Variation in human ventilatory control-genetic influence on the hypoxic ventilatory response.

Studies in human subjects have shown considerable variation in the ventilatory response to hypoxia among individuals. The potential influence of genetic factors was initially suggested by the finding of clusters of low responses in families of patients with unexplained hypoventilation and endurance athletes. Further evidence of a genetic effect was evident in studies which found greater similarity of hypoxic ventilatory response in monozygotic than in dizygotic twins. The apparently selective effect on the hypoxic versus the hypercapnic response suggests that the genetic influence is related to peripheral chemosensitivity. Studies in cats and rats also point to a genetic effect on the carotid body.

Potential genetic contributions to control of the pulmonary circulation and ventilation at high altitude.

This review examines evidence that genetic factors may be important determinants of response of the pulmonary circulation and ventilation at high altitude. Early observations of cattle at high altitude with brisket disease-pulmonary hypertension with right heart failure-found that the disorder ran in families. Subsequent studies confirmed a genetic determination of the pulmonary vasoconstrictor response to hypoxia by selective breeding of cattle for high and low responses. Clear interspecies and interstrain differences in the hypoxic pulmonary pressor response also underscore a major role for genetic influence in animals. In humans, differences in pulmonary hemodynamics are also evident among discrete populations living at altitude in the Andes, Himalayas, and North America suggesting an evolutionary, genetic influence on the response of the lung circulation to the hypoxia of altitude. Ventilation is increased by the hypoxia of high altitude. The strength of the ventilatory response to hypoxia shows considerable variation among individuals at low altitude. Family clusters of high and low responses and greater concordance among identical than fraternal twins suggest a strong genetic modulation of the human hypoxic ventilatory response. Similar effects are seen in interstrain differences among inbred strains of rats and mice. Differences among diverse altitude populations support the possible influence of genetic variation in the hypoxic response on ventilation and adaptation at altitude. Mechanisms linking genetic influences to variation in the hypoxic pulmonary pressor and ventilatory responses are unknown, but could reflect effects on hypoxic sensor, mediator or effector limbs of the response.

Chronic mountain sickness. A view from the crow's nest.

Chronic mountain sickness (CMS) is a poorly understood syndrome, characterized by hypoxemia and polycythemia and occurring in persons residing at high altitude. To better characterize the disorder, we have reviewed measurements in more than 750 men and 200 women living at altitude as published and as submitted by colleagues. In men, blood hemoglobin concentration (Hb) and arterial oxygen saturation (SaO2) related to altitude (r=0.72). There was greater variability in both SaO2 and hemoglobin above than below 3000 m, largely due to inter-individual variations in effective ventilation. For the entire cohort, a linear relationship (r=0.72) of an index of hematopoietic response (Hb) to an index of stimulus (SaO2) was independent of age, altitude, duration of altitude residence greater than one year, ethnic origin, geographic location, presence or absence of CMS and nearly independent of gender. A potentially important and usually unrecognized variation in the hypoxic stimulus was desaturation during sleep. Contributions to variation in response include ingested toxins, such as cobalt, and nutritional deficiencies, including iron. Pulmonary hypertension was related to chronic hypoxia, with an uncertain contribution from polycythemia. In CMS there were profound hypoxemia at night, decrease in cerebral blood flow, and loss of cerebral blood flow regulation, possibly causing the cerebral symptoms. We speculate that the relationship of Hb to SaO2 is more useful than of hemoglobin to altitude, that hypoventilation awake and asleep are the primary causes accentuating altitude-hypoxia, and that the brain is the primary target organ in the disorder.

Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium.

Increased adherence of sickle red blood cells (RBC) to endothelium is implicated as an initiating event of vaso-occlusion in sickle cell disease. Although much is known about the humoral influences of this interaction, there has been little investigation regarding endothelial contributions. Endothelial derived nitric oxide (NO) inhibits adhesion of platelets and leukocytes to endothelium and decreases expression of VCAM-1, an endothelial adhesion site implicated in sickle RBC/endothelial adherence. However, whether NO inhibits RBC adherence to endothelium is unexplored. We tested this hypothesis with endothelial monolayers exposed to RBC from normal (Hb AA) and sickle cell (Hb SS) volunteers in a parallel plate flow chamber. To decrease NO production, endothelial monolayers were exposed to 100 microM nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, resulting in an 87% increase in normal RBC adherence (P = 0.002). Because adherence of normal RBC to endothelium was low, the effect of DETA-NO, an NO donor, was tested after activation of endothelium with TNF-alpha increased adherence by 130% (P < 0.001). Subsequent addition of 2 mM DETA-NO produced a 75% decrease in adherence of normal RBC to endothelium (P = 0.03). At baseline, sickle RBC were significantly more adherent than normal RBC (P < 0.001) and DETA-NO decreased sickle RBC adherence by 54% (P = 0.04). Thus, NO inhibits both normal and sickle RBC adherence to endothelium. Strategies that enhance NO activity may be therapeutic in sickle cell disease.

Hypoxia reduces airway epithelial sodium transport in rats.

Ascent to high altitude leads to pulmonary edema formation in some individuals. Recent laboratory evidence supports the hypothesis that hypoxia may impair the function of the alveolar epithelium and thus augment edema accumulation via reduced clearance of lung liquid. We investigated the effect of hypobaric hypoxia on epithelial sodium transport in adult Sprague-Dawley rats by measuring the nasal transepithelial potential difference (PD) as an index of airway sodium transport. Baseline PDs were similar to those previously reported in other species. Administration of amiloride resulted in a significant fall in nasal PD, as did ouabain administration for 24 h (-27.8 vs. -18.8 mV; P = 0.001; n = 5 rats). Exposure to hypobaric hypoxia (0.5 atm) for 24 h caused a significant fall in nasal PD (-23.7 vs. -18.8 mV; P = 0.002; n = 15 rats), which was not additive to the changes in nasal PD produced by amiloride or ouabain. We conclude that subacute exposure to moderate hypobaric hypoxia can inhibit sodium transport by the airway epithelium in rats.

Strain-associated differences in hypoxic chemosensitivity of the carotid body in rats.

Studies in humans indicate genetic effects on the ventilatory response to hypoxia, but the site of these effects is unknown. The present study explores the question of whether there are genetically directed effects on the intrinsic hypoxic chemosensitivity of the carotid body. The approach was to study these responses in two inbred rat strains [spontaneously hypertensive rats (SHR) and Fischer 344 (F-344)] and to measure in vivo carotid chemosensitivity as the change in carotid sinus nerve (CSN) activity during progressive, isocapnic hypoxia and the isolated, in vitro responses of excised superfused carotid bodies, loaded with the fluorimetric indicator fura 2, measured as the cytosolic calcium response to moderate hypoxia (PO2 = 55 mmHg). CSN responses in F-344 rats (n = 12) were uniformly low, with a shape parameter A of 13.8 +/- 6.59 (SE), whereas responses in SHR (n = 15) were sevenfold higher (108 +/- 24.1; P < 0.002) and showed greater variation. In vitro, intracellular calcium responses of superfused carotid bodies estimated from the fluorimetric ratio (340/380 nm) showed a greater peak increase during hypoxia in carotid bodies from SHR (140 +/- 4.7%) than from F-344 rats (114 6.0%; P < 0.01). Our results indicate strain-related differences in hypoxic chemosensitivity that are intrinsic to the carotid body and that could mediate genetic effects on ventilatory responsiveness to hypoxia.

Role of endogenous female hormones in hypoxic chemosensitivity.

Effective alveolar ventilation and hypoxic ventilatory response (HVR) are higher in females than in males and after endogenous or exogenous elevation of progesterone and estrogen. The contribution of normal physiological levels of ovarian hormones to resting 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 hypercapnic ventilatory responses (HCVR) before and 3 wk after ovariectomy in five female cats. We also compared carotid sinus nerve (CSN) and central nervous system translation responses to hypoxia in 6 ovariectomized and 24 intact female animals. Ovariectomy decreased serum progesterone but did not change resting ventilation, end-tidal PCO2, or HCVR (all P = NS). Ovariectomy reduced the HVR shape parameter A in the awake (38.9 +/- 5.5 and 21.2 +/- 3.0 before and after ovariectomy, respectively, P < 0.05) and anesthetized conditions. The CSN response to hypoxia was lower in ovariectomized than in intact animals (shape parameter A = 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 in ovariectomized 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.

Abnormal vascular function following ischemia-reperfusion injury.

Ischemia-reperfusion injury as a general rule is accompanied by dramatic changes in basal and reactive vascular function in most organs. There are similarities in altered organ vascular function, particularly in the first 24 to 48 hours, with decreased basal organ blood flow, hypersensitivity to vasoconstrictor stimuli, attenuated responses to vasodilators, and increased vascular permeability. The reduced responsiveness to endothelium-dependent vasodilators may be due to reduced endothelial NOS activity or to spontaneous maximal activation of NOS/NO activity, which cannot be stimulated further by endothelium-dependent agents. There are also notable quantitative and qualitative differences in ischemia-reperfusion injury vasoreactive response in organs such as kidney, heart, and brain, the basis of which is unexplored, but may reflect regional differences in endothelium and/or organ parenchyma. Further examination of both the mechanisms and consequences of ischemia-reperfusion injury to the vasculature, as well as the clinical implications, should be a rewarding pursuit in organ pathophysiology.

Decreased carotid body hypoxic sensitivity in chronic hypoxia: role of dopamine.

Previously we showed that prolonged exposure to severe hypoxia produces decreased peripheral chemoreceptor responsiveness to hypoxia and attenuates central nervous system (CNS) chemosensory translation, which together may contribute to the decreased hypoxic ventilatory response (HVR) in chronic hypoxia. In this study, we sought to determine whether the central or peripheral activity of endogenous dopamine modulates this decreased HVR. We examined the effects of peripheral and central dopamine receptor blockade on HVR and carotid sinus nerve (CNS) response to hypoxia in controls and in cats exposed to a simulated altitude of 5500 m for 3 weeks. Domperidone increased CSN response to hypoxia in hypoxic cats to levels similar to those observed in controls. HVR was also augmented by domperidone in hypoxic cats, but remained below that of controls. As a result, the CNS chemosensory translation remained reduced in hypoxic animals. We further treated animals with haloperidol. However, this combined treatment with domperidone and haloperidol led to no further increase in CSN or ventilatory responses to hypoxia, or in CNS chemosensory translation in hypoxic cats. Thus, decreased HVR in hypoxic cats is mediated both by depression of hypoxic sensitivity of the carotid body, which is largely dopaminergic, and by decreased CNS chemosensory translation which must involve non-dopaminergic mechanisms.

Possible role of dopamine in ventilatory acclimatization to high altitude.

Ventilatory acclimatization to high altitude is accompanied by increased hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses which may reflect increased carotid body chemosensitivity. Dopamine is an inhibitory neuromodulator of the carotid body and its activity may be reduced by hypoxic exposure. To determine whether decreased dopaminergic activity could account for the increased chemosensitivity of acclimatization, we examined the response to peripheral dopamine receptor (D2) blockade with domperidone on HVR and HCVR in awake cats before and after exposure to simulated altitude of 14,000 ft for 2 days. During anesthesia, we also examined the effects of domperidone on carotid body responses to hypoxia and hypercapnia in acclimatized and low altitude cats. Two days' exposure to hypobaric hypoxia produced an increase in HVR and HCVR. Before acclimatization, domperidone augmented HVR and HCVR, but there was no effect after acclimatization. In anesthetized low altitude cats, domperidone increased carotid body responses to hypoxia and hypercapnia, but had no effect in acclimatized cats. These results indicate that decreased endogenous dopaminergic activity may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia and hypercapnia during hypoxic ventilatory acclimatization.

Effects of testosterone on hypoxic ventilatory and carotid body neural responsiveness.

Hypoxic (HVR) and hypercapnic ventilatory responses (HCVR) are known to be influenced by the administration of testosterone, but whether the hormone acts centrally or peripherally is unknown. To determine whether testosterone alters HVR, HCVR, and carotid sinus nerve (CSN) responsiveness to hypoxia, we compared the ventilatory and CSN responses of neutered male cats treated with testosterone with those of placebo-treated cats. Testosterone treatment increased resting ventilation and CO2 production but did not change end-tidal or arterial PCO2, implying that alveolar ventilation per unit CO2 production was unaltered. Testosterone treatment raised the HVR shape parameter A value 63% in the awake animals (from 16.9 +/- 4.2 to 28 +/- 4, p < 0.05) and 69% in the anesthetized cats (from 22.4 +/- 0.9 to 37.8 +/- 3.7, p < 0.05). Testosterone also augmented the HCVR slope S in awake cats (from 0.17 +/- 0.02 to 0.25 +/- 0.04, p < 0.05). Placebo treatment did not change HVR or HCVR. The CSN response to hypoxia was greater in the testosterone-treated than in the placebo-treated animals (A = 53.6 +/- 7.1 versus 27.1 +/- 5.5 respectively, p < 0.05). The crossplot of the simultaneously measured CSN activity and ventilation during progressive hypoxia showed that the central nervous system translation of CSN output into ventilation was similar in the hormone- and placebo-treated groups. Unilateral, proximal sectioning of the CSN decreased the ventilatory and the CSN responses to hypoxia in the testosterone-treated animals but not in the placebo group. These results indicated that testosterone increased hypoxic and hypercapnic ventilatory responsiveness and increased hypoxic sensitivity of the carotid body.(ABSTRACT TRUNCATED AT 250 WORDS)

Sea-level PCO2 relates to ventilatory acclimatization at 4,300 m.

There is considerable variation among individuals in the extent of, and the time required for, ventilatory acclimatization to altitude. Factors related to this variation are unclear. The present study tested whether interindividual variation in preascent ventilation or magnitude of hypoxic ventilatory response related to ventilatory acclimatization to altitude. Measurements in 37 healthy resting male subjects at sea level indicated a wide range (34-48 Torr) of end-tidal PCO2 values. When these subjects were taken to Pikes Peak, CO (4,300 m, barometric pressure 462 mmHg), the end-tidal PCO2 values measured on arrival and repeatedly over 19 days were correlated with the sea-level end-tidal PCO2. At 4,300 m, subjects with high end-tidal PCO2 had low values of arterial oxygen saturation (SaO2). Also, sea-level end-tidal PCO2 related to SaO2 after 19 days at 4,300 m. Twenty-six of the subjects had measurements of isocapnic hypoxic ventilatory response (HVR) at sea level. The end-tidal PCO2 values on arrival and after 19 days residence at 4,300 m were inversely related to the sea-level HVR values. Thus both the PCO2 and the HVR as measured at sea level related to the extent of subsequent ventilatory acclimatization (decrease in end-tidal PCO2) and the level of oxygenation at altitude. The finding in our cohort of subjects that sea-level end-tidal PCO2 was inversely related to HVR raised the possibility that among individuals the magnitude of the hypoxic drive to breathe influenced the amount of ventilation at all altitudes, including sea level.

Peripheral bypass-induced pulmonary and coronary vascular injury. Association with increased levels of tumor necrosis factor.

BACKGROUND: Although cardiopulmonary bypass is associated with systemic complement activation and neutrophil sequestration, it is unclear whether bypass-induced vascular injury is localized and dependent on organ ischemia. We hypothesized that other factors perhaps related to placement of a bypass circuit or to blood perfusion of a pump-oxygenator system may produce vascular injury caused by systemically circulating mediators. In dogs, we determined whether application of a systemic venoarterial bypass circuit with pump-oxygenator perfusion but without pulmonary or cardiac flow diversion (peripheral bypass) leads to vascular injury. Since several features of the postperfusion syndrome after bypass resemble sequelae of endotoxin exposure, we also measured circulating endotoxin and tumor necrosis factor levels. METHODS AND RESULTS: Anesthetized dogs underwent 2 hours of exposure to a pump-oxygenator with peripheral venoarterial bypass. We used a double indicator measurement of pulmonary and coronary vascular permeability (protein leak index [PLI]) as indexes of vascular injury. Compared with controls (n = 7), the pulmonary PLI of dogs undergoing bypass (n = 11) increased more than threefold (18.8 +/- 2.3 vs 63.3 +/- 7.6 x 10(-4) min-1; P < .05) and the coronary PLI increased more than twofold (P < .05). The rate of disappearance of intravascular radiolabeled protein increased threefold after bypass (disappearance t1/2, 241 +/- 35 vs 84 +/- 15 minutes, control vs bypass; P < .05), suggesting a generalized increase in vascular permeability. Circulating endotoxin was detectable in blood samples from 8 of 8 bypass animals (range, 0.24 to 4.56 ng/mL) compared with 2 of 5 controls (P < .05). Tumor necrosis factor levels increased significantly with bypass (6.7 +/- 3.8 vs 146.7 +/- 33.6 U/mL, baseline vs bypass; P < .05) and were only slightly and nonsignificantly increased in controls (7.0 +/- 4.4 vs 18.2 +/- 5.9 U/mL; P = NS). Peak tumor necrosis factor but not peak endotoxin levels correlated with pulmonary and with coronary protein leak. As expected, circulating complement (CH50) levels decreased significantly during bypass, reflecting systemic complement activation. However, the levels correlated poorly with the severity of vascular injury. CONCLUSIONS: We conclude that peripheral pump-oxygenator bypass causes coronary and pulmonary vascular injury that is independent of blood flow diversion and is associated with the appearance of circulating levels of endotoxin and tumor necrosis factor, which may play a role in bypass-induced vascular injury.

Effects of haloperidol and domperidone on ventilatory roll off during sustained hypoxia in cats.

In a previous work, we showed that the adult cat demonstrates a ventilatory decline during sustained hypoxia (the "roll off" phenomenon) and that the mechanism responsible for this secondary decrease in ventilation lies within the central nervous system (J. Appl. Physiol. 63: 1658-1664, 1987). In this study, we sought to determine whether central dopaminergic mechanisms could have a role in the roll off. We studied the effects of haloperidol, a peripheral and centrally acting dopamine receptor antagonist, on the ventilatory response to sustained isocapnic hypoxia (end-tidal PO2 40-50 Torr, 20-25 min) in awake cats. In vehicle control cats (n = 5), sustained hypoxia elicited a biphasic respiratory response, during which an initial ventilatory stimulation is followed by a 24 +/- 6% (P less than 0.01) reduction. In contrast, in haloperidol- (0.1 mg/kg) treated cats (n = 5) the ventilatory roll off was virtually abolished (-1 +/- 1%; P = NS). We also measured ventilatory, carotid sinus nerve (CSN) and phrenic nerve (PhN) responses to sustained isocapnic hypoxia in anesthetized animals (n = 6) to explore the influence of haloperidol on peripheral and central response during the roll off. Control responses to hypoxia showed an initial increase in ventilation, PhN, and CSN activity, followed by a subsequent decline in ventilation and PhN activity of 17 +/- 3 and 17 +/- 5%, respectively (P less than 0.05). In contrast, CSN activity remained unchanged during the roll off. Administration of haloperidol (1 mg/kg) reduced the initial increment in ventilation, while the initial increase in CSN activity was augmented.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary vascular injury due to ischemia-reperfusion is reduced by pentoxifylline.

Myocardial ischemia and reperfusion cause coronary vascular injury involving both the large epicardial arteries and the microcirculation. Although the mechanisms are unclear, leukocytes appear to play an important role. Since the methylxanthine derivative pentoxifylline (PTX) decreases neutrophil activity in vitro, we hypothesized that it might diminish coronary vascular injury due to ischemia and reperfusion. We investigated the effects of PTX on coronary microvascular and epicardial artery injury in open chest, anesthetized dogs undergoing moderate (60 min) or more prolonged (90 min) ischemia due to left anterior descending coronary artery occlusion followed by 60 min of reperfusion. As an index of microvascular injury, we assessed regional permeability with a dual radioisotope protein leak index (PLI) method. Both ischemic periods with reperfusion increased the PLI of severely ischemic (flow less than or equal to 20/ml/min/100 g) myocardium by 2.5- and 3-fold, respectively, compared to nonischemic (flow greater than or equal to 100 ml/min/100 g) myocardium. Treated dogs received PTX (20 mg/kg bolus plus 0.1 mg/kg/min infusion) before ischemia. PTX reduced the increase in the PLI by 40% after 60 min of ischemia (PLI = 5.87 +/- 0.48 vs. 4.10 +/- 0.52 untreated vs. PTX-treated; P less than .05), and by 25% after 90 min of ischemia (6.84 +/- 0.49 vs. 4.84 +/- 0.42; P less than .05). The amount of protein leak was inversely related to ischemic blood flow, and the magnitude of this relationship was significantly reduced in PTX-treated animals. In arterial rings from untreated dogs exposed to 90 min of ischemia followed by reperfusion, there was impaired relaxation to ADP and acetylcholine, but not to sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Influences of gender and sex hormones on hypoxic ventilatory response in cats.

Hypoxic ventilatory response (HVR) is known to be increased by female as well as male sex hormones, but whether there are differences in HVR between men and women remains unclear. To determine whether gender differences exist in HVR, we undertook systematic comparisons of resting ventilation and HVR in awake male and female cats. Furthermore to explore the potential contribution of sex hormones to gender differences observed, we compared neutered and intact cats of both sexes. Resting ventilation differed among the four groups, but differences disappeared with correction for body weight. Intact females had a lower end-tidal PCO2 than intact male cats (females: 31.6 +/- 0.4 Torr vs. males: 33.6 +/- 0.4 Torr, P less than 0.05), indicating an increased alveolar ventilation per unit CO2 production. HVR expressed as the shape parameter A was similar among the four groups of animals. However, baseline (hyperoxic; end-tidal PO2 greater than 200 Torr) minute ventilation [VI(PO2 greater than 200)] differed among the groups. Therefore we normalized HVR by dividing the shape parameter A by VI(PO2 greater than 200) to compare the relative hypoxic chemosensitivity among the various groups of animals. In addition, we further normalized HVR for body weight, because body size influences ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Pentoxifylline lessens the endotoxin-induced increase in albumin clearance across pulmonary artery endothelial monolayers with and without neutrophils.

Pentoxifylline, a methylxanthine with phosphodiesterase inhibitor activity, attenuates endotoxin-induced pulmonary vascular protein leak and decreases lung neutrophil accumulation in vivo. In vitro, pentoxifylline decreases neutrophil activation as measured by superoxide release and phagocytosis of latex beads. To test the hypothesis that the beneficial effect of pentoxifylline may be via a direct effect on the endothelial cells as well as via prevention of neutrophil activation, we incubated bovine pulmonary artery endothelial cell monolayers with endotoxin and pentoxifylline in the presence or absence of human neutrophils. Albumin clearance across the monolayers was used as an index of endothelial permeability. Endotoxin (1.0 micrograms/ml) increased albumin clearance in a dose- and time-dependent fashion (207.5 +/- 25%, P less than 0.05). Co-incubation with neutrophils enhanced this effect. Pentoxifylline significantly attenuated the endotoxin-induced increase in albumin clearance both with and without neutrophils, and lessened endotoxin-induced cell lysis (chromium release) and morphologic changes. Because increased endothelial cyclic adenosine monophosphate (cAMP) levels may decrease protein permeability and pentoxifylline increases cAMP in neutrophils, we measured cAMP levels in endothelial cells. Incubation with pentoxifylline failed to raise cAMP levels in endothelial cells, in contrast to incubation with aminophylline. In conclusion, pentoxifylline attenuates endotoxin-induced increase in albumin clearance across endothelial monolayers both in the presence and absence of neutrophils. These results suggest that part of the protective effect of pentoxifylline may be mediated via effects on endothelium. Furthermore, this pentoxifylline-mediated endothelial barrier effect appears to be independent of an effect on cAMP.

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)