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J Appl Physiol 86: 1544-1551, 1999;
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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


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 (VE) was measured breath by breath. Arterial oxyhemoglobin saturation (%SaO2) was determined by ear oximetry. After the switch into hyperoxia, VE remained unchanged from the steady-state exercise prehyperoxic value (60.6 ± 6.5 l/min) during Acz. During control studies (Con), VE decreased from the prehyperoxic value (52.4 ± 5.5 l/min) by ~20% (VE nadir = 42.4 ± 6.3 l/min) within 20 s after the switch into hyperoxia. VE increased during Acz and Con after the switch into hypoxia; the hypoxic ventilatory response was significantly lower after Acz compared with Con [Acz, change (Delta ) in VE/Delta SaO2 = 1.54 ± 0.10 l · min-1 · SaO2-1; Con, Delta VE/Delta SaO2 = 2.22 ± 0.28 l · min-1 · SaO2-1]. 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


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

INHIBITION OF CARBONIC ANHYDRASE (CA), the enzyme responsible for the rapid hydration of CO2 and dehydration of bicarbonate (HCO-3), results in increased minute ventilation (VE) 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 VE and pulmonary CO2 output (VCO2) 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 VE 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 VE 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.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 (VO2) and the ventilatory threshold (VET) 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 VET was defined as the VO2 at which there was a systematic increase in the ventilatory equivalent for VO2 (VE/VO2) and end-tidal PO2 (PETO2), with no concomitant increase in the ventilatory equivalent for VCO2 (VE/VCO2) 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 VO2 equal to 80% of VET. 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 (VET) 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.

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 (VO2, VCO2) and VE 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 VE 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 VE 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 VE. 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 VE, PETO2 (Delta VE/Delta PETO2), and SaO2 (Delta VE/Delta 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.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 VO2 at 80% of the VET (76.9 ± 2% VET) 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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  		Table 1.   Physical characteristics of subjects



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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.

Ventilatory response during loadless cycling. The effects of acute Acz administration on VE, breathing pattern, and gas exchange are presented in Table 2. Compared with Con, acute Acz administration resulted in a higher VE (14.6%) during loadless cycling. The higher VE 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 VO2 and VCO2 were unchanged from Con conditions with Acz, the ventilatory equivalents for VO2 (VE/VO2) and VCO2 (VE/VCO2) were higher during Acz than Con because of the higher VE after Acz administration.

                              
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  		Table 2.   Effects of acetazolamide administration on ventilation, breathing pattern, and gas exchange during loadless cycling

Ventilatory response during steady-state exercise and hyperoxia. All subjects achieved a steady-state response (i.e., VE, VCO2, and VO2) to the step increase in exercise intensity within ~4 min of the onset of the transition. The effects of acute Acz administration on VE, 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, VE 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

During the hyperoxic step (PETO2 ~450 Torr), VE remained unchanged from prehyperoxic values during Acz (Table 4, Fig. 3). In contrast, VE 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 VE response was observed within 20-25 s after the step into hyperoxia.

                              
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  		Table 4.   Magnitude of the ventilatory decline in response to 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 (open circle ). Dotted line represents onset of hyperoxic challenge.

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 VE, 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 Delta VE/Delta PETO2 and Delta VE/Delta 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 Delta VE, despite the higher absolute VE induced by the administration of Acz.


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  		Fig. 4.   Group mean (±SE) hypoxic ventilatory response expressed as a function of change (Delta ) in PETO2 (left) and arterial oxyhemoglobin saturation (SaO2; right) during control (solid bars) and after acetazolamide administration (open bars). VE, minute ventilation. a Significantly different compared with control (P < 0.05).

The PETCO2 response agreed with the ventilatory response such that the fall in PETCO2 was less (P < 0.05) during Acz (Delta PETCO2, 5.7 ± 1.2 Torr) compared with Con (Delta 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.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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-HCO-3 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-HCO-3 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 HCO-3 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 VE 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 VE 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 Delta SaO2 and Delta 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 VE-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 VE 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 VE 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, VE 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 VE 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 VE 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 VE may occur during severe hypoxia (PETO2 <60 Torr), where the sensitivity of the pRc is functioning on the steep part of the VE-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 VE. 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.


    ACKNOWLEDGEMENTS

The authors thank the participants who took part in this study. The technical support offered by Brad Hansen was greatly appreciated.


    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.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Cain, S. M., and A. B. Otis. Carbon dioxide transport in anesthetized dogs during inhibition of carbonic anhydrase. J. Appl. Physiol. 16: 1023-1028, 1961[Abstract/Free Full Text].

2.   Cunningham, D. J. C., P. A. Robbins, and C. B. Wolff. Integration of respiratory responses to changes in alveolar partial pressure of CO2 and O2 and in arterial pH. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 2, chapt. 15, p. 475-528.

3.   Dejours, P. Chemoreflexes in breathing. Physiol. Rev. 42: 335-358, 1962[Free Full Text].

4.   Giacobini, E. A cytochemical study of the localisation of carbonic anhydrase in the nervous system. J. Neurochem. 9: 169-177, 1962[Medline].

5.   Griffiths, T. L., L. C. Henson, and B. J. Whipp. Influence of inspired oxygen concentration on the dynamics of the exercise hyperpnoea in man. J. Physiol. (Lond.) 380: 387-403, 1986[Abstract/Free Full Text].

6.   Kowalchuk, J. M., G. J. F. Heigenhauser, J. R. Sutton, and N. L. Jones. The effect of acetazolamide on gas exchange and acid-base control after maximal exercise. J. Appl. Physiol. 72: 278-287, 1992[Abstract/Free Full Text].

7.   Kowalchuk, J. M., G. J. F. Heigenhauser, J. R. Sutton, and N. L. Jones. The effect of chronic acetazolamide administration on gas exchange and acid-base control after maximal exercise. J. Appl. Physiol. 76: 1211-1219, 1994[Abstract/Free Full Text].

8.   Lahiri, S. Carbonic anhydrase and chemoreception in carotid and aortic bodies. In: The Carbonic Anhydrases. Cellular Physiology and Molecular Genetics, edited by S. J. Dogdson, S. J. Tashian, R. F. Gros, and N. D. Carter. New York: Plenum, 1991, p. 341-344.

9.   Lee, K. D., and H. Mattenheimer. Biochemistry of the carotid body. Enzymol. Biol. Clin. 4: 199-216, 1964.

10.   Masuda, A., P.-E. Paulev, Y. Sakakibara, B. Ahn, S. Takaishi, M. Pokorski, Y. Nishibayashi, and Y. Honda. Estimation of peripheral chemoreceptor contribution to exercisse hyperpnea in man. Jpn. J. Physiol. 38: 607-618, 1988[Medline].

11.   Rapanos, T., and J. Duffin. The ventilatory response to hypoxia below the carbon dioxide threshold. Can. J. Appl. Physiol. 22: 23-36, 1997[Medline].

12.   Rigual, R., C. Iñiguez, J. Carreres, and C. Gonzalez. Carbonic anhydrase in the carotid body and the carotid sinus nerve. Histochemistry 82: 577-580, 1985[Medline].

13.   Robbins, P. A., G. D. Swanson, A. J. Micco, and W. P. Schubert. A fast gas-mixing system for breath-by-breath respiratory control studies. J. Appl. Physiol. 52: 1358-1362, 1982[Abstract/Free Full Text].

14.   Scheuermann, B. W., J. M. Kowalchuk, D. H. Paterson, and D. A. Cunningham. VCO2 and VE kinetics during moderate- and heavy-intensity exercise after acetazolamide administration. J. Appl. Physiol. 86: 1534-1543, 1999[Abstract/Free Full Text].

15.   Sherrill, D. L., and G. D. Swanson. Application of the general linear model for smoothing gas exchange data. Comput. Biomed. Res. 22: 270-281, 1989[Medline].

16.   St. Croix, C. M., D. A. Cunningham, D. H. Paterson, and J. M. Kowalchuk. Peripheral chemoreflex drive in moderate-intensity exercise. Can. J. Appl. Physiol. 21: 285-300, 1996[Medline].

17.   Swenson, E. R., and J. M. B. Hughes. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J. Appl. Physiol. 74: 230-237, 1993[Abstract/Free Full Text].

18.   Swenson, E. R., and T. H. Maren. A quantitative analysis of CO2 transport at rest and during maximal exercise. Respir. Physiol. 35: 129-159, 1978[Medline].

19.   Teppema, L. J., F. Rochette, and M. Demedts. Ventilatory response to carbonic anhydrase inhibition in cats: effects of acetazolamide in intact vs. peripherally chemodenervated animals. Respir. Physiol. 74: 373-382, 1988[Medline].

20.   Tojima, H., F. Kunitomo, S. Okita, Y. Yuguchi, H. Tatsumi, T. Kuriyama, S. Watanabe, and Y. Honda. Difference in the effects of acetazolamide and ammonium chloride acidosis on ventilatory responses to CO2 and hypoxia in humans. Jpn. J. Physiol. 36: 511-521, 1986[Medline].

21.   Travis, D. M. Molecular CO2 is inert on the carotid body chemoreceptors. Demonstration by inhibition of the carbonic anhydrase. J. Pharmacol. Exp. Ther. 178: 529-540, 1971[Abstract/Free Full Text].

22.   Wagenaar, M., L. Teppema, A. Berkenbosch, C. Olievier, and H. Folgering. The effect of low-dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat. J. Physiol. (Lond.) 495: 227-237, 1996[Abstract/Free Full Text].

23.   Ward, S. A. Peripheral and central chemoreceptor control of ventilation during exercise in humans. Can. J. Appl. Physiol. 19: 305-333, 1994[Medline].

24.   Ward, S. A., and J. W. Bellville. Peripheral chemoreflex suppression by hyperoxia during moderate exercise in man. In: Modelling and Control of Breathing, edited by B. J. Whipp, and D. M. Wiberg. Amsterdam: Elsevier, 1983, p. 54-61.

25.   Ward, S. A., L. Blesovsky, S. Russak, A. Ashjian, and B. J. Whipp. Chemoreflex modulation of ventilatory dynamics during exercise in humans. J. Appl. Physiol. 63: 2001-2007, 1987[Abstract/Free Full Text].

26.   Wasserman, K., B. J. Whipp, S. N. Koyal, and M. G. Cleary. Effect of carotid body resection on ventilatory and acid-base control during exercise. J. Appl. Physiol. 39: 354-358, 1975[Abstract/Free Full Text].

27.   Weil, J. V., E. Byrne-Quinn, I. E. Sodal, J. S. Kline, R. E. McCullough, and G. F. Filley. Augmentation of chemosensitivity during mild exercise in man. J. Appl. Physiol. 33: 813-819, 1972[Free Full Text].

28.   Whipp, B. J. Peripheral chemoreceptor control of hyperpnea in humans. Med. Sci. Sports Exerc. 26: 337-347, 1994[Medline].

29.   Whipp, B. J., and K. Wasserman. Carotid bodies and ventilatory control dynamics in man. Federation Proc. 39: 2668-2673, 1980[Medline].

30.   Wistrand, P. J. The importance of carbonic anhydrase B and C for the unloading of CO2 by the human erythrocyte. Acta Physiol. Scand. 113: 417-426, 1981[Medline].

J APPL PHYSIOL 86(5):1544-1551
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