Am J Physiol Regulatory Integrative Comp Physiol
279: R1378–R1385, 2000.
Circadian rhythms of body temperature and activity
levels during 63 h of hypoxia in the rat
B. BISHOP,1 G. SILVA,1 J. KRASNEY,1 A. SALLOUM,1 A. ROBERTS,1
H. NAKANO,1 D. SHUCARD,2 D. RIFKIN,2 AND G. FARKAS3
Departments of 1Physiology and Biophysics, 2Neurology, and 3Physical Therapy and
Exercise Science, State University of New York at Buffalo, Buffalo, New York 14214
Received 4 January 2000; accepted in final form 26 April 2000
stress that evokes a variety of
behavioral, neural, cardiopulmonary, and hormonal responses. Moderate hypoxia also may lead to long-lasting neuropsychological changes (3), whereas severe
hypoxia may result in irreversible neurocognitive and
sensorimotor deficits (24). Arterial hypoxia is a stress
on health at high altitude and in aircraft cabins, as
well as in disease states including congenital cardiopulmonary disorders, obstructive lung disease, sleep
apnea, and acute altitude illnesses. In small mammals,
including newborn human infants (1, 10, 35), a brief
exposure to acute arterial hypoxia elicits a hypothermic-hypometabolic response that is allometrically related to body mass, with larger animals less likely to
display the response (9). This hypothermic-hypometabolic response has been postulated to be protective
against hypoxia-induced cellular damage, particularly
in the brain (36), as well as to minimize the ventilatory
response (32). It has been shown that small decreases
in the brain temperature limit the magnitude of cellular injury resulting from a prolonged exposure to 10%
O2 combined with ischemia (13).
In most previous studies the hypoxic exposure has
been limited to between 15 min and 2 h and carried out
at various ambient temperatures (Ta), well below the
reported thermoneutral zone of the rat (29–31°C) (14).
The low Ta clearly could influence the parameters of
the hypoxic-hypothermic response (32). Thus our intent was to characterize the full hypoxic effect on the
circadian rhythms of body temperature (Tb) and level
of activity (La) in rats maintained at 29°C, the lower
limit of the thermoneutral zone for rats (14). The rats
were habituated and acclimated to the 29°C Ta (34),
and then the circadian patterns of Tb and La of the rats
were recorded and analyzed for 48 h before, 63 h
during, and 48 h after exposure to an inspired gas
mixture of 10% O2 in N2. Tb normally oscillates in
phase with dark-light cycles. The circadian rhythm of
Tb depends on whether an animal is nocturnal or
diurnal. In the nocturnal rat Tb has its peak during the
night (the dark cycle) and its nadir in the day (light
cycle) (33). The La of the rat also shows a circadian
rhythm that is time-locked to an imposed 12:12-h darklight cycle.
After our study was submitted for publication, Mortola and Seifert (23) published results of a similar
study in which rats were subjected to 10.5% O2 for 7
days but without specifying Ta. They found, as have we,
Address for reprint requests and other correspondence: B. Bishop,
Dept. of Physiology and Biophysics, Sherman Hall/South Campus,
State Univ. of NY at Buffalo, Buffalo, NY 14214 (E-mail:
[email protected]).
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.
adaptations to hypoxia; hypothermic response to hypoxia;
hyperthermic response to hypoxia; hypoxia on activity
HYPOXIA IS A PHYSIOLOGICAL
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0363-6119/00 $5.00 Copyright © 2000 the American Physiological Society
http://www.ajpregu.org
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Bishop, B., G. Silva, J. Krasney, A. Salloum, A. Roberts, H. Nakano, D. Shucard, D. Rifkin, and G. Farkas.
Circadian rhythms of body temperature and activity levels
during 63 h of hypoxia in the rat. Am J Physiol Regulatory
Integrative Comp Physiol 279: R1378–R1385, 2000.—The
hypothermic response of rats to only brief (⬃2 h) hypoxia has
been described previously. The present study analyzes the
hypothermic response in rats, as well as level of activity (La),
to prolonged (63 h) hypoxia at rat thermoneutral temperature (29°C). Mini Mitter transmitters were implanted in the
abdomens of 10 adult Sprague-Dawley rats to continuously
record body temperature (Tb) and La. After habituation for 7
days to 29°C and 12:12-h dark-light cycles, 48 h of baseline
data were acquired from six control and four experimental
rats. The mean Tb for the group oscillated from a nocturnal
peak of 38.4 ⫾ 0.18°C (SD) to a diurnal nadir of 36.7 ⫾
0.15°C. Then the experimental group was switched to 10% O2
in N2. The immediate Tb response, phase I, was a disappearance of circadian rhythm and a fall in Tb to 36.3 ⫾ 0.52°C. In
phase II, Tb increased to a peak of 38.7 ⫾ 0.64°C. In phase III,
Tb gradually decreased. At reoxygenation at the end of the
hypoxic period, phase IV, Tb increased 1.1 ⫾ 0.25°C. Before
hypoxia, La decreased 70% from its nocturnal peak to its
diurnal nadir and was entrained with Tb. With hypoxia La
decreased in phase I to essential quiescence by phase II. La
had returned, but only to a low level in phase III, and was
devoid of any circadian rhythm. La resumed its circadian
rhythm on reoxygenation. We conclude that 63 h of sustained
hypoxia 1) completely disrupts the circadian rhythms of both
Tb and La throughout the hypoxic exposure, 2) the hypoxiainduced changes in Tb and La are independent of each other
and of the circadian clock, and 3) the Tb response to hypoxia
at thermoneutrality has several phases and includes both
hypothermic and hyperthermic components.
HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
that the hypoxia-induced hypothermia did not persist
but reversed and climbed. As will be shown, the amplitude of the rise in Tb at an Ta of 29°C is inconsistent
with the results reported in the paper by Mortola and
Seifert (23).
METHODS
Animals
Experimental Conditions
The all-weather room was soundproof and equipped with
automated systems that permitted tight control of Ta and
lighting cycles over a prolonged period of time. In the present
experiment Ta was set at 29°C and the lighting cycle was set
at a 12:12-h dark-light cycle, switching at 0600 and 1800.
Data Detection
Each cage was placed on a receiver for the temperature
and activity signals transmitted by the implanted probe.
Cages housing the hypoxic rats resided within a large plastic
chamber through which either room air or a 10% O2 in N2 gas
mixture was delivered at a flow rate of 5 l/min (Fig. 1).
Additional cages for the control rats were placed on top of the
plastic chamber, each over a Mini Mitter receiver identical to
those under the cages of the hypoxic group. Each animal was
fed ad libitum and left untethered and undisturbed throughout the 159 h of the experiment.
Creating the Hypoxic Environment
To induce normobaric hypoxia, a nitrogen flood valve was
opened initially for purposes of rapid induction. As the O2
concentration in the chamber approached 10%, preset valves
were opened to maintain a continuous hypoxic (10% O2)
mixture in the chamber. The reduction of chamber gas to the
10% O2 level required 35–40 min and was always initiated at
1700 when Tb and La were rising in their circadian cycles.
Chamber CO2 concentration was always ⬍0.1%. After 63-h
exposure to the hypoxic gas all the valves were closed, and
the chamber was unsealed, making reoxygenation essentially instantaneous. The afternoon after reoxygenation, each
rat was again weighed.
Data Acquisition and Reduction
The Mini Mitter telemetry system permitted collection of
continuous data for the entire 159 h of the experiment. The
temperature-specific frequency and the instantaneous position of an animal were transmitted through a multiplexer
and relayed to a computer in an adjacent room. A Windowsbased software program (VitalView, Mini Mitter) converted
the frequency of the probe to temperature. The probes were
calibrated both before implantation and at the end of an
experiment. All recorded changes in Tb were expressed in
degrees centigrade, and each change in the position of an
animal was expressed as a “count” of activity. Results for
both parameters were tabulated every 15 min. These telemetry signals were converted to an ASCII file format and
entered into the Microsoft Excel Workbook file format.
Graphs of Tb and La over the duration of an experiment (159
h) were generated for each animal.
Data Analysis
Data from animals in each group (i.e., the control and
hypoxic groups) were pooled, when appropriate, and analyzed for a variety of variables, including the averages and
magnitudes of circadian rhythms, the diurnal nadirs, the
nocturnal peaks, and rise and decay times.
RESULTS
Effects of hypoxia on body weight. In Table 1 the
mean body weights for the control and experimental
hypoxic groups before and at the end of the experiment
are listed. After 63-h exposure to 10% O2, the hypoxic
group lost ⬎40 g or about 10% of their body mass. In
contrast, none of the controls lost weight, and some
gained about 10 g over the 159 h.
Fig. 1. Experimental setup in an environmental room
in which temperature and lighting were regulated at a
near constant 29°C and a 12:12-h dark-light cycle for
the duration of an experiment. Each cage, housing one
rat, sat on a telemetry receiver for determining the
body temperature (Tb) and level of activity (La) every 15
min. Cages of the control group sat on top of the sealed
Plexiglas chamber containing the hypoxic group. This
chamber was flushed continuously with room air or
10% O2 at 5 l/min.
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This study was reviewed and approved by the University
at Buffalo Institutional Animal Care and Use Committee.
Ten adult male Harlan Sprague-Dawley rats, with body
weights ranging from 268 to 497 g, were studied. Before the
experiments, a sterile Mini Mitter probe (diameter 10 mm)
for detecting Tb and La was implanted under aseptic conditions in the abdominal cavity of each rat under pentobarbital
sodium anesthesia (40 mg/kg ip). On recovery from surgery
each rat was weighed and then placed in its own cage in an
all-weather room. All animals were exposed to identical baseline conditions. Four of the animals were selected at random
to be included in the experimental hypoxia group.
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HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
Table 1. Mean body weights for control and hypoxic
groups of adult Sprague-Dawley rats at beginning
and end of 159-h experiment conducted at 29°C
Controls
Hypoxics
n
Initial Wt, g
Final Wt, g
%Change
6
4
381.2 ⫾ 38.2
403.1 ⫾ 32.5
390.8 ⫾ 31.7
361.6 ⫾ 31.6
⫹3%
⫺10%
Values are means ⫾ SD; n ⫽ no. of rats. Hypoxic group was
exposed to 63 h of 10% O2.
Body Temperature Responses To Hypoxia
Tb before 10% O2. The oscillations in Tb for the
control animals, as shown by the representative plot in
Fig. 2, peaked at a group average of 38.4 ⫾ 0.18°C (SD)
during the dark cycle and decreased to an average
nadir of 36.7 ⫾ 0.15°C during the light cycle.
Changes in Tb during 10% O2. At the onset of hypoxia Tb decreased dramatically in each of the four rats
(Fig. 3). This hypothermic component of the hypoxiainduced response was similar in magnitude, direction,
and pattern in all animals. For convenience of analysis
we defined four well-demarcated components or phases
in Tb response to hypoxia (Fig. 4). Phase I was from
onset of hypoxia to Tb nadir. Phase II spanned the
elevation of Tb from the nadir to the hyperthermic
peak. Phase III included the decline in Tb from the
hyperthermic peak to the end of the hypoxia. Phase IV
occurred with the termination of hypoxia.
Fig. 2. Typical circadian rhythms and ultradian
oscillations of the Tb (top trace) and of La (bottom
trace) of a rat breathing room air. The periods of the
oscillations are in phase with the 12:12-h darklight cycling. The mean values for this animal were
Tb 37.5°C, nocturnal peak 38.4°C, and daytime
nadir 37.0°C.
Fig. 3. Tb responses of the individual rats in the experimental group
during hypoxia. Responses are plotted for only the hypoxic period.
Data for each rat are represented by a different color.
Phase I, the hypothermic component of the response.
The mean Tb values for the hypoxic group are plotted
along with the mean Tb values for the control group in
Fig. 4. With the onset of hypoxia not only was the Tb
circadian rhythm totally abolished, but Tb, which had
been rising toward its normal nocturnal peak at the onset
of hypoxia, reversed and fell 1.17 ⫾ 0.25°C at an average
rate of ⬃0.50 ⫾ 0.34°C/h (SD) to reach a nadir over the
next 3.5 ⫾ 0.68 h. This decrease carried Tb to a temperature significantly below its normal diurnal nadir. At the
same point in time, Tb for the control group increased by
an average of 0.95 ⫾ 0.19°C to its peak of 37.8°C. Figure
4 shows that the average Tb for the hypoxic group decreased to a minimum of 36.29 ⫾ 0.52°C from its initial
value of 37.42 ⫾ 0.31°C. This initial decline in Tb, comprising phase I of the response, has been reported previously for small mammals (9).
Phase II, the hyperthermic component of the response. Tb, after reaching its hypothermic nadir, reversed and over the next 24 h rose 2.4°C at a rate of
0.10 ⫾ 0.04°C/h to a peak of 38.7 ⫾ 0.3°C. This Tb peak
significantly exceeded the normal prehypoxic noctur-
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Prehypoxic circadian rhythms of Tb and La. As exemplified by the traces from a single animal in Fig. 2,
Tb and La oscillated in phase with the dark-light cycles
in the control rats. Tb oscillated about 1°C around the
mean of 37.0°C with the peak at 38.1°C during the
dark cycle and the mean nadir of 37.1°C during the
light cycle. These rhythms persisted in every control
rat throughout the entire experiment. The magnitudes
of these oscillations were not different from the baseline data recorded in the prehypoxic period from the
hypoxic rats. All Tb prehypoxic traces were superimposable.
HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
nal peak by 0.9°C. This hyperthermia was followed
over the next 13 h by an 0.8°C decline in Tb. The
decline continued but became more gradual, falling to
an average of 37.1 ⫾ 0.4°C. The decline continued at
this slower rate until the termination of the hypoxia.
Phase III of the hypoxia-induced Tb response. The hyperthermia waned slowly over the 35 h following the
hyperthermic peak to an average of 37.1°C, a value not
different from that of the control animals at that point in
time. Whether circadian cycling would have returned if
the hypoxic period had been extended is not known. We
limited hypoxia to 63 h to avoid intrusion of the many
other physiological changes that accompany prolonged
hypoxia. These changes include increases in blood oxygen
capacity, ventilation, and elevated tissue oxygenation
and would confound interpretation enormously.
Reoxygenation. When the hypoxic chamber was
opened to room air Tb increased by 1.1°C over 3 h from
37.1–38.1 ⫾ 0.3°C, its prehypoxic nocturnal peak. The
magnitude of this rise in Tb was equivalent to the
decline in Tb at the onset of hypoxia. Tb remained
above the Tb of the control group until the onset of the
next nocturnal cycle. Over the next two dark-light
cycles a circadian rhythm was reinstated, but the diurnal nadir remained elevated. By this time the Tb
normal circadian rhythm had been reestablished, but
the full range of Tb oscillation was not achieved.
Activity Responses to Hypoxia
Circadian rhythm of La before 10% O2. Before hypoxia, La oscillated in phase with the dark-light cycles
(control data in Fig. 2, and the prehypoxic data in Fig.
5A). As would be expected in a nocturnal animal, the La
oscillations reached a peak of ⬃50 counts/15 min during the dark cycle and a nadir of ⬃7 counts/15 min
during the light cycle. The absolute La varied among
animals. Nonetheless, the periods of the average La
cycles were not different from those for either Tb or the
dark-light cycles.
Changes in La during 10% O2. La, which was rising
at the time the hypoxia was imposed, changed dramatically with the onset of hypoxia as shown in Fig. 5B and
the bottom trace of Fig. 6. The circadian rhythm of La
was totally disrupted, and La gradually fell toward
silence as Tb declined in phase I. Within 7 h of the
onset of hypoxia (i.e., during phase I of the Tb response)
La counts had decreased from their nocturnal peak of
50 counts/15 min to 7 counts/15 min. By the time Tb
reached its hypoxic nadir, La became essentially quiescent despite the fact that the dark cycle was still in
progress. La remained significantly depressed throughout Tb phase II response. In fact, it was during this
phase that La was most depressed by the hypoxia.
During phase II of the Tb response, the activity counts
for the hypoxic rats remained near zero, well below
those of the control group. About 25 h after the onset of
hypoxia, at the onset of phase III when Tb was falling,
La increased somewhat, but remained well below that
of the prehypoxic phase I period or the La of the control
group.
La gradually increased and displayed low-amplitude
oscillations (25 vs. 15 counts/15 min) compared with
the recordings in the prehypoxic period or those of the
control group (50 vs. 7 counts/15 min).
Reoxygenation. In phase IV (and over the first 10 h
after reoxygenation) the amplitude and period of the La
circadian rhythm were fully restored to their normal
prehypoxic values (Figs. 5B and 6).
DISCUSSION
Hypoxia-induced weight loss. The weight gain of the
control group and the weight loss of the hypoxic group
over the 159 h of the experiment (Table 1) support the
concept that hypoxia has important effects on metabolism (10, 26). Sustained hypoxia reduces oxygen consumption by 56% (23).
Circadian rhythms. The Sprague-Dawley rats in this
study were acclimated and maintained at their thermal neutral temperature of 29°C and habituated to
12:12-h dark-light cycles. These oscillations, obtained
at 29°C, are not different from those reported in other
studies in which no mention is made of the Ta (14, 23).
The fact that Tb is tightly entrained to the imposed
12:12-h dark-light cycle, regardless of Ta, is evidence
that the circadian timing system tightly controls the
thermal regulatory machinery independently of Ta.
La also oscillated in phase with the dark-light cycles.
As would be expected in the nocturnal rat, La peaked
during the dark cycle and decreased to a nadir (near
zero) during the light cycle (Fig. 5), confirming the
recent findings of Mortola and Seifert (23). La was more
variable on a moment-to-moment basis than Tb. How-
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Fig. 4. Mean Tb of the control group (black) and hypoxic group (gray)
derived from the continuous recordings during the 6.5 days of the
experiment. The double-headed arrow (near bottom) horizontal bar
indicates onset, duration, and termination of 10% O2 delivery to the
chamber. The arbitrary phases I-IV of the Tb response to hypoxia are
depicted by the vertical lines on the traces of the hypoxic group. With
onset of hypoxia Tb decreases to its nadir in 3 h. This phase I is the
acute hypoxic-hypothermic component of the response. It is followed
by a progressive rise in Tb, the phase II hyperthermic component of
the Tb response. Phase III is the adaptive phase, and phase IV occurs
on reoxygenation.
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HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
ever, the moving averages of La across the dark-light
cycles were relatively reproducible.
Effects of hypoxia on the circadian rhythms. With the
onset of hypoxia the circadian rhythms of both Tb and
La were abolished for the entire 63-h hypoxic exposure
Fig. 6. Average responses of La occurring in relation to the various phases of the Tb response of the
hypoxic group.
(Fig. 6). Hypoxia affected Tb and La differently. The Tb
response to hypoxia was multiphasic, whereas La was
totally suppressed initially and then returned but remained at a low level devoid of circadian rhythm for
the duration of the hypoxia. These differences provide
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Fig. 5. Continuous recordings of La shown as
points of raw data (counts/15 min) and the moving
average (solid line). A: recordings for control
group. B: recordings for the hypoxic group before
and during 10% O2 (as indicated by the doubleheaded arrow).
HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
Potential Mechanisms Underlying the Hypothermia of
the Hypoxia-Induced Responses
Mechanisms inducing the hypothermia remain to be
determined. For hypothermia to occur, heat loss must
exceed heat production (15). This imbalance could be
achieved by decreasing heat production, by increasing
heat loss, or by both. In the rat, the tail serves as a
major thermoregulatory organ (30). In an Ta below the
thermoneutral range, the tail is maximally constricted
(14, 30). In warm environments vasodilation of tail
vessels is a major way a rat loses heat. Another is by
grooming the pelt with saliva, which accelerates evaporative heat loss. In rats acclimated to prolonged heat
stress the parotid saliva glands undergo excessive
growth (14). In the dog, hypoxia acts peripherally on
the oxygen-sensitive receptors in the carotid body to
evoke reflex noncholinergic cutaneous vasodilation (2),
and systemic hypoxia causes cutaneous vasodilation
(4).
Hypoxia is thought to act centrally at innumerable
sites. These include the circadian pacemaker in the
suprachiasmic nucleus (SCN) (6), the thermosensitive
neurons in the thermoregulatory areas of the anterior
and posterior hypothalamus (5, 21), the pontine and
medullary neurons involved in respiratory and cardiovascular control (10), and the raphe nuclei and other
brain regions involved in sleep states. It remains to be
determined what the exact roles of any of these brain
regions, or the central or peripheral chemoreceptors
(10, 19), play in the hypoxia-induced hypothermia or
the subsequent hyperthermia.
Potential Mechanisms Underlying Hyperthermia of
Hypoxic-Induced Responses
Acute hypoxia stimulates an increase in dry heat
loss in the rat (15). The heat loss response is markedly
affected by Ta. At 22°C, the increase in heat loss is
robust; however, at 30°C, there is a modest rise in heat
loss and then a decrease with continued hypoxia. At
32°C, hypoxia causes a decrease in dry heat loss. This
reduction in the heat loss response with rising Ta may
explain the hyperthermic response of hypoxia observed
in this study.
Potential Mechanisms for Hypoxia-Induced Changes
In La
The underlying mechanisms for the sustained suppression of La with the onset and duration of the
sustained hypoxia are not known. It seems highly
unlikely that La was suppressed to minimize heat
production because La suppression was greatest when
Tb was climbing to its hyperthermic peak (phase II)
and was least when Tb was falling during phase III.
For the same reason, it is unlikely that the suppression
of La is a nonspecific response occurring secondary to
the changes in Tb (31). Perhaps some as yet unidentified centrally driven suppression of motor systems is
activated by hypoxia. Hypoxia is known to depress
shivering, nonshivering, and behavioral thermogenesis
by decreasing the set point for thermogenesis (10, 23).
In humans, an acute exposure to hypoxia results in
nausea and vomiting and a general malaise (17). Rats
do not vomit, but their sudden and sustained decrease
in activity in response to hypoxia could be a reflection
of a malaise induced by the hypoxic environment. It
may be that La could serve as a general indicator of the
level of “acute altitude illness” experienced by the rat
along with reduced food and water intake (17).
During hypoxia endogenous opioids are elevated (16)
and may contribute to a decline in the Tb set point (22).
Arginine vasopressin is upregulated, and this response
has been postulated to contribute to the hypoxic response (36). However, Brattleboro rats, which lack
arginine vasopressin, display a prominent hypoxic response (5). Histamine is released centrally during hyp-
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evidence that Tb and La, although interrelated through
metabolic mechanisms (31), do not have obligatory
linkages.
Phase I of the hypoxia-induced Tb response. The
abrupt fall in Tb after the onset of hypoxia was striking
and suggested an immediate activation of mechanisms
designed to drive core temperature to a critical value
that is optimum for maintaining a suitable balance of
oxygen supply vs. demand (25). This hypoxia-induced
hypothermia (phase I, Fig. 5) was not unexpected.
Many species of small animals, along with human
infants, lower their Tb when exposed to hypoxia (1, 9,
35). This fall in Tb and the accompanying fall in metabolism (10) are considered to have survival advantage (36). It has been proposed that this hypoxiainduced hypothermia may confer protection on certain
organs, particularly the brain (36). Small changes in
brain temperature during hypoxia have a marked influence on the magnitude of cellular damage (13).
Phases II and III of the hypoxia-induced Tb response.
Before the Mortola and Seifert (23) study we had not
expected either the transiency of the hypothermic component (phase II) of the Tb response to prolonged hypoxia nor the subsequent hyperthermia. In their rats
(23) the hypoxia-induced hypothermia never rose
above the nadir of the prehypoxic oscillations. In other
words, the Tb in their rats failed to reach the normal
nocturnal Tb, let alone a hyperthermic Tb. In fact, only
after hypoxia was terminated did the peak Tb rise to its
normal nocturnal level in their rats. Both their study
and ours used Sprague-Dawley rats and a sustained
exposure to ⬃10% inspired O2. A likely difference between the protocols in the two studies was the Ta.
Unfortunately, Mortola and Seifert (23) did not report
the Ta at which their study was performed. Our rats
were acclimated and maintained at 29°C for the entire
study. This thermoneutral temperature was selected
for the express purpose of minimizing the need of the
rats to initiate thermoregulatory responses. We now
know, based on unpublished results obtained in our
laboratory, that Ta strongly influences each phase of
the hypoxia-induced response of Tb and La, thereby
accounting for the differences between our results and
those of Mortola and Seifert (23).
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HYPOXIA ABOLISHES RAT TEMPERATURE AND ACTIVITY RHYTHMS
Hypoxic Suppression of Circadian Rhythms
Hypoxia elicited important disturbances of circadian
rhythms for both Tb and La. This observation confirms
the previous study of Poncet et al. (28) who reported
that hypoxia disturbs daily rhythms of central neurotransmitters and the most recent report of Mortola and
Siefert (23). The response patterns of Tb in our study
were independent of the response patterns of La. La
remained suppressed even though Tb rose rapidly in
phase II (Fig. 6). Hypoxia could either affect directly
the output of the circadian pacemaker in the SCN (6) or
the response of the SCN to the zeitgebers; however, no
specific data are available on this point. It is also
probable that hypoxia interferes at some point(s) along
the effector pathways from the SCN to thermoregulatory and motor control centers. These influences may
be due to the direct effects of hypoxia, due to mediators
released by hypoxia, or due to input from specific reflexes such as those evoked by the arterial chemoreceptors. Mortola and Siefert (23) postulated that hypoxia
more likely influences hypothalamic thermoregulatory
centers as opposed to the SCN because a reduction in
the amplitude of the Tb rhythm appeared later in their
hypoxic exposure. However, this notion requires further experimental support as the restoration of the
rhythm could have simply represented partial relief of
hypoxia due to respiratory acclimatization. In any
case, the abolition of circadian patterns by reduced
oxygenation has profound implications for maintaining
important physiological functions such as sleep (27)
and intake of food and water. These functions are
clearly disturbed in this situation (17). Moreover, it is
uncertain as to how long these disturbed circadian
patterns would persist if hypoxia were continued beyond 63 h. Further studies are required to explore this
question.
In summary, this study has revealed that when
adult rats are exposed for 63 h to a sustained 10% O2 in
a 29°C environment, they initially drop their Tb, depress their La, and lose their circadian rhythms for
both variables. When hypoxia is extended past 2 h, the
initial hypothermia (phase I) is followed first by a
relative hyperthermia (phase II) and then a gradual
return toward a “normal” Tb (phase III). This hyperthermic component of the Tb response to prolonged
hypoxia has not been reported previously. The Ta of
29°C is the likely cause. Putative physiological mechanisms are considered to account for each event in this
multifaceted response to prolonged hypoxia.
Perspectives
Hypoxia is a common stimulus encountered whenever one experiences sleep apnea, climbs mountains, or
suffers a pulmonary disease. Hypoxia has long been
recognized as a powerful stimulus that evokes responses in numerous physiological and biochemical
regulatory systems including those controlling the circadian rhythms of Tb and La, respiration, circulation,
thermogenesis, metabolism, and erythropoiesis. The
importance of this study is the demonstration that hypoxia, when introduced in a thermoneutral environment of
29°C, immediately disrupts the circadian rhythms of Tb
and La, causes a severe depression of La, and evokes a
complex three-component response in Tb. On reoxygenation the circadian rhythms of Tb and La immediately
reappear. The challenge for the future is the identification of the physiological, biochemical, and molecular
mechanisms by which hypoxia causes these widespread
and drastic effects.
We acknowledge Dr. David Megirian’s continuing interest and
constructive criticisms throughout this work.
A Multidisciplinary Pilot Project Grant from the University at
Buffalo supported this investigation.
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