The effects of intermittent exposure to hypoxia during endurance exercise training on the ventilatory responses to hypoxia and hypercapnia in humans

The present study was performed to investigate the effects of a combination of intermittent exposure to hypoxia during exercise training for short periods on ventilatory responses to hypoxia and hypercapnia (HVR and HCVR respectively) in humans. In a hypobaric chamber at a simulated altitude of 4,500 m (barometric pressure 432 mmHg), seven subjects (training group) performed exercise training for 6 consecutive days (30 min · day⁻¹), while six subjects (control group) were inactive during the same period. The HVR, HCVR and maximal oxygen uptake (V˙O_{2 max}) for each subject were measured at sea level before (pre) and after exposure to intermittent hypoxia. The post exposure test was carried out twice, i.e. on the 1st day and 1 week post exposure. It was found that HVR, as an index of peripheral chemosensitivity to hypoxia, was increased significantly (P < 0.05) in the control group after intermittent exposure to hypoxia. In contrast, there was no significant increase in HVR in the training group after exposure. The HCVR in both groups was not changed by intermittent exposure to hypoxia, while V˙O_{2 max} increased significantly in the training group. These results would suggest that endurance training during intermittent exposure to hypoxia depresses the increment of chemosensitivity to hypoxia, and that intermittent exposure to hypoxia in the presence or absence of exercise training does not induce an increase in the chemosensitivity to hypercapnia in humans. Accepted: 18 March 1998     

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.     

Ventilatory chemosensitive adaptations to intermittent hypoxic exposure with endurance training and detraining.

The present study was performed to clarify the effects of intermittent exposure to an altitude of 4,500 m with endurance training and detraining on ventilatory chemosensitivity. Seven subjects (sea-level group) trained at sea level at 70% maximal oxygen uptake (VO2 max) for 30 min/day, 5 days/wk for 2 wk, whereas the other seven subjects (altitude group) trained at the same relative intensity (70% altitude VO2 max) in a hypobaric chamber. VO2 max, hypoxic ventilatory response (HVR), and hypercapnic ventilatory response, as an index of central hypercapnic chemosensitivity (HCVR) and as an index of peripheral chemosensitivity (HCVRSB), were measured. In both groups VO2 max increased significantly after training, and a significant loss of VO2 max occurred during 2 wk of detraining. HVR tended to increase in the altitude group but not significantly, whereas it decreased significantly in the sea-level group after training. HCVR and HCVRSB did not change in each group. After detraining, HVR returned to the pretraining level in both groups. These results suggest that ventilatory chemosensitivity to hypoxia is more variable by endurance training and detraining than that to hypercapnia.     

Relationship between resting ventilatory chemosensitivity and maximal oxygen uptake in moderate hypobaric hypoxia.

This study tested the hypothesis that the extent of the decrement in (.)Vo(2max) and the respiratory response seen during maximal exercise in moderate hypobaric hypoxia (H; simulated 2,500 m) is affected by the hypoxia ventilatory and hypercapnia ventilatory responses (HVR and HCVR, respectively). Twenty men (5 untrained subjects, 7 long distance runners, 8 middle distance runners) performed incremental exhaustive running tests in H and normobaric normoxia (N) condition. During the running test, (.)Vo(2), pulmonary ventilation (Ve) and arterial oxyhemoglobin saturation (Sa(O(2))) were measured, and in two ventilatory response tests performed during N, a rebreathing method was used to evaluate HVR and HCVR. Mean HVR and HCVR were 0.36 +/- 0.04 and 2.11 +/- 0.2 l.min(-1).mmHg(-1), respectively. HVR correlated significantly with the percent decrements in (.)Vo(2max) (%d(.)Vo(2max)), Sa(O(2)) [%dSa(O(2)) = (N-H).N(-1).100], and (.)Ve/(.)Vo(2) seen during H condition. By contrast, HCVR did not correlate with any of the variables tested. The increment in maximal Ve between H and N significantly correlated with %d(.)Vo(2max). Our findings suggest that O(2) chemosensitivity plays a significant role in determining the level of exercise hyperventilation during moderate hypoxia; thus, a higher O(2) chemosensitivity was associated with a smaller drop in (.)Vo(2max) and Sa(O(2)) under those conditions.     

Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans.

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.     

Effect of caffeine on ventilatory responses to hypercapnia, hypoxia, and exercise in humans

The effect of oral caffeine on resting ventilation (VE), ventilatory responsiveness to progressive hyperoxic hypercapnia (HCVR), isocapnic hypoxia (HVR), and moderate exercise (EVR) below the anaerobic threshold (AT) was examined in seven healthy adults. Ventilatory responses were measured under three conditions: control (C) and after ingestion of either 650 mg caffeine (CF) or placebo (P) in a double-blind randomized manner. None of the physiological variables of interest differed significantly for C and P conditions (P greater than 0.05). Caffeine levels during HCVR, HVR, and EVR were 69.5 +/- 11.8, 67.8 +/- 10.8, and 67.8 +/- 10.9 (SD) mumol/l, respectively (P greater than 0.05). Metabolic rate at rest and during exercise was significantly elevated during CF compared with P. An increase in VE from 7.4 +/- 2.5 (P) to 10.5 +/- 2.1 l/min (CF) (P less than 0.05) was associated with a decrease in end-tidal PCO2 from 39.1 +/- 2.7 (P) to 35.1 +/- 1.3 Torr (CF) (P less than 0.05). Caffeine increased the HCVR, HVR, and EVR slopes (mean increase: 28 +/- 8, 135 +/- 28, 14 +/- 5%, respectively) compared with P; P less than 0.05 for each response. Increases in resting ventilation, HCVR, and HVR slopes were associated with increases in tidal volume (VT), whereas the increase in EVR slope was accompanied by increases in both VT and respiratory frequency. Our results indicate that caffeine increases VE and chemosensitivity to CO2 inhalation, hypoxia, and CO2 production during exercise below the AT.     

Control of ventilation and aerobic work capacity in elite climbers

Hypoxic ventilatory response (HVR), hypercapnic ventilatory response (HCVR), and maximal oxygen uptake (VO2max) were measured in elite male climbers (Clim.: n = 4) and physically active controls (Con.: n = 8). Although mean value of S, an index of HCVR, showed almost the same values in both groups (Clim.: 2.26 +/- 0.62 vs. Con.: 1.85 +/- 0.58 l.min-1.Torr-1), mean value of A, an index of HVR, was significantly higher in climbers than controls (Clim.: 237.8 +/- 109.2 vs. Con.: 111.3 +/- 62.0 l.min-1.Torr-1). Mean value of VO2max in climbers was not different from that in controls (Clim.: 49.3 +/- 2.9 vs. Con.: 47.5 +/- 5.7 ml.kg-1.min-1). These results demonstrate that elite climbers are characterized by their enhanced ventilatory response to hypoxia rather than prominency in aerobic work capacity. It is speculated that enhanced HVR in climbers makes compensation for decreased VO2max at high altitude. The enhanced HVR in elite climbers who have ordinary values in VO2max may be one of factors in their successful performance at extreme altitude.     

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.     

Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D(2) receptors.

We used genetically engineered D(2) receptor-deficient [D(2)-(-/-)] and wild-type [D(2)-(+/+)] mice to test the hypothesis that dopamine D(2) receptors modulate the ventilatory response to acute hypoxia [hypoxic ventilatory response (HVR)] and hypercapnia [hypercapnic ventilatory response (HCVR)] and time-dependent changes in ventilation during chronic hypoxia. HVR was independent of gender in D(2)-(+/+) mice and significantly greater in D(2)-(-/-) than in D(2)-(+/+) female mice. HCVR was significantly greater in female D(2)-(+/+) mice than in male D(2)-(+/+) and was greater in D(2)-(-/-) male mice than in D(2)-(+/+) male mice. Exposure to hypoxia for 2-8 days was studied in male mice only. D(2)-(+/+) mice showed time-dependent increases in "baseline" ventilation (inspired PO(2) = 214 Torr) and hypoxic stimulated ventilation (inspired PO(2) = 70 Torr) after 8 days of acclimatization to hypoxia, but D(2)-(-/-) mice did not. Hence, dopamine D(2) receptors modulate the acute HVR and HCVR in mice in a gender-specific manner and contribute to time-dependent changes in ventilation and the acute HVR during acclimatization to hypoxia.     

Depressed Hypoxic and Hypercapnic Ventilatory Responses at Early Stage of Lethal Avian Influenza A Virus Infection in Mice

H5N1 virus infection results in ~60% mortality in patients primarily due to respiratory failure, but the underlying causes of mortality are unclear. The goal of this study is to reveal respiratory disorders occurring at the early stage of infection that may be responsible for subsequent respiratory failure and death. BALB/c mice were intranasally infected with one of two H5N1 virus strains: HK483 (lethal) or HK486 (non-lethal) virus. Pulmonary ventilation and the responses to hypoxia (HVR; 7% O₂ for 3 min) and hypercapnia (HCVR; 7% CO₂ for 5 min) were measured daily at 2 days prior and 1, 2, and 3 days postinfection (dpi) and compared to mortality typically by 8 dpi. At 1, 2, and 3 dpi, immunoreactivities (IR) of substance P (SP-IR) in the nodose ganglion or tyrosine hydroxylase (TH-IR) in the carotid body coupled with the nucleoprotein of influenza A (NP-IR) was examined in some mice, while arterial blood was collected in others. Our results showed that at 2 and 3 dpi: 1) both viral infections failed to alter body temperature and weight, V˙CO2, or induce viremia while producing similarly high lung viral titers; 2) HK483, but not HK486, virus induced tachypnea and depressed HVR and HCVR without changes in arterial blood pH and gases; and 3) only HK483 virus led to NP-IR in vagal SP-IR neurons, but not in the carotid body, and increased density of vagal SP-IR neurons. In addition, all HK483, rather than HK486, mice died at 6 to 8 dpi and the earlier death was correlated with more severe depression of HVR and HCVR. Our data suggest that tachypnea and depressed HVR/HCVR occur at the early stage of lethal H5N1 viral infection associated with viral replication and increased SP-IR density in vagal neurons, which may contribute to the respiratory failure and death.     

Control of ventilation in extreme-altitude climbers

Ten climbers who participated in the Nepal-Japan Kangchenjunga Expedition (altitude, 8,478-8,586 m) in 1984 were examined for their hypercapnic and isocapnic hypoxic ventilatory responses (HCVR and HVR) at sea level before and after the expedition. Five climbers who reached an altitude higher than 8,000 m, [designated high-performance climbers (HPC)] exhibited significantly higher HVR than five climbers who did not [low-performance climbers (LPC)]. On the other hand, no significant difference in HCVR was seen between HPC and LPC. Our results were in agreement with the findings reported by Schoene et al. (J. Appl. Physiol. 56: 1478-1483, 1984) obtained in the American Medical Research Expedition to Everest in 1981. Significant depression in HVR in five climbers was found even 35-40 days after the expedition, which was accompanied by decreased arterial partial pressure of CO2 and increased pH at rest. Hence, the effect of altitude acclimatization in the climbers exposed to extreme altitude may have still persisted at the time of the postexpedition study. Our results confirmed that HRV evaluated at sea level may be used as an indicator of a climber's capability at great high altitude.     

Effect of hypercapnia and hypoxia on respiratory muscle activation in humans

We studied the electromyographic activity of the diaphragm (EMGdi) and abdominal external oblique (EMGeo) muscles in response to progressive hypercapnia (HCVR) and hypoxia (HVR) in five normal males. The slopes of the regression lines relating log EMGdi activity to minute volume of ventilation (VE) were steeper during HVR runs than HCVR runs (mean +/- SE, 0.03201 +/- 0.00724 vs. 0.02729 +/- 0.00676, P less than 0.03). Phasic expiratory EMGeo activity was seen in 15 of 15 HCVR runs but in only 6 of 15 HVR runs. Furthermore, the maximum level of VE attained before the onset of EMGeo activity was significantly lower during HCVR runs than during HVR runs (23.1 +/- 2.5 vs. 34.8 +/- 4.01/min, P less than 0.003). We conclude that in awake humans 1) the diaphragm is activated to a greater extent by hypoxia than hypercapnia at a given VE and 2) hypercapnia causes a more consistent recruitment of abdominal expiratory activity at lower VE than does hypoxia.     

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)     

Chemoreflex control of breathing during wakefulness in healthy men and women.

This study used a modified CO(2) rebreathing procedure to examine the effect of gender on the chemoreflex control of breathing during wakefulness in healthy men (n = 14) and women (n = 14). Women were tested in the follicular phase of the menstrual cycle. During rebreathing trials, subjects hyperventilated to reduce the partial pressure of end-tidal CO(2) (Pet(CO(2))) below 25 Torr and were then switched to a rebreathing bag containing a normocapnic hypoxic or hyperoxic gas mixture. During the trial, Pet(CO(2)) increased, while O(2) was maintained at a constant level. The point at which ventilation began to rise as Pet(CO(2)) increased was identified as the ventilatory recruitment threshold (VRT). Ventilation below the VRT was measured, and the slope of the ventilatory response above the VRT was determined. Gender had no effect on the hyperoxic or hypoxic VRT for CO(2). Central chemoreflex sensitivity was significantly greater in men than women but not after correction for forced vital capacity. Measures of peripheral chemoreflex sensitivity were similar between genders. However, the slope of the tidal volume (Vt) response to hyperoxic and hypoxic CO(2) rebreathing (corrected and uncorrected) was greater in men than women, respectively. We conclude that central chemoreflex sensitivity is greater in men compared with women as reflected by differences in ventilatory (uncorrected) and Vt (corrected and uncorrected) responses to CO(2). However, gender has no significant effect on the central chemoreflex VRT for CO(2). The peripheral chemoreflex control of breathing during wakefulness is similar between men and women.     

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)     

Role of endogenous female hormones in hypoxic chemosensitivity

Tatsumi, Koichiro, Cheryl K. Pickett, Christopher R. Jacoby,John V. Weil, and Lorna G. Moore. Role of endogenous female hormones in hypoxic chemosensitivity. J. Appl.Physiol. 83(5): 1706-1710, 1997.Effective alveolar ventilation and hypoxicventilatory response (HVR) are higher in females than in males andafter endogenous or exogenous elevation of progesterone and estrogen.The contribution of normal physiological levels of ovarian hormones toresting ventilation and ventilatory control and whether their site(s) of action is central and/or peripheral are unclear.Accordingly, we examined resting ventilation, HVR, and hypercapnicventilatory responses (HCVR) before and 3 wk after ovariectomy in fivefemale cats. We also compared carotid sinus nerve (CSN) and centralnervous system translation responses to hypoxia in 6 ovariectomized and 24 intact female animals. Ovariectomy decreased serum progesterone butdid not change resting ventilation, end-tidalPCO₂, or HCVR (allP = NS). Ovariectomy reduced theHVR shape parameter A in the awake(38.9 ± 5.5 and 21.2 ± 3.0 before and after ovariectomy, respectively, P < 0.05) andanesthetized conditions. The CSN response to hypoxia was lower inovariectomized than in intact animals (shape parameterA = 22.6 ± 2.5 and 54.3 ± 3.5 in ovariectomized and intact animals, respectively,P < 0.05), but central nervous system translation of CSN activity into ventilation was similar inovariectomized and intact animals. We concluded that ovariectomy decreased ventilatory and CSN responsiveness to hypoxia, suggesting that the presence of physiological levels of ovarian hormones influences hypoxic chemosensitivity by acting primarily at peripheral sites.

     

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.     

Increased metaboreflex activity is related to exercise intolerance in heart transplant patients

Heart transplantation does not normalize exercise capacity or the ventilatory response to exercise. We hypothesized that excessive muscle reflex activity, as assessed by the muscle sympathetic nerve activity (MSNA) response to handgrip exercise, persists after cardiac transplantation and that this mechanism is related to exercise hyperpnea in heart transplant recipients (HTRs). We determined the MSNA, ventilatory, and cardiovascular responses to isometric and dynamic handgrips in 11 HTRs and 10 matched control subjects. Handgrips were followed by a post-handgrip ischemia to isolate the metaboreflex contribution to exercise responses. HTRs and control subjects also underwent recordings during isocapnic hypoxia and a maximal, symptom-limited, cycle ergometer exercise test. HTRs had higher resting MSNA (P < 0.01) and heart rate (P < 0.01) than the control subjects. Isometric handgrip increased MSNA in HTRs more than in the controls (P = 0.003). Dynamic handgrip increased MSNA only in HTRs. During post-handgrip ischemia, MSNA and ventilation remained more elevated in HTRs (P < 0.05). The MSNA and ventilatory responses to hypoxia were also higher in HTRs (both P < 0.04). In HTRs, metaboreflex overactivity was related to the ventilatory response to exercise, characterized by the regression slope relating ventilation to CO(2) output (r = +0.8; P < 0.05) and a lower peak ventilation (r = +0.81; P < 0.05) during cycle ergometer exercise tests. However, increased chemoreflex sensitivity (r = +0.91; P < 0.005), but not metaboreflex activity, accounted for the lower peak ventilation during exercise in a stepwise regression analysis. In conclusion, heart transplantation does not normalize muscle metaboreceptor activity; both increased metaboreflex and chemoreflex control are related to exercise intolerance in HTRs.     

Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O₂ saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O₂-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.     

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Andean high-altitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O(2) saturation (Sa(O(2))). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10-12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia (r = -0.36, P = 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r = -0.50, P = 0.005) and ventilatory equivalent (VE/Vo(2), r = -0.51, P = 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the well-known blunted HVR (10, 35, 36, 57, 62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua.