxia and the HVR
1. Ventilatory acclimatization to chronic hypoxia
We define chronic hypoxia as exposure to hypoxia or
high altitude lasting several hours to days, weeks, or
months. A hallmark of adaptation to high altitude is a
gradual rise in ventilation with a time course depending
on the altitude (ventilatory adaptation to high altitude,
VAH). In humans, at very high altitudes (8,000 m and
higher), this may take at least 30 days (839). At less
extreme altitudes, complete VAH requires ⬃10 days (see
Ref. 68 and references cited therein), although at 3,800 m
ventilation appeared not to have reached a plateau yet
after 12 days (683). Dogs, goats, and ponies acclimatize
much faster and reach complete adaptation after 3, 4 – 6,
and 30 h, respectively (references in Ref. 68). When ex-
posed to a simulated altitude of ⬃4,600 m, cats show a
large decrease in arterial PCO2 after 48 h (809), but accli-
matization may not yet be complete after this period in
this species since at 5,500 m arterial PCO2 continued to fall
for 10 –12 days (774). Qualitatively, in the rat, VAH is
rather similar to that in humans albeit with a somewhat
faster time course, and this species is considered an
adequate animal model for the adaptation in humans
(569).
Initially it was suggested that VAH could be attrib-
uted to changes in arterial and later to brain stem acid-
base status, but eventually it became clear that alterations
in acid-base status during VAH should be considered the
consequence of ventilatory changes rather than the cause
(178). Here we do not focus on studies aimed at elucidat-
ing the role of the central chemoreceptors in VAH, and the
reader is referred to excellent reviews on this subject (68,
540, 543). Briefly, there is no conclusive evidence for an
essential role of the central chemoreceptors, for example,
because the time courses of medullary extracellular fluid
pH and VAH do not run in parallel (534, 543). Future
studies are warranted, however, to unmask a possible
role of central chemoreceptors in VAH for a reason not
anticipated before: during hypoxia in the rat, central
chemoreceptors in the retrotrapezoid nucleus are
strongly activated via a glutamatergic pathway from
carotid body projection areas in the NTS (753). Thus,
Physiol Rev • VOL
711
during chronic hypoxia, these neurons may receive a
time-dependent progressively increasing synaptic input
that may overcome inhibitory influences of a lower
PCO2 and may thus contribute to VAH.
2. VAH is associated with an increase of the HVR
Studies in the last two decades have convincingly
shown that VAH is associated with a time-dependent aug-
mentation of the HVR that at least partly is due to an
increased carotid body sensitivity. Initial studies in dogs,
ponies, goats, and rats had already demonstrated that
carotid body denervation abolished or at least minimized
VAH (reviewed in Ref. 68). Below we summarize the most
important studies in goats, cats, rats, and humans show-
ing the crucial role of both the carotid bodies and the CNS
in mediating an increase in the HVR in chronic hypoxia.
1. Animal studies
In goats (mainly awake) with vascularly isolated ca-
rotid bodies, Bisgard, Forster, and co-workers collected
many data on the mechanism of VAH that can be summa-
rized as follows (66, 67, 105, 200, 216, 546, 836; further
references in Ref. 68). 1) Animals exposed to chronic
hypoxia show complete VAH within 4 – 6 h. 2) Isolated
CNS hypoxia and/or hypocapnia do not evoke VAH, indi-
cating that it must have a peripheral origin. 3) VAH re-
quires intact carotid bodies that are perfused by hypox-
emic blood; isolated carotid body hypercapnia results in a
rapid sustained rise in ventilation but does not induce the
time-dependent fall in arterial PCO2 typical for VAH.
4) Both chronic poikilocapnic and isocapnic carotid body
hypoxias increase the isocapnic acute hypoxic response
(AHR), indicating that the enhanced sensitivity develops
regardless of the PCO2 at the carotid bodies. 5) During
isocapnic carotid body hypoxia for 6 h, carotid sinus
nerve afferents of anesthetized goats show a progressive,
time-dependent increase in impulse frequency that quantita-
tively can account for VAH.
When exposed to a barometric pressure of 460 – 440
Torr for 2–3 days, cats demonstrated a large time-depen-
dent drop in end-tidal CO2, increases in both the HVR, and
afferent carotid sinus nerve activity as well as an aug-
mented isocapnic carotid body sensitivity to hypoxia
(771, 808). Animals exposed to 10% O2 exhibited a higher
isocapnic carotid sinus nerve sensitivity to hypoxia after
21 days but not during the initial few hours (34). In
animals kept at a constant end-tidal O2 of 30 Torr for 7 h,
nerve activity started to increase after 3 h (181). However,
Lahiri et al. (428) were unable to demonstrate an increase
in afferent nerve sensitivity to hypoxia after acclimatiza-
tion to 10% O2 for 21–24 days. Finally, Tatsumi et al. (768),
after keeping cats at 375 Torr for 3– 4 wk, reported a
time-dependent decrease in end-tidal CO2 along with a
decreased HVR and isocapnic hypoxic carotid sinus nerve
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712 LUC J. TEPPEMA AND ALBERT DAHAN
sensitivity. An altitude-dependent decrease in HVR along
with VAH had already been reported in earlier studies
(e.g., Ref. 774; further references in Ref. 68). Thus, after a
few days of hypoxia, cats appear to have an augmented
HVR and an increased carotid body sensitivity, but after
more than 2–3 wk, they show both a blunted HVR and
carotid body sensitivity. So, perhaps an increase in ca-
rotid body sensitivity is sufficient for VAH in the first few
days, but other mechanisms manifest after 2–3 wk.
The rat develops an augmented poikilocapnic HVR
and ventilation in the initial few days of chronic hypoxia
followed by a gradual return of the HVR to control or even
slightly below at the end of the first week (51, 91, 252,
811). However, a fast “blunting” of the HVR in the rat has
not been demonstrated very convincingly, for example,
because in all these studies, it was measured under
poikilocapnic conditions. Rather, it may be a manifesta-
tion of a gradual attenuation of acclimatization as also
occurs in other species, but without blunting of the HVR
(68). Aaron and Powell (1) showed a clear increase in
isocapnic HVR in rats after 7 wk at 380 Torr. Note that
after acclimatization this enhanced HVR was measured
at a constant arterial PCO2 that was lower than in control
by as much as 6 – 8 Torr, whilst both control and acclima-
tized animals showed a positive O2-CO2 interaction (1).
These authors also compared isocapnic HVRs of acclima-
tized animals with that of controls that were made slightly
hypercapnic to achieve matching of minute ventilation
(613). In control animals, the constant arterial PCO2 was
kept at a level that was higher than in acclimatized ani-
mals by ⬃9 Torr, but despite this, the HVR in the latter
was much higher, suggesting that either the carotid bod-
ies had undergone an impressive increase in O2 sensitivity
and/or that the translation of afferent carotid body activ-
ity into ventilatory output (CNS gain) was greatly facili-
tated. It would be interesting to compare HVRs at equal
hypercapnic PCO2 levels in control and acclimatized rats,
because it cannot be excluded that a negative O2-CO2
interaction (145, 172) may have played a role in the ob-
servations of Powell et al. (613).
Dwinell and Powell (201) found a large increase in
the CNS gain of a standard electrical input from the
carotid sinus nerve in acclimatized rats (380 Torr, 1 wk).
However, cats exposed to 440 Torr for 48 h developed
both a greater isocapnic HVR and hypoxic carotid sinus
nerve response but did not show an increased CNS gain
(808). In goats, the effect of NaCN (assumed to cause
maximal carotid body stimulation) on ventilation was not
different before and after 4 h of isocapnic or poikilocap-
nic hypoxia (215), but this does not preclude changes in
CNS gain during prolonged hypoxia in this species (615).
Thus, in the rat, the most frequently used animal model to
study VAH, an increased central gain has clearly been
demonstrated, while it cannot be excluded to exist also in
humans, goats, and ponies (references in Refs. 178, 615).
Physiol Rev • VOL
2. Studies in humans
In Table 3, we have collected studies mainly per-
formed over the last 15 years (for a review of earlier
studies, see Ref. 68). Despite all the distinct exposure
paradigms (stimulus level and duration, hypobaric hyp-
oxia, or just lowered inspired O2), techniques and analysis
methods that make quantitative comparisons very diffi-
cult if not impossible, the outcomes of all these studies
have two things in common: an increase in resting and, if
measured, hyperoxic ventilation and an augmented (acute)
hypoxic ventilatory response that develops during the
first 4 – 8 h of acclimatization.
Robbins (659) made considerable efforts to spell out
the mechanisms of ventilatory adaptation to chronic hyp-
oxia. Apart from a consistent increase in hyperoxic ven-
tilation and an augmented acute response to hypoxia, he
found the following: 1) in agreement with results obtained
from goats, isocapnic and poikilocapnic hypoxias have
the same effect. 2) Neither eucapnic nor hypocapnic pas-
sive hyperventilation evokes VAH or an enhanced HVR,
indicating that hypocapnia or hyperpnea per se will not
play a significant role. 3) The effect of hypoxia to induce
the adaptations is due to the low PO2 rather than to low
oxygen content. 4) The mechanism underlying the in-
crease in the acute response to hypoxia is fast (observ-
able within a few hours as in goats), sensitive (end-tidal
O2 10 Torr below resting is sufficient to evoke it), inde-
pendent of peripheral adrenergic and dopaminergic sys-
tems, and insensitive to general autonomic blockade (ref-
erences in Table 3).
Chronic isocapnic and poikilocapnic hypoxia also
alter peripheral ventilatory CO2 sensitivity. Using dy-
namic end-tidal forcing (see sect. VI) and sophisticated
analysis methods, Fatemian and Robbins showed an in-
crease in CO2 sensitivity that most likely can be attributed
to an increase in sensitivity of the carotid bodies (e.g.,
Refs. 228, 229; further references in Table 3). In a study at
4,300 m (629), the amount of VAH correlated well with the
magnitude of the HVR at sea level, also supporting an
important role of the peripheral chemoreflex loop.
In a more recent study, Herigstad et al. (320) exposed
subjects to 8 h of isocapnic hypoxia prior to an incremen-
tal exercise protocol. The exposure resulted in a decrease
in end-tidal PCO2 that was essentially maintained at all
work loads until exhaustion. According to the alveolar
ventilation equation, this means that ventilation must
have increased in proportion to metabolism. The data
from this study also implied that an altered acid-base
balance (isocapnia was maintained) or long-lasting in-
creases in ventilation (days) are not required for this
phenomenon to occur. Thus VAH augments the ventila-
tory response to exercise and in this sense resembles the
effect of hypoxia or carotid body stimulants (references
in Ref. 320). Exercise also augments the stimulatory effect
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 713

TABLE 3. Carotid body adaptations to chronic hypoxia

Does the Adaptation Increase or

Species Effects and Comments Decrease CB Sensitivity or the HVR? Reference Nos.

Neurochemical adaptations
Dopaminergic system
Rat Upregulation of TH 65, 614 and references
cited therein
Cat TH upregulation 820
Cat CH augments HVR after 2 days at 4,600 m Increase 771
but domperidone fails to further
increase it, suggesting dopaminergic
downregulation
Cat Prolonged hypoxia decreases HVR; Decrease 770
domperidone restores it to control
level, suggesting a role of DA
upregulation in long-term adaptation
Cat Dopaminergic system in efferent Decrease 429
inhibitory fibers in the CSN is
upregulated not supporting disinhibition
of this system in CH
Rat After 5 and 2–3 wk of CH, domperidone Decrease 252, 811
restored “blunted” poikilocapnic HVR,
attributed to increased CB DA content
Rat 1–2 days of CH attenuate dopaminergic Increase and decrease, 51, 342
inhibition of the HVR, but after 8 days respectively
it has increased compared to control
Rat CB D2R decreased by 59% after 2 days of Increase and decrease, 344
CH, but increased by 274 % after ⬃11 respectively
days
Rabbit After 2 days of CH, CB 关DA兴 decreased, ? 343
but 2 days after termination of an 8-day
lasting exposure it was higher than
control
Mice Male D2R⫺/⫺ mice failed to show VAH Increase, but note possible 343
and augmented HVR after 2–8 days of central effects
CH
Rat Type I cells of juvenile rats show ? 355
exaggerated basal DA release
Goat The peripheral DA antagonist Neither 358, 359
domperidone had equal effects in
acclimatized and control animals, and
local CB application of DA did not
influence the time course and
magnitude of VAH
Human Effects of DA and domperidone did not Neither 590
change after 8 h of CH
Norepinephrine
Cat CH for 24–36 h reduced the inhibitory Increase 110
effect of ␣2-adrenergic antagonism,
suggesting downregulation of CB
noradrenergic mechanisms
Various Upregulation of CB NE Decrease References in 65, 278, 818
species
Goat CB sympathectomy did not alter the time Neither 672
course of VAH, the acute HVR and the
inhibitory effects of NE and DA
Human VAH and CH-induced augmentation of the Neither 134, 452, 520
HVR are not affected by ␤-adrenergic
and autonomic ganglion blockade
Acetylcholine
Rat In CB preps from animals exposed to CH Increase 309
for 9–22 days, ACh had a larger
excitatory effect on CSN discharge
compared with control; however, the
nAChR antagonist mecamylamine failed
to cause any reduction in hypoxia-
induced increase in CSN activity

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714 LUC J. TEPPEMA AND ALBERT DAHAN

TABLE 3. —Continued

Does the Adaptation Increase or

Species Effects and Comments Decrease CB Sensitivity or the HVR? Reference Nos.

Rat In type I cells cultured in normoxia Increase 355

mecamylamine did not alter basal DA
release, but in those cultured in hypoxia
for ⬃12 days it completely inhibited it,
possibly explaining its failure to inhibit the
hypoxia-induced rise in the preparation of
He et al. (309)
ATP
Rat In superfused CB preps from rats exposed to Increase 307
CH for 9–16 days, P2X2 purinergic but not
nicotinic antagonists retained the ability to
block hypoxia-induced rise in CSN activity,
suggesting an altered purinerg/cholinergic
balance; afterdischarge in CSN from
acclimatized animals was blocked by
purinergic blockers suggesting prolonged
ATP release as its cause and hypothetically
providing a mechanism for continuous
hyperventilation upon return to normoxia
from high altitude (deacclimatization)
Nitric oxide
Rat Upregulated in hypoxia Decrease 65, 865 for review
Rat In CB-CSN preps from rats exposed to CH Decrease 308
for ⱕ16 days, L-NAME caused a
progressively greater stimulation and an
NO donor a larger inhibition
Substance P
Cat CB Substance P downregulated in animals Decrease 820
exposed to 10% O2 for 2 wk
Endothelin-1
Rat Upregulation of ET1, and ETA receptors in Increase 128
type I cells from animals exposed to CH
for ⱕ16 days. Selective inhibition of ETA
receptors reduced basal CSN activity on
day 0 by 11%, but halved it at day 16
Rat During CH for 16 days, daily administration Increase 129
of the ETA/B antagonist bosentan
diminished the increase in hypoxic CSN
activity and also greatly reduced CB
enlargement and mitotic type I cell activity
Human CH for 4 h increased plasma 关ET-1兴; Increase, assuming a stimulatory 755
continuous infusion of ET-1 during a 4 h effect of ET-1 on the CB
bout of CH exaggerated the increase in
HVR
Angiotensin II
Rat 10% O2 for 4 wk progressively increased CB Increase 431, 432, 443
angiotensinogen mRNA, upregulated AT1
receptors and ACE, and increased CB
sensitivity to ANG II
Proinflammatory
cytokines
Rat Upregulation of IL-1, IL-6, and TNF-␣ and Increase 433
their receptors in type I cells from rat
exposed to 10% O2 for 3, 7 and 28 days;
after CH, the hypoxia-induced rise in
关Ca2⫹兴i was enhanced by the cytokines
Rat Rats exposed to a barometric pressure of 380 Increase 455
Torr for 4 wk showed increased CB 关IL-1␤兴
and 关TNF-␣兴 after 1 day, well before
macrophage invasion; cytokine levels
normalized after 28 days, except IL-6 due
to increased production by the CB;
ibuprofen and dexamethasone inhibited
CH-induced increase in hypoxic CSN
activity

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 715

TABLE 3. —Continued

Does the Adaptation Increase or

Species Effects and Comments Decrease CB Sensitivity or the HVR? Reference Nos.

Melatonin
Rat Exposing rats to 10% O2 for 4 wk Increase 785
increased CB melatonin receptor mRNA
Adaptations of ion channels and membrane currents
Maxi-K channels Rat Decrease in K⫹ current density but not Increase 114
that caused by maxi-K channels,
proposed to result in a relative larger
contribution of the latter to the resting
membrane potential and an increased
hypoxia-induced catecholamine release
Sodium current Rat Higher current density in type I cell Increase 726, 727
isolated from 5- to 12-day-old rat and
cultured in hypoxia for 1–2 wk
“Oxygen-sensitive Rabbit In type I cells cultured in hypoxia for Increase 368
and -insensitive” Kv 72 h, potassium channels responsible
channels for an O2-insensitive component of the
K⫹ current were downregulated and
those contributing to the O2 sensitive
component upregulated; thus K⫹
current inhibition by hypoxia was
increased
Sodium channel Rat CB from animals exposed to 10-11% O2 Increase 106
Nav1.1 for 1 wk contained type I cells with
upregulated voltage-gated sodium
(Nav1.1) channels; the sodium channel
activator veratridine caused a
severalfold greater increase in CA
release in these cells, compared with
those from control animals
Gap junctions Rat Exposure to an ambient pressure of 380 Increase? 127
Torr was followed by increased
expression of the gap junctional protein
connexin43 in type I cells and petrosal
ganglion neurons
Morphologic adaptions of the carotid body
Various Organisms living at high altitude have Increased in short-term CH but 19, 209, 419, 818
species enlarged CB decreased in prolonged
hypoxia
Rat CH induces vascular remodeling, Unknown 135, 419, 420, 784, 818
endothelial proliferation, and
vasodilation
Rat Hyperplasia of type I cells during the first Increase 818, 819
week of CH, no further increase
thereafter; newly formed cells can
survive for 1 mo
Mice Exposing mice to CH for 20 days resulted Increase 581
in cell division in CB after 1 day, but
new type I cells appeared after 5 days.
Initially type II cells start to divide and
are replaced by “progenitor,” i.e., stem
cells that differentiate into type I cells
with normal electrophysiological
features. Upon return to normoxia, 50%
of the type I cells are freshly formed
and the total amount gradually returns
to normal

ACh, acetylcholine; ACE, angiotensin converting enzyme; ANG II, angiotensin II; AT1 receptor, angiotensin I receptor; CH, chronic hypoxia;
CA, catecholamine; CSN, carotid sinus nerve; CB, carotid body; DA, dopamine; D2R, dopamine 2 receptor; ET, endothelin; L-NAME, NG-nitro-L-
arginine methyl ester, an inhibitor of NO synthase; HVR, hypoxic ventilatory response; IL, interleukin; NE, norepinephrine; nAchR; nicotinic
acetylcholine receptor; NO, nitric oxide; TH, tyrosine hydroxylase; TNF, tumor necrosis factor; VAH ventilatory adaptation to chronic hypoxia or
high altitude.

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716 LUC J. TEPPEMA AND ALBERT DAHAN
of hypoxia on ventilation, but this interaction is reduced
by a prior exposure to chronic hypoxia, and this phenom-
enon will be one of the determinants of the magnitude of
the HVR at high altitude (848).
A decrease in intercept of the hyperoxic CO2 re-
sponse curve was not observed by Fatemian and Robbins
(228, 229), suggesting that the increase in resting and
hyperoxic ventilation is due to a higher (peripheral) CO2
sensitivity. In one study, a leftward shift of the ventilatory
CO2 response curve was found after as long as 75 h of
poikilocapnic but not isocapnic hypoxia (148). Studying
the effect of chronic hypoxia with modified rebreathing
(see sect. VI) yields a decrease in intercept of both the
hypoxic and hyperoxic CO2 response curves at high alti-
tude, but, possibly related to variation in altitude and
acclimatization period, no consistent increase in periph-
eral CO2 sensitivity (9, 719).
Two major mechanisms, to be discussed in the fol-
lowing paragraphs, may contribute to the augmented HVR
in chronic hypoxia: an augmented carotid body sensitivity
and, as particularly studied in the rat, an increase in CNS
gain. Animal studies do not provide direct evidence for an
important role of the sympathetic nervous system (e.g.,
Ref. 672). In humans, prolonged hypoxia causes a large
increase in sympathetic activity, but how this may influ-
ence the HVR is unknown (107, 300). Also, note that the
chronic hypoxia-induced HVR augmentation in humans
was reported to be unaltered after autonomic ganglion
blockade (452). Neonates and adults adapt differently to
chronic hypoxia. This is schematically shown in Figure 9.
3. Chronic hypoxia increases carotid body sensitivity
Chronic hypoxia elicits morphological, neurochemi-
cal, and membrane-electrophysiological adaptations in
. .
VI VI
FIG. 9. Comparison of chronic hypoxia in neonates and adults.
Effects of chronic hypoxia in neonates, within the critical time window
for developmental respiratory plasticity, compared with those in adults.
Question marks concern unresolved or controversial issues. V̇I, inspired
ventilation. For explanations see text.
Physiol Rev • VOL 90 • APRIL 2010 •
the carotid bodies that act together to increase hypoxic
sensitivity. These adaptations occur in parallel, so their
separate contribution to the increase in carotid body gain
is difficult to assess. This is especially true for the contri-
bution of neurotransmitters and/or modulators, some of
which have a controversial role in the carotid bodies. For
example, the dopaminergic system seems to be upregu-
lated in chronic hypoxia, but although dopamine is gen-
erally considered an inhibitory neurotransmitter (mainly
based on observations on the effects of exogenous ap-
plied agonists and antagonists), the significance of this
adaptation is uncertain because endogenous dopamine
may well have excitatory effects on the carotid bodies
(for a discussion on the controversial role of dopamine in
the carotid body, see Refs. 278, 283, 869). Both an inhib-
itory and excitatory role has also been suggested for
norepinephrine (references in Refs. 68, 278). In Table 4,
we have summarized recent studies on various adapta-
tions of the carotid bodies to chronic hypoxia. We have
added a column containing the suggested effects of single
adaptations on carotid body sensitivity, but we emphasize
that with regard to neurotransmitters these must be con-
sidered hypothetical, because what eventually matters is
the total balance between excitatory and inhibitory trans-
mitters. In a recent review, Prabhakar (621) has proposed
the simultaneous presence of excitatory and inhibitory
transmitters to result in a “push-pull” mechanism between
both that, rather than causing exhaustion in the absence
of inhibitors, produces sustained activation in their pres-
ence. This would be especially effective in the adaptation
chronic hypoxia (621).
4. Increase of CNS gain during chronic hypoxia
An increased CNS gain as observed in the rat could
result from neuroplasticity of the brain stem respiratory
circuitry that processes the afferent input from the carotid
bodies. Below we discuss some mechanisms potentially un-
derlying the increase in CNS gain in chronic hypoxia.
A) CATECHOLAMINERGIC SYSTEM. Rats challenged with 10%
O2 for 1 wk showed a reduced brain dopamine turnover
and an increased carotid body dopamine content (571). In
rats exposed to chronic hypoxia for 2 wk, Schmitt et al.
(685) found a positive correlation between the rise in
ventilation and tyrosine hydroxylase (TH) protein level in
the caudal NTS, i.e., the preferential projection area of
chemoafferent fibers. The same area, containing the A2
noradrenergic cell group, displayed an upregulation of TH
after 1 wk of chronic hypoxia, but this effect was reversed
after 2 and 3 wk of exposure, respectively (722). When
administered in the NTS, dopamine has a stimulatory
influence on ventilation (for references, see Ref. 345), and
thus an increased tyrosine hydroxylase production may
facilitate respiratory output in chronic hypoxia. In male
normoxic mice systemic droperidol, a dopamine antago-
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
TABLE 4. Chronic hypoxia in humans
Protocol
Operation Everest II: subjects
acclimatized to 428 and 305 Torr
Exposure to PB 447 Torr for 7 days
Stay at 4,300 m for 19 days
pH: 5 days at 3,810 m
pH: 12 days at 3,810 m
pH: 1 and 2 days at 5,050 m
iH or pH (PETO2 55 Torr) during 8 h
iH or pH (PETO2 55 Torr) during 8 h
iH or pH (PETO2 55 Torr) during 8 h
iH or pH (PETO2 60 Torr) during 48 h
iH or pH (PETO2 55 Torr) during 8 h
Normobaric iH or pH (PETO2 55 Torr)
during 8 h
8 h of normobaric iH without drug,
with dopamine and with
domperidone, respectively
iH (PETO2 50 Torr) for 8 h with and
without propranolol
Decreasing CaO2 for 8 h with lowered
isocapnic PETO2 of 55 Torr,
phlebotomy (500 ml) or 10% COHb
6 h of hypocapnic (PETCO2 ⫺10 Torr)
or eucapnic hyperventilation
pH or poikilocapnic hyperoxia, for 5
days, respectively by maintaining
PETO2 10 Torr below or above
resting
HVR Measurement
Progressive isocapnic rebreathing at
PETCO2 of ambient air breathing
Progressive isocapnic rebreathing at
a PETCO2 of ambient air breathing
Progressive isocapnic rebreathing at
sea level only; serial ventilation
and gas measurements from day 1
to 19
Stepwise decreases in SpO2 to 77%.
PETCO2 at hyperoxic value with
V̇I ⫽140 ml 䡠 min⫺1 䡠 kg⫺1
Modified rebreathing; PETCO2 at
hyperoxic value with V̇I ⫽140
ml 䡠 min⫺1 䡠 kg⫺1
Modified rebreathing; PETCO2 at
about resting value at sea level
HVR not tested
DEF, square-wave and saw-tooth
stimuli; analysis of HVR with first-
order model; PETCO2 1.5 Torr
above initial resting in all tests
Testing the effects of isocapnic step
hyperoxia
Idem
No testing of HVR, testing overall
CO2 sensitivity
No HVR testing, testing effect on
peripheral and central CO2
sensitivity with DEF and model
analysis
DEF, square-wave stimuli, model
analysis; PETCO2 1.5 Torr above
initial resting in all tests
Idem
Idem
Idem
Idem
Physiol Rev • VOL 90 • APRIL 2010 •
717
Reference
Effects on HVR, Comments Nos.
1 iHVR about equal at both pressures. 686
Further elevation upon return to sea
level but note that the test PETCO2
was ⬎10 Torr higher than at the
lowest pressure
1 iHVR 2–4 days after exposure; 273
postacclimatization resting PETCO2,
however, not provided.
Higher HVR at sea level predicts lower 629
PETCO2 during the entire period
Gradual increase of iHVR from 1-5 683
days; test PETCO2 varied between 45
and 33 Torr
HVR doubled after 12 days; at altitude 682
hyperoxic PETCO2 with V̇I ⫽140
ml 䡠 min⫺1 䡠 kg⫺1 decreased by 8-10
Torr
1 iHVR (5- to 7-fold after 1 and 2 348
days, respectively)
Time-dependent rise of V̇I in iH, not pH 338
1 iAHR over 8 h; no difference 337
between protocols, suggesting no
influence of the PCO2; both iH and
pH increased baseline hyperoxic
ventilation and peripheral ventilatory
CO2 sensitivity
Time-dependent rise in hyperoxic 762
ventilation in both protocols that
continued for at least 8 h
postexposure
1 iAHR over this period in both 763
protocols, gradually reversing over
the subsequent recovery period; no
influence of PCO2
Increase in CO2 sensitivity after both 228
protocols; no change in x-intercept
of the CO2 response curve
Overall increase in CO2 sensitivity due 229
to increase in peripheral gain.
Contribution, however, of central
chemoreceptors could not be
excluded. No change in x-intercept
of CO2 response curve
1 iAHR after 8 h; dopamine and 590
domperidone elicited equal effects on
the HVR before and after the iH,
indicating no carotid body
dopaminergic involvement in the
effect of iH
1 iAHR after 8 h uninfluenced by ␤- 134
adrenergic blockade
1 iAHR after low PETO2 only, 640
indicating no role of lower oxygen
content
No change in AHR, suggesting that the 641
increase in AHR during pH and iH
are caused by low PO2 itself;
hypocapnic, but not eucapnic
hyperventilation shifts the hyperoxic
CO2 response curve to the left
1 iAHR after mild hypoxia and 2 192
after mild hyperoxia
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718 LUC J. TEPPEMA AND ALBERT DAHAN

TABLE 4. —Continued

Reference
Protocol HVR Measurement Effects on HVR, Comments Nos.

iH: PETO2 50 Torr, 8 h, followed by iv
infusion of the ganglion blocker
trimethaphan
iH 3 h in NHC at PETO2 ⫽50 Torr
pH during 8 h using a facemask
pH: 8 wk at 3,800 m
pH for 8 h using a facemask
5 days at 3,480 m
pH: 9-day ascent to ⬎5,000 m and
then immediate testing at 3,840 m
Stay at 1,560 m for 12 days
Idem
Isoxic hypoxic and hyperoxic CO2
response curve with modified
rebreathing
Modified rebreathing; PETCO2 at
about resting value
Stepwise decreases in SpO2 to 90
and 80%; PETCO2 ⬃4 Torr above
resting in ambient conditions
Modified rebreathing PETCO2 at about
resting value at sea level
Isoxic hypoxic and hyperoxic CO2
response curve with modified
rebreathing
Isoxic hypoxic and hyperoxic CO2
response curve with modified
rebreathing
Poikilocapnic response to sustained
(20 min) hypoxia (12% O2)
1 iHVR not influenced by autonomic 452
blockade
Decrease in threshold, not sensitivity of 483
the peripheral chemoreflex loop at
the early stages of CH
1 iHVR by 70% but impaired forearm 268
hypoxic vasodilation
1 iHVR already after 48 h, sustained 346
at 8 wk. Generally test PETCO2 about
5–6 Torr lower than at sea level
1 iHVR by ⬎90% 757
Decreases in the x-intercepts of the 719
hyperoxic and hypoxic CO2 response
curves of 12.8 and 9.8 Torr,
respectively, without changes in
slope
Difference in slope between hyperoxic 9
and hypoxic CO2 rebreathing became
larger at high altitude, indicating
increased hypoxic sensitivity
Peak but not sustained poikilocapnic 8
HVR response increased

CaO2, arterial oxygen content; iH, isocapnic hypoxia; pH, poikilocapnic hypoxia; iAHR, isocapnic acute hypoxic response; CH, chronic
hypoxia; iHVR, isocapnic hypoxic ventilatory response; DEF, dynamic end-tidal forcing; NHC, normobaric hypoxic chamber; V̇I, inspired minute
ventilation; PB, barometric pressure; PETCO2, end-tidal PCO2; PETO2, end-tidal PO2; SpO2, arterial hemoglobin oxygen saturation.

nist that penetrates into the brain, increased ventilation,
suggesting a predominance of the inhibitory carotid body
dopaminergic system on respiratory output in normoxia
(572). However, mice kept in 10% O2 for 10 days re-
sponded to droperidol with a decrease in ventilation in-
dicating a dominance of the central excitatory dopami-
nergic system in hypoxia (572). This seems consistent
with data from mice lacking the dopamine D2 receptor
(D2 R⫺/⫺) that failed to show VAH and an augmented HVR
after 8 days of acclimatization, an effect that was not yet
demonstrable after 2 days (343). These studies suggest
that a shift from peripheral to central dopaminergic dom-
inance may contribute to VAH. How this can be recon-
ciled with an increase in carotid body dopamine content
in prolonged hypoxia remains to be seen. Upregulation
during chronic hypoxia of TH and norepinephrine was
also observed in the in the locus coeruleus of rats (684),
but its contribution to VAH is difficult to assess because
this region is the source of a widespread noradrenergic
network in the brain.
B) NMDA RECEPTORS. During hypoxia, glutamatergic
NMDA and non-NMDA receptors in the caudal NTS play a
crucial role in the transmission of afferent impulses from
the carotid body (287, 516, 565, 801 and references
therein). Reeves et al. (634) showed an early upregulation
of the NR1 subunit of the NMDA receptor in the dorsal
caudal brain stem of rats which had resolved after 30 days
of chronic hypoxia. The caudal NTS of rats exposed
to 10% O2 for 7– 8 days contained higher levels of the ␣-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptor subunit glutamate receptor 2 (GluR2), which
was thought to contribute to an enhanced glutamatergic
synaptic transmission of arterial chemoreceptors inputs
into the NTS (873). NMDA receptors in the medulla of
mice were upregulated following exposure to 10% O2
during 2 wk (210; see also sect. VE). In rats exposed to 10%
O2 for 9 days, the NMDA antagonist MK-801 had a larger
inhibitory effect on hypoxic ventilation than in unaccli-
matized controls (638).
C) PDGF-␤ RECEPTORS. Administration of PDGF-BB in
the NTS decreased the early HVR in rats, and mutant mice
heterozygous for the PDGF-␤ receptor showed a reduced
HVD (see also sect. IIID). This led to the suggestion that
that downregulation of PDGF-␤ receptors during chronic
hypoxia might contribute to VAH (287, 289). During 14
days in 10% O2, rats demonstrated a posttranscriptional
downregulation of PDGF-␤ receptor protein in the dorso-
caudal brain stem after 7 days, significantly correlated
with VAH, while the attenuation of the HVR by local
PDGF-BB application in the NTS decreased over time and
actually was absent from day 7 on (14). In addition to
PDGF, other growth factors such as brain-derived neuro-
trophic factor (BDNF), located in petrosal ganglion neu-
rons and possibly acting postsynaptically, could also con-
tribute to plastic changes within the NTS during chronic
hypoxia.

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
D) NO-RELATED MECHANISMS. As discussed in section
IIIC3, NO is an important central mediator of the HVR with
a stimulatory effect on the HVR. Thus upregulation of
neuronal NOS could also enhance CNS gain. Mice ex-
posed to 10% O2 for 2 wk had higher medullary neuronal
NOS levels, which seemed related to VAH but not to the
increased HVR: the former was reduced while the latter
remained unaffected by a specific neuronal NOS inhibitor
(210). Upregulation of neuronal NOS (but not the endo-
thelial isoform) was also shown in peripheral and central
neurons in rats after 12–24 h in hypobaric hypoxia (618).
The hypoxia-induced rise in intracellular NO in the NTS
may be one of the secondary consequences of NMDA
receptor activation (references in Ref. 287). Thus, in the
NTS, a feed-forward mechanism could exist between
NMDA receptor activation and release of NO to enhance
the CNS gain (562). The above-cited work by El-Hasnaoui
et al. (210) does not directly support this hypothesis. Rats
exposed to 12% O2 for 2 wk and receiving a continuous
intracerebroventricular infusion of the NOS inhibitor
L-NAME showed a lower normoxic ventilation than con-
trols after this period, indicating a reduced VAH. How-
ever, their HVR was indistinguishable from that in accli-
matized controls not receiving the enzyme inhibitor (688).
These scarce data raise the impression that upregulated
NO in the medulla may contribute to VAH but not to the
increase in HVR.
E) ERYTHROPOIETIN. Mice overexpressing human eryth-
ropoietin (Epo) in the brain without elevation of plasma
Epo and hematocrit (Tg21 mice) were reported to show
larger increases in ventilation and HVR in chronic hyp-
oxia, even after carotid sinus nerve section (716). Female
(but not male) mice with increased peripheral and central
Epo expression (Tg6 mice) were reported to have an
augmented HVR (717). However, another study in Tg6
mice (sex not mentioned) reported no difference in HVR
compared with wild types; after acclimatization, VAH and
an augmented HVR were clearly present in wild types but
totally absent in the Tg6 genotype, and this was suggested
to be related to upregulated carotid body dopaminergic
mechanisms (804). Finally, infusion into the brain of the
soluble Epo receptor, that normally is downregulated in
chronic hypoxia thus increasing Epo bioavailability, re-
versed VAH in normal mice (715).
F) CENTRAL OXYGEN-SENSING NEURONS. In the initial phase
of VAH (10% O2 for 4 –5 days), O2-sensitive cells in the
RVLM displayed an increased O2 sensitivity in vitro that in
later stages (9 –10 days) of acclimatization was offset,
possibly due to an altered neurotransmitter balance or
other processes decreasing membrane excitability (554).
In both normoxia and hypoxia, the C1 region and the
pre-Bötzinger complex show a constitutive expression of
HO-2 (501). Placing rats in 10% O2 for 10 days induced
HO-1 but not HO-2 in the ventral medulla. At this stage,
however, the significance of this observation is unclear
Physiol Rev • VOL
719
since the role of the former isoform in O2 sensing by
central neurons is unknown (501), whereas in unacclima-
tized condition, the isoform HO-2 seems to be required for
oxygen sensing in neurons of the pre-Bötzinger and C1
regions (153). These scarce data could suggest a contri-
bution of central oxygen sensors to the increased CNS
gain in chronic hypoxia. Isolated central hypoxia, how-
ever, does not lead to VAH in the goat (836).
G) EXPRESSION PROFILE OF ION CHANNELS IN THE NTS. Neu-
rons in slice preparations from rat containing NTS neu-
rons receiving monosynaptic input from the carotid bod-
ies respond to hypoxia with an outward potassium cur-
rent via activation of KATP channels (i.e., ATP-sensitive
potassium channels that close in the presence of high ATP
concentrations; Ref. 872). In slices from rats exposed to
10% O2 for 1 wk, this current was reduced, and this was
possibly caused by an alteration of the expression profile
of regulatory subunits of these channels. This then may
have increased both the excitability of these neurons and
CNS gain (872).
H) PLASTICITY-INDEPENDENT MECHANISMS TO INCREASE THE CNS
GAIN. The brain contains high concentrations of O2-sensi-
tive (human tandem P domain) TREK-1 potassium chan-
nels, predominantly in GABAergic inhibitory interneu-
rons, that play a key role in setting the resting membrane
potential (references in Ref. 511). In human embryonic
kidney (HEK-293) cells, these background K⫹ channels
are inhibited by low PO2, in a range relevant for brain
tissue and also, in an additive way, by intracellular alka-
losis (511). Inhibition of these channels in GABAergic
inhibitory interneurons by mild alkalosis might then be of
physiological significance especially at the background of
hypoxia-induced alkalosis (511). In the rat, an additional
way of increasing CNS gain could exist in a negative
peripheral-central interaction (145, 172, 613; see sect. VD).
The time-dependent fall in PCO2 in the early acclimatiza-
tion phase could augment the central response to carotid
body hypoxia, thus increasing ventilation and the HVR.
Isocapnia should then be expected to decrease the mag-
nitude of these adaptations, but this has not been system-
atically investigated in the rat.
Many of the above modulations and adaptations in
both the carotid bodies and CNS are undoubtedly the
consequence of altered gene expression induced by
HIF-1. Rats exposed to chronic hypoxia (0.5 atm, 3 wk)
displayed accumulation of HIF-1␣ in neurons, astrocytes,
ependymal cells, as well as endothelial cells and also
showed upregulation of genes with hypoxia-responsive
elements (126). HIF-1␣⫹/⫺ mice lack an increase in ca-
rotid sinus nerve activity in response to hypoxia (not to
NaCN) but increase their ventilation, which is initiated by
the aortic bodies. Ventilatory adaptation to a 3-day bout of
hypoxia does not occur in these animals (388). Chronic
hypoxia induces carotid body expression of both HIF-1␣,
HIF-2␣, and HIF-3␣, which all contribute to morphologi-
90 • APRIL 2010 • www.prv.org
720 LUC J. TEPPEMA AND ALBERT DAHAN
cal and neurochemical adaptations (434, 584, 614, 784 for
further references). Humans with an impaired degrada-
tion rate of HIF-1␣ in normoxia (Chuvash polycythemia;
see sect. IV) have an exaggerated acute HVR and low
resting PCO2 much similar to VAH (712). The contribution
of HIF-1 in both the carotid bodies and the CNS to VAH is
recently reviewed by Powell and Fu (614).
Other transcription factors also are involved. For
example, a role of activator protein-1 (AP-1) is indicated
by the finding that mice lacking the fosB gene (a member
of the fos family of immediate early genes), although
having a normal HVR when kept in normoxia, do not
exhibit VAH and an increase in HVR when exposed to
chronic hypoxia (486).
Chronic hypoxia may also recruit additional oxygen
sensing mechanisms that are silent in a normoxic condi-
tion.
G. Chronic Intermittent Hypoxia and the HVR
1. Episodic hypoxia induces phrenic and
ventilatory LTF
In awake rats, dogs, and goats, the termination of
episodic hypoxia, for example, a challenge with repeated
hypoxia of short duration (mostly 1–5 min) interrupted by
short periods of reoxygenation, is followed by a pro-
longed increase in ventilatory motor output, a phenome-
non that is known as LTF (112, 506, 568, 792). Sustained
hypoxia of short duration does not evoke the phenome-
non (27). At the level of phrenic and hypoglossal motor
outputs, LTF can be evoked by intermittent electrical
stimulation of the carotid sinus nerve and/or continuous
stimulation of medullary raphe obscurus neurons in anes-
thetized, (mostly) vagotomized animals (244, 305, 495,
512, 513) or by repetitive hypoxia (23, 245, 387, 504). LTF
requires an intact serotonergic system with neurons in
medullary raphe nuclei playing a crucial role (23, 506,
514).
We briefly summarize the main underlying mecha-
nisms of phrenic LTF as far as they may also be relevant
for (plastic changes of) the HVR in chronic intermittent
hypoxia (references in Refs. 230, 447, 480, 481). During
episodic hypoxia, raphe serotonergic neurons in the me-
dulla are activated resulting in serotonin release in the
vicinity of brain stem respiratory neurons and spinal mo-
toneurons. Each hypoxic episode triggers a release of
5-HT. One of the downstream cascades then activates
several protein kinases that may phosphorylate glutamate
receptor proteins, thus increasing synaptic strength by
enhancing NMDA receptor currents. Some phosphates,
on the other hand, may lay a constraint on LTF (refer-
ences in Ref. 481). A key role in LTF is played by BDNF.
During episodic hypoxia, the synthesis of this neurotro-
phin in the spinal cord increases; application of BDNF in
Physiol Rev • VOL
the spinal cord of rats is sufficient to evoke LTF. In
addition, when BDNF translation and new protein synthe-
sis is prevented, episodic hypoxia does not induce LTF
(28). BDNF is thought to act through the tyrosine kinase
B receptor which then can lead to the facilitation of
glutamatergic transmission via several pathways (28). Ki-
nases and phosphatases relevant for LTF are sensitive to
ROS, explaining the inhibitory effects of antioxidants on
LTF. An important source of ROS in various cell types
(e.g., motoneurons and carotid body cells) is NADPH
oxidase. Depending on the cell type, this enzyme can be
activated in hypoxia, upon reoxygenation as well as via
membrane-bound receptors such as 5-HT2A receptors.
Phrenic LTF can be inhibited by serotonin receptor block-
ers, antioxidants, and inhibitors of NADPH oxidase, re-
spectively (480, 481). Finally, repetitive spinal injections
of 5-HT induce phrenic LTF, even without hypoxia. So the
working model of episodic hypoxia-induced phrenic LTF
is that it is mediated by a release of serotonin, the acti-
vation of NADPH oxidase, and increased production of
BDNF and ROS with facilitation of glutamatergic synaptic
transmission in the phrenic motor nucleus as the eventual
result (27, 28, 230, 447, 480, 481 and references cited
therein). In both artificially ventilated and spontaneously
breathing rats, LTF is substantially reduced by NMDA
antagonists injected in the phrenic motor nucleus (447).
2. Chronic intermittent hypoxia augments LTF,
sensitizes the carotid bodies in animals, and
increases the HVR
Following three 5-min episodes of isocapnic hypoxia,
the phrenic neurogram of rats showed a somewhat in-
creased baseline amplitude that further increased over
time to become significantly greater than the prestimulus
amplitude after 30 and 60 min, respectively, indicating
LTF (448). Exposing rats to chronic continuous alterna-
tions of 5 min of hypoxia (11–12% O2) and 5 min of air for
12 h/night for 7 days, i.e., chronic intermittent hypoxia,
augmented the acute phrenic response to episodic mild
hypoxia and, via a serotonergic pathway, increased LTF
(448). This suggests that the chronic intermittent hypoxia
had resulted in an augmented carotid body sensitivity to
hypoxia and/or increased CNS gain. Electrical carotid
sinus nerve stimulation now resulted in an enhanced ac-
tivation of the phrenic nerve, indicating an increased CNS
gain (448). In conscious rats, however, not all these find-
ings could be confirmed at the level of minute ventilation
because a similar chronic intermittent hypoxia protocol
induced ventilatory LTF but no increase in the HVR (505,
506). Similar to episodic hypoxia-induced LTF, the effect
of chronic intermittent hypoxia to augment its magnitude
is a NMDA receptor-related mechanism; however, the
serotonin subtype involved may be a different one: a
5-HT2 subtype in episodic hypoxia, and a 5-HT6 and/or
90 • APRIL 2010 • www.prv.org
 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
5-HT7 subtype in the chronic intermittent hypoxia-in-
duced augmentation (447).
These chronic protocols with relatively long dura-
tions of mild hypoxia in rats were not directly intended to
mimic the rapid and more severe hypoxic swings that are
experienced by sleep apnea patients but were mainly
aimed at studying the plasticity of the neuronal network
shaping the HVR. Peng and Prabhakar (597) have ex-
tended the above observations on the effects of episodic
hypoxia by imposing hypoxic episodes lasting seconds
rather than minutes, a stimulus pattern more relevant to
sleep apnea. They showed that conditioning rats with
chronic intermittent hypoxia consisting of 15 s hypoxia
alternated with 5 min of normoxia, 9 cycles/h for 8 h/day
during 10 consecutive days, augmented the episodic hyp-
oxia-induced phrenic LTF, which was absent in animals
exposed to sustained hypoxia with a comparable cumu-
lative duration (597). Combining chronic intermittent hyp-
oxia conditioning with daily administration of a superox-
ide dismutase (SOD) mimetic prevented this LTF augmen-
tation (597). Subsequently, they showed in the rat that
chronic intermittent hypoxia: 1) evoked episodic hypoxia-
induced LTF in the carotid sinus nerve (“sensory LTF”)
that was prevented with a SOD mimetic; 2) reduced both
aconitase activity in the carotid bodies and the activity of
mitochondrial complex I; and 3) increased hypoxic but
not hypercapnic sensitivity of the in vivo and in vitro
carotid body, which was prevented by scavenging super-
oxide radicals and could be reversed by subsequent ad-
aptation to normoxia (585, 595–597). This functional ca-
rotid body plasticity occurred without macroscopic mor-
phological changes (585, 596).
Additional studies in mice with a partial deficiency
for HIF-1␣ (HIF-1␣⫹/⫺) revealed that, in contrast to wild
types, these animals did not respond to chronic intermit-
tent hypoxia with increases in HVR and carotid body
sensitivity. Also, the heterozygous animals did not accu-
mulate ROS and showed no upregulation of HIF 1-␣ (600).
Prabhakar and colleagues (536) proposed a working
model of chronic intermittent hypoxia in which oxidative
stress leads to ROS generation (presumably by increased
NADPH oxidase activity and/or inhibition of mitochon-
drial complex I), upregulation of HIF-1 and induction of
many genes by this transcription factor that together help
to sensitize the carotid bodies. Other transcription factors
and posttranscriptional phosphorylation of proteins also
play an important role (414, 536).
NO could also be involved in chronic intermittent
hypoxia-induced LTF and carotid body sensitization. Mice
deficient in neuronal NOS have an augmented HVR but
show an attenuated episodic hypoxia-induced ventilatory
LTF; the effect of chronic intermittent hypoxia in these
mice was not studied (387). Mice deficient in endothelial
NOS have a blunted O2 response (390); the effect of
Physiol Rev • VOL
721
chronic intermittent hypoxia in these animals are un-
known.
An increase in the sustained, but not acute, HVR was
reported in rats after alternations of 10 and 21% O2 every
90 s, continuously applied during 30 days (634). Challeng-
ing cats with alternations of 90 s hypoxia with ⬃5 min
normoxia, 8 h/day for 2– 4 days enhanced the in vivo basal
discharge and hypoxic sensitivity of the carotid sinus
nerve, upregulated carotid body ET-1 by a factor of ⬃10
and shifted the hypoxic response curve of their in vitro
vascularly perfused carotid bodies to the right (643). Sub-
sequently, a chronic intermittent hypoxia-induced upregu-
lation of carotid body ETB but not ETA receptors was
shown, and it was proposed that upregulation of the
endothelin system would increase carotid body sensitivity
by modulating blood flow (642). Recently, it was sug-
gested that, similar to its facilitatory effect on synaptic
transmission in the NTS, ET-1 may also stimulate the
carotid body by augmenting the excitatory effect of glu-
tamate (456). Rats exposed to chronic intermittent hyp-
oxia for 3 wk showed upregulation of carotid body NR1,
and NR2, NMDA receptor subunits, and in contrast to
controls, carotid body baseline activity in these animals
was enhanced by infusion of NMDA without altering the
sensitivity to hypoxia. The NMDA antagonist MK-801 not
only reversed this increase in baseline activity but also
inhibited the stimulatory effect of ET-1 (456). So, although
probably not directly involved in O2 sensing, NMDA re-
ceptors may play a functional role in the adaptation of the
carotid bodies to chronic intermittent hypoxia.
Chronic intermittent hypoxia will not only initiate
plastic changes in the carotid bodies. In NTS neurons
receiving afferent input from the carotid bodies of rats
exposed to chronic intermittent hypoxia, dose-dependent
currents induced by AMPA were increased whilst NMDA-
activated currents were reduced (174). Reeves et al. (634)
showed a chronic hypoxia-induced increase in the expres-
sion of the NR1, NR2A, and NR2B NMDA receptor subtypes
in the dorsocaudal brain stem. Another factor contribut-
ing to a centrally mediated HVR plasticity may be platelet-
activator factor (PAF). In an attempt to gain insight into
the role of this phospholipid, Reeves and Gozal (630)
compared the effects of a chronic (30 day) intermittent
hypoxic paradigm in mice deficient for the PAF receptor
(PAFR) with those in their wild-type littermates. The
results were somewhat contradictory. On the one hand,
unlike wild-type mice, PAFR⫺/⫺ mice failed to show an
increase in normoxic ventilation after the challenge, indi-
cating a role of PAF in chronic intermittent hypoxia-
induced ventilatory LTF. On the other hand, over the
period of 30 days, both genotypes showed an equally
robust time-dependent increase in the response to sus-
tained (20 min) hypoxia (630). Thus the precise role of
PAF in the chronic intermittent hypoxia-induced augmen-
tation of the HVR remains to be determined.
90 • APRIL 2010 • www.prv.org
722 LUC J. TEPPEMA AND ALBERT DAHAN
After exposure to chronic intermittent hypoxia,
anesthetized rats showed a rise in blood pressure and
an augmented preganglionic sympathetic nerve re-
sponse to acute hypoxia (294). Conscious rats re-
sponded with an increase in the hypoxic response of
the renal sympathetic nerve (339). Chronic intermittent
hypoxia has a profound influence on the oxidative sta-
tus of the brain cortex and leads to protein and nucleic
acid oxidation, lipid peroxidation, and apoptosis, a pic-
ture that is mitigated in mice overexpressing Cu,Zn-
SOD (857). ROS induced specific enzymatic changes in
the brain stem of rats exposed to chronic intermittent
hypoxia that eventually led to enhanced ␣-amidation of
neuropeptides such as substance P and neuropeptide Y
that thereby become biologically active (699). Many
neuropeptides are operating in central neuronal net-
works, so similar mechanisms may also contribute to
chronic intermittent hypoxia-induced changes in the
HVR and sympathetic chemoreflex sensitivity.
In summary, in animals and across species, chronic
intermittent hypoxia leads to an augmented episodic hyp-
oxia-induced LTF at the level of carotid bodies, phrenic
nerve, and ventilation. Carotid body sensitivity is in-
creased and the HVR is enhanced. These adaptive
changes are mediated by ROS-related HIF-1␣ stabilization
and gene expression resulting in adaptations in the sig-
naling-transduction cascade in the carotid bodies and
plastic changes within the central respiratory neural net-
work. As was also the case for chronic hypoxia, chronic
intermittent hypoxia has different effects in neonates and
adults. This is schematically shown in Figure 10.
3. Chronic intermittent hypoxia increases the HVR
in humans
Protocols used in humans to produce chronic inter-
mittent hypoxia vary widely in total duration (days to
weeks), severity, and length of individual hypoxic expo-
sures. In a minority of cases, isocapnia was maintained.
Data we have collected from a number of recent studies
are shown in Table 5. The paradigms employed do not
exactly mimic the swings in PO2 and PCO2 that are encoun-
tered in sleep apnea syndrome wherein hypoxic episodes
are shorter, 20 s on average, and accompanied by hyper-
capnia (242). Rather, they may represent time courses of
prolonged hypoxic episodes that can occur in patients
with chronic obstructive pulmonary disease (COPD)
and/or severe heart failure. With only a few exceptions,
paradigms of chronic intermittent hypoxia in humans re-
sult in an increase in the HVR, which can be accompanied
by a rise in resting normoxic ventilation and drop in
end-tidal CO2. In cases where isocapnic HVRs were mea-
sured at resting end-tidal CO2 levels (Table 5), the effects
may even have been underestimated (postexposure end-
tidal CO2 levels mostly being lower).
Physiol Rev • VOL
.
VI
.
VI
FIG. 10. Comparison of chronic intermittent hypoxia in neonates
and adults. Effects of chronic intermittent hypoxia in neonates (within
the critical time window for developmental respiratory plasticity) and in
adults. Question marks concern unresolved or controversial issues. V̇I,
inspired ventilation; LTF, long-term facilitation. In the adult, ventilatory
LTF can be the result of sensory LTF and LTF in major respiratory motor
nuclei such as the phrenic and/or hypoglossal motor nuclei and inter-
costal motor neurons. In the adult, sensory LTF in the carotid bodies
may tend to augment carotid body sensitivity and thus destabilize
breathing, but LTF in motor nuclei may have a stabilizing effect. For
example, if the phenomenon would exist in the hypoglossal (and
phrenic) nucleus in humans with obstructive apnea, the chronic inter-
mittent hypoxia in these patients may tend to limit the occurrence of
upper airway collapse. For further explanation, see text.
If it is accepted that the peripheral chemoreceptors
mediate the initial hypoxia-induced rise in ventilation,
enhancement of the acute HVR (8, 10, 11, 253, 484) is most
probably due to an increase in carotid body sensitivity. A
higher ventilation during hypoxia combined with an also
higher arterial oxygen saturation is compatible with an
increased slope of the ventilation-SaO2 relationship (e.g.,
Ref. 53). It is not easy, however, to assess the precise
quantitative contribution of the carotid bodies to the aug-
mented HVR: isocapnic progressive hypoxic tests lasting
5–9 min are associated with increases in CBF and central
hypocapnia and may also be accompanied by a rapidly
developing HVD (see sect. III). The fact that chronic inter-
mittent hypoxia induces augmented cerebrovascular O2
and CO2 sensitivities should also be taken into account (8,
395).
The mechanisms of a chronic intermittent hypoxia-
induced increase in carotid body sensitivity in humans
remain elusive, but plastic changes as described for ani-
mals could well operate in humans also. Like in animals,
the increase in HVR may depend on stimulus intensity, the
number of deoxygenation/reoxygenation periods, and to-
tal exposure length. Exposing humans to a chronic inter-
90 • APRIL 2010 • www.prv.org

TABLE 5. Chronic intermittent hypoxia in humans
Protocol
5 min isocapnic hypoxia (12%
O2) alternated by 5 min
normoxia for 1 h, 12 days
(protocol 1) versus 30 min
isocapnic 12% O for 12 days
(protocol 2); interruption of
protocols on days 6 and 7
FIO2 0.13 for 2 h/day for 12 days
Daily exposure to a barometric
pressure of 432 Torr for 1 h,
7 days
Daily three 6-min bouts of
isocapnic hypoxia with PETO2
50-35 Torr interspersed with
normoxia within 30 min, for
14 days
Decompression to 15.5 or 12.3
% O2 for 1 h/day for 1 wk
12% O2 for 5 min, poikilocapnic,
followed by 5 min normoxia,
for 1 h, 10 days
FIO2 0.12, isocapnic for 5 min,
followed by 5 min 0.21, 4
times/day for 10 days, men
60–74 yr old
12 times 5 min poikilocapnic
12% O2, 5 min normoxia daily
for 7 days SDIH versus 60
min poikilocapnic 12% O2
daily, 7 LDIH in the same
subjects
5 min 12% O2, 5 min 21% O2 for
90 min during 10–12
consecutive days
60 min of isocapnic hypoxia
(SaO2 ⬃80%) for 10
consecutive days
Sleeping for 5 consecutive
nights with FIO2 ⬃0.14
14 nights (9 h) of sustained
SaO2 ⬃84%
20 min of isocapnic (eucapnic)
hypoxia (FIO2 ⫽ 0.10) daily
for 14 consecutive days
THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
HVR Measurement
Progressive isocapnic hypoxia to
SaO2 ⬃75 %; PETCO2 at resting
values
Step decrease in FIO2 from 0.3 to
0.13; PETCO2 at level causing a
hyperoxic V̇I of 15
ml/min⫺1 䡠 kg⫺1
Progressive isocapnic hypoxia at
eucapnic PETCO2
Progressive isocapnic rebreathing
to FIO2 8-7% at constant
eucapnic PETCO2
Progressive isocapnic hypoxia to
SaO2 ⬃75 %; PETCO2 at resting
values
Isocapnic progressive hypoxia to
SaO2 ⬃75%; PETCO2 at resting
values.
Isocapnic progressive hypoxia to
SaO2 ⬃85%; PETCO2 at resting
values
Isocapnic progressive hypoxia
until SaO2 ⬃80 %; measured on
7 consecutive days; PETCO2
kept at resting values in all
conditions
Poikilocapnic response to acute
and sustained (20 min) hypoxia
(12% O2)
Progressive isocapnic hypoxia to
SaO2 ⬃75% and then
maintained for another 20 min;
PETCO2 at resting values.
iAHR determined from six
descending PETO2 steps with
DEF technique; PETCO2 kept at
⬃1.5 Torr above resting
Isocapnic progressive hypoxia to
SaO2 ⬃80%
Isocapnic steps in hypoxia daily;
modified rebreathing to
determine thresholds and
sensitivities both before and
after isocapnic hypoxic studies
Physiol Rev • VOL 90 • APRIL 2010 •
723
Effects on HVR, Comments Reference Nos.
1 iHVR by 37% on day 12, 241
recovery on day 17; no
difference between both
protocols; no changes in
resting V̇I and PETCO2
Max 1 of iAHR, on day 5 and 253
then gradually decreasing to
control on day12; isocapnic
PETCO2 after hypoxia ⬃1.5
Torr lower
HVR, defined as the constant of 376
the hyperbolic V̇I-PaO2
relationship, increases by 73
%; no change in resting PETCO2
1 HVR by ⬃50%, no change in 695 (in which many studies in the
resting PETCO2 former Sovjet Union are
reviewed).
1 iHVR only after 12.3 % O2 by 374 (More data from the same
⬃25%, indicating an influence authors in ref, 373, 375–377)
of the depth of hypoxia; no
changes in resting PETCO2 and
resting V̇I
No change in iHVR, resting 623
PETCO2 somewhat lower after
CIH
No change in iHVR, neither in 700
fit, nor in sedentary men; no
change in resting PETCO2
1 iHVR by ⬃50% after both 393
SDIH and LDIH, max effect
reached after 3 days; CO2
threshold (from modified
rebreathing) decreased after
both protocols
Acute, but not sustained pHVR 8
response increased; no
change in resting PETCO2
Sustained (20 min) iHVR 478
doubles, no change in resting
V̇I and resting PETCO2
Mean iAHR more than doubles, 10, 11
baseline ventilation increased,
resting PETCO2 fell by ⬃3.5
Torr
iHVR slope increases ⬃2.5-fold, 269
increase in baseline
ventilation; resting [paco2]
lower by 3.3 Torr
AHR but not sustained HVR 484
increased; augmented AHR
ascribed to decrease in
peripheral CO2 threshold
because the threshold of the
hypoxic, not the hyperoxic
CO2 rebreathing curve
decreased. Sustained HVR not
increased because of HVD,
ascribed to an increase in
peripheral CO2 threshold
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724 LUC J. TEPPEMA AND ALBERT DAHAN

TABLE 5. —Continued

Protocol HVR Measurement Effects on HVR, Comments Reference Nos.

20 consecutive nights with FIO2
0.163 (Pl) versus 4 blocks of
5 nights with each block
interspersed with 2 nights of
normoxia (P2). “Living high,
training low” in athletes
4 consecutive days with cycling
between 2 min PETO2 ⫽45
Torr and 2 min at 88 Torr
during 6 h in awake humans
Subjects slept during 8-9 h/day
in 13% O2 during 2 and 4 wk,
respectively, and were
exposed overnight to 30
cycles/h of reoxygenation
Isocapnic progressive hypoxia to
SaO2 ⬃75%
Acute isocapnic HVR with DEF;
hypoxic sensitivity defined as
the ratio delta ventilation over
delta SaO2
Progressive isocapnic hypoxic
test; HVR defined as the ratio
delta ventilation over delta
SaO2
Time-dependent increase in 787
HVR in both P1 and P2; effect
of P1⬎ P2. HVR expressed
both as linear V̇I-SaO2 and
hyperbolic V̇I-PaO2
relationships. Resting PETCO2
lower after both P1 and P2
Time-dependent increase in the 605
acute hypoxic response that
after 4 days was ⬃80%. The
increase was correlated with
an increased production of
reactive oxygen species.
Doubling of the HVR after 2 wk; 756
in fact, this protocol consisted
of two CIH paradigms
superimposed on each other.
Sleeping in a hypoxic
environment alone also
increases the HVR (e.g., see
Refs. 10 and 269) and a
control group not subjected
to the reoxygenation cycles
was not included. An
interesting observation was
that the hypopneas associated
with reoxygenation were
followed by arousals.

iH, isocapnic hypoxia; pH, poikilocapnic hypoxia; iAHR, isocapnic acute hypoxic response (3-min hypoxic ventilatory response); iHVR,
isocapnic hypoxic ventilatory response; pHVR, poikilocapnic hypoxic ventilatory response; HVD, hypoxic ventilatory decline; DEF, dynamic
end-tidal forcing; V̇I, inspired minute ventilation; FIO2, oxygen fraction of inspired air; PETCO2, end-tidal PCO2; PETO2, end-tidal PO2; SaO2, arterial
hemoglobin oxygen saturation; CH, chronic hypoxia; CIH, chronic intermittent hypoxia; SDID, short-duration intermittent hypoxia; LDIH, long-
duration intermittent hypoxia.

mittent hypoxia protocol with hypoxic episodes of 12% O2
led to an increase in oxidative plasma biomarkers and a
decrease in antioxidant capacity that were not observed
with 15% O2 (817). Katayama et al. (374) reported an
increase in HVR by a protocol incorporating 12.3% O2 but
not 15.5%. Patients with obstructive sleep apnea show an
increase in plasma biomarkers of oxidative stress and
ROS production in leukocytes (202, 365). A recent study
in healthy young subjects showed that after 4 days of
intermittent hypoxia, the acute ventilatory response to
hypoxia increased, which was correlated with an aug-
mented production of ROS (605).
Long-term chronic intermittent hypoxia in humans
has pathophysiological consequences that are recently
reviewed elsewhere (242). Briefly, it leads to an in-
crease in (muscle nerve) sympathetic activity, impaired
baroreflex, increased production of ET-1 by enhanced
shear stress, decreased NO bioavailability, impaired
vasodilation, and hypertension. Increased production
of ROS causes upregulation of genes encoding factors
that elicit inflammation, platelet aggregation, and ath-
erosclerosis (242). Chronic intermittent hypoxia as ex-
perienced by patients with a sleep apnea syndrome will
tend to increase their HVR. An increase in chemoreflex
sensitivity elicits higher sympathetic activity and even-
tually results in hypertension in many of these patients
(372, 537, 548).
5. Different effects of chronic hypoxia and chronic
intermittent hypoxia
The effects of chronic hypoxia and chronic inter-
mittent hypoxia may be difficult to compare. For exam-
ple, differences in the duration and severity of individ-
ual hypoxic episodes, total exposure time to hypoxia,
and the large variation in cycle number of intermittent
hypoxic paradigms render it hard to define one single
effect chronic intermittent hypoxia. Some protocols
may comprise both chronic hypoxia and chronic inter-
mittent hypoxia or repetitive cycles with different
lengths. Protocols with long uninterrupted exposures,
e.g., during long nights spent in hypoxia (e.g., Refs. 11,
269) lead to increased carotid body sensitivity and
periodic breathing and an ensuing additional, chronic
intermittent (hypercapnic) hypoxia superimposed on
the experimental one. This may be a confounding factor
in studying the effects of “chronic hypoxia” during long
stays at high altitude.

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
The effect of chronic intermittent hypoxia clearly
depends on the pattern of the hypoxic exposures. For
example, rats exposed to chronic intermittent hypoxia
with long uninterrupted hypoxic episodes did not man-
ifest an augmented carotid body sensitivity, in contrast
to those challenged with hypoxia of equal total duration
but with many oxygenation-reoxygenation cycles; the
former animals may have experienced a milder oxida-
tive stress compared with the latter (598). The produc-
tion of ROS will widely vary not only with the length
and severity of the hypoxic episodes but also on the
number of reoxygenation periods. A single bout of
hypoxia and reoxygenation produce ROS, and this ef-
fect is amplified by repetitive hypoxia/reoxygenation
(857, 867).
Some of the reported different consequences of
chronic hypoxia and chronic intermittent hypoxia can
be listed as follows. 1) In contrast to chronic hypoxia,
a specific chronic intermittent paradigm did not lead to
morphological changes in the carotid bodies (585, 596).
2) In PC12 cells, the time course and magnitude of
HIF-1␣ expression differed between the two paradigms:
chronic intermittent hypoxia was more potent in in-
creasing HIF-1␣ protein, and the elevated levels were
sustained for longer periods of time (references in Ref.
536). 3) Another study reported that in contrast to
chronic hypoxia, chronic intermittent hypoxia did not
enhance HIF-1␣ mRNA in the rat carotid body, while
both paradigms augmented the expression of HIF-2␣
and HIF-3␣ (434). 4) In the dorsocaudal brain stem of
the rat, chronic intermittent hypoxia was associated
with an increase in the expression of the NR2A and
NR2B subunits of the NMDA receptor that did not occur
in chronic hypoxia (634). The authors of this study
related this to the less pronounced presence of HVD
after the chronic intermittent compared with the
chronic protocol (634). 5) As discussed in section VG1,
in the rat, chronic intermittent but not chronic hypoxia
augmented the magnitude of LTF (597).
Using a systems biology approach, Wu et al. (850)
studied the expression of genes, sets of genes, and genetic
networks and found different temporal expression pat-
terns in chronic- and chronic intermittent hypoxia in the
lungs of male rats. The gene encoding the estrogen
receptor 1 (Esr-1) was unmasked as an important reg-
ulator of the response to chronic intermittent but not to
chronic hypoxia. Increased expression of Esr-1 also
resulted in upregulation of ⬎200 target genes of the
ESR-1 protein, for example, the P2X2 purinergic recep-
tor. In addition, ESR-1 closely interacted with gene
networks that already were known to play key roles in
hypoxia, for example, a hub node around HIF-1␤ and
vascular endothelial growth factor (VEGF). Chronic
hypoxia acutely induced a different set of genes that
were overrepresented by those involved in the immune
Physiol Rev • VOL
725
response. The network activated by chronic hypoxia
included the hub nodes with vascular endothelial
growth factor, nuclear factor- ␬ B and transforming
growth factor-␤, all of which are known to play a role in
pulmonary hypertension (850). This interesting ap-
proach awaits application in the carotid bodies.
VI. MEASURING, EXPRESSING, AND MODELING
THE HYPOXIC VENTILATORY RESPONSE
A. Measuring the HVR
Techniques used to measure the human HVR can be
divided into five groups: 1) steady-state techniques involv-
ing fixed inspired O2 and CO2 concentrations, 2) single or
double breath tests involving transient hypoxia or hyper-
oxia for no more than a few breaths, 3) progressive
hypoxia tests involving the rebreathing of a gas mixture
from a rebreathing bag or circuit with CO2 absorption
allowing control of end-tidal CO2, 4) step hypoxic tests in
which rapid decreases in end-tidal O2 are performed while
maintaining end-tidal CO2 constant, and 5) via measure-
ment of isoxic hypoxic and hyperoxic ventilatory CO2
responses.
The HVR obtained with steady-state hypoxic tests
(test 1) is a mixture of the acute effects of hypoxia and
its central depressant effects. Hence, the response is
“contaminated” by HVD. These tests were applied in a
time and age in which there was little knowledge on
HVD. Consequently, steady-state tests are considered
outdated (871). Dejours et al. (177) developed the sin-
gle breath test (test 2) in which after several control
breaths the subject inhales one vital capacity of a test
gas (100% O2 or 100 N2 with or without the addition of
CO2). The change in ventilation during the next few
breaths is a measure of hypoxic sensitivity. While this
test is not contaminated by HVD, it does not allow the
development of the full HVR, and isocapnia is not main-
tained during the test. Furthermore, to avoid random
effects from the background variation in ventilation,
the test has to be repeated frequently (411). Finally,
quantification of the small and short-lived change in
ventilation is difficult (628), and therefore, the test
should be just considered a qualitative measure of pe-
ripheral chemoreceptor activity. At present, most pop-
ular tests are those that use progressive (test 3) and
step hypoxia (test 4) and those that measure the HVR
via the V̇I-CO2 responses at hyperoxia and hypoxia
(test 5).
1. Progressive hypoxic tests
Over the years, various progressive hypoxic tests
have been designed (143, 272, 411, 458, 485, 626 – 628,
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726 LUC J. TEPPEMA AND ALBERT DAHAN
833). Techniques differ in depth of hypoxia, steepness of
the hypoxic ramp (and linked to this the duration of the
test), and the technique to keep end-tidal CO2 constant.
Weil et al. (833) published their method in 1970: subjects
breathed sequentially three gas mixtures for 3–5 min
(room air, 10 and 8.5% O2 in N2) causing a slow (15 min)
progressive isocapnic decline in alveolar PO2 to ⬃40 Torr.
Isocapnia was maintained by adding CO2 to the inspira-
tory limb of the breathing circuit. Godfrey et al. (272)
adapted the CO2 rebreathing technique developed by
Read (624) in such a way that hypoxia developed progres-
sively over 5– 8 min. The subjects rebreathed from a cir-
cuit that included a CO2 absorber allowing the mainte-
nance of isocapnia. The initial gas mixture contains 25–30% O2
in N2, and as the subjects consumes oxygen, the oxygen
concentration of the bag decreases. During the course of
rebreathing, arterial PO2 drops from 130 to ⬃30 Torr.
Rebuck et al. (627) and later Rebuck and Campbell (626)
described a rebreathing technique similar to that of God-
frey et al. (272). The “Rebuck” approach involves re-
breathing from a 6-liter bag containing a gas mixture of 7%
CO2 and 22–24% O2 in N2. The obvious problem with this
technique is that the ensuing HVR is due not only to the
progressive decline in PO2 but also to the step increase in
PCO2 (658). In a modified approach, the high PCO2 level is
kept constant for 6 min before beginning to rebreathe
from the bag (485). As pointed out by Robbins and Zhang
(658), the later description of the modified “Rebuck re-
breathing technique” by Rebuck and Slutsky (628) does
not make it clear that the original technique is seriously
flawed. See Figure 11A for a description of the apparatus
used by Rebuck and colleagues. It is important to be
aware that rebreathing methods have the potential for
systematic errors due to contamination by HVD when
tests last longer than 5 min (411, 612).
2. Step hypoxic tests
A sophisticated method to obtain ventilatory re-
sponses to steps into and out of hypoxia is by using the
computer-controlled DEF technique, developed by Swan-
son and Bellville in the late 1960s and early 1970s in
Stanford, California (56, 747, 748). Originally DEF was
used to measure the V̇I-CO2 response and quantify the
contribution of the central and peripheral chemoreflex
loops to total ventilation (56). Not much later, it was
adopted by several research teams to study step and
sinusoidal hypoxic responses (176, 655, 822). DEF (see
Fig. 11B) allows manipulation of the inspired PO2 and PCO2
to induce specific waveforms in end-tidal gas concentra-
tions independent of the ventilatory response and venous
return. Feedback/forward loop algorithms are applied to
anticipate and compensate for the respiratory response to
a desired end-tidal gas concentration on a breath-to-breath
basis. The control of the end-tidal gas concentrations with
Physiol Rev • VOL
DEF is good, with standard deviations of the end-tidal
concentrations over time ⬍0.6 Torr (161). The main ad-
vantage of DEF is its ability to obtain an open-loop esti-
mation of ventilatory responses within a short period of
time, something that is impossible under closed-loop con-
ditions.
The technique has the disadvantage that relatively
complex apparatus is required. As a result, less sophisti-
cated techniques are utilized more frequently using con-
tainers with preset hypoxic mixtures and/or adaptations
of the inspired oxygen concentrations by hand to obtain
the desired end-tidal values (204, 370, 683, 705). Often
isocapnia is maintained by using a rebreathing circuit
(683), otherwise by adding CO2 to the inspiratory limb of
the apparatus (204).
One variant of the step hypoxic test is the application
of randomly modulated sequences in hypoxia and hyper-
capnia (863). This computer-driven technique requires
mathematical modeling to obtain an indication of the
magnitude of the HVR and its interaction with CO2. While
of great value in the characterization of the ventilatory
control system (see also sect. VIC), it is of lesser practical
applicability.
3. Measuring HVR via the V̇I-CO2 response
Various authors derive the HVR from isoxic hypoxic
and hyperoxic V̇I-CO2 response curves (195, 349, 411, 547,
628, 720). Most frequent studied PO2 values for hyperoxia
are 150 –250 Torr and for hypoxia are 40 –50 Torr. Sever-
inghaus defines the hypoxic response as the increase in
ventilation at an interpolated end-tidal CO2 going from
hyperoxia to hypoxia (⌬V̇40 when a 40 Torr hypoxic level
is chosen, Ref. 683). Others use the change in slope going
from hyperoxia to hypoxia (⌬S) or the ratio of the slopes
(S40/S200) as well as the change in the position of the
response curves (195, 628). When the isoxic V̇I-CO2 re-
sponse curve is assessed using steady-state methods at a
hypoxic background, an appreciable effect of HVD on the
response occurs. To overcome this problem, some au-
thors use the (modified) CO2 rebreathing procedure
according to Read (624). Note, however, that the Read-
rebreathing technique, although relatively simple in per-
formance, contains inherent difficulties that are not al-
ways appreciated (155). For example, abolishing the
mixed venous-to-arterial PCO2 gradient, one of the key
features of the Read-rebreathing technique (624), is not
enough to reduce the brain tissue-arterial PCO2 gradient
sufficiently to zero to cause equilibration between arterial
and brain tissue PCO2 (155).
4. The choice of method of measuring HVR
A) THE CHOICE OF TEST END-TIDAL PCO2. There is no
consensus on defining the test end-tidal or arterial PCO2
(696). Some investigators raise the end-tidal value ar-
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 727

FIG. 11. Experimental set-up to measure the HVR. A: setup used by Rebuck and Slutsky to measure the ventilatory response to hypoxia. The
DC pump draws gas from the bag through the soda lime and returns the gas to the end of the bag (arrows). [Adapted from Rebuck and Slutsky (628).]
B: experimental setup used in Leiden to apply dynamic end-tidal forcing of oxygen and carbon dioxide. There are two computer subunits, one to
apply control signals to the mass flow controllers, which sets the desired inspiration oxygen and carbon dioxide fractions, and one to collect the
end-tidal data.

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728 LUC J. TEPPEMA AND ALBERT DAHAN

bitrarily (e.g., to 45 Torr), and others use a fixed in-
crease relative to baseline end-tidal CO2 (e.g., ⫹5 Torr
above resting) or a value set to achieve equal back-
ground central drive throughout the hypoxic experi-
ment (for example, by using a end-tidal CO2 value at
which ventilation in hyperoxia equals 4 l/m2 per min or
140 ml 䡠 min⫺1 䡠 kg⫺1), presumably to prevent a possible
confounding influence of central-peripheral interaction
(195, 696, 720). The method of choice of the end-tidal
CO2 is of importance when studying the effect of spe-
cific interventions, such as high altitude, acid-base al-
terations, or pharmacological agents, on the HVR. An
insightful and acceptable alternative to the measure-
ment of HVR at a fixed end-tidal PCO2 would be the
assessment of HVR at two to three PCO2 values (Fig. 12).
Alternatives could be ⌬S or S40/S200.
B) THE CHOICE OF BASELINE END-TIDAL PO2. When study-
ing HVR, the baseline oxygen level chosen is sometimes
hyperoxic (end-tidal PO2 150 –250 Torr; Refs. 195, 696).
This is done to “silence the peripheral chemoreflex
response to CO2” (195). Whether this is achieved at
mild hyperoxia is doubtful. Data from Pedersen et al.
(591) indicate that at 200 Torr, the fast peripheral com-
ponent of the V̇I-CO2 response remains present in hu-
mans (mean peripheral component was 27% of total
CO2 sensitivity). Even at much “deeper” levels of hy-
peroxia (end-tidal PO2 ⬎500 Torr), the human carotid
bodies remain active with an average 13% contribution
of the peripheral component to total CO2 sensitivity
(156). Furthermore, high oxygen levels affect central
respiratory drive via the Haldane effect and a reduction
of brain blood flow (this effect is independent of any
CO2 inhalation), causing a rise in brain tissue PCO2
(156). High oxygen may also cause the formation of
excitatory substances in the brain (e.g., NO, glutamate,
ROS). Although these components seem of lesser im-
portance during mild hyperoxia (140 –250 Torr), we
cannot exclude some excitatory effect on breathing
from even brief increases in O2 (see Fig. 13; Ref. 613).
With all of the above taken into account, our first
choice would be to assess the HVR using a normoxic
baseline level. The choice of a hyperoxic baseline level
has little or no advantage, and in addition, from a
physiological view point, hyperoxia does not represent
a realistic ambient state.
C) A PROPOSAL FOR MEASUREMENT OF HVR. Over the years,
Severinghaus and others made several attempts to
reach consensus on the HVR methods (131, 195, 696,
697). Consensus is required to overcome “lack of com-
parability between results obtained by various groups
due to their variety in methods, definitions, choice of
isocapnic PCO2 and duration of hypoxia” (696). In the
so-called “proposed Lake Louise HVR Methods,” Sever-
inghaus (696) proposes three tests (Table 6): 1) an
isocapnic HVR (iHVR) to determine the hypoxic sensi-
tivity of the carotid bodies lasting no longer than 5 min
and 2) a poikilocapnic HVR (pHVR) lasting 20 min to
predict the response to high altitude. In both tests,
baseline (prehypoxia) conditions are hyperoxic (150 ⬍
end-tidal PO2 ⬍ 250 Torr). 3) The iHVR may be pro-
longed to get an indication of the isocapnic HVD. Duffin
(195) proposes three tests (Table 6): 1) the assessment
of peripheral chemoreflex responsiveness by measure-
ment of the ventilatory response to CO2 at hyperoxia
(150 Torr) and hypoxia (40 Torr) preferentially per-
formed by using the modified Read-rebreathing test (or
alternatively performing 5-min isocapnic steps from
hyperoxia to hypoxia); 2) to get an indication of HVD

FIG. 12. Protocol to measure the ventilatory response to hypoxia. A: measuring the isocapnic ventilatory response to hypoxia (iHVR) at
three arterial PCO2 levels using the “Leiden” approach (test 1 in Table 1) in an awake healthy 30-year-old male volunteer. At each CO2 level,
the arterial PO2 is lowered from 100 mmHg (closed data points) to 45 mmHg and kept constant for 5 min (open data points). The ventilatory
increase is depicted by the arrows. The lines through the data are obtained from linear regression and are the post hoc steady-state normoxic
and acute hypoxic V̇I-CO2 response curves. B: the hypoxic response, expressed as ⌬V̇I/⌬SpO2, is plotted for each arterial CO2 concentration
(open squares and broken line). The O2/CO2 interaction (i.e., the carotid body-induced increase in hypoxic sensitivity at increasing levels of
arterial CO2) is abolished when the experiment is repeated during the inhalation of 0.15 end-tidal percent halothane.

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS 729

FIG. 13. Measuring the hypoxic ventilatory response at three constant levels of end-tidal PCO2. A: isocapnic ventilatory responses to hypoxia
and hyperoxia at three arterial PCO2 levels obtained in a healthy 28-year-old female volunteer. Normoxic, hyperoxic (arterial PO2 ⫽ 140 mmHg), and
hypoxic (arterial PO2 ⫽ 45 mmHg) data points are given. The data points form post hoc steady-state V̇I-CO2 response curves in normoxia, hyperoxia,
and acute hypoxia (lines through the data points derived from linear regression). The left shift of the hyperoxic V̇I-CO2 response curve relative to
the normoxic curve is due to the central stimulatory effects from even mild hyperoxia. Consequently, using the hyperoxic data as a measure of the
isocapnic HVR (see Table 1) makes data interpretation difficult if not impossible. B: the data in these graphs are obtained by using a small adaptation
to the test 1 of the “Leiden proposal” of Table 6. The top graph shows the imposed end-tidal fractions of O2 (continuous line) and CO2 (dotted line).
In between the normoxic and hypoxic exposures, a 7-min isocapnic hyperoxic exposure (PO2 ⫽ 140 mmHg, measured in arterial blood) was added.
The middle graph shows the measured arterial O2-Hb saturation using pulse-oximetry. The bottom graph shows the measured inspired ventilation.
Each data point is one breath.

the first procedure is repeated before and after 20-min
of hypoxia (or alternatively performing a 20-min iso-
capnic hypoxic response); and 3) a 20-min poikilocap-
nic step hypoxic response is performed to mimic the
response to environmental hypoxia.
Our proposal is a modification of the methods out-
lined by Severinghaus and Duffin (Table 6: the “Leiden”
proposal). Similar to the other proposals, we suggest
performing three distinct tests. In test 1, 5-min step re-
sponses into hypoxia (arterial PO2 45–50 Torr) are per-
formed at three different arterial PCO2 levels (e.g., ⫹2, ⫹4,
and ⫹8 Torr above resting). However, in contrast to the
previous proposals, baseline oxygen levels are normoxic
(arterial PO2 ⫽ 100 Torr). One is now able to calculate the
acute hypoxic response (i.e., hypoxic sensitivity), and
since the responses are obtained at various PCO2 levels,
one gets a full characterization of O2-CO2 interaction, a
phenomenon most likely originating at the peripheral che-
moreceptors (see also sect. VD; Fig. 12). Tests 2 and 3 are
similar to the ones proposed by Severinghaus but with
normoxic rather than hyperoxic baseline states to prevent
any excitatory effect of even mild hyperoxia. A transition
from hyperoxia to hypoxia will change central ventilatory
drive more than the transition from normoxia to hypoxia
(see sect. VIA4B). This will affect the position of the V̇I-CO2
response causing a leftward shift (Fig. 13). Of equal im-
portance is the fact that hyperoxia does not silence the
peripheral chemoreceptors. Furthermore, we refrain from
obtaining V̇I-CO2 responses curves at different PO2 levels
as proposed by Duffin (195) as ion channel and neuro-
transmitter responses to low oxygen and high PCO2/low
pH stimulation at the carotid bodies may differ and, as is
also important, arterial PO2 is a separate stimulus at the
peripheral chemoreceptors (277). Furthermore, by per-
forming step hypoxic tests, one may decide to use peak
hypoxic ventilation rather than 5 min of hypoxia as hy-
poxic measurement point. This is especially important
when the temporal profile of the response indicates that
HVD is apparent at times ⬍5 min of hypoxia (see also Fig.
13 for an example).

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730 LUC J. TEPPEMA AND ALBERT DAHAN

TABLE 6. Proposed methods to measure the hypoxic ventilatory response

Proposed Methods to Measure Hypoxic Ventilatory Response

“Lake Louise HVR Method proposal” (696)

Test 1: isocapnic HVR (iHVR) to assess the hypoxic
sensitivity of the carotid bodies
Baseline oxygen level 150 ⬍ end-tidal PO2 ⬍250 Torr for 10 min
Hypoxic test Reduce the inspired O2 level such that the SpO2 is rapidly lowered and maintained
at 80% (range 75–85%) for 5 min
PCO2 Keep the end-tidal PCO2 constant at a level causing hyperoxic ventilation to rise to
a standard, e.g., 140 ml 䡠 min⫺1⫺kg⫺1
Expression of response iHVR ⫽ ⌬V̇I/⌬SpO2 where ⌬V̇I ⫽ the increase in V̇I from baseline to the 5th min of
hypoxia
Test 2: measuring the isocapnic hypoxic ventilatory
decline (iHVD)
Hypoxic test Expand test 1 to 20 min of isocapnic hypoxia
Expression of iHVD % fall in ⌬V̇I from the 5th to the 20th min
Test 3: poikilocapnic HVR (pHVR) to predict the HVR at
altitude
Baseline oxygen level 150 ⬍ end-tidal PO2 ⬍250 Torr for 10 min
Hypoxic test Inspiration of a O2/N2 gas mixture (e.g., 12 % O2) to
Reduce SpO2 to 80% for 20 min pHVR ⫽ ⌬V̇I/⌬SpO2
Expression of response pHPR ⫽ ⌬PETCO2/⌬SpO2
The “Ontario proposal” (195)
Test 1: measuring peripheral chemoreflex sensitivity
Hypoxic test* Ventilatory response to CO2 at an isoxic high (150 Torr) and an isoxic low (40
Torr) oxygen tension using the modified Read-rebreathing test
Expression of response Differences in hyperoxic and hypoxic V̇I-CO2 sensitivities and position of the curves
Test 2: measuring the hypoxic ventilatory decline (HVD)
Hypoxic testⴱⴱ Ventilatory response to CO2 at an isoxic high (150 Torr) and an isoxic low (40
Torr) oxygen tension using the modified Read-rebreathing test (lasting no longer
than 5 min) performed before and after 20 min of hypoxia
Expression of response As in test 1
Test 3: measuring the poikilocapnic HVR (pHVR)
Hypoxic test Step reduction in end-tidal PO2 from hyperoxia (150 Torr) to hypoxia lasting 20 min
Expression of response ⌬V̇I from baseline to 20th min of hypoxia at a specified O2 level
⌬CO2 from baseline to 20th min of hypoxia
The “Leiden proposal” (2010)
Test 1: isocapnic HVR (iHVR) to assess the hypoxic
sensitivity and O2/CO2 interaction of the carotid
bodies
Baseline oxygen level Arterial PO2 ⫽ 100 Torr for 10 min
Hypoxic test Step reduction in arterial PO2 to 45–50 Torr, which is kept constant for 5 min
PCO2 The test is performed at three arterial PCO2 levels, e.g., ⫹2, ⫹5 and ⫹12 Torr
above resting. In between tests there is a 15- to 30-min rest period
Expression of response HVR ⫽ ⌬V̇I/⌬SpO2; an alternative could be HVR ⫽ ⌬V̇I /⌬log PO2 (units L/min) if in
humans ventilation would appear to be linearly related to log PO2 below 100
Torr (but ⬎10 Torr)
where ⌬V̇I ⫽ the increase in V̇I from baseline to the 5th min of hypoxia. PO2 is
arterial (preferred) or end-tidal PO2
Test 2: isocapnic hypoxic ventilatory decline (iHVD)
Baseline oxygen level Arterial PO2 ⫽ 100 Torr for 5–10 min
Hypoxic test Step reduction in arterial PO2 to 45–50 Torr, which is kept constant for 20 min
PCO2 The test is performed at one constant arterial PCO2 levels, e.g., ⫹2 or ⫹4 Torr
above resting
Expression of response ⌬V̇I from baseline to 20th min of hypoxia at a specified O2 level
Test 3: poikilocapnic HVR (pHVR)
Baseline oxygen level Inspired oxygen concentration ⫽20.8% for 5–10 min
Hypoxic test Step reduction in inspired O2 concentration (e.g. to 10%), which is kept constant
for 20 min
PCO2 CO2 concentrations remains not controlled throughout the test
Expression of response ⌬V̇I from baseline to 20th min of hypoxia at a specified O2 level
⌬CO2 from baseline to min 20 of hypoxia

*An alternative is the measurement of a three-point steady-state V̇I-CO2 responses performed at hyperoxia and hypoxia. **An alternative test
is an isocapnic 20-min step hypoxic test as suggested by Severinghaus (696). iHVR, isocapnic hypoxic ventilatory response; pHVR, poikilocapnic
hypoxic ventilatory response; pHPR, response of the end-tidal PCO2 to poikilocapnic hypoxia; SpO2, arterial Hb oxygen saturation as determined by
pulse oximetry; PETCO2, end-tidal PCO2; V̇I, inspired minute ventilation.

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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
B. Expressing the Steady-State HVR
Mathematical expressions of the HVR have to take
into account the fact that the steady-state relationships
between ventilation and arterial and end-tidal PO2 are
nonlinear. The HVR has been quantified using hyperbolic
and exponential expressions (411, 697), and there is no
physiological reason to select one over the other.
The hyperbolic expression (457, 697, 833)
V̇ I ⫽ V̇ 0 ⫹ A/(PO2 ⫺ C)
where V̇0 is the horizontal asymptote in V̇I for infinite high
PO2 values, A is the hypoxic sensitivity, and C is the
vertical asymptote in PO2 for infinite high V̇I values. In
most studies, the asymptote C is fixed to 32 Torr, which
causes a bias in the estimation of the parameter A (214).
Bayesian estimation schemes using soft constraints on C are
advocated to improve the estimation of parameter A (214).
The hyperbolic expression indicates that the reciprocal of
ventilation versus PO2 is a linear relationship, an observation
that has been established experimentally (272). The expo-
nential expression (58, 176, 411, 697)
V̇I ⫽ V̇0 ⫹ G 䡠 exp共⫺D 䡠 PO2兲
where V̇0 is V̇I for infinite high PO2 values, G is the hypoxic
sensitivity, and D is a shape parameter. The shape param-
eter is often fixed to a specific value (e.g., to 0.29%⫺1; Ref.
824). This is done when the O2 input is not rich enough to
provide an estimation of D (e.g., when employing single
steps into hypoxia). This value of D has been estimated by
fitting an exponential through the function 100 ⫺ Z, where
Z is the saturation calculated from the Hill model of the
oxygen dissociation curve (824). The use of an exponen-
tial model is equivalent to the empirically linear relation
of log dV̇I to PO2 as used by Kronenberg et al. (411).
Since there is an empirical linear relationship be-
tween V̇I and blood oxygen desaturation (626, 628), a
more simple approach would be to express ventilation as
a linear function of oxygen saturation
V̇I ⫽ V̇0 ⫹ S/关SpO2共0兲 ⫺ SpO2兴
where V̇0 and SpO2(0) are prehypoxic ventilation and
saturation, respectively, and S is the hypoxic sensitivity
(units, L 䡠min⫺1 䡠%⫺1). There are several reasons, how-
ever, why saturation may not be the most appropriate tool
to express the HVR. Oxygen saturation is not the stimulus
to the oxygen sensors at the carotid bodies (e.g., Ref.
313). The V̇I-SpO2 relationship is not under all circum-
stances and protocols linear (159, 336, 384). And, most
importantly, a change in the position of the oxygen dis-
sociation curve (reflected in a change in P50) creates an
Physiol Rev • VOL
731
artifact with an incorrect calculation of HVR (613). For
example, a metabolic acidosis increases P50 and changes
the value of ⌬V̇I/⌬SpO2 without any change in the rela-
tionship between V̇I and PO2 and hence of the HVR. And
from a technical point of view, it is our experience that at
low saturation levels (⬍ 80%), measurements derived
from pulse oximetry are a less reliable measure of the
actual arterial HbO2 saturation.
In the cat, it has been demonstrated that in the
hypoxic range, ventilation is a linear function of log PaO2,
(1) while hypoxic sensitivity, defined as the ratio ⌬V̇I/⌬log
PaO2, is linearly related to the arterial H⫹ concentration
(650). Recently, we found that in humans relative changes
in hypoxic sensitivity induced by alterations in arterial
PCO2 are the same regardless of how the sensitivity was
defined, either as ⌬V̇I/⌬log PaO2 or as ⌬V̇I/⌬SpO2 (775). As
in cats, humans also showed a linear relationship between
hypoxic sensitivity (defined as ⌬V̇I/⌬log PaO2) and arterial
H⫹ concentration (see Fig. 7; Ref. 775). Future studies in
humans are warranted to see if, as in the cat, ventilation
is a linear function of log PaO2 in the hypoxic range. If this
would appear to be the case, then we would suggest the
use of the expression ⌬V̇I/⌬log PO2 to estimate hypoxic
sensitivity, with end-tidal O2 but preferentially arterial PO2
as input. It is a simple approach, alike to the use of oxygen
(2)
saturation but without the confounders that are inher-
ently present in the use of SpO2. When performing multi-
ple steps into hypoxia (e.g., at three different background
PCO2 levels), it further enables the description of O2-CO2
interaction (see Figs. 7 and 12) and the effects that drugs
may have on this important feature of the peripheral
chemoreceptors (such as abolishment of O2-CO2 interac-
tion by inhalational anesthetics).
C. Modeling the HVR
Several models allow the estimation of physiologi-
cally relevant parameters (hypoxic sensitivities/gains and
time constants) from single experimental data sets. Initial
mathematical models of the ventilatory response to iso-
capnic hypoxia consisted of two additive components: an
initial stimulating component arising from the carotid
(3) bodies and a second, slower component that causes a
decline in ventilation (176, 824). These models were un-
able to fit human responses into and out of hypoxia
simultaneously due to the asymmetry in the magnitude of
the fast on- and off-transients (824). The model proposed
by DeGoede et al. (176) is an exponential expression, in
which the two components differ with respect to their
dynamics (expressed by a time constant or ␶), gain values,
and input latencies. One of the first human studies (824)
yielded the following parameter values: fast component:
␶ ⫽ 6 s, gain of response into hypoxia 50 l/min, gain of
response out of hypoxia 30 l/min; slow component: ␶ ⫽ 4
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732 LUC J. TEPPEMA AND ALBERT DAHAN
min, gain of response into hypoxia ⫺40 l/min (i.e., HVD),
gain of response out of hypoxia ⫺20 l/min (relief of HVD).
The asymmetry in the gain values suggests modulation
of the peripheral component during sustained hypoxia as
the cause of HVD (cf. Ref. 162).
Khamnei and Robbins (382) examined how HVD is
best incorporated in models of the HVR. They concluded
that modulation of the peripheral chemoreflex gain during
sustained hypoxia consistently describes the human data
in contrast to models in which hypoxic depression is
modeled as an additive component or as a modulator of
central or total CO2 sensitivity (382). In a quantitative
modeling study (by assuming that the peripheral gain
term is a linear function of arterial oxygen saturation),
this was confirmed and moreover allowed (the asymme-
try of) the ventilatory response into and out of hypoxia to
be analyzed simultaneously (577). However, in some sub-
jects, the description of the response out of hypoxia (the
off-transient) remained inadequate. Therefore, to opti-
mize the model, a further model expansion was tested in
which HVD was modeled by modulation of the peripheral
chemoreflex gain (577) combined with a component that
is independent of the peripheral chemoreflex loop (445).
The extended model yielded significantly better fits in just
two of six subjects. Both had a chemoreflex-independent
HVD component ⬎50%. This contrasts with a value of
⬃10% in the four other subjects examined. Liang et al.
(445) concluded that in some subjects, but not others,
there might be a component of HVD that is independent of
the peripheral chemoreflex sensitivity.
Some studies, human and animal, indicate that the
fast hyperventilatory response to isocapnic hypoxia is
best described by a fast and a slower component (58, 198,
384, 550) with time constants for the fast and slow com-
ponents of 2–3 s and 70 –100 s, respectively (58, 550).
Possibly, the slow peripheral component is a manifesta-
tion of central neuronal dynamics, equivalent to the slow
component observed when the carotid sinus nerve is
electrically stimulated (211). This then suggests that the
HVR must be modeled by at least three components, two
of peripheral origin, one of which (or both?) is modulated
by central hypoxia, and in some subjects a peripheral
chemoreflex loop independent HVD component.
Finally, studies that strictly control end-tidal PCO2
levels during HVR measurement may be influenced by a
slow increase in ventilation that occurs upon the induc-
tion of isohypercapnia. Tansley et al. (764) show a pro-
gressive increase in ventilation lasting 2– 8 h during expo-
sure to isohypercapnia (end-tidal PCO2 ⫽ 6.5 Torr above
resting levels). The increase in ventilation is slow and
most prominent during the first 2 h of exposure (⬃66
ml/min for the first 2 h). This varying effect of baseline
ventilation may hamper proper assessment of the HVR
irrespective of the method chosen to measure the HVR.
Although there are various ways to take this effect into
Physiol Rev • VOL
account (e.g., by subtracting the variations in ventilation
by performing additional isohypercapnic experiments or
performing hypoxic experiments just above resting end-
tidal PCO2 levels), we suggest adding a trend term in the
analysis. Such an approach has been applied successfully
in studies assessing central and peripheral CO2 chemo-
sensitivity yielding significant values for a trend in the
order of 70 ml/min2 (156).
VII. COMMENTS AND FUTURE CHALLENGES
At sea level, hypoxia is a relatively rare event in
healthy individuals, except in utero and perhaps during a
neonatal period in which irregular breathing is not un-
common, or during sleep when wakefulness drive is ab-
sent and one may sometimes discontinue breathing. When
healthy individuals are exposed to inspired oxygen ten-
sions lower or higher than normal, for example, at high
altitude or in an experimental setting, the respiratory
system responds in a way that critically depends on the
stage of maturation (neonates show different responses
than adults), the physiological background condition
(e.g., CO2 and exercise increase the HVR), the intensity of
the stimulus, and, last but not least, the time pattern and
duration of the exposure. Acute, chronic, and episodic
hypoxia with or without a chronic character all have
different effects on ventilatory control. Both in neonates
and adults, the respiratory system displays remarkable
plasticity when exposed to intermittent and/or chronic
hypoxic paradigms that lead to changes in HVR pheno-
types. Animal studies show that when hypoxic stimulus
paradigms (or environmental factors such as nicotine
exposure or maternal separation) are imposed during a
neonatal critical time window, plastic changes persist into
adulthood and are difficult to reverse, if at all. An impor-
tant challenge for future research is to examine whether
the underlying mechanisms that are responsible for these
changes also apply in humans.
An important circumstance that mediates plasticity-
induced respiratory changes in rodents is neonatal oxida-
tive stress. Rats exposed to chronic intermittent hypoxia
develop an augmented carotid body sensitivity and an
increased HVR, changes that persist into adulthood (585;
note, however, that as explained in section II, the increase
in HVR is not without controversy). If translatable to
human newborns, this raises a number of clinically rele-
vant issues. Newborn babies, especially when premature,
display irregular breathing that can be accompanied by
frequent apneic events. Does this disturb a normal matu-
ration of the HVR in premature babies, and might this lead
to sensitization of the carotid bodies thereby destabilizing
breathing just like in animals? Further destabilizing
breathing might lead to a higher frequency of apneic
events, an increase in the number of deoxygenation/
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 THE VENTILATORY RESPONSE TO HYPOXIA IN MAMMALS
reoxygenation cycles, and finally to an increased produc-
tion of ROS that would further aggravate the oxidative
stress (in neonatal rats the augmented carotid body sen-
sitivity is a ROS-related phenomenon; Ref. 586). And can
possible changes in the HVR be reversed at adult or
possibly at earlier age? An important difference between
newborn and adult rats is the much higher sensitivity to
chronic intermittent hypoxia of the former with respect to
the effects on carotid body sensitization, morphological
changes (e.g., hyperplasia), and reversibility (see Fig. 10;
Ref. 585).
In neonatal animals, within a critical time window of
plasticity in the period after birth, chronic hypoxia im-
pairs carotid body maturation and O2 sensitivity, causes
degenerative changes in glomus cells and sinus nerve
afferents, and reduces both the CNS gain and the HVR
(Fig. 9). The fact that at the level of ventilation the dimin-
ished response to hypoxia persists into adulthood indi-
cates that at least some of these adaptations are perma-
nent and perhaps difficult to reverse. If similar mecha-
nisms are operating in humans, the question arises as to
whether chronic hypoxia in newborn babies, when un-
treated, may have similar deleterious effects that ulti-
mately may lead to a decreased ability to respond to an
asphyxic stimulus, long-lasting exposures to hypoxia, and
failure to autoresuscitate. However, at least in the west-
ern world, the clinical relevance of this issue may be
limited because when newborn babies are hypoxemic, for
example, due to hypoventilation, ventilation perfusion
mismatch, intrapulmonary or cardiac shunts, anemia, etc.,
they will be rapidly treated with oxygen. On the other
hand however, apart from the well-known detrimental
side effects of oxygen (for example, retinopathy; see Ref.
816 for further references), a permanently reduced HVR
(from chronic oxygen therapy) in these children that per-
sists into adulthood cannot be excluded. In rats, neonatal
chronic hyperoxia can cause a reduced HVR at adult age
depending on the level of hyperoxia and the duration of
the neonatal exposure (41, 71, 72).
An important point to consider when putting data
from neonatal animals into the context of newborn babies
is relative maturity at birth. If 1- to 5-day-old rats resemble
preterm babies in their development of the HVR (73), the
findings from this species may be less relevant for term
babies. This, however, does not obviate the need to focus
attention on possible adverse effects of neonatal oxida-
tive stress (both hypoxia and hyperoxia) on the HVR in
both preterm and term babies.
In adult healthy humans, chronic intermittent hyp-
oxia results in an augmented HVR, presumably related to
oxidative stress (increased production of ROS; Refs. 374,
605, 817). Studies in humans on the effects of chronic
intermittent hypoxia are often aimed at mimicking
hypoxic episodes that occur in patients with obstructive
sleep apnea (OSA). This chronic disease is associated
Physiol Rev • VOL
733
with an enhanced sympathetic activity, systemic hyper-
tension, and an augmented HVR. Similar to animals ex-
posed to chronic intermittent hypoxia, OSA patients dis-
play increased production of ROS (202, 365). The in-
creases in both systemic blood pressure and HVR can be
reversed with nasal continuous positive airway pressure
treatment (790, 791). To mimic the complex events that
occur in OSA in a laboratory setting may be elusive in the
sense that (awake) healthy subjects do not display the
increase in resting tone of upper airway dilator muscles
that in OSA patients serves to compensate for a decreased
patency of the upper airways. This may well be one of the
reasons why it is difficult if not impossible to evoke LTF
of upper airway dilator muscles in healthy sleeping sub-
jects but less so in snorers with upper airway flow limi-
tations (21). Apart from the absence of obstructive ap-
neas, an additional limitation of studies in awake healthy
subjects is the lack of arousals that in sleeping OSA
patients may play a crucial (albeit not clearly defined) role
and the absence of the influences of sleep itself on the
control of breathing. And finally, in OSA patients, apneic
events followed by hyperventilation are associated with
alternating episodes of low and high PCO2, which makes
the stimulus paradigm fundamentally different from that
in most laboratory studies in which the hypoxic episodes
are hypocapnic or at best isocapnic (Table 5). On the
other hand, studies in animals and healthy humans are of
considerable interest because they can uncover mecha-
nisms by which chronic intermittent hypoxia by itself can
lead to maladapations such as inflammation, endothelial
dysfunction, atherosclerosis, and other cardiovascular pa-
thology.
From studies over the last decade, the picture
emerges that oxygen sensing by the carotid bodies occurs
via several parallel pathways. The key role of potassium
channel species is well established, but identification of
individual members involved is complicated by species-
and even strain-related differences in potassium channel
regulation by hypoxia. AMP-activated protein kinase
(AMPK), an enzyme considered to play a key role in
cellular metabolism, has been identified as a link between
hypoxia-induced changes in mitochondrial metabolism
and potassium channel activity. Mice deficient in the ␣2
subunit of AMPK show an attenuated frequency response
to hypoxia in vivo (222). A possible role of AMPK in
glucose sensing by the carotid bodies, in the adaptation to
high altitude, as well as in exercise remain interesting
subjects for further study. To uncover the role of the
numerous individual type I cell neurotransmitters in the
integrated response of the carotid body to hypoxia is
another challenging issue.
A fascinating example of respiratory plasticity at
adult age becomes manifest during adaptation to chronic
hypoxia. In fact, all elements in the carotid bodies and
CNS known to participate in the hypoxia signaling trans-
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734 LUC J. TEPPEMA AND ALBERT DAHAN
duction cascade undergo plastic changes during chronic
hypoxia. How does the organism manage to orchestrate
so many changes (recalibrations) at the same time with-
out losing control over system stability? One of the master
regulators now identified is HIF-1, a transcription factor
that regulates the expression of numerous genes encod-
ing elements involved in improving tissue oxygenation
(HVR, erythropoiesis, angiogenesis, etc.) and in metabolic
adaptations (increased ATP supply from glycolysis, opti-
mization, and reduction of oxidative phosphorylation).
Systems biology approaches are currently used to map
individual genes, untangle genetic networks, and identify
their hubs (441, 850). Systems biology also offers an im-
portant avenue to discover cross-talk between hypoxia
and other key signaling mechanisms. For example, it has
been shown that angiogenesis in hypoxia is induced by
cross-talk with notch signaling (441); notch receptors are
highly conserved transmembrane proteins thought to be
involved in cell-to-cell communication and cell differenti-
ation (references in Ref. 441). Similar mechanisms may
operate in the carotid bodies, but efforts to examine this
have not yet been undertaken.
How hypoxia influences the stability and activity of
transcription factors is also focus of current interest. The
fact that transcription factors may also undergo posttran-
scriptional modification independent of hypoxia is an in-
teresting but complicating factor in the interpretation of
these studies because hypoxia-independent pathways
may then autonomously influence the expression of genes
involved in the adaptation of the HVR to chronic condi-
tions. For example, HIF-1␣ can be stabilized by NO-me-
diated S-nitrosylation and by heat shock protein 90, and
both processes are hypoxia independent (692). With re-
gard to HIF-1␣, targeting its stability independent of the
PO2 may appear to open new treatment options of HIF-1-
related pathology. For example, an interesting recent ob-
servation in humans is the reversal of hypoxia-induced
pulmonary hypertension by iron supplementation (713;
further references in Refs. 441, 692).
Animal studies indicate an important effect of geno-
type on the HVR phenotype (i.e., the HVR magnitude).
With the relatively large effect of environment and pre-
frontal cortex on the magnitude and variability of HVR
taken into account, a genetic influence seems hard to
discover from human studies. However, in certain popu-
lations and patient groups, the genotype may be the more
dominant factor. An important question that so far has
received little attention is whether linking of the genotype
to magnitude of HVR is of clinical importance. Does a
HVR risk phenotype exist which leads to an increased risk
for adverse respiratory events? And is this phenotype
linked to an increase in morbidity and mortality? This is,
for example, of importance for patients with central or
obstructive sleep apnea or patients receiving respiratory
depressants in the perioperative setting.
Physiol Rev • VOL
Finally, the method of measuring the HVR, especially
in humans, remains a topic of intense discussion. We
propose a standardized method (the Leiden protocol) that
allows measurement of the HVR with as few problems as
possible in its interpretation. Adoption of this protocol
will enable simple comparisons of physiological and phar-
macological studies on HVR between laboratories.
ACKNOWLEDGMENTS
We thank Dr. Egbert Lakke for making Figure 4.
Address for reprint requests and other correspondence:
L. J. Teppema, Dept. of Anesthesiology, Leiden University Med-
ical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
(e-mail: l.j.s.m.teppema@lumc.nl).
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Luc J. Teppema and Albert Dahan
Physiol Rev 90:675-754, 2010. doi:10.1152/physrev.00012.2009

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