J Appl Physiol 116: 858–866, 2014.

Review First published December 26, 2013; doi:10.1152/japplphysiol.01126.2013.

HIGHLIGHTED TOPIC Hypoxia

Role of chemoreception in cardiorespiratory acclimatization to, and

deacclimatization from, hypoxia
Jerome A. Dempsey,1 Frank L. Powell,2 Gerald E. Bisgard,1 Gregory M. Blain,3 Marc J. Poulin,4
and Curtis A. Smith1
1
University of Wisconsin-Madison, Madison, Wisconsin; 2University of California-San Diego, La Jolla, California;
3
University of Nice Sophia Antipolis, Nice, France; and 4University of Calgary, Calgary, Alberta, Canada
Submitted 9 October 2013; accepted in final form 11 December 2013

Dempsey JA, Powell FL, Bisgard GE, Blain GM, Poulin MJ, Smith CA.
Role of chemoreception in cardiorespiratory acclimatization to, and deacclimati-
zation from, hypoxia. J Appl Physiol 116: 858 – 866, 2014. First published Decem-
ber 26, 2013; doi:10.1152/japplphysiol.01126.2013.—During sojourn to high alti-
tudes, progressive time-dependent increases occur in ventilation and in sympathetic
nerve activity over several days, and these increases persist upon acute restoration
of normoxia. We discuss evidence concerning potential mediators of these changes,
including the following: 1) correction of alkalinity in cerebrospinal fluid; 2) increased
sensitivity of carotid chemoreceptors; and 3) augmented translation of carotid chemo-
receptor input (at the level of the central nervous system) into increased respiratory
motor output via sensitization of hypoxic sensitive neurons in the central nervous
system and/or an interdependence of central chemoreceptor responsiveness on
peripheral chemoreceptor sensory input. The pros and cons of chemoreceptor
sensitization and cardiorespiratory acclimatization to hypoxia and intermittent
hypoxemia are also discussed in terms of their influences on arterial oxygenation,
the work of breathing, sympathoexcitation, systemic blood pressure, and exercise
performance. We propose that these adaptive processes may have negative impli-
cations for the cardiovascular health of patients with sleep apnea and perhaps even
for athletes undergoing regimens of “sleep high-train low”!
carotid chemoreceptor; CSF [H⫹]; chemoreceptor interdependence; CNS sensiti-
zation

DURING SOJOURN TO THE HYPOXIA of high altitudes, a progressive
time-dependent hyperventilation occurs over the initial several
days of sojourn. On return to sea level normoxia, the hyper-
ventilation persists, slowly returning to presojourn levels
(Fig. 1). This time-dependent ventilatory acclimatization and
deacclimatization also occurs during all sleep states (7) and is
slightly more pronounced during exercise (24). These features
are also present in several mammals, including the rat, goat,
and pony, although these species complete ventilatory accli-
matization in a shorter time period than humans, who continue
to increase the intensity of hyperventilation even over 10 –15
days or more (11, 23, 60). Note in Fig. 1 that arterial PO2 (PaO2)
increases substantially as ventilatory acclimatization proceeds,
which means, by definition, that the ventilatory response to the
prevailing hypoxemia is increasing with time. Most of the
continued hyperventilation on return to normoxia is completed
within 1–3 days, although the duration of this continued
hyperventilation will depend on the duration of the stay in
hypoxia (25, 48).
Address for reprint requests and other correspondence: J. A. Dempsey,
Univ. of Wisconsin-Madison, 4245 MSC, 1300 Univ. Ave., Madison, WI
53706 (e-mail: jdempsey@wisc.edu).
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How are ventilatory acclimatization and deacclimatization
mediated? These processes are complex and multifaceted and,
to date, have been only partly resolved. We now examine
hypotheses that include separate, independent contributions
from peripheral and central chemoreceptors, as originally pro-
posed 50 years ago, as well as current hypotheses that incor-
porate newer (and controversial) concepts of cardioventilatory
control based on plasticity of chemosensitivity, multiple sites
of hypoxic sensing, interdependence of central and peripheral
chemoreceptors, and an upregulation of central nervous system
(CNS) neurons comprising respiratory and sympathetic regu-
latory pathways.
INCREASED CENTRAL CHEMORECEPTOR INPUT FROM THE
COMPENSATION OF CSF [Hⴙ]
This concept proposed that acute hypoxia stimulated the
carotid chemoreceptors, causing hyperventilation and systemic
and cerebral spinal fluid (CSF) hypocapnia and respiratory
alkalosis, and that, over time, while arterial pH remained
alkaline, CSF and, therefore, central chemoreceptor pH would
be quickly restored to normal, achieved via “active transport”
of bicarbonate across the blood-brain barrier. This compensa-
tory process would gradually return the central chemoreceptor
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Cardiorespiratory Acclimatization and Deacclimatization
Fig. 1. Time course of ventilatory acclimatization to hypoxia (over 11 days)
and deacclimatization from hypoxia (over 24 h of normoxic restoration) in
resting sea level (SL) natives sojourning at 4,300 m altitude (Mt. Evans, CO).
Note the alkalization of arterial plasma and to a nearly identical extent
cerebrospinal fluid (CSF), throughout the sojourn at high altitude. Changes in
arterial PCO2 (PaCO2) reflect the degree of hyperventilation according to the
alveolar gas equation: PACO2 ⫽ 863/[(V̇E/V̇CO2) ⫻ (1 ⫺ VD/VT)], where PACO2
is alveolar PCO2, V̇E is minute ventilation, V̇CO2 is CO2 production, VD is dead
space volume, and VT is tidal volume. In this example at 4,300 m, the 13- to
15-Torr total reduction in PaCO2 represents a 35– 40% increase in alveolar
ventilation from chronic normoxia to 10 –11 days in hypoxia. PaO2, arterial
PO2. [Adapted from Forster et al. (35).]
drive to breathe back to normal, which, when combined with a
constant excitatory input from the hypoxic carotid chemore-
ceptors, would gradually increase ventilation, thereby account-
ing for time-dependent ventilatory acclimatization. Then, on
acute restoration of normoxia and reduction of peripheral
chemoreceptor inputs, the small initial increase in arterial PCO2
would acidify the CSF (with an already reduced [HCO⫺ 3 ]) and
maintain hyperventilation at greater than control (chronic nor-
moxic) levels until CSF [HCO⫺ 3 ] and pH were gradually
restored to normal (17, 53, 70). This attractive, integrative
hypothesis has been shown to be unlikely for several reasons.
1) CSF pH during acclimatization was shown to be incom-
pletely compensated with the same time course and to the same
extent (i.e., 60 –70%) as that in arterial plasma. Thus CSF
alkalinity increased or remained constant as hyperventilation
intensified over time (23, 86) (see Fig. 1). Similarly, on acute
reoxygenation following acclimatization, CSF pH was either
equivalent to, or alkaline to, sea level control values in the face
of continued hyperventilation (25).
2) Equally important, over time during recovery in normoxia
or “deacclimatization” from hypoxia, CSF pH changed in an
acid direction as the level of hyperventilation was gradually
reduced, and PCO2 in arterial blood and CSF rose over the first
24 h of restoration of normoxia (25).
Thus, during either acclimatization to or recovery from
chronic hypoxia, CSF pH appeared to be primarily determined
by, rather than a determinant of, ventilatory acclimatization
and deacclimatization. These data, obtained by measuring
lumbar CSF acid-base status in humans, were confirmed via
cisternal CSF measurements in nonhuman species (11, 25).
Finally, arterial hypocapnic alkalosis does not appear to be
required for ventilatory acclimatization to or deacclimatization
from hypoxia. When end-tidal PCO2 was precisely controlled at
normocapnic levels (via increased inspired fraction of CO2)
over several hours of constant hypoxia, a normal, time-depen-
dent ventilatory acclimatization occurred in awake goats (9).
Similarly, in humans, following many hours of hypoxic expo-
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• Dempsey JA et al. 859
sure, significant hyperventilation continued on acute restora-
tion of normoxia (or acute hyperoxia) whether end-tidal PCO2
was maintained normocapnic or allowed to fall during the
hypoxic exposure (32, 79). Furthermore, spontaneous hyper-
ventilation was shown to persist following 26 h of voluntarily
maintained hypocapnia in humans, and the level of this spon-
taneous, sustained hyperventilation was greater when the day-
long hypocapnia was accompanied by hypoxia. This additional
sustained stimulatory effect of hypoxemia on ventilation in the
posthypoxic period occurred even though the arterial and CSF
pH were identical (and significantly alkaline to normocapnic
control levels) at the termination of both the normoxic and
hypoxic hypocapnic periods (26).
CAROTID CHEMORECEPTOR SENSITIZATION
There is now substantial evidence showing the critical im-
portance of carotid chemoreceptors and their time-dependent
sensitization to ventilatory acclimatization to chronic hypoxia.
1) Bilateral carotid body (CB) denervation prevents ventila-
tory acclimatization to high altitude, even in the face of very
severe levels of hypoxemia (PaO2 29 –31 Torr) (75). Even
though brain lactic acidosis is greatly augmented and brain
intracellular acidosis occurs in these conditions of extreme
hypoxia (56), this is not sufficient, in the absence of carotid
chemoreceptors, to elicit ventilatory acclimatization.
2) Recordings of single-unit carotid sinus nerve (CSN)
activity in anesthetized goats showed an increase and then a
plateau over the initial hour of hypoxia, but thereafter in-
creased progressively over the remaining 3 h (58). These data
demonstrated that CB sensitization occurs relatively early in
the time course of exposure to hypoxia. Cross-sectional studies
in anesthetized cats also confirmed that several days of hypoxic
exposure elicited increases in CSN activity at any given PaO2
during superimposed acute hypoxia (3, 84). Upregulation of
neuromodulators ATP (42), endothelin-1 (16), and angiotensin
II (43) have all been implicated in this carotid chemoreceptor-
specific sensitization (64).
3) When the carotid chemoreceptor of the awake goat was
isolated and perfused with hypoxic blood for 6 h (via an
extracorporeal gas exchanger), ventilatory acclimatization pro-
ceeded normally (see Fig. 2). Time-dependent ventilatory ac-
climatization did not occur (i.e., beyond the acute response) if
the isolated, perfused carotid chemoreceptor was stimulated
with hypercapnia, rather than hypoxia (8).
4) Increased protein expression occurred in rat carotid
chemoreceptors over the first few days of moderate hypoxic
exposure (85), and these newly generated type I glomus cells in
the CB remained for several weeks after return to normoxia
(85). Thus, in contrast to the hypoxic-induced apoptosis or cell
death often reported in the CNS (2), the carotid chemoreceptor
glomus cells appear to thrive and multiply under conditions of
sustained oxygen lack.
While the critical role of CB sensitization in ventilatory
acclimatization to hypoxia seems clear, it is less clear that this
sensitization, by itself, accounts for the continued hyperventi-
lation on acute return to normoxia. On the positive side, in the
rat, Chen et al. (16) reported an elevation in CSN activity
(above that in chronic normoxia) on restoration of acute nor-
moxia after the third day (but not during the first 2 days) of
hypoxic exposure. Furthermore, as noted above, new type I
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860 Cardiorespiratory Acclimatization and Deacclimatization • Dempsey JA et al.

In awake, CB denervated animals, physiological levels of

Fig. 2. Perfusion of the isolated carotid chemoreceptor in the intact awake goat
showed that a hypoxic carotid chemoreceptor combined with a normoxic
systemic circulation resulted in a normal ventilatory acclimatization and
deacclimatization on return to normoxia. Additional studies with this prepa-
ration also showed that, unlike carotid body (CB) hypoxemia, CB hypercapnia
increased ventilation acutely but did not elicit a time-dependent hyperventila-
tion. [Adapted from Bisgard and Forster (11).]
glomus cells in the CB remained for several weeks after return
to normoxia (85). On the negative side, the CSN activity was
shown to return immediately to control on reoxygenation after
4 h of rising activity during isocapnic hypoxia in the anesthe-
tized goat (10). Furthermore, even after hypoxic acclimatiza-
tion was complete in the intact animal, bilateral CB denerva-
tion reduced, but did not eliminate, continued hyperventilation
on acute restoration of normoxia (3).
ENHANCED CNS TRANSLATION OF CAROTID
CHEMORECEPTOR INPUT
hypoxia usually have no significant effect on ventilation (13,
19). In contrast, when awake or sleeping animals with a
vascularly isolated, intact carotid chemoreceptor that is per-
fused with normoxic, normocapnic blood are exposed to hyp-
oxia via reduced inspired fraction of O2, a dose-dependent
mildly tachypneic hyperventilation is observed. This response
is initiated within 20 –25 s of hypoxic onset, persists for 25 min
or longer, and amounts to ⬃20 –30% of the total ventilatory
response to combined CB and CNS hypoxia (11, 19, 30) (see
Fig. 4). These findings are consistent with the hypoxic-induced
depolarization of many (but not all) cardiorespiratory neurons
in the ventral-lateral medulla (59, 67). Given the tachypneic
nature of the ventilatory response to CNS hypoxia in the awake
animal (Fig. 4), this hyperventilatory response might also be
attributed to depression of cortical neurons, which, in turn,
would remove the inhibitory influence normally exerted by the
cortex on “rate-facilitating” neurons in the diencephalon (80).
So, acute CNS hypoxia, per se, elicits ventilatory stimulation
in the unanesthetized animal so long as an intact carotid
chemoreceptor provides tonic (normal) input to the medulla.
However, use of the isolated carotid chemoreceptor prepara-
tion in the goat exposed to 6 h of systemic hypoxemia (with
isolated carotid bodies maintained normoxic and normocapnic)
showed that sustained CNS hypoxia, per se, in the absence of
increased carotid chemoreceptor stimulation, does not elicit a
further time-dependent hyperventilation, i.e., beyond that ob-
tained in acute CNS hypoxia (14). These negative findings
speak against a time-dependent effect of CNS hypoxia per se.
However, the possibility remains that the sustained increases in
CSN activity in chronic hypoxia may enhance the stimulatory
effect of CNS hypoxia and possibly other inputs to the auto-
nomic control system as well (also see SUMMARY below).

Dwinell and Powell used a unique approach in the anesthe-

tized rat to show that 1 wk of hypoxia significantly increased
the phrenic nerve response to supramaximal electrical stimula-
tion of the CSN, as measured in a background of acute hyperoxia
following prolonged hypoxic exposure (29) (see Fig. 3).
These data suggest that sensitivity is increased at the level of
those CNS neurons concerned with translation of CSN input
into ventilation (also see below). Indirect findings in humans
(36) and rats (87) also showed that chronic hypoxia markedly
augmented the ventilatory response to a pharmacological CB
stimulus (doxapram HCl), again when the stimulus was applied
in an acutely hyperoxic background following acclimatization
to moderate hypoxia (36).
In summary, the available data would attribute ventilatory
acclimatization and deacclimatization to both time-dependent
sensitization of carotid chemoreceptor sensory input, as well as
a “central enhancement” of this input. We now discuss two
potential means whereby this central enhancement might oc-
cur, namely via hypoxic-sensitive neurons in the CNS and/or
as a consequence of central/peripheral chemoreceptor interde-
pendence.
CNS Hypoxia Fig. 3. Increased response of phrenic nerve activity to carotid sinus nerve
(CSN) electrical stimulation in anesthetized rats in chronic normoxia and in
Acute CNS hypoxia in anesthetized animals resulted in no acute normoxia following seven days in hypoxia. [From Dwinell and
change in ventilation or a ventilatory depression (50, 57, 83). Powell (29).]

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Cardiorespiratory Acclimatization and Deacclimatization • Dempsey JA et al. 861

Fig. 4. Ventilatory effects of hypoxia presented to both the CB chemoreceptors and central nervous system (CNS) or isolated to the CNS. Inspired fraction of
O2 was reduced for 5–7 min each at three levels of hypoxemia during quiet wakefulness or non-rapid eye movement sleep in 11 (mean ⫾ SE) canines under
1) intact, control conditions in which both the carotid chemoreceptors and the CNS were exposed to the hypoxemia (); and 2) with the vascularly isolated CB
chemoreceptor, which was maintained normoxic and normocapnic via extracorporeal circulation ({), thereby allowing only the CNS to be exposed to the
hypoxemia. Note the dose-dependent tachypneic hyperventilatory response to CNS hypoxemia alone, which averaged about one-third the ventilatory response
observed in the intact condition where both CB and CNS are hypoxic. Mean inspiratory flow (V̇I) rate [VT/inspiratory time (TI)] and rate of rise of diaphragm
electromyogram (EMG) (not shown) were also increased significantly with CNS hypoxia conditions alone. Normoxic control values from intact and CB isolated
conditions, respectively, averaged 3.8 and 4.8 l/min V̇I (A), 42 and 40 Torr PaCO2 (B), 0.4 and 0.4 liter VT (C), and 10 and 13 beats/min breathing frequency (fb;
D). Data were obtained from Ref. 19, combined with additional unpublished observations from the author’s laboratory.

Peripheral Chemoreceptor Influences On Central CO2
Chemosensitivity
Recent evidence points to an interdependence of central
medullary chemoreceptor activity on input from several
sources. Guyenet and associates (38, 39) have recorded directly
from CO2 sensitive neurons in the retrotrapezoid nucleus
(RTN) of the rat medulla. They found 1) that a direct glutamin-
ergic pathway exists to the RTN from carotid chemoreceptors
via the nucleus tractus solitarius; 2) that central CO2 chemo-
sensitive neurons also increased their activity in response to
systemic hypoxia or to sodium cyanide, and that this response
was eliminated following CB denervation; and 3) that inputs to
the RTN from other areas, such as the hypothalamus and
pulmonary stretch receptors from the lung, also influence the
activity of RTN CO2-sensitive cells. In other words, the re-
sponsiveness of the central CO2 chemoreceptors in the RTN is
not dependent only on the CO2/H⫹ in their immediate envi-
ronment (23, 70). Rather, in addition, they appear to also be
dependent on the magnitude and source of several synaptic
inputs that these neurons receive, and the carotid chemorecep-
tors are one important source of input affecting central chemo-
receptor function.
The functional consequences of these neuronal connections
to ventilatory control have been addressed in a variety of
experimental preparations. The findings remain highly contro-
versial, as summarized recently in a three-sided debate with
proponents representing additive, hypoadditive, or hyperaddi-
tive effects on ventilation resulting from carotid chemorecep-
tor-central chemoreceptor interactions (28, 81, 88). We rea-
soned that, given the neuronal interconnections (39), the testing
of their functional importance would require an experimental
preparation wherein chemoreceptors were anatomically sepa-
rated, major sources of influence on both sets of chemorecep-
tors were uncompromised, and in which chemosensitivity re-
mained in the physiological range. Accordingly, we used the
isolated, perfused CB preparation in the awake canine in which
we superimposed central hypercapnia (via increased inspired
fraction of CO2) on a background of normal, inhibited or
stimulated input from the isolated carotid chemoreceptor. As
summarized in Fig. 5 (12), we found a hyperadditive effect of

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862 Cardiorespiratory Acclimatization and Deacclimatization • Dempsey JA et al.

Fig. 6. Schematic of central-peripheral chemoreceptor interdependence. Shown

Fig. 5. Interdependence of carotid and medullary chemoreceptors. In a canine, are the traditional concept supporting only separate chemoreceptor functions
the carotid chemoreceptor is denervated on one side. The remaining carotid (solid lines) and the newer concept of interdependent chemoreceptor function
chemoreceptor is vascularly isolated from the systemic and cerebral circulation (dashed lines). NTS, nucleus tractus solitarius; RTN, retrotrapezoid nucleus;
and perfused extracorporeally. The central chemoreceptor response to CO2, by CPG, central pattern generator. See Fig. 5 and text for explanation and
itself, is determined by steady-state inhalation of CO2-enriched air. Animals references to original research.
were studied during quiet wakefulness. Note that, when the isolated CB is
inhibited (CB PCO2 ⫽ 20 Torr and CB PO2 ⬎ 500 Torr), the central CO2
response was reduced to about one-fifth of normal, and when the isolated CB and then remains elevated on return to normoxia, even after up
was stimulated (CB PO2 ⫽ 40 Torr, CB PCO2 ⫽ 40 Torr), the central CO2 to 3–5 days in normoxia (40) (see Fig. 7). As explained above
response increased an average of twofold. The data shown here in one animal
were typical of the hyperadditive responses observed in 8 dogs. The ventilatory for ventilation, the carotid chemoreceptors are also critical to
response slope changes shown here were accompanied by comparable changes the acute sympathetic response, and carotid chemoreceptor
in VT, fb, VT/TI, and diaphragm EMG. [Borrowed with permission from Blain sensitization and its central amplification coincides with the
et al. (12).] time-dependent increase in MSNA. Furthermore, the continued
elevation in MSNA on return to normoxia may rely, at least in
part, on residual, sustained increases in CSN activity (62) (see
carotid chemoreceptor input on central chemoreceptor CO2 also SUMMARY below). Other similarities are that only hypoxic
responsiveness, whereby stimulating the isolated CB with and not CO2-induced increases in MSNA elicited a persistent
hypoxia increased and inhibiting CB input via hyperoxic, after-effect on normoxic restoration (90), and also that hypoxic
hypocapnia markedly reduced the ventilatory response to cen- receptors in the rostral ventrolateral medulla have been shown
tral CO2. These findings are consistent with the substantial to drive a sympathetic response to CNS hypoxia (77). On the
suppressive effect of bilateral CB denervation on ventilatory other hand, a clear difference between sympathetic vs. venti-
responses to focal medullary CO2-induced acidosis in the latory responses to hypoxia in the human is that a substantial,
awake goat (44), to steady-state hyperoxic CO2 inhalation in sustained after-effect of hypoxia on elevating MSNA (upon
the awake (68) or anesthetized dog (6) and awake human, as
well as the so-called “late phase” CO2 ventilatory response in
the human (5, 21, 31). We propose that this hyperadditive
effect of carotid chemoreceptor output on central chemorecep-
tor gain (see Fig. 6) might contribute importantly to time-
dependent ventilatory acclimatization as carotid chemorecep-
tor sensitivity increases over time in hypoxia. Moreover, we
suspect that the time-dependent increase in carotid chemore-
ceptor input also elicits changes in elements of the control
system itself that might contribute to the continued, gradually
diminishing hyperventilation upon return to normoxia (also see
SUMMARY below). Of course this possibility awaits resolution of
the controversy over the functional nature of peripheral-central
interdependence.

SYMPATHETIC ACCLIMATIZATION/DEACCLIMATIZATION TO
HYPOXIA
There are many similarities in the ventilatory and sympa-
thetic vasoconstrictor responses to chronic hypoxia (18, 47).
Like ventilation, muscle sympathetic nerve activity (MSNA) in
humans increases slightly on acute hypoxic exposure, is sub-
stantially further augmented over several days at high altitude,
Fig. 7. Muscle sympathetic nerve activity (MSNA) recorded via microneu-
rography from the peroneal nerve in three healthy SL natives (A–C) in
chronic normoxia (SL), after 4 wk at 5,260 m altitude, and after 3 days’
descent to SL normoxia. The increase in MSNA in chronic hypoxia was
accompanied by significant increases in systemic mean arterial blood
pressure, reductions in limb blood flow, and increase in vascular resistance.
[Borrowed with permission from Hansen et al. (40).]

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Cardiorespiratory Acclimatization and Deacclimatization
Fig. 8. Contrast of the ventilatory and respiratory gas exchange responses to
exercise at 3,100-m altitude in acclimatized sojourners (solid line) vs. native or
long-term resident highlanders (dashed line). V̇O2, O2 consumption; Q̇c, pul-
monary blood flow. Note the greater hyperventilation (lower PaCO2) during all
exercise levels in the sojourners in contrast to the near isocapnic hyperpnea in
the highlander. However, the PaO2 is similar between the groups because the
lung diffusion capacity (DLCO) is greater, and the alveolar PO2-to-PaO2 differ-
ence ([A-a]DO2) narrower in the highlander. Shading indicates confidence
limits around the mean. [Data compiled from Refs. 15, 24.]
return to normoxia) occurred after only 20 –30 min of hypoxic
exposure and at a time when ventilation had returned com-
pletely to control levels (55, 90).
SUMMARY
Different sets of overlapping mechanisms may account for
ventilatory and sympathetic acclimatization to, vs. deacclima-
tization from, chronic hypoxia. First, it is likely that CB
sensitization, per se, contributes importantly to the time-depen-
dent ventilatory acclimatization during the hypoxic exposure.
Furthermore, we speculate that this CB sensitization in chronic
hypoxia also contributes to the “central enhancement” of CSN
input by further sensitizing hypoxic-sensitive respiratory neu-
rons in the CNS and/or CO2-sensitive neurons in the RTN. On
the other hand, given the continued hyperventilation obtained
on the acute application of normoxia or even hyperoxia, we
must also conclude that an ongoing raised CSN activity (in the
posthypoxic period) is not required to be present for this
continued hyperventilation to occur. Rather, as has been dem-
onstrated recently in rodent models of prolonged intermittent
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• Dempsey JA et al. 863
hypoxia with attendant CB sensitization (62), the persistent
elevation of respiratory motor output and sympathetic nerve
activity on return to normoxia was dependent on ongoing tonic
hyperactivity of neurons at the level of the paraventricular
nucleus (72) and the rostral ventrolateral medulla (37, 49, 74).
These sustained neuroadaptive responses coincided with up-
regulation of the renin-angiotensin system (33) and of angio-
tensin II type 1 (AT1) receptors in the paraventricular nucleus
(20). Based on these findings, we predict that chronic constant
hypoxia may also elicit chemoreceptor input-dependent long-
term CNS adaptive responses that induce tonic hyperactivity
and acute hyperexcitability of neurons comprising respiratory
and sympathetic regulatory pathways with cardiorespiratory
effects that outlast the hypoxic stimulus.
PHYSIOLOGICAL CONSEQUENCES OF CHEMORECEPTOR
SENSITIZATION AND CARDIORESPIRATORY
ACCLIMATIZATION
Excessive Hyperventilation
The time-dependent increases in ventilation in hypoxia are
critical to minimizing the reduction in alveolar PO2 (and there-
fore arterial O2 saturation) as inspired PO2 is reduced with
increasing altitude. For example, note the progressive rise in
PaO2 over time in Fig. 1, amounting to an increase in arterial
HbO2 saturation from ⬃75% on day 1 to 85% on day 14. The
enhanced hyperventilation and accompanying high alveolar
PO2 are especially critical during heavy-intensity exercise in
the sojourner at high altitude to minimize the magnitude of
exercise-induced arterial hypoxemia in the face of an exercise-
induced widening of the alveolar PO2 to PaO2 difference (24)
(see also Fig. 8). At the same time, during exercise in chronic
hypoxia, the “excess” hyperventilation means a markedly in-
creased work of breathing (82), as well as increased suscepti-
bility to expiratory flow limitation, leading to hyperinflation
and severe dyspneic sensations. Accordingly, studies using
mechanical ventilation to unload the respiratory muscles have
shown that this excessive ventilation and work of breathing in
hypoxia may contribute significantly to exercise performance
limitation because of enhanced respiratory muscle fatigue,
Fig. 9. Acute effects of cyclical sleep apneas and attendant intermittent
hypoxemia on MSNA and systemic blood pressure in a patient with obstructive
apnea during sleep at SL. Each apneic event terminated with a transient arousal
pattern in the EEG (not shown). [Adapted from Dempsey et al. (27).]
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864 Cardiorespiratory Acclimatization and Deacclimatization
resulting in a faster rate of development of locomotor muscle
fatigue (1). In turn, this link between respiratory muscle work
and fatigue and locomotor muscle fatigue may be explained by
a sympathetically mediated redistribution of blood flow from
locomotor to respiratory muscles (41).
In contrast to the sojourner, most long-term high-altitude
residents or natives have blunted (rather than enhanced) hy-
poxic chemosensitivity at both rest (34, 54) and during exercise
(24). Thus highlanders show only minimal hyperventilation
during exercise (i.e., beyond that at rest), in their hypoxic
environment. However, they preserve their PaO2 and O2 satu-
ration during exercise at about the same level as in the
markedly hyperventilating sojourner (24). This highly efficient
preservation of arterial oxygenation occurs because, unlike the
sojourner, the long-term resident highlander has undergone
adaptive morphological changes in the lung parenchyma,
which produce a greatly enhanced alveolar-capillary diffusion
surface area and, therefore, minimizes the alveolar PO2 to PaO2
difference during exercise (15, 24, 45) (see Fig. 8).
Excessive Sympathetic Vasoconstrictor Activity
Theoretically, the enhanced, time-dependent increase in
sympathetic vasoconstrictor activity in chronic hypoxia (40,
66) should help maintain systemic blood pressure by opposing
the vasodilatory effects of systemic local hypoxemia. In acute
hypoxia, this balance appears to occur as systemic blood
pressure is normally unchanged from control. However, after
days to weeks at high altitudes, the vasoconstrictor effects of
excessively high sympathetic outflow in the sojourner appear
to dominate, as manifested in the occurrence of systemic
hypertension throughout the waking and sleeping hours (66,
89). These dominant vasoconstrictor hypertensive effects also
persist for several days on return to sea level (71, 89).
Of clinical relevance, a persistent sympathoexcitatory effect
in the normoxic recovery period following acute hypoxia has
also been observed at sea level (90). This “carry-over” effect
on MSNA has been implicated in the high prevalence of
persistent daytime systemic hypertension in patients with se-
vere obstructive sleep apnea accompanied by nocturnal inter-
mittent hypoxemia (see Fig. 9) (4, 91). Furthermore, when the
intermittent hypoxemia normally attending obstructive sleep
apnea was mimicked (via inspired fraction of O2 manipulation)
in healthy young adults for 8 –10 h/day over 2- to 3-wk periods,
significant increases occurred in daytime (normoxic) MSNA
and systemic BP, together with an increased hypoxic ventila-
tory response, reductions in baroreceptor sensitivity, and in-
creased inflammatory markers (63, 78).1 Studies in the rodent
have shown that chronic intermittent hypoxemia sensitizes
carotid chemoreceptors so that CSN activity remains elevated
on acute return to normoxia (65). A contributive role of
inflammatory cytokines (46) and an upregulation of angioten-
1
In addition to OSA and hypoxemia, excessive sympathetic nerve activity
has been also shown in both animal and clinical experiments to contribute to
the development and progression of hypertension present in congenital hyper-
tension, insulin resistance, and heart failure (61). Afferent signals from the
kidney appear to underlie some of this excess sympathetic drive seen in these
states (69). However, the carotid chemoreceptors have also been implicated,
especially in heart failure, and clinical trials are currently underway to
determine the efficacy of treating at least some types of sympathetically-
mediated diseases via CB denervation (61).
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• Dempsey JA et al.
sin II AT1 receptors (52) in this CB sensitization has been
proposed. The persistence of elevated sympathetic nerve ac-
tivity following intermittent hypoxemia also coincides with
neuroadaptation at several sites of cardiorespiratory regulation
within the CNS (see SUMMARY section above). In the healthy
sojourner to high altitude, periodic breathing during sleep is
common and attributable to increased carotid chemoreceptor
gain effects on sensitizing the hypocapnia-induced apneic
threshold (22). It is likely that this nocturnal periodic breathing
with attendant intermittent hypoxemia contributes to the so-
journer’s daytime hypertension and heightened MSNA.
It is important to determine if these same substantial after-
effects of intermittent hypoxemia on the cardiovascular system
are also produced by the popular practice of “live high:train
low” training regimens (51). Although these athletes are ex-
posed to constant environmental hypoxia (i.e., reduced inspired
PO2) for up to 10 –12 hours/day, cyclical intermittent arterial
hypoxemia will occur when periodic breathing is present. Thus
negative cardiovascular consequences are most likely to occur
in those who choose exposure altitudes greater than 3,000 m at
which periodic breathing during sleep and attendant intermit-
tent hypoxemia are prevalent (7). Perhaps the deleterious
effects of repetitive, cyclical type of intermittent hypoxemia on
endothelial function and the hypersensitization of the carotid
chemoreceptors leading to increased sympathetic vasoconstric-
tion, especially during exercise (76), may counteract the nor-
mal benefits of physical training on blood flow distribution and
O2 transport. In turn, these negative consequences may account
for at least some of the marked heterogeneity of changes in
exercise performance routinely experienced with live high-
train low regimens (51, 73). These hypotheses concerning the
potential complex cardiovascular consequences of sleeping in
hypoxia remain to be tested. In the meantime, we strongly urge
those conducting sleep high-train low regimens to routinely
measure O2 saturation as a marker of periodic breathing and
intermittent hypoxemia during sleep in the hypoxic environ-
ment and to monitor systemic blood pressure in the posthy-
poxic periods. Hopefully, this monitoring process would lead
to a practice of titrating the inspired PO2 in the individual
athlete to achieve a level of nocturnal hypoxemia (i.e., duration
and severity) sufficient to stimulate a positive erythropoetic
effect without triggering cyclical periodic breathing and inter-
mittent hypoxemia. We would predict that achieving this
optimal combination will present a substantial challenge.
GRANTS
The original research reported in this review was funded by National Heart,
Lung, and Blood Institute R01-15469 (J. A. Dempsey), 081823 (F. L. Powell),
15473 (G. E. Bisgard), and 50531 (C. A. Smith) and by an American Heart
Association Association Post-Doctoral Fellowship (G. M. Blain).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: J.A.D. and C.A.S. prepared figures; J.A.D. drafted
manuscript; J.A.D., F.L.P., G.E.B., G.M.B., M.J.P., and C.A.S. edited and
revised manuscript; J.A.D., F.L.P., G.E.B., G.M.B., M.J.P., and C.A.S. ap-
proved final version of manuscript.
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