Vol. 86, Issue 5, 1544-1551, May 1999
Peripheral chemoreceptor function after carbonic anhydrase
inhibition during moderate-intensity exercise
Barry W.
Scheuermann1,
John M.
Kowalchuk1,2,
Donald H.
Paterson1, and
David A.
Cunningham1,2
1 Centre for Activity and
Ageing, School of Kinesiology, and
2 Department of
Physiology, The University of Western Ontario,
London, Ontario, Canada N6A 3K7
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ABSTRACT |
The effect of carbonic anhydrase inhibition with
acetazolamide (Acz, 10 mg/kg) on the ventilatory response to an abrupt
switch into hyperoxia (end-tidal PO2 = 450 Torr) and hypoxia (end-tidal
PO2 = 50 Torr) was examined in five
male subjects [30 ± 3 (SE) yr]. Subjects
exercised at a work rate chosen to elicit an
O2 uptake equivalent to 80% of
the ventilatory threshold. Ventilation
(
E) was measured breath by breath.
Arterial oxyhemoglobin saturation
(%SaO2) was determined by ear oximetry.
After the switch into hyperoxia, E
remained unchanged from the steady-state exercise prehyperoxic value
(60.6 ± 6.5 l/min) during Acz. During control studies (Con),
E decreased from the prehyperoxic value
(52.4 ± 5.5 l/min) by ~20% (E
nadir = 42.4 ± 6.3 l/min) within 20 s after the switch into
hyperoxia. E increased during Acz and Con after the switch into hypoxia; the hypoxic ventilatory response was
significantly lower after Acz compared with Con [Acz, change (
) in
E/SaO2 = 1.54 ± 0.10 l · min
1 · SaO21;
Con,
E/SaO2 = 2.22 ± 0.28 l · min1 · SaO21].
The peripheral chemoreceptor contribution to the ventilatory drive after acute Acz-induced carbonic anhydrase inhibition is not
apparent in the steady state of moderate-intensity exercise. However,
Acz administration did not completely attenuate the peripheral chemoreceptor response to hypoxia.
carotid bodies; control of breathing; hypoxia; hyperoxia
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INTRODUCTION |
INHIBITION OF CARBONIC ANHYDRASE (CA), the enzyme
responsible for the rapid hydration of
CO2 and dehydration of bicarbonate (HCO3), results in increased minute
ventilation (E) and a fall in alveolar
PCO2 in dogs (1) and humans (17, 18,
20). Although the effect of CA inhibition on
CO2 transport and reaction
kinetics during exercise in humans has been previously investigated
(18), the mechanism(s) mediating the ventilatory response after CA
inhibition is less well described.
We recently reported (14) that acute CA inhibition with acetazolamide
(Acz) slows the rate of adaptation of E
and pulmonary CO2 output
(CO2) for a step increase in
work rate from loadless to moderate-intensity exercise. Because the
peripheral chemoreceptors (pRc)
mediate the kinetics of ventilatory response to a step increase in work
rate (5, 26), it remains possible that the slowed E kinetics after Acz may reflect reduced
pRc chemosensitivity. The most
widely used noninvasive method for determining the contribution of the
pRc to the ventilatory drive is
the Dejours O2 test (3). The
Dejours test assumes that the drive to breathe from the
pRc is effectively silenced by an
abrupt switch in the inspirate from either hypoxia or euoxia to 100%
O2 (3). The magnitude of the transient ventilatory decline, the nadir of which is reached in ~20 s
after the hyperoxic exposure, is a measure of the ventilatory drive
arising from the pRc before the
hyperoxic bout (for review see Refs. 23, 28).
Recently, Swenson and Hughes (17) examined the effect of acute Acz
administration on the ventilatory response to hypoxia, and to
hypercapnia in a background of hyperoxia and of hypoxia in humans under
resting conditions. Compared with the uninhibited condition, acute Acz
administration resulted in a similar hyperoxic hypercapnic ventilatory
response and reduced hypoxic hypercapnic ventilatory response.
Furthermore, the eucapnic hypoxic ventilatory response (HVR) was
completely abolished by acute Acz administration (17). It was concluded
from these observations that CA inhibition resulted in an attenuated
pRc response. These findings are
consistent with studies in animal models that have demonstrated, by
direct measurement of carotid body output, reduced
pRc activity after CA inhibition
with Acz (19, 21).
Few studies have examined ventilatory control mechanisms in humans
after Acz administration (17, 20), and none has examined the
ventilatory response during moderate-intensity exercise after the acute
administration of Acz. Moderate-intensity exercise was used in the
present study to determine whether the slowed
E kinetics observed previously at
exercise onset after acute Acz administration (14) could be attributed
in part to an Acz-induced attenuation of the
pRc drive. Therefore, the first
purpose of the present study was to utilize a modified Dejours
O2 test to determine the
peripheral chemoreflex contribution to the ventilatory drive after
Acz-induced CA inhibition. Second, we wished to extend the previous
findings of an Acz-induced suppression of the HVR under
resting conditions (17) to conditions during moderate-intensity exercise, thereby further demonstrating a role for CA in the
ventilatory response to hypoxia.
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METHODS |
Subjects and protocol.
Five male subjects participated in this study. All subjects were
nonsmokers with no prior history of cardiovascular or respiratory disease. The study requirements, experimental protocol, and all possible risks associated with participation in the study were outlined, and informed consent was obtained from each subject participant. The research protocol was approved by the University's Review Board for Health Sciences Research involving Human Subjects.
Preliminary testing of each subject was performed for the determination
of peak O2 uptake
(O2) and the ventilatory
threshold (ET) by using a progressive
exercise test to volitional fatigue on an electrically braked cycle
ergometer (model H-300-R, Lode) in which the work rate was increased as
a ramp function at a rate of 25 W/min. The
ET was defined as the
O2 at which there was a
systematic increase in the ventilatory equivalent for
O2
(E/O2) and end-tidal PO2
(PETO2), with no
concomitant increase in the ventilatory equivalent for
CO2
(E/CO2)
or decrease in end-tidal PCO2
(PETCO2).
The subjects reported to the laboratory after consuming only a light
meal and abstaining from exercise and beverages containing caffeine for
at least 12 h preceding the test. The exercise tests were performed at
the same time of the day for each subject. Before each of the Acz
studies, the subjects rested supine while a percutaneous Teflon
catheter (Angiocath, 21 gauge) was placed into a dorsal hand vein
followed by Acz infusion (10 mg/kg iv over a 3-min period). The
subjects rested for a further 30 min (15 min supine, 15 min upright)
before being moved to the cycle ergometer.
The subjects performed a step increase in work rate from a baseline of
loadless pedaling to a work rate estimated to elicit a
O2 equal to 80% of
ET. The exercise intensity was chosen to avoid the additional complications associated with a sustained lactic acidosis that accompanies heavy exercise and was similar to the
exercise intensity used previously (14). A schematic of the
hyperoxia-hypoxia experimental protocol is presented in Fig.
1. After 6 min of accommodation to exercise
and euoxia (i.e., PETO2 set
to ~100 Torr), inspired PO2 was
abruptly increased to achieve an
PETO2 of 450 Torr for a
duration of 8 min. A 6-min euoxic recovery period followed the
hyperoxic step, after which the subject was given a 2-min hypoxic step
(PETO2 = 50 Torr). The
protocol ended with 2 min of euoxic recovery. Throughout the test,
PETCO2 was not clamped
(i.e., poikilocapnic).
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Fig. 1.
Schematic representation of poikilocapnic hyperoxic and hypoxic
protocol. After 2 min of rest (not shown), 2 min of loadless cycling
were initiated, and end-tidal
PO2
(PETO2) was clamped at
~100 Torr. End-tidal PCO2
(PETCO2) was not
controlled during the protocol (i.e., poikilocapnic). At 2 min, a
step transition in work rate corresponding to
O2 uptake at 80% of ventilatory
threshold (ET) was initiated, which was
performed for the remainder of the protocol. At minute
6 of moderate-intensity exercise, an abrupt hyperoxic
step (PETO2 = 450 Torr)
occurred, lasting for 8 min. After the hyperoxic bout,
PETO2 was returned to ~100
Torr for a 6-min period. After this recovery period, a 2-min step into
hypoxia (PETO2 = 50 Torr)
was performed, which was followed by 2 min of recovery with
PETO2 returned to ~100
Torr.
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Respiratory apparatus and gas analysis.
During testing, subjects were seated on a cycle ergometer and breathed
through a mouthpiece with the nose occluded. Inspired and expired
ventilation flow rates were measured by using a low-resistance, low-dead-space (90 ml) bidirectional turbine (VMM 110, Alpha
Technologies) and volume transducer (VMM-2A, Sensor Medics), which were
calibrated before each test by using a syringe of known volume (3.01 liters). Respiratory flow and timing were determined by using a
pneuomotachograph (model 3800, Hans Rudolph) and a differential
pressure transducer (MP45-871, Validyne). Inspired and expired air
were sampled continuously (20 ml/min) at the mouth and analyzed by a
mass spectrometer (MGA 2000, Airspec) for fractional concentrations of
O2,
CO2, and
N2. The mass spectrometer was
calibrated before each test by using precision-analyzed gas mixtures.
Analog signals from the turbine, pressure transducer, and mass
spectrometer were sampled and digitized every 20 ms by computer.
Breath-by-breath computations for pulmonary gas exchange
(O2,
CO2) and
E were performed after delays in the
analysis system and fluctuations in lung gas stores in the computer
algorithms were accounted for (15). Corrections for temperature and
water vapor pressure were made for conditions measured near the mouth.
Heart rate was continuously monitored by using an electrocardiogram
with electrodes placed in a modified V5 configuration. Arterial
oxyhemoglobin saturation
(SaO2) was measured
noninvasively by using an ear probe (OXI3 Pulse Oximeter, Radiometer).
Two computers were used during testing. A data-acquisition computer
collected the experimental variables every 20 ms and stored them on
disk for later analysis.
PETO2 was accurately controlled by using a computer-controlled fast gas-mixing
system, which was similar to that previously described in detail (13). The control computer compared the actual measured
PETO2 with the target
PETO2, which was entered
into a forcing function program before the start of the experimental
protocol. The difference between the measured and target
PETO2 served as the feedback
signal, determined at the end of each breath, from which the control
computer adjusted the gas mixture to force the
PETO2 toward the target
value. The inspired PO2 required to
achieve the desired PETO2
was converted by an algorithm into appropriate values for flows of
O2 and
N2.
PETCO2 was not controlled in
the present study.
Data analysis.
The experimental protocol was repeated twice during each visit to the
laboratory on two separate occasions for each of the control (Con) and
Acz conditions. For each subject, the breath-by-breath data for each
condition were time aligned, interpolated over 1-s intervals, and
ensemble averaged to yield a single response for each subject per
condition to increase the signal-to-noise ratio. The prehyperoxic and
prehypoxic E were taken as the mean
(determined from the ensemble-averaged response for each subject)
during the last 30 s before the hyperoxic and hypoxic step,
respectively. Previous work from our laboratory (16) has shown that the
nadir in E typically occurs within
20-30 s of the switch into hyperoxia and that no difference is
observed in the nadir with the use of either 1- or 5-s averaged data
for determination of the decline in E.
Thus the data during hyperoxia were averaged over 5-s intervals from
time 0 to 1 min, over 15-s intervals
from 1 to 3 min, and over 30-s intervals from 3 to 8 min. The nadir of
the individual ventilatory response to hyperoxia, determined from the
5-s mean data, was analyzed by using Student's paired
t-test. The HVR was determined from
the changes in E,
PETO2 (E/PETO2),
and SaO2
(E/SaO2)
averaged over the last 60 s of hypoxia. Differences in the HVR
between Con and Acz were analyzed by using Student's paired
t-test. Statistical significance was
accepted at P < 0.05. All values are
reported as means ± SE.
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RESULTS |
The physical characteristics of the subjects and the results of the
maximal ramp exercise test are presented in Table
1. The work rate for the
moderate-intensity, constant-load exercise tests corresponded to the
O2 at 80% of the
ET (76.9 ± 2%
ET) and ranged from 132 to 197 W for the
five subjects. The group mean response to the hyperoxic-hypoxic
experimental protocol is presented in Fig.
2.
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Fig. 2.
Mean ventilatory, PETCO2,
and PETO2 responses to
hyperoxic and hypoxic protocol during control
(A) and after acute acetazolamide
administration (B). Mean response
represents individual subject responses, which were interpolated to 1-s
intervals and ensemble averaged, with each subject contributing 4 repetitions for each of control and acetazolamide
conditions. Dotted lines represent onset and end of hyperoxic and
hypoxic challenges, respectively.
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Ventilatory response during loadless cycling.
The effects of acute Acz administration on
E, breathing pattern, and gas exchange
are presented in Table 2. Compared with Con, acute Acz administration resulted in a higher
E (14.6%) during loadless cycling. The
higher E was attributed to the 13.3% higher tidal volume during Acz, because there were no
differences in either inspiratory or expiratory duration or breathing
frequency between conditions. At the onset of loadless cycling and
during moderate-intensity exercise,
PETO2 was set at
~100-105 Torr, resulting in similar values for Con and
Acz conditions throughout the test. During loadless cycling, Acz
resulted in a lower PETCO2 than did Con. Although O2 and
CO2 were unchanged from Con conditions with Acz, the ventilatory equivalents for
O2
(E/O2) and CO2
(E/CO2)
were higher during Acz than Con because of the higher
E after Acz administration.
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Table 2.
Effects of acetazolamide administration on ventilation, breathing
pattern, and gas exchange during loadless cycling
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Ventilatory response during steady-state exercise and hyperoxia.
All subjects achieved a steady-state response (i.e.,
E,
CO2, and
O2) to the step increase in
exercise intensity within ~4 min of the onset of the transition. The
effects of acute Acz administration on
E, breathing pattern, and gas
exchange during steady-state exercise (i.e., prehyperoxic values) are
presented in Table 3. During the 30-s
interval before hyperoxia, E
was 15.4% higher during Acz than Con, which is attributed to the
16.5% higher tidal volume during Acz compared with Con; breath timing (inspiratory and expiratory time) and breathing frequency were similar
between conditions. With exercise,
PETCO2 increased above
loadless cycling values during both Acz and Con conditions; PETCO2 was lower during Acz
compared with Con.
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Table 3.
Effects of acetazolamide administration on ventilation, breathing
pattern, and gas exchange during the steady state of moderate-intensity
exercise before the step changes into hyperoxia and hypoxia
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During the hyperoxic step
(PETO2 ~450 Torr),
E remained unchanged from prehyperoxic
values during Acz (Table 4, Fig.
3). In contrast,
E decreased transiently during Con (9.9 ± 1.5 l/min; 20.4 ± 4.4%) before returning to prehyperoxic
values (Table 4, Fig. 3). In all subjects, the nadir of the individual E response was observed within 20-25
s after the step into hyperoxia.
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Fig. 3.
Group mean (±SE) ventilatory response before (Pre) and during
hyperoxic step during control ( ) and after carbonic anhydrase
inhibition with acetazolamide ( ). Dotted line represents onset of
hyperoxic challenge.
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Ventilatory response during steady-state exercise and hypoxia.
After the hyperoxic bout, the
PETO2 was returned to
~100-105 Torr for 6 min to establish a steady state before the hypoxic step. The effects of acute Acz administration on
E, breathing pattern, and gas exchange
during steady-state exercise before the hypoxic step were similar to
conditions before the hyperoxic period (Table 3).
The HVR results are presented in Fig. 4.
The HVR was lower after Acz than Con as indicated by both the
E/PETO2 and
E/SaO2.
There were no differences between Acz and Con conditions during hypoxia
for either PETO2 (Acz, 49.3 ± 0.3 Torr; Con, 49.2 ± 1.1 Torr) or
SaO2 (Acz, 78.3 ± 0.9%; Con, 78.5 ± 0.9%). Thus the reduced HVR during Acz was attributed to a lower
E, despite the higher absolute
E induced by the administration of Acz.
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Fig. 4.
Group mean (±SE) hypoxic ventilatory response expressed as a
function of change () in
PETO2
(left) and arterial oxyhemoglobin
saturation (SaO2;
right) during control (solid bars)
and after acetazolamide administration (open bars).
E, minute ventilation.
a Significantly different
compared with control (P < 0.05).
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The PETCO2 response agreed
with the ventilatory response such that the fall in
PETCO2 was less
(P < 0.05) during Acz
(PETCO2, 5.7 ± 1.2 Torr) compared with Con
(PETCO2, 8.1 ± 1.5 Torr), resulting in similar PETCO2 values (Acz,
31.2 ± 1.1 Torr; Con, 32.3 ± 0.35 Torr) at the time of comparison.
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DISCUSSION |
This study examined the effect of CA inhibition after an acute
administration of Acz on the hyperoxic ventilatory response and HVR in
the steady state of moderate-intensity exercise in humans. The results
of this study suggest that, in humans, acute Acz administration
(at a dose of 10 mg/kg) effectively abolishes the ventilatory response
to hyperoxia and reduces the ventilatory response to hypoxia, probably
by a reduced drive from the peripheral chemoreflex
(pRc).
Limitations due to CA inhibition.
The experiment was begun 30 min after an acute infusion of Acz to
examine the ventilatory response to acute CA inhibition without the
confounding effects of a metabolic acidosis that develops with longer
periods of Acz administration (7, 18). Although arterial
PCO2
(PaCO2) and pH were not measured during this protocol, we have previously demonstrated that an acute infusion of Acz does not produce a metabolic acidosis under resting conditions, as determined by measurements made on equilibrated blood samples (6,
14). The determination of PaCO2 and pH
in vivo is complicated by the fact that the effective inhibition of
erythrocyte CA activity results in
CO2-HCO3
disequilibrium. The incomplete equilibration of
CO2 species between erythrocytes
and plasma during the transit through the pulmonary capillaries causes
a widening of the arterial-alveolar
PCO2 difference, particularly at
higher exercise intensities (18). This apparent arterial-alveolar PCO2 difference reflects the
measurements made at equilibrium but does not reflect the in vitro
conditions at the time of sampling.
As a consequence of the
CO2-HCO3
disequilibrium in the postpulmonary capillary blood, it is not possible to accurately determine the PaCO2 or pH
that either the pRc or central
chemoreceptor (cRc) may be
sensing. Swenson and Maren (18) calculated the half-time for the
dehydration reaction of HCO3 to
CO2 to be 1.5 and 0.4 s for rest
and maximal exercise, respectively. Because the lung-to-carotid-body transit time is ~7 s in moderate-intensity exercise (24, 29), the
predicted level of PCO2 that either
the pRc or
cRc is sensing would be higher
than that estimated from
PETCO2. Whether the
magnitude of the rise in PaCO2 would be
great enough to cause an equivalent level of stimulation at the carotid
bodies during Acz and Con cannot be determined with certainty from the results of this study. However, if the assumption is made that the
pRc and
cRc are sensing
PaCO2 values close to the equilibrated value, then the results of our previous study (14) suggest that the
PaCO2 is actually higher at the
chemoreceptor sites during Acz than Con.
We did not measure CA activity; however, we estimate, assuming an even
distribution of Acz in the vascular and extracellular compartment, that
the extracellular fluid concentration of Acz would be ~225 µmol/l
(or ~45 µmol/kg). The dose of Acz used in the present study (10 mg/kg Acz) would result in a plasma concentration of Acz severalfold
higher than required to inhibit >99.95% of the total erythrocyte CA
activity (30). In addition, the dose used in the present study was
similar to that used in a study by Maren and Swenson (18) in which they
reported the erythrocyte isozymes CA I and CA II to be ~93.3 and
99.3% inhibited, respectively, with a dose of 7-10 mg/kg Acz.
The purpose of this study required human subjects to perform whole body
exercise, and thus a further limitation is our inability to state with
certainty which CA isozymes (other than erythrocyte isozymes) may have
been affected by the infusion of Acz. Specifically, CA has been
localized in the glomus cells of the carotid bodies (9, 12) and in
glial cells neighboring the cRc
(4), both which may be susceptible to Acz administration.
Ventilatory response to hyperoxia.
A unique finding of this study was that a transient decrease in
E at the onset of hyperoxic breathing was
completely abolished after CA inhibition. The
pRc contribution to the
ventilatory drive, which we found to be ~20%, is in close agreement
with earlier estimates for moderate-intensity exercise (5, 10, 16, 25). The results of this study provide indirect evidence for a suppression of pRc drive to breathe after
acute Acz administration during moderate-intensity exercise in humans.
Our results are in agreement with a previous study (17) that
demonstrated a suppressed pRc drive determined by the ventilatory response to hyperoxic and hypoxic
hypercapnic breathing after acute Acz administration in resting humans.
Direct assessment of peripheral and central chemoreflex output and,
therefore, their role in the modulation of
E is not possible in humans. Teppema and
colleagues (19) observed a reduction in
pRc activity in anesthetized cats
given a much larger dose of Acz (50 mg/kg) than used in the present
study. However, at doses as low as 4 mg/kg (i.e., the lowest dosage
possible without causing an alveolar-arterial
PCO2 gradient), a decrease in
pRc sensitivity to
CO2 was still apparent in this cat
preparation (22).
We are not aware of any reports that specifically identify the
mechanism of action of Acz-induced CA inhibition on the carotid bodies.
Although CA is found within the glomus cells of the carotid bodies (9),
its function in chemoreception is not well understood. It has been
suggested that, during CA inhibition, the uncatalyzed hydration
reaction is slowed, resulting in a slowed generation of
H+, which is required to stimulate
pH-sensitive receptors and thereby allow chemotransduction to proceed
normally (8). This mechanism may also affect the ventilatory response
to hypoxia (discussed in Ventilatory response to
hypoxia) because the
pRc response to hypoxia is
dependent on the response to CO2
(8).
Ventilatory response to hypoxia.
In the present study, the HVR was attenuated for the same
SaO2 and
PETO2 after Acz compared
with the uninhibited condition (Fig. 4). Suppression of hypoxic
ventilatory sensitivity with Acz is consistent with CA inhibition
affecting the pRc input to the
central respiratory center. The complete suppression of ventilatory
sensitivity and carotid body output to hypoxia has been demonstrated in
anesthetized cats during Acz-induced CA inhibition (19, 21), adding
support to the contention that Acz may indeed reduce
pRc activity in humans.
The blunted HVR found in the present study is in partial agreement with
previous reports that have examined the possible mechanisms responsible
for the mediation of the ventilatory response to CA inhibition in
humans at rest (17, 20). In contrast to the attenuated HVR with Acz in
our study, Swenson and Hughes (17) reported a complete suppression of
hypoxic ventilatory responsiveness under isocapnic conditions after an
acute infusion of Acz in resting humans. It is difficult to reconcile
the difference in the HVR between these studies. It is interesting
that, in the present study,
PETCO2 was not controlled
during either Con or Acz conditions; however, in the study by Swenson
and Hughes, PETCO2 was
maintained at levels similar to the uninhibited condition by adding
CO2 to the inspirate, a condition
that may be expected to further augment the HVR. Moreover, of
significant importance in the study by Swenson and Hughes, the HVR was
determined in only mild hypoxia (SaO2 = 88%). In the present study, SaO2 was ~78%, which represents a greater hypoxic ventilatory stimulus (i.e., steep portion of the
E-alveolar
PO2 curve). In addition, Weil and
colleagues (27) have shown that the HVR is potentiated when hypoxia is
introduced during moderate-intensity exercise. Although
these researchers suggested that the increased HVR was associated with
augmented pRc sensitivity, they
could not conclude that central chemoreception did not play a role.
Although the reason(s) for the varied HVR during acute Acz
administration is not readily apparent, a number of factors may have
contributed to the divergent ventilatory responses. Under normal
conditions, hypoxia-induced increases in
E cause a progressive decrease in
PaCO2 and arterial
H+ concentration. Consequently,
this reduction in PaCO2 and arterial H+ concentration acting at the
pRc to reduce
E may result in an underestimation of the
true HVR if it is not corrected for by the addition of
CO2 to the inspirate to maintain
isocapnia. During Acz,
PETCO2 was lower before the
hypoxic bout and, therefore, cannot be discounted as possibly
attenuating the HVR during CA inhibition. We do not believe this to be
the case, however, because the relative decrease in
PETCO2 during the hypoxic
challenge was actually greater during Con than Acz so that at the end
of the hypoxic period PETCO2
was similar in both conditions. The wide acceptance that the
interaction of hypoxia and CO2
occurs at the carotid bodies (2) supports the notion that CA inhibition directly affects the HVR through actions at the
pRc. In addition, the fact that
the isocapnic HVR was completely abolished with acute Acz in resting
humans (17) provides further evidence that the
pRc is directly affected by CA inhibition.
Ventilatory response in hyperoxia vs. hypoxia during CA inhibition.
The brief hypoxic exposure was given only 6 min after the hyperoxic
bout, and, therefore, the degree of
pRc inhibition should not have
changed in this brief time period. Thus it is somewhat difficult to
reconcile the observations that Acz completely suppressed pRc function during the step into
hyperoxia but only attenuated the response during the hypoxic step.
Possible mechanisms contributing to the ventilatory response to
hyperoxia and hypoxia during Acz are discussed below.
Recently, Rapanos and Duffin (11) confirmed that, under resting
conditions, E does not increase in
response to hypoxia if the
PETCO2 (and presumably
PaCO2) is lower than the peripheral
chemoreflex threshold for CO2 of
~39 Torr. Determination of the peripheral chemoreflex threshold as
reported by Rapanos and Duffin requires that
CO2 be rapidly equilibrated in the
postpulmonary capillaries. The disequilibrium of
CO2 species in the postpulmonary capillaries consequent to CA inhibition will result in a widening of
the end-tidal-arterial difference as blood flows toward the pRc, and thus the
PETCO2 will underestimate
the PaCO2 that the
pRc is sensing. Although
PETCO2 was lower during Acz
than Con before the hyperoxic step,
PETCO2 was similar in Acz
studies before the hyperoxic (36.5 ± 0.8 Torr) and hypoxic (36.9 ± 0.5 Torr) bouts. The immediate increase in
E during hypoxia suggests that
PaCO2 was not below the
CO2 threshold for pRc stimulation, and thus the lack
of a ventilatory decline in hyperoxia does not appear to be a function
of low CO2 stimulus (i.e., below
the CO2 threshold).
Previous studies in resting humans (17, 20) have demonstrated a
hypoxia-mediated increase in E after
chronic Acz. This finding has lead to the hypothesis that CA inhibition
at the pRc is not complete,
allowing for some residual activity to respond to the low
PO2. Possibly, if the
pRc response is not completely
inhibited by Acz, an increase in E may
occur during severe hypoxia
(PETO2 <60 Torr), where
the sensitivity of the pRc is
functioning on the steep part of the
E-alveolar PO2 curve. Similarly, reduced
pRc sensitivity because of CA
inhibition in combination with the relatively low gain of the
pRc normally present at high
O2 levels may explain the lack of
a ventilatory response to the hyperoxic step.
Summary.
In summary, this study examined the effects of acute CA inhibition with
Acz on the ventilatory response to poikilocapnic hyperoxia and hypoxia
during moderate-intensity exercise in humans. There does not appear to
be any pRc contribution to the
ventilatory drive in the steady state of moderate-intensity exercise
after Acz-induced CA inhibition, as indicated by the failure of an
abrupt hyperoxic stimulus to induce a decline in
E. However, acute Acz administration did
not completely attenuate the pRc
response to hypoxia. These findings suggest that CA inhibition affects ventilatory control mechanisms in humans in a very complex manner that
must consider changes in acid-base status and the inhibition of
pRc.
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ACKNOWLEDGEMENTS |
The authors thank the participants who took part in this study. The
technical support offered by Brad Hansen was greatly appreciated.
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FOOTNOTES |
Financial support was provided to J. M. Kowalchuk by an operating grant
from the Natural Sciences and Engineering Research Council of Canada.
B. W. Scheuermann was supported by an National Sciences and Engineering
Research Council Graduate Scholarship.
This research was carried out at The Centre for Activity and Ageing
(affiliated with the Faculty of Health Sciences, School of Kinesiology,
and the Faculty of Medicine at The University of Western Ontario and
The Lawson Research Institute at the St. Joseph's Health Centre).
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. §1734 solely to indicate this fact.
Address for reprint requests: J. M. Kowalchuk, School of Kinesiology,
Thames Hall, The Univ. of Western Ontario, London, Ontario, Canada N6A
3K7 (E-mail: jkowalch{at}julian.uwo.ca).
Received 15 May 1998; accepted in final form 12 January 1999.
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