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Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Because metabolism is a determinant of
the ventilatory chemosensitivity, we tested the hypothesis that the
ventilatory response to acute and prolonged hypercapnia is adjusted to
the circadian oscillations in oxygen consumption
(
O2). Adult rats were instrumented for
measurements of body temperature (Tb) and activity by
telemetry. Pulmonary ventilation (E) was measured by
the barometric method and O2 by the
flow-through method. In the acute experiments, 16 conscious rats
entrained to a 12:12-h light (L)-dark (D) cycle (lights on 7:00 AM)
were exposed to air, 2%, and then 5% CO2 in normoxia
(30-45 min each) at 11:00 AM and 11:00 PM. In a separate group of
seven rats, simultaneous recordings of all variables were made
continuously for 3 consecutive days in air followed by 3 days in 2%
CO2 in normoxia, in a 12:12-h L-D cycle (lights on 7:00
AM). In air, all variables were significantly higher at night, whether
rats were studied acutely or chronically. Acute CO2
exposure had similar significant effects at 11:00 AM and 11:00 PM on
E (~25 and 100% increase with 2 and 5%
CO2, respectively) and O2
(~8% drop with 5% CO2), such that the hyperventilatory response (% increase in
E/O2 from air) was
similar at both times. Chronic CO2 breathing increased
E at all times of the day, but less so during the L
phase (~15 vs. 22% increase in L and D, respectively), when activity
was lower. However, O2 was reduced from
the air level (~10% drop) in the L, such that the E/O2 response was
similar between L and D. The same result was obtained when the
E/O2 response was
compared between the L and D phases for the same level of activity.
These results suggest that, throughout the day, the hypercapnic
hyperpnea, whether during acute or prolonged CO2, is
perfectly adjusted to the metabolic level.
control of breathing; chemosensitivity; barometric method; oxygen consumption
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN MAMMALS AND
BIRDS, blood gas homeostasis depends on the matching of pulmonary
ventilation (E) to metabolism. Indeed, a close
coupling between E and oxygen consumption
(O2) has been found under a variety of
conditions where O2 is either raised or
lowered (20). Variations in metabolism are also associated with changes in E chemosensitivity
(19). A higher O2, as during muscular exercise (35) or cold exposure
(12), is accompanied by a greater absolute increase in
E in response to acute hypoxia or hypercapnia,
whereas reflex hyperpnea is lower when
O2 is reduced, such as with
myxedema (36) or semi-starvation (6). Hence,
the E chemoreflex response seems to track
O2. This would tend to minimize
fluctuations in blood gases in normoxia and when chemosensory drive is elevated.
Oxygen consumption presents a circadian oscillation. Although the daily
high values of O2 generally occur when
an animal is more active, the oscillation persists without changes in
activity (1, 3, 33). In conscious rats in which the
breathing pattern was measured continuously for several days, we found
a daily oscillation in E resembling that commonly
obtained for O2, body temperature (Tb), and activity (32). It would therefore
seem reasonable to suggest that the absolute increase in
E during chemoreceptor stimulation should be greater
when O2 and E are
higher, such that the degree of hyperventilation (increase in
E/O2)
remained similar throughout the day. Indeed, in awake newborn rats
maintained under a 12:12-h light-dark cycle, the E
response relative to O2 was similar in
the morning and evening during acute exposure to hypoxia
(30), despite differing levels of hyperpnea. A similar conclusion can be reached from data from adult rats in acute
hypercapnia, although the interpretation is complicated by
inconsistencies in the normocapnic data to which the hypercapnic values
were compared (25). On the other hand, in humans, awake
and under constant ambient conditions for 40 h, the acute
hypercapnic E response showed a circadian pattern
that could not be linked to changes in metabolism (33,
34). The persistence of this situation with chronic hypercapnia
would imply the presence of significant oscillations in the coupling
between air convection and metabolism and, therefore, in blood gases.
In the present study, we further examined the question of whether the
daily oscillation in O2 influences the
E response to hypercapnia, following the hypothesis
that the hyperpnea is greater when O2 is
higher. In conscious rats, we compared E, O2, and Tb during acute
CO2 exposure, using two CO2 concentrations, in
the morning and in the evening. In addition, these variables, along
with activity, were monitored continuously for 3 days in air followed
by the same period of CO2 breathing under a 12:12-h light-dark cycle. Different from the acute experiments, the chronic exposure allowed us to determine whether an increase in chemosensory drive alters the effectiveness of
E-O2 coupling
throughout the day.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed on Sprague-Dawley adult male rats. The study was approved by the Animal Ethics Committee of McGill University. When not under study, rats were housed individually, with voluntary access to rat chow and water, and maintained in a 12:12-h light-dark cycle (lights on 7:00 AM-7:00 PM). Separate groups of animals were used for the acute and chronic exposures to hypercapnia.
Protocols.
For the acute measurements, 2 h before recordings began rats
[n = 16, body wt = 240 ± 3.4 (SE) g] were
placed in a 1,700-ml Plexiglas chamber that was continuously flushed at
1,200 ml/min STPD. In each rat, E,
O2, and Tb were measured
twice, at 11:00 AM and 11:00 PM. The time of the first experiment was
randomized, and 24-48 h separated the trials, between which rats
were returned to their cages. All experiments were conducted in the
light at an ambient temperature of 23 ± 0.1°C. Data were
collected only after the rat appeared quiet but awake for 
10 min.
Measurements were taken in air, 2% CO2, and finally 5%
CO2 in normoxia (delivered from calibrated pressurized
tanks), always in that order. The CO2 exposures lasted 45 min, with no return to air between them. Data were collected 30-45
min after the onset of each exposure, well beyond the chamber washout
time (~2 min).
E,
O2, Tb, and activity were
monitored simultaneously in air for 3 consecutive days and then in 2%
fractional concentration of inspired CO2 in normoxia
(FICO2) for a further 3 consecutive days
in a 12:12-h light-dark cycle (lights on 7:00 AM-7:00 PM, light
intensity 20-30 lx) at 23.4 ± 0.1°C. The switch of the
inspired gas to the CO2 mixture occurred at 6:00 PM. The
experimental setup was placed in an isolated quarter and was left
undisturbed except for cage cleaning every ~24-36 h and
equipment checks, both done at arbitrary times.
Tb and activity. A few days before the measurements, rats were instrumented with an intra-abdominal transmitter. In the acute experiments, a frequency signal proportional to Tb was emitted by the transmitter (VM-FH, Mini-Mitter) and monitored by a receiver (RLA3000, Data Sciences International) connected to a multimeter. In the chronic experiments, the transmitter was powered by an energizer-receiver unit (series 4000E, Mini-Mitter) for measurements of Tb and activity. Tb was obtained from the frequency of the transmitter, and activity was the total score of counts registered by the radiating coils of the energizer-receiver platform over a period of 2 min. These were recorded simultaneously (sampling rate 1 Hz) by standard telemetric techniques and stored on a computer as previously described (23).
O2.
O2 was measured by the open-flow method
(11). The inflowing and outflowing gas concentrations were
monitored by a calibrated polarographic O2 analyzer (OM-11,
Beckman) and by an infrared CO2 analyzer (CD-3A, Applied
Electrochemistry or LB-2, Beckman). In the chronic experiments, a
programmable solenoid valve switched the sampling port of the
O2 and CO2 analyzers from the outflow to the
inflow pathway of the chamber for 1 min every 30 min to check for
drifts in the recording system. O2 was
computed as the product of the flow and the inflow-outflow
concentration difference of O2 and calculated in
milliliters STPD (1 ml O2 STPD = 0.0446 mmol O2) normalized to the animal's body weight in
kilograms. The small error introduced by a respiratory quotient less
than unity (10) was neglected.
E.
The barometric technique was used for measurements of breathing
pattern. Tidal volume (VT; at BTPS, normalized
to the animal's body weight in kg) was computed using the equation
proposed by Drorbaugh and Fenn (7).
O2
samples were obtained, the inlet and outlet of the respirometer were
sealed for ~1 min, and oscillations in chamber pressure were
monitored by a sensitive pressure transducer (±5 cmH2O;
DP45, Validyne) and recorded on paper at 10 mm/s. The pressure signal
was calibrated for volume by injecting a known amount of air into the
chamber using a syringe. Chamber temperature was monitored by two
tungsten-constantan thermocouples (DP30, Omega) positioned at opposite
ends of the chamber. Relative humidity was taken as 100%, as
condensation was often observed on the chamber walls.
The barometric chamber used for the chronic experiments permitted
continuous monitoring of E for several days without
investigator intervention (32). A double pump system, with
one pump pushing air into the chamber and the other sucking air out
through very tiny openings, enabled the chamber to be flushed
continuously (at ~2 l/min) despite behaving as a functionally closed
system. The average time constant for a step increase in pressure to
dissipate through the openings was 2.1 s, or ~10 times longer
than the inspiratory time of the rat. Chamber pressure was measured by
a sensitive transducer (±2.5 cmH2O; #DUXL3OD, Data
Instruments), and temperature and relative humidity were measured by a
thermistor (55033, Yellow Springs) and a humidity sensor (HIH-3602-C,
Honeywell). Data were acquired by computer (sampling rate 100 Hz). The
chamber pressure root mean square (RMS) was also continuously recorded.
Data filtering criteria included an empirically derived RMS threshold,
used to eliminate gross body movements, breathing rate >300
breaths/min to eliminate high-frequency periods such as during
sniffing, and pressure oscillations <0.001 mmHg, as these were within
the noise level of the setup.
Data analysis.
In the acute experiments, ventilatory data are based on 100 consecutive breaths per condition. The records were analyzed with the
help of a graphics table connected to a minicomputer to obtain inspiratory and expiratory time (TI and TE,
respectively, in s) and VT (ml, at BTPS). Total
breath duration (TTot, in s) was calculated as the sum of
TI and TE, breathing rate (f,
breaths/min) as 60/TTot, and E
(ml/min) as the product of f and VT. Data
measured during CO2 breathing were analyzed as the percent
change (E, O2, E/O2)
or the difference (Tb) from the corresponding normocapnic value.
O2 was
measured at half-hour intervals and ventilatory, Tb, and
activity data were averaged over 30 min. In each rat, data at
corresponding times were averaged over the 3 days in air to obtain mean
daily air patterns. Over the course of the 3-day hypercapnic exposure,
no systematic changes were found in the response to 2% CO2
(see RESULTS, Fig. 2). Hence, as for the air values, data
at corresponding times were averaged over the 3 days in
CO2. The light and dark phase values in each condition (air
and hypercapnia) were defined in each rat as the average value for the
middle 8 h of each phase (light: 9:00 AM-5 PM; dark: 9:00 PM-5:00
AM), and analysis was done on these mean light and dark values.
Although rats are nocturnal animals, they do have periods of activity
during the light phase. Hence, for each variable, it was also possible
to compare E and O2
between the light and dark phases for 15-min epochs of the same level of high activity (see RESULTS, Table 2). At least four such
epochs, each comprising >500 breaths, were analyzed during the light
and dark phases in all rats.
Values are presented as means ± SE. Data were compared by
two-tailed paired t-test or two-way repeated-measures ANOVA
followed by post hoc limitations (Bonferroni's) to compare values in
CO2 to the corresponding air values and, for each
FICO2, to compare variables at different
times of the day, namely 11:00 AM vs. 11:00 PM in the acute experiments
and light vs. dark in the chronic experiments. In all cases, a
significant difference was defined at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Acute measurements.
Table 1 provides the values of all
variables measured in air at 11:00 AM and 11:00 PM.
E, O2, and
Tb were all significantly higher at 11:00 PM compared with
the corresponding morning value. Although breathing rate was similar at
both times, there was a small but significant decrease in
TI/TTot at 11:00 PM compared with
11:00 AM (0.39 vs. 0.36, P < 0.05).
E and O2 rose
proportionately from 11:00 AM to 11:00 PM (~14%), and
E/O2 at
11:00 PM was, therefore, unchanged from the 11:00 AM value.
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E/O2,
Fig. 1) was achieved solely by hyperpnea (~30% increase in
E), whereas in 5% CO2 a slight
hypometabolism (~8% drop in O2) in
addition to the hyperpnea (approximately +95%) contributed to the
E/O2
response. These response patterns occurred at both 11:00 AM and 11:00
PM, and the degree of hyperventilation, expressed as the percentage of
the normocapnic
E/O2,
was similar between 11:00 AM and 11:00 PM for 2 and 5%
CO2. Both concentrations of CO2 increased
TI/TTot, and the extent of the
increase was similar at 11:00 AM and 11:00 PM (~6 and 17% for 2 and
5% CO2, respectively).
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Chronic measurements.
The daily patterns of all variables during the days in air and in
hypercapnia are presented in Fig. 2. In
air, the level of each variable was lower during the light phase but
started to climb toward the higher dark phase level before the lights
were switched off (Fig. 3, open symbols).
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E was higher in the dark phase
(+27 ± 2%) due to increases in both VT (+17 ± 1%) and f (+9 ± 1%). Also,
O2 was increased in the dark, but disproportionately less so than E (+15 ± 0.5%), such that their ratio,
E/O2,
was significantly higher in the dark compared with the light phase by
~11%. The same patterns were apparent when the light-dark difference
in activity was excluded as a variable by comparing the light and dark
phases at the same level of very high activity (Table 2,
bottom).
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E in hypercapnia was
significantly higher than during the corresponding phase in air
(+107 ± 16 and +203 ± 21 ml · kg
1 · min1 in light
and dark, respectively), and this was contributed to by increases in
both VT and f. During the light phase, the
hyperpnea was accompanied by a significantly reduced
O2 (
3 ± 1 ml · kg1 · min1). The
absolute increase in
E/O2
was significant for both phases (+9 ± 1 and +9.5 ± 1 in
light and dark, respectively; Fig. 4A), and the degree of
hyperventilation (~32% increase in
E/O2) was essentially the same at all times of the day (Fig. 4B).
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O2 such that the hyperventilatory
response, expressed as the percent increase in
E/O2 from the
normocapnic value, was the same during the light and dark phases (Fig.
5A).
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O2 with hypercapnia were no longer
apparent in the light phase. The hyperpneic responses became similar
between the light and dark phases (+24% ± 5 in light vs. +25 ± 5% in dark), due primarily to a rise in the response during the light
phase from that observed when activity was low. Consequently, the
degree of hyperventilation (% increase in
E/O2)
remained similar between the light and dark phases.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding of this study was that the hypercapnic
hyperventilatory response, defined as the percentage increase in E/O2,
was similar throughout the day, whether the CO2 exposure was acute or prolonged and whether activity varied between the light
and dark phases.
Considerations of methodology.
The barometric method is ideally suited for circadian studies because
of its noninvasive nature. However, the technique has potential errors,
mostly related to the assumption that the heat and humidity added to
the inspired air are fully recovered during expiration. In fact,
expired air more closely approaches nasal rather than chamber
conditions, depending on nasal temperature, the temperature and
humidity of the chamber, and
TI/TTot. Overlooking these
factors could lead to a substantial underestimation of VT that worsens as TI/TTot and/or
the expired temperature at the nares increases (9, 14).
The question is whether these factors could have affected the daily
pattern of hypercapnic hyperventilation. Assuming that nasal
temperature maintains its proportionality to Tb throughout
the day and using the values of
TI/TTot measured in the acute
experiments, VT may be underestimated by as much as ~20%
in the light and ~23% in the dark phase; that is, the error remains
similar throughout the day. This argument applies equally to the air
and hypercapnic conditions, because the Tb oscillation was
similar, and TI/TTot, although
slightly higher in CO2, retained the light-dark
relationship that it had in air. Hence, it seems unlikely that
technicalities related to the barometric method need to be considered
when interpreting the daily pattern of the hypercapnic
E response.
Circadian pattern of chemosensitivity.
In normocapnia, the daily fluctuations in Tb,
O2, and E were
similar to what we observed previously in adult rats under synchronized
conditions (23, 32). Throughout the prolonged CO2 exposure, E continued to oscillate,
but at a level exceeding that in normocapnia. Although the absolute
increase in E was greater in the dark phase, there
was a small drop in O2 during the light
phase such that the
E/O2
response, expressed as the percent increase from the normocapnic level,
showed no systematic variation throughout the day. After constraining
the analysis to epochs of the same level of high activity during the
light and dark phases, the light-dark differences in
O2 and E were no
longer apparent, and the
E/O2
response remained similar between the two phases. Finally, the
E/O2
response to acute hypercapnia was similar between 11:00 AM and 11:00
PM, whether it was achieved by hyperpnea alone during the 2% exposure
or in combination with hypometabolism during 5% CO2. These
results support the notion that the gain of the hypercapnic
E response was adjusted to the metabolic level, as
has been found under other conditions of changed metabolism such as
exercise and cold-induced thermogenesis (20). The
mechanisms that control the coupling between metabolism and
E are unknown, although evidence points to a role
for the metabolically produced CO2 (22, 27).
O2 either drops or
changes little depending on the normoxic thermogenic status, the
metabolic effects of moderate concentrations of hypercapnia
(2-5%) are mixed and unpredictable (20). The latter
may be related to the relative degree of sympathoadrenal activation and
acidemia elicited by hypercapnia, as these effects would have opposing
actions on O2 (24). We
found a drop in O2 with hypercapnia in
the light phase of the chronic exposure, when activity was low and,
similar to Peever and Stephenson (25), during the acute
experiments when rats were quiet. Hence, during hypercapnia, relatively
low levels of stress may favor a drop in
O2, whereas more stressful situations,
such as when animals were active in the present study or restrained
(15, 31), could mask a hypometabolic effect or lead to an
increase in O2.
In humans studied under 40 h of constant ambient conditions and
wakefulness, E per unit change in end-tidal
CO2, assessed every few hours by rebreathing, followed a
circadian pattern (33, 34). Different from rats, this
occurred either in the absence of any circadian variation in metabolic
rate (34) or was poorly correlated to the metabolism
oscillation (33). Differences in the frequency and method
of testing the acute CO2 response are considerations when
comparing the results in rats and humans. Because circadian
rhythms may be irregularly shaped and superimposed by ultradian
oscillations, the brief intermittent measurements used in both species
to evaluate the acute response may give misleading results concerning
the circadian pattern. The rebreathing method carries with it the
possibility that brain tissue and end-tidal PCO2 do not change together. However,
theoretical considerations suggest that their relationship is linear
and insensitive to changes in cerebral blood flow when rebreathing is
initiated with 7% inspired CO2 (28), as was
done in the human studies. Hence, it seems unlikely that circadian
alterations in cerebral blood flow (4, 8) are at the basis
of the circadian pattern in acute hypercapnic E
response in humans. Another consideration is related to a possible
time-of-day effect of the acidemia accompanying the hypercapnia; acidemia is likely to have been little compensated during the rebreathing trials in humans, but it is likely to have been better compensated in the rats after 30 min of CO2 breathing. This
view would predict that the circadian pattern in E
chemosensitivity would no longer be apparent in humans with prolonged
hypercapnia, such as in patients who retain CO2.
Factors affecting the hypercapnic hyperventilatory response.
Hypercapnia causes a multitude of changes that can secondarily affect
the E response, such as acidosis, a reduction in
Tb, and enhanced catecholamine release. The magnitude of
these effects depends on the severity of the hypercapnia (15, 16,
31), and their recovery during a prolonged exposure can occur
with different time courses (15). Therefore, it was of
interest to compare the
E/O2
response at different times of the day for different CO2
concentrations and durations of exposure. We found a similar time of
day
E/O2
response irrespective of both the CO2 concentration and the
duration of the exposure. This suggests that the acidemia, which would
have been greater with the 5% than with the 2% acute CO2
exposure, and the compensatory mechanisms operating to return arterial
pH toward the normal value during prolonged CO2 breathing
did not alter the daily pattern of the hyperventilatory response.
E
sensitivity to CO2, at least in humans, dogs, and cats
(26). Hence, it would not have been surprising to find a
lower
E/O2
response during the light phase, when most of the sleep in rats occurs. In fact, we did not find a difference in the hypercapnic
hyperventilatory response between the light and dark phases, suggesting
that sleep did not blunt the response. The
E/O2
response was also similar between the light and dark phases when
compared at the same level of high activity, further supporting the
notion that the hypercapnic E sensitivity was not
influenced by the state of arousal. Why rats should differ in this
regard from humans and other larger species is not clear. One
possibility relates to differences in the daily organization of
sleep-wake behavior; the rest phase in rats, and presumably in other
small species, is characterized by alternating bouts of sleep and
activity, whereas humans typically sleep in one continuous episode.
A blunting effect of low Tb on CO2
chemosensitivity has been previously suggested, with a central, via the
brain stem or hypothalamus (2, 5, 18), rather than a
peripheral site of action (13). A reduction in
Tb has been associated with a decrease in not only the
hyperpneic response (17) but also in the
E/O2
response (21, 31). The similarity in the
E/O2
response throughout the day in the present study therefore suggests
that circadian variations in Tb played an irrelevant role
in determining the daily pattern of E sensitivity to
hypercapnia. The same conclusion was reached in human subjects, based
on a substantial (~6 h) phase difference between the circadian
rhythms of hypercapnic E sensitivity and
Tb (33). It is possible that the circadian
changes in Tb were too small to have an appreciable effect
on the hypercapnic response. Yet, it is noteworthy that, in rats, a
modest (~1°C) fall in Tb was associated with an ~30%
decrease in the
E/O2 response to 4% CO2 (21). The mechanisms
governing the Tb change may be a factor. Circadian
Tb oscillations involve changes in the thermoregulatory set
point (29), whereas the Tb changes in the
above-mentioned studies likely represent deviations from the set point.
To better evaluate a potential influence of the circadian
Tb changes on hypercapnic E
responsiveness, the daily E/O2
pattern during CO2 breathing could be compared among animals with very different Tb oscillations.
In conclusion, the hyperventilatory response to CO2 in rats
was similar throughout the day, whether the hypercapnic exposure was
acute or chronic. This result was achieved through a degree of
hyperpnea that was perfectly adjusted to the metabolic level at a given
time of the day. Hence, the advantage of a biological clock and the
oscillations of numerous physiological variables do not appear to pose
a limit on the rat's ability to respond to hypercapnic challenges.
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ACKNOWLEDGEMENTS |
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T. LeBel participated in preliminary experiments.
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FOOTNOTES |
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This study was financially supported by funds from the Canadian Institutes of Health Research.
Address for correspondence: J. P. Mortola, Dept. of Physiology, McGill Univ., McIntyre Basic Sciences Bldg., Rm. 1121, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6 (E-mail: jacopo{at}med.mcgill.ca).
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.
10.1152/ajpregu.00290.2001
Received 23 May 2001; accepted in final form 28 September 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and at 11:00 PM (
), bars
represent + SE. Responses to increased fractional concentration of
inspired CO2 (FICO2; 2 and 5%
CO2 in normoxia) are represented as the difference from
normocapnia (body temperature) or as the percent of the corresponding
normocapnic value (all other variables). #Significant difference
between air and hypercapnia (P < 0.05, repeated-measurements ANOVA with 6 post hoc Bonferroni limitations).
None of the values differed significantly between 11:00 AM and 11:00
PM.
