J Appl Physiol
88: 18401852, 2000.
Ventilatory responses to specific CNS hypoxia
in sleeping dogs
AIDAN K. CURRAN, JOSHUA R. RODMAN, PETER R. EASTWOOD,
KATHLEEN S. HENDERSON, JEROME A. DEMPSEY, AND CURTIS A. SMITH
The John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine,
University of Wisconsin, Madison, Wisconsin 53705
Curran, Aidan K., Joshua R. Rodman, Peter R. East-
wood, Kathleen S. Henderson, Jerome A. Dempsey, and
Curtis A. Smith. Ventilatory responses to specific CNS
hypoxia in sleeping dogs. J Appl Physiol 88: 18401852,
2000.Our study was concerned with the effect of brain
hypoxia on cardiorespiratory control in the sleeping dog.
Eleven unanesthetized dogs were studied; seven were pre-
pared for vascular isolation and extracorporeal perfusion of
the carotid body to assess the effects of systemic [and,
therefore, central nervous system (CNS)] hypoxia (arterial
PO2 5 52, 45, and 38 Torr) in the presence of a normocapnic,
normoxic, and normohydric carotid body during non-rapid
eye movement sleep. A lack of ventilatory response to sys-
temic boluses of sodium cyanide during carotid body perfu-
sion demonstrated isolation of the perfused carotid body and
lack of other significant peripheral chemosensitivity. Four
additional dogs were carotid body denervated and exposed to
whole body hypoxia for comparison. In the sleeping dog with
an intact and perfused carotid body exposed to specific CNS
hypoxia, we found the following. 1) CNS hypoxia for 525 min
resulted in modest but significant hyperventilation and hypo-
capnia (minute ventilation increased 29 6 7% at arterial
PO2 5 38 Torr); carotid body-denervated dogs showed no
ventilatory response to hypoxia. 2) The hyperventilation was
caused by increased breathing frequency. 3) The hyperventila-
tory response developed rapidly (,30 s). 4) Most dogs main-
tained hyperventilation for up to 25 min of hypoxic exposure.
5) There were no significant changes in blood pressure or
heart rate. We conclude that specific CNS hypoxia, in the
presence of an intact carotid body maintained normoxic and
normocapnic, does not depress and usually stimulates breath-
ing during non-rapid eye movement sleep. The rapidity of the
response suggests a chemoreflex meditated by hypoxia-
sensitive respiratory-related neurons in the CNS.
carotid body; hypoxic depression; chemoreceptors; hypocap-
nia
OUR STUDY WAS CONCERNED with the effect of brain
hypoxia on cardiorespiratory control in the sleeping
dog. The effects of central nervous system (CNS) hyp-
oxia are controversial; some of this controversy may
result because the effects of CNS hypoxia appear to be
critically dependent on the experimental preparation
used. Hypoxic depression of ventilation has been clearly
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked advertisement in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
1840 8750-7587/00 $5.00 Copyright r 2000 the American Physiological Society
demonstrated in anesthetized animals that have been
carotid body denervated, have been made hypoxemic
with CO (27, 28, 32), or have specific pontomedullary
hypoxia (51). In contrast, when hypoxia was applied to
carotid body-denervated awake animals, most studies
reported that ventilation was unchanged or increased
rather than depressed (46, 8, 13, 20, 22, 25, 35, 45).
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However, Miller and Tenney (29) did observe alveolar
hypoventilation in response to hypoxia in unanesthe-
tized, carotid body-denervated cats. In awake goats
with carotid bodies maintained normoxic and normocap-
nic by means of extracorporeal perfusion, a marked
ventilatory stimulation was observed in response to
specific CNS normocapnic hypoxia (11).
On the basis of the limited data available in physi-
ological preparations, the effects of CNS hypoxia on
ventilatory control appear to be critically dependent on
such key factors as state of consciousness, whether the
carotid chemoreceptors are intact, and the duration of
hypoxia (3). Our studies provide new information about
the controversial problem of CNS hypoxic effects on
ventilatory control, because 1) we used a preparation
with an intact, as opposed to denervated, carotid body,
2) we studied the effects of CNS hypoxia in non-rapid
eye movement (REM) sleep, and 3) we examined the
cardiorespiratory responses to CNS hypoxia over a
wide range of systemic hypoxia [arterial PO2 (PaO2) 5
3555 Torr] and duration of hypoxic exposure (seconds
to minutes).
METHODS
Seven mixed-breed female dogs (2025 kg) were used in
the study. Our protocol and methods were approved by the
Animal Care and Use Committee of the University of Wiscon-
sin, Madison.
Chronic Instrumentation
Two surgical sessions were required, separated by $2 wk.
All surgery was performed under general anesthesia (,1%
halothane in O2) with use of sterile technique. Appropriate
pre- and postoperative medications were administered (anti-
biotics and analgesics).
In the first surgical session, we implanted a catheter in the
abdominal aorta via a small branch of the right femoral
artery. Fine-wire electrodes were sewn into the crural dia-
phragm via a small thoracotomy at T89. A five-lead electroen-
cephalogram (EEG)/electrooculogram montage was installed
subcutaneously over the cranium and near each orbit. All
catheters and electrode leads were tunneled subcutaneously
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 CNS HYPOXIA IN SLEEP
and exteriorized near the scapulae. Arterial catheters were
filled with 10,000 U/ml heparin solution when not in use.
In the second session, we prepared one group of dogs for
carotid body perfusion (Fig. 1) (48). We confirmed vascular
isolation of the carotid sinus region by manually occluding
the common carotid artery and external carotid artery and
withdrawing blood via the cannulated lingual artery. The
carotid sinus region would visibly collapse and remain col-
lapsed if vascular isolation was successful. Catheters were
tunneled subcutaneously and exteriorized in the dorsal as-
pect of the neck. Catheters were filled with 10,000 U/ml
(arterial) or 1,000 U/ml (venous) heparin solution when not in
use. The animals were allowed $24 h of recovery before
studies began. No studies were performed until body tempera-
ture and breathing frequency were within normal limits for a
given dog.
In a second group of dogs, we performed bilateral carotid
body denervation by isolating both carotid sinus regions and
stripping away the surrounding tissue. Successful denerva-
tion was confirmed after recovery (12 days postdenervation)
by means of bolus injections of sodium cyanide.
Carotid Body Perfusion
Dogs lay unrestrained on a bed in an air-conditioned,
sound-attenuated chamber. The extracorporeal perfusion cir-
cuit was primed with ,800 ml of saline, 120 ml of autologous
blood, and 5,000 U of heparin (derived from beef lung;
supplemented with 2,500 U/h). PCO2, PO2, and pH in the
perfusion circuit were matched to a given dogs eupneic
values by adjustment of the gas concentrations supplying the
circuit and by addition of NaHCO3. The carotid sinus region
was perfused at flow rates ,100 ml/min, which raised the
pressure in the sinus region by 510 Torr. Before data
acquisition, a 30-min period of normal perfusion of the carotid
sinus region was used to ensure uniformity between systemic
and extracorporeal circuit blood.
1841
Measurements
Ventilatory variables were obtained via a tight-fitting
facemask connected to a heated pneumotachograph. Crural
diaphragm electromyogram (EMG) signals were amplified
and recorded as raw signals and as a moving time average
(rectified; 100-ms time constant; CWE). One-milliliter arte-
rial and circuit blood samples were obtained at regular
intervals from the aortic catheter or circuit and analyzed for
pH, PCO2, and PO2 on a blood-gas analyzer (model ABL-300,
Radiometer). The blood-gas analyzer was validated daily
with dog blood tonometered with three different combinations
of PO2 and PCO2 covering the range encountered in the
experiments. Samples were corrected to the dogs rectal
temperature and also for any tonometer corrections. Except
during blood sampling, blood pressure was recorded continu-
ously from the aortic catheter. Airway PO2 and PCO2 were
recorded continuously from the facemask and analyzed by a
mass spectrometer (model MGA-1100, Perkin-Elmer).
Protocol
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Normocapnic, normoxic, and normohydric carotid body
perfusion was maintained throughout each trial, thus main-
taining normal conditions at the carotid body, despite sys-
temic (CNS hypoxia) hypoxia. Each trial was performed
during stable non-REM sleep (occasional brief state changes
were encountered, but data from these periods were not
used), and there were 614 trials per dog. Each carotid body
perfusion trial consisted of a 5- to 10-min control period
followed by 525 min of systemic hypoxia at one of three
levels: mild (PaO2 > 52 Torr), moderate (PaO2 > 45 Torr), and
severe (PaO2 > 38 Torr). Each dog underwent a similar
protocol before the carotid sinus isolation surgery to provide
the whole body hypoxic response data reported here (i.e.,
both carotid bodies and CNS were hypoxic).
Fig. 1. Schematic of isolated carotid body
(CB) perfusion in dog (ventral view). On dogs
left side, arterial supply to brain is left intact
but carotid body is removed (CBX). On dogs
right side, lingual artery is cannulated and
internal carotid, occipital, cranial laryngeal,
and cranial pharyngeal arteries are ligated.
Extracorporeal perfusion of carotid body is
shown in progress. External carotid occluder
is inflated. Blood is withdrawn from venous
cannula and passed through an extracorpo-
real oxygenator (which allows investigators to
control blood-gas tensions) and then contin-
ues through circuit to perfuse carotid body/
carotid sinus region. During carotid body per-
fusion, flow (,100 ml/min) is retrograde
through carotid body/carotid sinus region at a
pressure that is slightly (510 Torr) greater
than systemic pressure. Endogenous perfu-
sion of carotid body can be reestablished in
,2 s by deflating occluder on external carotid
and turning stopcocks to cause recirculation
of blood within extracorporeal circuit. jv, Jugu-
lar vein; ca, common carotid artery.
1842 CNS HYPOXIA IN SLEEP

The carotid body-denervated dogs were exposed to three
levels of hypoxia similar to those described above for 510
min each during periods of wakefulness or non-REM sleep. At
least 15 min elapsed between trials.
Data Analysis
Mean data were collected from 1-min segments of data for a
given condition and time point. Statistical comparisons were
made with Friedmans repeated-measures test on ranks
combined with Dunnetts test for multiple comparisons with
control. Changes were considered significant if P , 0.05.
RESULTS
Eupneic Control
Eupneic, air-breathing control measurements were
obtained in each dog in two different conditions: 1)
before surgical preparation for carotid body perfusion
(i.e., both carotid bodies were intact) and 2) after the
dogs had been surgically prepared for carotid body
per se has no effect on ventilation when perfusate blood
gases and pH values are matched to eupneic values.
Transient Ventilatory Responses to Hypoxia
Whole body hypoxia. We use data from our most
severe level of hypoxia (PaO2 5 37.5 6 0.8 Torr) to
illustrate the transition from air breathing to hypoxia
(Fig. 2). All dogs responded rapidly to hypoxia; inspired
minute ventilation (VI) and VT increased significantly
and end-tidal PCO2 (PETCO2) decreased significantly by
2040 s of hypoxic exposure (P , 0.05). Breathing
frequency also tended to increase slightly, particularly
after ,40 s of hypoxic exposure, but did not achieve
statistical significance. Occasional brief episodes of
changes in sleep state occurred in some dogs during
these trials; data from these periods were not used.
The time course of the ventilatory responses obtained
during the transitions from air breathing to mild or
moderate hypoxia was similar to that obtained with

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perfusion (i.e., with unilateral carotid body denervation
and perfusion catheters in place; see METHODS). In the
second condition the dogs were carotid body perfused
for $5 min with blood that closely approximated their
normal, non-carotid body-perfused eupneic values while
breathing room air (carotid body PCO2 5 38.4 6 1.3 Torr,
carotid body PO2 5 99.7 6 3.9 Torr, carotid body pH 5
7.386 6 0.02). In both conditions, measurements were
obtained after $5 min of air breathing during non-
REM sleep before each trial of systemic hypoxia in-
duced via reduced inspired O2 fraction. In both types of
eupnea, typical canine arterial blood gases and pH and
stable ventilatory patterns were observed (Table 1),
although the postoperative controls showed a mild
hyperpnea due to increased breathing frequency and
tidal volume (VT). All dogs manifested this mild hyper-
pnea (but not hyperventilation) postoperatively, prob-
ably because of the slightly elevated body temperatures
(0.2 6 0.2C) encountered in the postoperative period.
We showed previously (47) that carotid body perfusion
severe hypoxia, but the responses were smaller in
magnitude and usually did not achieve statistical sig-
nificance within the first 2 min of hypoxic exposure. We
illustrate this point with the PETCO2 data for these
conditions in Fig. 3.
CNS hypoxia. We use a polygraph record (Fig. 4) and
data from our most severe level of hypoxia (PaO2 5
37.9 6 1.2 Torr; Fig. 2) to illustrate the transition from
air breathing to hypoxia. All dogs responded rapidly to
hypoxia; PETCO2 decreased significantly by 2040 s of
hypoxic exposure, and breathing frequency increased
significantly by 4060 s of hypoxic exposure. Breath-by-
breath VI was clearly tending to increase after 2040 s
of exposure to hypoxia in most dogs but did not quite
achieve statistical significance (P , 0.072). Unlike the
situation in whole body hypoxia, the early increase in
ventilation was mediated exclusively by increased
breathing frequency, inasmuch as there was no signifi-
cant change or even a discernible trend in VT for at
least the first 2 min of hypoxic exposure in all dogs.

Table 1. Control values for whole body and CNS hypoxia

PaCO2 , PaO2 , [HCO2
3 ], TI, TE, f, VI, VT,
n pH Torr Torr mmol/l s s breaths/min l/min VT/TI liter TI/TT

Whole body hypoxia

Premild hypoxia control 7 7.361 39.2 99.1 21.6 2.19 4.08 9.83 3.72 0.18 0.38 0.36
6 0.007 6 0.5 6 1.0 6 0.2 6 0.10 6 0.29 6 0.43 6 0.32 6 0.02 6 0.02 6 0.02
Premoderate hypoxia control 7 7.364 39.0 98.1 21.5 2.26 4.10 9.85 4.01 0.19 0.41 0.36
6 0.007 6 0.7 6 1.8 6 0.3 6 0.11 6 0.37 6 0.55 6 0.42 6 0.02 6 0.03 6 0.02
Presevere hypoxia control 6 7.373 40.9 96.2 23.0 2.24 4.22 9.83 3.81 0.18 0.40 0.36
6 0.007 6 1.1 6 1.3 6 0.6 6 0.14 6 0.49 6 0.75 6 0.38 6 0.02 6 0.04 6 0.02
CNS hypoxia
Premild hypoxia control 7 7.375 41.8 96.3 22.8 1.50 2.55 14.71 5.32 0.26 0.40 0.36
6 0.015 6 1.4 6 3.1 6 0.6 6 0.11 6 0.34 6 1.10 6 0.33 6 0.02 6 0.07 6 0.01
Premoderate hypoxia control 6 7.345 39.8 98.7 21.3 1.41 2.09 18.37 5.81 0.24 0.33 0.40
6 0.012 6 1.6 6 3.6 6 0.7 6 0.11 6 0.33 6 2.88 6 0.86 6 0.02 6 0.02 6 0.03
Presevere hypoxia control 7 7.346 41.5 94.5 22.0 1.65 2.85 15.00 4.74 0.22 0.35 0.39
6 0.010 6 1.0 6 3.1 6 0.4 6 0.08 6 0.63 6 1.86 6 0.52 6 0.03 6 0.05 6 0.05
Values are means 6 SE; n, number of dogs. CNS, central nervous system; PaO2 , arterial PO2 ; PaCO2 , arterial PCO2 ; [HCO2 3 ], HCO3
2

concentration; TI, inspiratory duration; TE, expiratory duration; f, breathing frequency; VI, inspired minute ventilation; VT/TI, inspiratory
duty cycle; VT, tidal volume; TT, respiratory cycle duration.
 CNS HYPOXIA IN SLEEP
Occasional brief episodes of changes in sleep state
occurred in some dogs during these trials; data from
these periods were not used.
The time course of the ventilatory responses obtained
during the transitions from air breathing to mild or
moderate hypoxia was similar to the observations
obtained with severe hypoxia, but the responses were
smaller in magnitude and usually did not achieve
statistical significance within the first 2 min of hypoxic
exposure. We illustrate this point with the PETCO2 data
for these conditions in Fig. 3.
1843
Fig. 2. Transient responses to severe
whole body hypoxia (A) and severe cen-
tral nervous system (CNS) hypoxia (B)
[arterial PO2 (PaO2) 5 38 6 0.8 and 38 6
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1.2 Torr, respectively] during non-rapid
eye movement (non-REM) sleep. Each
line represents breath-by-breath data
from 1 dog. Time 0 (vertical dashed
line), point at which end-tidal PO2 fell
below 60 Torr. Horizontal dashed line,
no change from normoxic control val-
ues. Gaps in lines represent excluded
data due to brief state changes. Note
rapid onset of ventilatory response in
whole body and CNS hypoxia. During
first 120 s, ventilatory response to CNS
hypoxia is mediated entirely by in-
creased breathing frequency (f). PETCO2,
end-tidal PCO2; VI, inspired minute ven-
tilation; VT, tidal volume.
Steady-State Responses (5 min)
Whole body hypoxia. Figure 5 summarizes the minute-
by-minute ventilatory responses to 5 min of whole body
hypoxia. Whole body hypoxia increased ventilation in a
graded way as the severity of hypoxia increased, reach-
ing a steady state by the 2nd min of hypoxic exposure.
This increased VI was due to increases in breathing
frequency and VT and inspiratory duty cycle (VT/TI) as
inspiratory and expiratory time (TI and TE, respec-
tively) decreased. The rate of rise of the moving time
1844 CNS HYPOXIA IN SLEEP

Fig. 3. Transient whole body (A and C)

and CNS (B and D) DPETCO2 responses
to mild and moderate hypoxia at PaO2 5
52 6 0.6 and 45 6 0.7 Torr (A and C,
respectively) and 52 6 1 and 44 6 0.6
Torr (B and D, respectively) during
non-REM sleep. Each line represents
breath-by-breath data from 1 dog.
Time 0, point at which PETO2 fell below
60 Torr. Horizontal dashed line, no
change. Although responses are smaller
in magnitude than those of severe hyp-
oxia, time course of hyperventilation is
similar.

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average of the crural diaphragm EMG increased in
about two-thirds of all trials. The increased ventilation
was a true hyperventilation, inasmuch as PETCO2 de-
creased progressively in all dogs as PaO2 decreased.
CNS hypoxia. Figure 5 summarizes the minute-by-
minute ventilatory responses to 5 min of CNS hypoxia.
CNS hypoxia increased ventilation in a graded way as
the severity of hypoxia increased, although the magni-
tude of the changes was smaller than that observed
during whole body hypoxia. The time course of response
was similar, reaching a steady state by the 2nd min of
hypoxic exposure. This increased VI was attributable

Fig. 4. Polygraph record of air breathing-to-hypoxia transition in a dog in which carotid bodies were maintained
normocapnic, normoxic, and normohydric via perfusion. Relative to control, between 20 and 40 s of CNS hypoxic
exposure (starting from point at which PETO2 # 60 Torr), breathing frequency increased 2 breaths/min, PETCO2
decreased 2 Torr, heart rate increased 11 beats/min, and mean arterial blood pressure increased 6 Torr. EMGdi,
diaphragmatic electromyogram; BP, blood pressure; EOG, electrooculogram; EEG, electroencephalogram.
CNS HYPOXIA IN SLEEP 1845

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Fig. 5. Minute-by-minute means of
PETCO2, VI, VT, inspiratory duty cycle
(VT/TI), and breathing frequency for
mild (PaO2 5 52 6 0.6 Torr) and severe
(PaO2 5 38 6 0.8 Torr) whole body
hypoxia (A; n 5 7) and mild (PaO2 5
52 6 1 Torr) and severe (PaO2 5 38 6 1
Torr) CNS hypoxia (B; n 5 5). Moderate
hypoxia is not shown because some 2-
to 4-min points could not be used due to
brief EEG arousals. Hyperventilatory
responses to whole body hypoxia were
progressive with severity of hypoxia
and due to increased VT and breathing
frequency; responses to CNS hypoxia,
although similar in time course, were
smaller in magnitude and due entirely
to increased breathing frequency. * Sig-
nificantly different from control (P ,
0.05).
1846 CNS HYPOXIA IN SLEEP
Fig. 6. Steady-state ventilatory re-
sponses to prolonged, severe, whole body
(A) and CNS (B) hypoxia in same 4
dogs. All points were obtained during
stable non-REM sleep. Each symbol
represents 1 dog. PaCO2, arterial PCO2.
entirely to increases in breathing frequency mostly as a
result of decreases in TE and lesser decreases in TI. VT
was unchanged or tended to decrease, so neither VT/TI
nor the rate of rise of the crural diaphragm EMG
changed significantly. The increased ventilation was a
true hyperventilation, inasmuch as PETCO2 decreased
progressively with severity of hypoxia in all dogs.
Prolonged Hypoxia (1025 min)
Whole body hypoxia. Four of the seven dogs were
exposed to our most severe level of whole body hypoxia
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(PaO2 5 37.5 6 0.8 Torr) for up to 1525 min. Occasional
brief EEG arousals occurred, but the steady-state data
shown in Fig. 6 were obtained in stable non-REM sleep.
Arterial PCO2 (PaCO2) tended to reach a plateau or
continued to decrease slightly after 5 min of hypoxia.
VT and breathing frequency were more variable, but
the net result was VI that reached a plateau by 5 min of
hypoxic exposure or decreased slightly relative to the
5-min point.
CNS hypoxia. The same four dogs were exposed to
our most severe level of whole body hypoxia (PaO2 5
 CNS HYPOXIA IN SLEEP 1847

37.9 6 1.2 Torr) for up to 1525 min while the carotid

bodies were maintained normoxic, normocapnic, and
normohydric via perfusion. Occasional brief EEG arous-
als occurred, but the steady-state data shown in Fig. 6
were obtained in stable non-REM sleep. PaCO2 de-
creased in three of the four dogs and reached plateaus
by 5 min of hypoxic exposure. One dog progressively
retained CO2 between 5 and 15 min of hypoxic expo-
sure. PaCO2 changes were generally reflected in changes
in VI. VT and breathing frequency were more variable,
but increased breathing frequency was usually the
dominant component of the increased VI.
Blood Pressure and Heart Rate Responses to Whole
Body and CNS Hypoxia
Whole body hypoxia. Figure 7 shows minute-by-
minute means of mean arterial blood pressure and
heart rate during exposure to our most severe level of
hypoxia (PaO2 5 37.5 6 0.8 Torr). Mean arterial blood

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Fig. 8. Ventilatory response to hypoxia (510 min at each level) in 4
dogs with carotid bodies intact (A) and after carotid body denervation
(B) during wakefulness (n 5 2) or non-REM sleep (n 5 2). All dogs had
a brisk hyperventilatory response to hypoxia when intact; these same
dogs had virtually no response 12 days after carotid body denerva-
tion.

pressure and heart rate increased progressively up to 4

Fig. 7. Blood pressure (MAP) and heart rate (HR) responses to severe
whole body (A) and CNS (B) hypoxia (PaO2 5 38 6 0.8 and 38 6 1.2
Torr, respectively). Note progressive increase in MAP and HR in
severe whole body hypoxia and lack of significant change in severe
CNS hypoxia. b/min, Beats/min.
min of hypoxic exposure.
CNS hypoxia. Figure 7 shows minute-by-minute
means of mean arterial blood pressure and heart rate
during exposure to our most severe level of hypoxia
(PaO2 5 37.9 6 1.2 Torr). The control values were
elevated relative to whole body controls. There were no
significant changes in mean arterial blood pressure or
heart rate in the first 3 min of hypoxic exposure,
although there was a slight trend toward increased
heart rate.
Hypoxia and Carotid Body Denervation
During non-REM sleep or wakefulness in four unanes-
thetized, carotid body-denervated dogs, there was no
overall ventilatory response (i.e., no change in PaCO2 or
VI) to a wide range of hypoxia (PaO2 5 3055 Torr; Fig.
8). However, in all four dogs, breathing frequency
1848 CNS HYPOXIA IN SLEEP
increased 26 breaths/min and VT decreased 50
100 ml.
DISCUSSION
In summary, we have found that 525 min of expo-
sure to specific CNS hypoxia (PaO2 5 3555 Torr)
during non-REM sleep in dogs did not depress ventila-
tion; rather, there was significant hyperventilation.
The hyperventilation was mediated entirely by in-
creased breathing frequency, unlike the larger hyper-
ventilation observed during whole body hypoxia, which
was mediated by increases in breathing frequency and
VT. Initiation of the ventilatory response to CNS hy-
poxia was rapid: the time course was comparable to
that observed during whole body hypoxia. Most dogs
maintained hyperventilation for up to 1525 min of
CNS hypoxia; only one of the four dogs studied over the
longer term manifested hypoxic ventilatory depression.
Blood pressure and heart rate did not change signifi-
cantly in response to CNS hypoxia.
We conclude that specific CNS hypoxia, when the
carotid bodies are intact and normoxic and normocap-
nic, usually stimulates breathing. The rapidity of the
response suggests a chemoreflex meditated by hypoxia-
sensitive respiratory-related neurons in the CNS.
Limitations of the Study
Adequacy of carotid body isolation. A crucial assump-
tion in our study is that the remaining carotid body is
completely isolated from the systemic circulation when
it is perfused and, therefore, cannot contribute to the
observed responses to arterial hypoxemia. A corollary of
this assumption is that the intact aortic bodies (or any
other putative peripheral chemosensors) have a negli-
gible effect on ventilation and blood pressure in the
range of hypoxia we used. We believe these are reason-
able assumptions, because large boluses of intravenous
sodium cyanide, known to elicit ventilatory responses
much larger than any we observed during CNS hy-
poxia, failed to produce any ventilatory or blood pres-
sure responses when given while the carotid body was
perfused (see METHODS). In addition, carotid body-
denervated dogs (with intact aortic chemoreceptors)
showed no ventilatory responses to the same doses of
sodium cyanide, which would seem to rule out a signifi-
cant contribution from aortic chemoreceptors. Also, the
ventilatory responses observed during CNS hypoxia
were qualitatively different from those observed during
whole body hypoxia (increased breathing frequency
only vs. mostly increased VT), suggesting that different
sets of receptors were stimulated.
Is brain blood flow compromised during carotid body
perfusion? Our technique requires temporary occlusion
of the external carotid artery and ligation of several
arterial branches in the carotid sinus region. It is well
known that the normal response of brain vasculature to
hypoxia is a vasodilatation leading to increased cere-
bral blood flow, which in turn results in CNS alkalosis
and, presumably, reduced stimulation of medullary
chemoreceptors. In fact, this is one of the mechanisms
proposed to explain ventilatory depression in response
to CNS hypoxia (31). We presume that this increased
cerebral blood flow also occurred in our studies of CNS
hypoxia, at least when PaO2 was ,50 Torr, but we
cannot be sure that this increase in cerebral blood flow
does indeed occur in our preparation with potentially
compromised cerebral blood flow. If this mechanism of
increased cerebral blood flow/CNS hypocapnia was
reduced in our preparation, then the net effect of any
direct hypoxic CNS stimulation and inhibition due to
hypocapnia would be biased against ventilatory depres-
sion. However, the absence of increased cerebral blood
flow would not explain the ventilatory stimulation we
showed with CNS hypoxia. We do not believe that brain
blood flow is compromised in our preparation because
of the extensive collateral circulation in the canine
brain (12) and the fact that basilar artery flow in the
dog has been shown to increase more than threefold
with acute occlusion of both common carotid arteries
(44). However, there is also evidence to suggest that the
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external carotid artery carries a significant amount of
the total cerebral blood flow, possibly as much as 40% of
the amount supplied by the internal carotid artery (23).
To our knowledge, the functional significance of ipsilat-
eral occlusion of the internal and external carotids is
unknown.
Poikilocapnia. We let PaCO2 change spontaneously
with breathing; usually this resulted in hypocapnia.
Consequently, we did not examine a pure effect of CNS
hypoxia but, rather, the combination of hypoxia and
hypocapnia. This implies that we probably underesti-
mated the ventilatory response to CNS hypoxia, and
this is supported by contrasting the present findings
with the 70% increase in ventilation in the carotid
body-perfused awake goat exposed to CNS hypoxia but
with systemic isocapnia maintained (11). We used
poikilocapnia, because we wished to avoid the problem
of even very small errors in PaCO2 while we were
attempting to maintain isocapnia, which might have
caused central chemoreceptor-induced ventilatory
stimulation. This approach also allowed us to deter-
mine the precise onset and time course of the ventila-
tory response from the initiation of systemic hypoxia.
Nevertheless, we recognize that our ventilatory re-
sponses beyond the first few breaths of hypoxia repre-
sent the net effect of hypoxic stimulation and hypocap-
nic inhibition. It would have been ideal to use isocapnic
and hypocapnic CNS hypoxia. However, our prepara-
tion had a finite life, permitting only a limited number
of trials, so we chose to do repeated poikilocapnic trials
across a range of PaO2.
Comparison With Other Models Used to Study
Ventilatory Effects of Central Hypoxia
Previous studies have used three basic approaches to
address the question of ventilatory responses to CNS
hypoxia. Although they were useful, each approach had
certain limitations that we hoped to avoid.
Anesthetized models. Depressive effects of CNS hy-
poxia on ventilation are seen consistently in anesthe-
tized preparations, usually with CO-induced hypox-
emia and with PaCO2 and blood pressure controlled (27,
 CNS HYPOXIA IN SLEEP
28, 32). The major limitation here is that anesthesia
obtunds the entire nervous system and therefore re-
sponses may not reflect the physiology of the unanesthe-
tized state.
Carotid body-denervated models. Awake, carotid body-
denervated dogs, in which denervation was confirmed
independently with cyanide injection, show virtually no
ventilatory response (i.e., 61 Torr PETCO2 or PaCO2) to
PaO2 between ,25 and 35 Torr (5, 20) (Fig. 8). The use of
sodium cyanide to test for peripheral chemosensitivity
is important in carotid body denervation studies, be-
cause it provides an independent test of peripheral
chemosensitivity; denervations can be incomplete, re-
turn of peripheral chemosensitivity is possible, and/or
other peripheral chemoreceptors (e.g., aortics) could be
upregulated over time. In awake rabbits, goats, and
ponies, again in which denervation was confirmed
independently with cyanide injection, virtually no ven-
tilatory response to acute hypoxia has been observed (5,
13, 45).
All the foregoing denervation studies were done
during wakefulness. One might predict that hypoxic
ventilatory depression in a carotid body-denervated
preparation would be most likely to occur during sleep,
when ventilatory drive is low. In the present study,
however, we found no ventilatory response (increase or
decrease) to hypoxia during non-REM sleep in the
unanesthetized, carotid body-denervated dog. It is note-
worthy, however, that ventilatory pattern changes still
occurred (see RESULTS). These findings are consistent
with those of Bowes et al. (6), who showed no discern-
ible change in ventilation when carotid body-dener-
vated, sleeping dogs were exposed to hypoxia.
Carotid body denervation models also have limita-
tions. Chiefly, these are the loss of tonic chemoreceptor
afferent input to the respiratory controller and the
potential for central remodeling when carotid sinus
afferents are destroyed (39). It would clearly be desir-
able to keep the carotid bodies intact but isolated from
the systemic circulation.
Intact but vascularly isolated and perfused carotid
bodies. Intact, awake goats with extracorporeal perfu-
sion of the vascularly isolated carotid body, in which
brain and carotid body O2, CO2, and pH were controlled
independently, manifested clear hyperpnea when the
systemic circulation (including the brain) was made
hypoxic (isocapnia maintained) and the carotid body
was maintained normoxic and normocapnic (11). Not
only was there a hyperpnea, but there was no effect of
CNS hypoxia on the ventilatory manifestation of short-
term potentiation after abrupt removal of hypoxic
carotid chemoreceptor stimulation, an effect that had
been thought to be quite labile to CNS hypoxia (2, 14).
Despite the fact that the foregoing study was done
during wakefulness and isocapnia, the results of the
present study are consistent with this idea, i.e., that
CNS hypoxia in unanesthetized, carotid body-intact
animals generally causes ventilatory stimulation rather
than depression.
In summary, we believe there are three major advan-
tages of our preparation compared with other prepara-
1849
tions reported in the literature. The first advantage is
lack of anesthesia. Anesthetized preparations consis-
tently depress ventilation in response to CNS hypoxia;
unanesthetized preparations do not. Another advan-
tage is intact carotid bodies. Preparations with one
intact carotid body maintain some low level of tonic
chemoreceptor input to the respiratory controller, and
the intact connections appear to prevent central remod-
eling that may occur in response to denervation. Fi-
nally, we believe that sleep is an advantage, in that
non-REM sleep eliminates behavioral responses unre-
lated to the ventilatory effects of CNS hypoxia. Further-
more, given the marked qualitative differences in the
response to CNS hypoxia between sleep and anesthe-
sia, it is clear that extrapolations from the anesthetized
to the unanesthetized but sleeping animal are unwar-
ranted.
CNS Hypoxia: Implications for Respiratory
and Cardiovascular Control in Sleep
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on January 19, 2017
and in Sustained Hypoxia
Non-REM sleep is a physiological state in which
baseline respiratory motor output is reduced, as are the
ventilatory responses to hypoxia and hypercapnia. Fur-
thermore, ventilatory depression and even apnea can
occur in non-REM sleep with even very small decreases
in PaCO2 (40). It has also been suggested that the
periodic breathing during sleep in hypoxia might be
attributed in part to the depressive effects of CNS
hypoxia, especially on the ventilatory manifestation of
short-term potentiation (2, 14), a known stabilizer of
breathing. Our data do not confirm this concept, be-
cause ventilation increased with CNS hypoxia, and this
increase was sustained for many minutes, even in the
presence of mild systemic hypocapnia during non-REM
sleep. Rather, as in the awake, carotid body-perfused
goat (11), our data would suggest that CNS and carotid
body hypoxic stimulation contribute to the elevated
ventilation normally attending hypoxia during sleep
(or wakefulness). Our studies were not sufficiently
comprehensive to permit a quantitative comparison of
CNS hypoxia effects between wakefulness and sleep.
The mechanisms mediating the increased blood pres-
sure and heart rate observed in response to hypoxia in
the intact animal are complex (7). The pressor response
is attributed to increased sympathetic vasoconstrictor
effects, which in turn are known to be mediated by
carotid body stimulation (7) and by CNS hypoxia (49).
In CNS hypoxia in our sleeping dogs, we observed a
slight tendency for blood pressure and heart rate to
increase, but this response was highly variable. We
found this surprising in view of the clear sympathetic
excitation elicited by brain hypoxia in the anesthetized
rat (48). It is also important to emphasize that we
observed no tendency toward depression of blood pres-
sure and heart rate with CNS hypoxia. We did not
measure blood flow or vascular resistance, and these
would be important to know to demonstrate whether
our unanesthetized, intact preparation showed a sym-
pathetically mediated vasoconstriction similar to that
seen with CNS hypoxia in anesthetized rats (42).
1850 CNS HYPOXIA IN SLEEP
A time-dependent ventilatory response to hypoxia
has been described whereby the response peaks in the
first few minutes and then gradually declines toward
control values (24). Furthermore, the ventilatory re-
sponse to acute hypoxia does not return for a substan-
tial time period after the sustained hypoxic exposure
(24). An effect of sustained hypoxia causing CNS depres-
sion of ventilation has been proposed to explain this
hypoxic ventilatory decline (roll-off) (31). However,
our data in CNS hypoxia sustained for up to 25 min
showed a persistent hyperventilatory response in three
of the four dogs tested, even in the face of a reduction in
PaCO2 (Fig. 6). These data in sleep confirm the persis-
tent hyperventilation seen over several minutes of
sustained CNS hypoxia in the awake goat with intact
perfused carotid bodies that were maintained normoxic
and normocapnic (11, 46). Accordingly, we favor the
explanation that the source of hypoxic ventilatory
decline in prolonged hypoxia may be the time-depen-
dent central inhibitory effects of sustained carotid
sinus nerve stimulation rather than CNS hypoxic de-
pression of ventilation per se (3). Indirect evidence in
support of this claim is the absence of any time-
dependent hypoxic ventilatory decline in carotid body-
denervated animals (25) and the increased release of
dopamine in the nucleus tractus solitarius with sus-
tained stimulation of carotid sinus nerve afferents (15).
However, a ventilatory depression was observed during
long-term hypoxic exposure in one dog in the present
study. An effect of the duration of CNS hypoxic expo-
sure and/or a threshold for CNS hypoxic depression
(which might vary between individuals and species)
cannot be excluded.
Mechanism of Ventilatory Stimulation
by CNS Hypoxia
Hypoxia-sensitive CNS neurons require tonic carotid
body afferent input. The hyperventilation observed in
response to CNS hypoxia in this study and the rapid
time course of response suggest a central O2-sensitive
chemosensor-like mechanism. Because the carotid bod-
ies cannot be directly involved, this must mean that
CNS neurons were responding to the hypoxia to medi-
ate the ventilatory and cardiovascular responses. Given
the different responses to CNS hypoxia between intact
and carotid body-denervated animals, we speculate
that tonic, low-level carotid body afferent input to the
CNS is required for the CNS-mediated hyperventila-
tory response to hypoxia. One approach to test this
hypothesis would be to assess central hypoxic re-
sponses while carotid chemoreceptor output was mini-
mized with a hyperoxic local perfusion.
A role for sympathetic efferents? In our experimental
model with an intact carotid body, it is important to
note that sympathetic efferent activity stimulated by
CNS hypoxia (48) could potentially modulate carotid
body sensitivity by altering blood flow through the
carotid body or by direct effects on the carotid chemore-
ceptor type I cells. This might explain an increase in
ventilation, even in the face of a carotid body main-
tained normoxic and normocapnic via perfusion. How-
ever, the role of carotid sinus nerve sympathetic effer-
ents, if any, is controversial. Electrical stimulation of
sympathetic fibers inhibits (36) or augments (30, 36)
carotid body output. Some found an augmentation of
the carotid body hypoxic response when sympathetics
to the carotid body were cut (16, 21, 41), whereas others
found no significant effect on the ventilatory responses
to acute or chronic hypoxia in awake (43) and anesthe-
tized (9, 26) preparations. Furthermore, we observed
that CNS hypoxia caused hyperventilation exclusively
by increased breathing frequency, whereas hypoxic
carotid body stimulation increased VT and breathing
frequency (11, 46). Regardless of whether sympathetics
have a role in the response to specific CNS hypoxia, it
seems clear to us that the hypoxia is sensed initially by
the CNS.
A role for CNS lactacidosis? Another possible mecha-
nism of the ventilatory response to CNS hypoxia is the
elaboration of lactic acid by the brain. It is known that
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on January 19, 2017
acidification occurs on the medullary surface when
systemic hypoxia is induced (18, 32). Arguing against
this mechanism is the fact that brain lactacidosis would
presumably also occur in the carotid body-denervated
preparation, yet no hyperventilatory response was
observed under these conditions. Also, the time course
of acidification does not correlate with the ventilatory
measurements observed in the present study; medul-
lary surface acidification required 1.52 min for the
initial response, whereas ventilation in the present
study began to change within 20 s of hypoxic exposure
(32, 52).
It is also not clear whether CNS lactacidosis is in fact
a ventilatory stimulant. Systemic pretreatment with
dichloroacetate (DCA), a blocker of lactic acid produc-
tion, enhanced the acute hyperventilatory response to
hypoxia (1) in awake goats. Similar findings were
obtained in the anesthetized cat (33); systemic DCA
treatment prevented the hypoxia-mediated fall in med-
ullary surface pH, yet phrenic activity was maintained
until extremely low arterial O2 contents were reached.
However, when applied topically to the surface of the
ventrolateral medulla in anesthetized cats, DCA again
prevented the hypoxia-mediated fall in medullary sur-
face pH, but the time course and magnitude of the
decrease in phrenic activity were essentially identical
to the pretreatment response (33). Taken together,
these data suggest that hypoxia-induced CNS lactacido-
sis is depressant to ventilation or has no role in
ventilatory control.
A role for higher centers? The fact that the hyperven-
tilatory response to CNS hypoxia in our animals con-
sisted of an increase in breathing frequency with
maintained VT might implicate an indirect role for
supramedullary structures, as proposed some time ago
by Tenney and colleagues (29, 38, 50). These authors
also observed a tachypneic response to various levels of
hypoxia in awake carotid body-denervated cats; how-
ever, unlike the hyperventilatory response in our ca-
rotid body-intact dogs, they showed a reduced VT and
VI with CO2 retention. Their subsequent studies in
decerebrate and decorticate animals led them to postu-
 CNS HYPOXIA IN SLEEP
late that this tachypneic response was due to CNS
hypoxic depression of cortical structures, which in turn
would remove the inhibitory influence normally ex-
erted by the cortex on rate-facilitating neurons in the
diencephalon, thereby facilitating the hypoxia-induced
increase in breathing frequency. This mechanism might
be especially important in non-REM sleep, during
which higher CNS structures may be more susceptible
to depression by hypoxia.
Our data do not permit us to say whether the
hyperventilation we observed is due to a true chemore-
flex or a hitherto unappreciated nonspecific effect of
CNS hypoxia. In any case, it has been demonstrated
that many respiratory- or cardiovascular-related neu-
rons in the medulla or hypothalamus depolarize in
response to hypoxia (10, 17, 19, 34, 42, 48, 49). The fact
that these neurons do depolarize in response to physi-
ological levels of hypoxia suggests a potential means of
transduction of CNS hypoxia to enhanced neural respi-
ratory motor output. On the other hand, many of these
same studies have shown that other medullary neurons
hyperpolarize in response to hypoxia. If indeed there is
a direct effect of hypoxia on these medullary or hypotha-
lamic neurons to cause the observed hyperventilatory
response to CNS hypoxia, then we must conclude that
the net effect is weighted in favor of excitation, even in
the sleeping state, where we would expect the baseline
(normoxic) activity of medullary neurons to be de-
pressed relative to the state of wakefulness (37).
The technical assistance of Maria Zayas and Andrew Neeb is
gratefully acknowledged.
This work was supported by National Heart, Lung, and Blood
Institute Grants HL-50531 and HL-07654.
Address for reprint requests and other correspondence: C. A.
Smith, 504 N. Walnut St., Madison, WI 53705-2368 (E-mail: casmith4
@facstaff.wisc.edu).
Received 7 June 1999; accepted in final form 11 December 1999.
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