Blunted hypoxic ventilatory drive in subjects susceptible to high-altitude pulmonary edema

It has been proposed that subjects susceptible to high-altitude pulmonary edema (HAPE) show exaggerated hypoxemia with relative hypoventilation during the early period of high-altitude exposure. Some previous studies suggest the relationship between the blunted hypoxic ventilatory response (HVR) and HAPE. To examine whether all the HAPE-susceptible subjects consistently show blunted HVR at low altitude, we evaluated the conventional pulmonary function test, hypoxic ventilatory response (HVR), and hypercapnic ventilatory response (HCVR) in ten lowlanders who had a previous history of HAPE and compared these results with those of eight control lowlanders who had no history of HAPE. HVR was measured by the progressive isocapnic hypoxic method and was evaluated by the slope relating minute ventilation to arterial O2 saturation (delta VE/delta SaO2). HCVR was measured by the rebreathing method of Read. All measurements were done at Matsumoto, Japan (610 m). All the HAPE-susceptible subjects showed normal values in the pulmonary function test. In HCVR, HAPE-susceptible subjects showed relatively lower S value, but there was no significant difference between the two groups (1.74 +/- 1.16 vs. 2.19 +/- 0.4, P = NS). On the other hand, HAPE-susceptible subjects showed significantly lower HVR than control subjects (-0.42 +/- 0.23 vs. -0.87 +/- 0.29, P less than 0.01). These results suggest that HAPE-susceptible subjects more frequently show low HVR at low altitude. However, values for HVR were within the normal range in 2 of 10 HAPE-susceptible subjects. It would seem therefore that low HVR alone need not be a critical factor for HAPE. This could be one of several contributing factors.     

Maternal hypoxic ventilatory response, ventilation, and infant birth weight at 4,300 m

To test the hypothesis that increased hypoxic ventilatory responsiveness (HVR) raised maternal ventilation and arterial oxygenation during high-altitude pregnancy and related to the birth weight of the offspring, we studied 21 residents of Cerro de Pasco, Peru (4,300 m), while eight of them were 36 +/- 0 wk pregnant and 15 of them 13 +/- 0 wk postpartum. HVR was low in the nonpregnant women (mean +/- SE shape parameter A = 23 +/- 8) but increased nearly fourfold with pregnancy (A = 87 +/- 17). The increase in HVR appeared to account for the 25% rise in resting ventilation with pregnancy (delta VE observed = 2.4 +/- 0.7 l/min BTPS vs. delta VE predicted from delta HVR = 2.6 +/- 1.7 l/min BTPS, P = NS). Hyperoxia decreased ventilation in the pregnant women (P less than 0.01) to levels similar to those measured when nonpregnant. The increased ventilation of pregnancy raised arterial O2 saturation (SaO2) from 83 +/- 1 to 87 +/- 0%, and SaO2 was correlated positively with HVR in the pregnant women. The rise in SaO2 compensated for a 0.9 g/100 ml decrease in hemoglobin concentration to preserve arterial O2 content at levels present when nonpregnant. Cardiac output in the 36th wk of pregnancy did not differ significantly from values measured postpartum. The increase in HVR correlated positively with infant birth weight. An increase in HVR may be an important contributor to increased maternal ventilation with pregnancy and infant birth weight at high altitude.     

Interindividual variation in hypoxic ventilatory response: potential role of carotid body

There is considerable interindividual variation in ventilatory response to hypoxia in humans but the mechanism remains unknown. To examine the potential contribution of variable peripheral chemorecptor function to variation in hypoxic ventilatory response (HVR), we compared the peripheral chemoreceptor and ventilatory response to hypoxia in 51 anesthetized cats. We found large interindividual differences in HVR spanning a sevenfold range. In 23 cats studied on two separate days, ventilatory measurements were correlated (r = 0.54, P less than 0.01), suggesting stable interindividual differences. Measurements during wakefulness and in anesthesia in nine cats showed that although anesthesia lowered the absolute HVR it had no influence on the range or the rank of the magnitude of the response of individuals in the group. We observed a positive correlation between ventilatory and carotid sinus nerve (CSN) responses to hypoxia measured during anesthesia in 51 cats (r = 0.63, P less than 0.001). To assess the translation of peripheral chemoreceptor activity into expiratory minute ventilation (VE) we used an index relating the increase of VE to the increase of CSN activity for a given hypoxic stimulus (delta VE/delta CSN). Comparison of this index for cats with lowest (n = 5, HVR A = 7.0 +/- 0.8) and cats with highest (n = 5, HVR A = 53.2 +/- 4.9) ventilatory responses showed similar efficiency of central translation (0.72 +/- 0.06 and 0.70 +/- 0.08, respectively). These results indicate that interindividual variation in HVR is associated with comparable variation in hypoxic sensitivity of carotid bodies. Thus differences in peripheral chemoreceptor sensitivity may contribute to interindividual variability of HVR.     

Influence of testosterone on ventilation and chemosensitivity in male subjects

There is increasing evidence that men have higher ventilatory responses to chemical stimuli than age-matched women and that certain disorders of respiratory rhythmicity, particularly sleep apnea, occur more commonly in men. Accordingly, we studied the influence of the male hormone, testosterone, on the control of breathing. Twelve hypogonadal males were studied at least 30 (mean +/- SE: 69.7 +/- 8.9) days after discontinuing testosterone replacement and again following hormone administration. In each subject plasma testosterone concentration, metabolic rate [O2 consumption (VO2) and CO2 production (VCO2)], minute ventilation (VE), and chemosensitivity [hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses] were determined on and off hormone replacement. With testosterone administration VO2 increased from 248 +/- 15 to 276 +/- 18 ml/min (P less than 0.05), with VCO2 showing a similar but nonsignificant trend. This was associated with an increase in VE from 8.41 +/- 0.78 to 9.91 +/- 0.75 l/min (P less than 0.05) but no change in PCO2. The HVR, expressed as A, increased 44% with hormone replacement from a value of 122 +/- 23 to 176 +/- 28 (P less than 0.01), whereas the HCVR was minimally affected by testosterone administration. These findings may in part explain the previously described differences between male and female subjects in hypoxic sensitivity.     

Increased HVR in pregnancy: relationship to hormonal and metabolic changes

In prior studies at high altitude, we have found that pregnancy increases maternal hypoxic ventilatory response (HVR) but the factors responsible are unknown. Changes in metabolic rate and hormones that occur during pregnancy have previously been shown to influence HVR. We therefore sought to determine the contribution of metabolic rate and hormonal changes to the pregnancy-associated rise in HVR. Pregnancy increased HVR in each of 20 normal, low-altitude (1,600 m) residents. As measured by the shape parameter A, HVR at week 36 was 237 +/- 26 (SE) or twofold higher than the 124 +/- 13 value measured 3 mo postpartum (P less than 0.01) despite the presence of the potentially depressant effects of hypocapnia [change in alveolar partial pressure of CO2 (delta PACO2) = -4 +/- 1 mmHg] and alkalosis [change in arterial pH (delta pHa) = 0.02 +/- 0.01 U] during pregnancy. Sixty percent of the increase in HVR values had occurred by week 20 of gestation at which time O2 consumption (VO2) and CO2 production (VCO2) were unchanged relative to values measured postpartum. The remaining 40% rise in HVR paralleled increases in VO2 and VCO2, and further elevation in VO2 and VCO2 with moderate exercise produced an additional increase in HVR. Serum estradiol and progesterone levels increased with pregnancy, but levels did not correlate with HVR. The women reporting the greatest symptoms of dyspnea had higher HVR A values at week 36 than the least dyspneic women (285 +/- 28 vs. 178 +/- 34, respectively, P less than 0.05). We concluded that factors intrinsic to pregnancy in combination with increased metabolic rate raised HVR twofold with pregnancy and may have contributed to the often-reported symptoms of dyspnea in pregnant women.     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure

Prolonged exposure to hypoxia is accompanied by decreased hypoxic ventilatory response (HVR), but the relative importance of peripheral and central mechanisms of this hypoxic desensitization remain unclear. To determine whether the hypoxic sensitivity of peripheral chemoreceptors decreases during chronic hypoxia, we measured ventilatory and carotid sinus nerve (CSN) responses to isocapnic hypoxia in five cats exposed to simulated altitude of 5,500 m (barometric pressure 375 Torr) for 3-4 wk. Exposure to 3-4 wk of hypobaric hypoxia produced a decrease in HVR, measured as the shape parameter A in cats both awake (from 53.9 +/- 10.1 to 14.8 +/- 1.8; P less than 0.05) and anesthetized (from 50.2 +/- 8.2 to 8.5 +/- 1.8; P less than 0.05). Sustained hypoxic exposure decreased end-tidal CO2 tension (PETCO2, 33.3 +/- 1.2 to 28.1 +/- 1.3 Torr) during room-air breathing in awake cats. To determine whether hypocapnia contributed to the observed depression in HVR, we also measured eucapnic HVR (PETCO2 33.3 +/- 0.9 Torr) and found that HVR after hypoxic exposure remained lower than preexposed value (A = 17.4 +/- 4.2 vs. 53.9 +/- 10.1 in awake cats; P less than 0.05). A control group (n = 5) was selected for hypoxic ventilatory response matched to the baseline measurements of the experimental group. The decreased HVR after hypoxic exposure was associated with a parallel decrease in the carotid body response to hypoxia (A = 20.6 +/- 4.8) compared with that of control cats (A = 46.9 +/- 6.3; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Augmented hypoxic ventilatory response in men at altitude.

To test the hypothesis that the hypoxic ventilatory response (HVR) of an individual is a constant unaffected by acclimatization, isocapnic 5-min step HVR, as delta VI/delta SaO2 (l.min-1.%-1, where VI is inspired ventilation and SaO2 is arterial O2 saturation), was tested in six normal males at sea level (SL), after 1-5 days at 3,810-m altitude (AL1-3), and three times over 1 wk after altitude exposure (PAL1-3). Equal medullary central ventilatory drive was sought at both altitudes by testing HVR after greater than 15 min of hyperoxia to eliminate possible ambient hypoxic ventilatory depression (HVD), choosing for isocapnia a P'CO2 (end tidal) elevated sufficiently to drive hyperoxic VI to 140 ml.kg-1.min-1. Mean P'CO2 was 45.4 +/- 1.7 Torr at SL and 33.3 +/- 1.8 Torr on AL3, compared with the respective resting control end-tidal PCO2 of 42.3 +/- 2.0 and 30.8 +/- 2.6 Torr. SL HVR of 0.91 +/- 0.38 was unchanged on AL1 (30 +/- 18 h) at 1.04 +/- 0.37 but rose (P less than 0.05) to 1.27 +/- 0.57 on AL2 (3.2 +/- 0.8 days) and 1.46 +/- 0.59 on AL3 (4.8 +/- 0.4 days) and remained high on PAL1 at 1.44 +/- 0.54 and PAL2 at 1.37 +/- 0.78 but not on PAL3 (days 4-7). HVR was independent of test SaO2 (range 60-90%). Hyperoxic HCVR (CO2 response) was increased on AL3 and PAL1. Arterial pH at congruent to 65% SaO2 was 7.378 +/- 0.019 at SL, 7.44 +/- 0.018 on AL2, and 7.412 +/- 0.023 on AL3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of body size and gender on control of ventilation

Hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses are influenced by both metabolic activity and hormonal factors. By studying 67 subjects of both sexes, including those at the extremes of stature, we examined the influence of gender, CO2 production (VCO2), O2 consumption (VO2), body surface area (BSA), and vital capacity (VC) on resting ventilation (VE), HVR, and HCVR. We measured resting VE, VO2, and VCO2 and then performed isocapnic progressive hypoxic and hypercapnic ventilatory responses. The effect of stature was reflected in higher VE and metabolic rate (both P less than 0.001) in tall men compared with short men that was ablated by correction for BSA. Perhaps because their heights vary less than those of the men, tall women were not statistically distinguishable from short women in any of these measured parameters. Tall men tended to have greater hypoxic chemosensitivity than short men but this was not significantly different (P = 0.07). Gender affected the control of ventilation in a number of ways. Men had higher VE (P less than 0.05) and metabolic rate (P less than 0.001) than women. Even after correction for BSA men still had higher metabolic rates. Women had higher VE/VCO2 than men (P less than 0.05) and lower resting end-tidal Pco2 (PETCO2) values (P less than 0.05). Both A, the shape parameter of the hyperbolic HVR curve, and HVR determined from mouth occlusion pressure (AP) were greater in women than in men, although only AP reached statistical significance. However, corrections of A for BSA (P less than 0.05), VCO2 (P less than 0.01), and VC (P less than 0.001) amplified these differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Breathing during sleep with mild hypoxia

To investigate ventilatory response to mild hypoxia during non-rapid-eye-movement sleep, we administered approximately 16% O2 (which corresponds to concentrations found in commercial high altitude air craft) to 12 normal subjects by using a Venturi mask, which did not alter the breathing pattern during this study. Under mild hypoxia, inspiratory minute ventilation during sleep showed an initial rapid increase (P less than 0.001) but then declined significantly (P less than 0.001) and stabilized. Stable levels differed among individuals and, compared with those measured before hypoxia, were significantly lower in some subjects, higher in one, and essentially unchanged in the others. The initial rapid increase in minute ventilation after mild hypoxia during sleep correlated with the respective values of hypoxic ventilatory response during the awake state (P less than 0.01), but the final lowered levels did not. We conclude that the ventilatory response after mild hypoxia during sleep is biphasic and hypoxic depression exerts considerable influence on ventilation under mild hypoxia during sleep. So we should take hypoxic depression into consideration to evaluate the response to hypoxia during sleep.     

Influence of pregnancy on ventilatory and carotid body neural output responsiveness to hypoxia in cats

Pregnancy increases ventilation and ventilatory sensitivity to hypoxia and hypercapnia. To determine the role of the carotid body in the increased hypoxic ventilatory response, we measured ventilation and carotid body neural output (CBNO) during progressive isocapnic hypoxia in 15 anesthetized near-term pregnant cats and 15 nonpregnant females. The pregnant compared with nonpregnant cats had greater room-air ventilation [1.48 +/- 0.24 vs. 0.45 +/- 0.05 (SE) l/min BTPS, P less than 0.01], O2 consumption (29 +/- 2 vs. 19 +/- 1 ml/min STPD, P less than 0.01), and lower end-tidal PCO2 (30 +/- 1 vs. 35 +/- 1 Torr, P less than 0.01). Lower end-tidal CO2 tensions were also observed in seven awake pregnant compared with seven awake nonpregnant cats (28 +/- 1 vs. 31 +/- 1 Torr, P less than 0.05). The ventilatory response to hypoxia as measured by the shape of parameter A was twofold greater (38 +/- 5 vs. 17 +/- 3, P less than 0.01) in the anesthetized pregnant compared with nonpregnant cats, and the CBNO response to hypoxia was also increased twofold (58 +/- 11 vs. 29 +/- 5, P less than 0.05). The increased CBNO response to hypoxia in the pregnant compared with the nonpregnant cats persisted after cutting the carotid sinus nerve while recording from the distal end, indicating that the increased hypoxic sensitivity was not due to descending central neural influences. We concluded that greater carotid body sensitivity to hypoxia contributed to the increased hypoxic ventilatory responsiveness observed in pregnant cats.     

Possible mechanisms of periodic breathing during sleep

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.     

Effect of inspiratory resistive loading on control of ventilation during progressive exercise

Eight healthy volunteers performed gradational tests to exhaustion on a mechanically braked cycle ergometer, with and without the addition of an inspiratory resistive load. Mean slopes for linear ventilatory responses during loaded and unloaded exercise [change in minute ventilation per change in CO2 output (delta VE/delta VCO2)] measured below the anaerobic threshold were 24.1 +/- 1.3 (SE) = l/l of CO2 and 26.2 +/- 1.0 l/l of CO2, respectively (P greater than 0.10). During loaded exercise, decrements in VE, tidal volume, respiratory frequency, arterial O2 saturation, and increases in end-tidal CO2 tension were observed only when work loads exceeded 65% of the unloaded maximum. There was a significant correlation between the resting ventilatory response to hypercapnia delta VE/delta PCO2 and the ventilatory response to VCO2 during exercise (delta VE/delta VCO2; r = 0.88; P less than 0.05). The maximal inspiratory pressure generated during loading correlated with CO2 sensitivity at rest (r = 0.91; P less than 0.05) and with exercise ventilation (delta VE/delta VCO2; r = 0.83; P less than 0.05). Although resistive loading did not alter O2 uptake (VO2) or heart rate (HR) as a function of work load, maximal VO2, HR, and exercise tolerance were decreased to 90% of control values. We conclude that a modest inspiratory resistive load reduces maximum exercise capacity and that CO2 responsiveness may play a role in the control of breathing during exercise when airway resistance is artificially increased.     

Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes.

This study determined whether "living high-training low" (LHTL)-simulated altitude exposure increased the hypoxic ventilatory response (HVR) in well-trained endurance athletes. Thirty-three cyclists/triathletes were divided into three groups: 20 consecutive nights of hypoxic exposure (LHTLc, n = 12), 20 nights of intermittent hypoxic exposure (four 5-night blocks of hypoxia, each interspersed with 2 nights of normoxia, LHTLi, n = 10), or control (Con, n = 11). LHTLc and LHTLi slept 8-10 h/day overnight in normobaric hypoxia (approximately 2,650 m); Con slept under ambient conditions (600 m). Resting, isocapnic HVR (DeltaVE/DeltaSp(O(2)), where VE is minute ventilation and Sp(O(2)) is blood O(2) saturation) was measured in normoxia before hypoxia (Pre), after 1, 3, 10, and 15 nights of exposure (N1, N3, N10, and N15, respectively), and 2 nights after the exposure night 20 (Post). Before each HVR test, end-tidal PCO(2) (PET(CO(2))) and VE were measured during room air breathing at rest. HVR (l. min(-1). %(-1)) was higher (P < 0.05) in LHTLc than in Con at N1 (0.56 +/- 0.32 vs. 0.28 +/- 0.16), N3 (0.69 +/- 0.30 vs. 0.36 +/- 0.24), N10 (0.79 +/- 0.36 vs. 0.34 +/- 0.14), N15 (1.00 +/- 0.38 vs. 0.36 +/- 0.23), and Post (0.79 +/- 0.37 vs. 0.36 +/- 0.26). HVR at N15 was higher (P < 0.05) in LHTLi (0.67 +/- 0.33) than in Con and in LHTLc than in LHTLi. PET(CO(2)) was depressed in LHTLc and LHTLi compared with Con at all points after hypoxia (P < 0.05). No significant differences were observed for VE at any point. We conclude that LHTL increases HVR in endurance athletes in a time-dependent manner and decreases PET(CO(2)) in normoxia, without change in VE. Thus endurance athletes sleeping in mild hypoxia may experience changes to the respiratory control system.     

Human ventilatory responsiveness to hypoxia is unrelated to maximal aerobic capacity.

Ventilatory responsiveness to hypoxia (HVR) has been reported to be different between highly trained endurance athletes and healthy sedentary controls. However, a linkage between aerobic capacity and HVR has not been a universal finding. The purpose of this study was to examine the relationship between HVR and maximal oxygen consumption (VO2 max) in healthy men with a wide range of aerobic capacities. Subjects performed a HVR test followed by an incremental cycle test to exhaustion. Participants were classified according to their maximal aerobic capacity. Those with a VO2 max of >or=60 ml x kg(-1) x min(-1) were considered highly trained (n = 13); those with a VO2 max of 50-60 ml x kg(-1) x min(-1) were considered moderately-trained (n = 18); and those with a VO2 max of <50 ml x kg(-1) x min(-1) were considered untrained (n = 24). No statistical differences were detected between the three groups for HVR (P > 0.05), and the HVR values were variable within each group (range: untrained = 0.28-1.61, moderately trained = 0.23-2.39, and highly trained = 0.08-1.73 l x min.%arterial O2 saturation(-1)). The relationship between HVR and VO2 max was not statistically significant (r = -0.1723; P > 0.05). HVR was also unrelated to maximal minute ventilation and ventilatory equivalents for O2 and CO2. We found that a spectrum of hypoxic ventilatory control is present in well-trained endurance athletes and moderately and untrained men. We interpret these observations to mean that other factors are more important in determining hypoxic ventilatory control than physical conditioning per se.     

Effects of CO2 breathing on ventilatory response to sustained hypoxia in normal adults

The relationship between CO2 and ventilatory response to sustained hypoxia was examined in nine normal young adults. At three different levels of end-tidal partial pressure of CO2 (PETCO2, approximately 35, 41.8, and 44.3 Torr), isocapnic hypoxia was induced for 25 min and after 7 min of breathing 21% O2, isocapnic hypoxia was reinduced for 5 min. Regardless of PETCO2 levels, the ventilatory response to sustained hypoxia was biphasic, characterized by an initial increase (acute hypoxic response, AHR), followed by a decline (hypoxic depression). The biphasic response pattern was due to alteration in tidal volume, which at all CO2 levels decreased significantly (P less than 0.05), without a significant change in breathing frequency. The magnitude of the hypoxic depression, independent of CO2, correlated significantly (r = 0.78, P less than 0.001) with the AHR, but not with the ventilatory response to CO2. The decline of minute ventilation was not significantly affected by PETCO2 [averaged 2.3 +/- 0.6, 3.8 +/- 1.3, and 4.5 +/- 2.2 (SE) 1/min for PETCO2 35, 41.8, and 44.3 Torr, respectively]. This decay was significant for PETCO2 35 and 41.8 Torr but not for 44.3 Torr. The second exposure to hypoxia failed to elicit the same AHR as the first exposure; at all CO2 levels the AHR was significantly greater (P less than 0.05) during the first hypoxic exposure than during the second. We conclude that hypoxia exhibits a long-lasting inhibitory effect on ventilation that is independent of CO2, at least in the range of PETCO2 studied, but is related to hypoxic ventilatory sensitivity.     

Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions.

Acetazolamide (Acz) is used at altitude to prevent acute mountain sickness, but its effect on exercise capacity under hypoxic conditions is uncertain. Nine healthy men completed this double-blind, randomized, crossover study. All subjects underwent incremental exercise to exhaustion with an inspired O(2) fraction of 0.13, hypoxic ventilatory responses, and hypercapnic ventilatory responses after Acz (500 mg twice daily for 5 doses) and placebo. Maximum power of 203 +/- 38 (SD) W on Acz was less than the placebo value of 225 +/- 40 W (P < 0.01). At peak exercise, arterialized capillary pH was lower and Po(2) higher on Acz (P < 0.01). Ventilation was 118.6 +/- 20.0 l/min at the maximal power on Acz and 102.4 +/- 20.7 l/min at the same power on placebo (P < 0.02), and Borg score for leg fatigue was increased on Acz (P < 0.02), with no difference in Borg score for dyspnea. Hypercapnic ventilatory response on Acz was greater (P < 0.02), whereas hypoxic ventilatory response was unchanged. During hypoxic exercise, Acz reduced exercise capacity associated with increased perception of leg fatigue. Despite increased ventilation, dyspnea was not increased.     

Combined effects of female hormones and metabolic rate on ventilatory drives in women

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.     

Sustained microgravity reduces the human ventilatory response to hypoxia but not to hypercapnia.

We measured the isocapnic hypoxic ventilatory response and the hypercapnic ventilatory response by using rebreathing techniques in five normal subjects (ages 37-47 yr) before, during, and after 16 days of exposure to microgravity (microG). Control measurements were performed with the subjects in the standing and supine postures. In both microG and in the supine position, the hypoxic ventilatory response, as measured from the slope of ventilation against arterial O(2) saturation, was greatly reduced, being only 46 +/- 10% (microG) and 52 +/- 11% (supine) of that measured standing (P < 0.01). During the hypercapnic ventilatory response test, the ventilation at a PCO(2) of 60 Torr was not significantly different in microG (101 +/- 5%) and the supine position (89 +/- 3%) from that measured standing. Inspiratory occlusion pressures agreed with these results. The findings can be explained by inhibition of the hypoxic but not hypercapnic drive, possibly as a result of an increase in blood pressure in carotid baroreceptors in microG and the supine position.     

Effect of brain blood flow on hypoxic ventilatory response in humans

To assess the effect of brain blood flow on hypoxic ventilatory response, we measured arterial and internal jugular venous blood gases and ventilation simultaneously and repeatedly in eight healthy male humans in two settings: 1) progressive and subsequent sustained hypoxia, and 2) stepwise and progressive hypercapnia. Ventilatory response to progressive isocapnic hypoxia [arterial O2 partial pressure 155.9 +/- 4.0 (SE) to 46.7 +/- 1.5 Torr] was expressed as change in minute ventilation per change in arterial O2 saturation and varied from -0.16 to -1.88 [0.67 +/- 0.19 (SE)] l/min per % among subjects. In the meanwhile, jugular venous PCO2 (PjCO2) decreased significantly from 51.0 +/- 1.1 to 47.3 +/- 1.0 Torr (P less than 0.01), probably due to the increase in brain blood flow, and stayed at the same level during 15 min of sustained hypoxia. Based on the assumption that PjCO2 reflects the brain tissue PCO2, we evaluated the depressant effect of fall in PjCO2 on hypoxic ventilatory response, using a slope for ventilation-PjCO2 line which was determined in the second set of experiments. Hypoxic ventilatory response corrected with this factor was -1.31 +/- 0.33 l/min per %, indicating that this factor modulated hypoxic ventilatory response in humans. The ventilatory response to progressive isocapnic hypoxia did not correlate with this factor but significantly correlated with the withdrawal test (modified transient O2 test), which was performed on a separate day. Accordingly we conclude that an increase in brain blood flow during exposure to moderate hypoxia may substantially attenuate the ventilatory response but that it is unlikely to be the major factor of the interindividual variation of progressive isocapnic hypoxic ventilatory response in humans.