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.     

Effects of chronic hypoxia on MK-801-induced changes in the acute hypoxic ventilatory response.

Chronic hypoxia increases the sensitivity of the central nervous system to afferent input from carotid body chemoreceptors. We hypothesized that this process involves N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms and predicted that chronic hypoxia would change the effect of the NMDA receptor blocker dizocilpine (MK-801) on the poikilocapnic hypoxic ventilatory response (HVR). Male Sprague-Dawley rats were studied before and after acclimatization to hypoxia (70 Torr inspiratory Po(2) for 9 days). We measured ventilation (VI) and the HVR before and after systemic MK-801 treatment (3 mg/kg ip). MK-801 resulted in a constant respiratory frequency (approximately 175 min(-1)) during acute exposure to 10% and 30% O(2) before and after acclimatization. MK-801 had no effect on tidal volume (VT) before acclimatization, but it significantly decreased Vt when the animals were breathing 10% O(2) after acclimatization. The net effect of MK-801 was to eliminate the O(2) sensitivity of Vi before (via changes in respiratory frequency) and after (via changes in VT) acclimatization. Hence, chronic hypoxia altered the effect of MK-801 on the acute HVR, primarily because of increased effects on Vt. This indicates that changes in NMDA receptor-mediated neurotransmission may be involved in ventilatory acclimatization to hypoxia. However, further experiments are necessary to determine the precise location of such plasticity in the central nervous system.     

Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia

Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.     

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.     

Genetic determinants of acute hypoxic ventilation: patterns of inheritance in mice.

Acutely lowering ambient O(2) tension increases ventilation in many mammalian species, including humans and mice. Inheritance patterns among kinships and between mouse strains suggest that a robust genetic influence determines individual hypoxic ventilatory responses (HVR). Here, we tested specific genetic hypotheses to describe the inheritance patterns of HVR phenotypes among two inbred mouse strains and their segregant and nonsegregant progeny. Using whole body plethysmography, we assessed the magnitude and pattern of ventilation in C3H/HeJ (C3) and C57BL/6J (B6) progenitor strains at baseline and during acute (3-5 min) hypoxic [mild hypercapnic hypoxia, inspired O(2) fraction (FI(O(2))) = 0.10] and normoxic (mild hypercapnic normoxia, FI(O(2)) = 0.21) inspirate challenges in mild hypercapnia (inspired CO(2) fraction = 0.03). First- and second-filial generations and two backcross progeny were also studied to assess response distributions of HVR phenotypes relative to the parental strains. Although the minute ventilation (VE) during hypoxia was comparable between the parental strains, breathing frequency (f) and tidal volume were significantly different; C3 mice demonstrated a slow, deep HVR relative to a rapid, shallow phenotype of B6 mice. The HVR profile in B6C3F(1)/J mice suggested that this offspring class represented a third phenotype, distinguishable from the parental strains. The distribution of HVR among backcross and intercross offspring suggested that the inheritance patterns for f and VE during mild hypercapnic hypoxia are consistent with models that incorporate two genetic determinants. These results further suggest that the quantitative genetic expression of alleles derived from C3 and B6 parental strains interact to significantly attenuate individual HVR in the first- and second-filial generations. In conclusion, the genetic control of HVR in this model was shown to exhibit a relatively simple genetic basis in terms of respiratory timing characteristics.     

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.     

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.     

Intermittent hypoxia increases ventilation and Sa(O2) during hypoxic exercise and hypoxic chemosensitivity.

The purpose of this study was 1) to test the hypothesis that ventilation and arterial oxygen saturation (Sa(O2)) during acute hypoxia may increase during intermittent hypoxia and remain elevated for a week without hypoxic exposure and 2) to clarify whether the changes in ventilation and Sa(O2) during hypoxic exercise are correlated with the change in hypoxic chemosensitivity. Six subjects were exposed to a simulated altitude of 4,500 m altitude for 7 days (1 h/day). Oxygen uptake (VO2), expired minute ventilation (VE), and Sa(O2) were measured during maximal and submaximal exercise at 432 Torr before (Pre), after intermittent hypoxia (Post), and again after a week at sea level (De). Hypoxic ventilatory response (HVR) was also determined. At both Post and De, significant increases from Pre were found in HVR at rest and in ventilatory equivalent for O2 (VE/VO2) and Sa(O2) during submaximal exercise. There were significant correlations among the changes in HVR at rest and in VE/VO2 and Sa(O2) during hypoxic exercise during intermittent hypoxia. We conclude that 1 wk of daily exposure to 1 h of hypoxia significantly improved oxygenation in exercise during subsequent acute hypoxic exposures up to 1 wk after the conditioning, presumably caused by the enhanced hypoxic ventilatory chemosensitivity.     

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.     

Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response

The early phase of the biphasic ventilatory response to hypoxia in mammals is critically dependent on NMDA glutamate receptor activation within the nucleus of the solitary tract. However, the mechanisms underlying the subsequent development of the typical ventilatory roll-off are unclear and could underlie important roles in the functional and molecular adaptation to oxygen deprivation. Because the growth factor platelet-derived growth factor (PDGF)-BB can modulate the open channel probability of NMDA receptors by activating PDGF-beta receptors, its contribution to hypoxic ventilatory roll-off was examined. Administration of PDGF-BB, but not PDGF-AA, in the nucleus of the solitary tract was associated with significant attenuations of the early hypoxic ventilatory response in conscious rats. Furthermore, marked reductions in the magnitude of hypoxic ventilatory roll-off occurred in mice heterozygous for a mutation in the PDGF-beta receptor. Administration of a PDGF-beta receptor antagonist to wild-type littermates elicited similar declines in hypoxic ventilatory roll-off. The relative abundance of PDGF-beta receptors was confirmed in the nucleus of the solitary tract and other nuclei implicated in the hypoxic ventilatory response. In nucleus of the solitary tract lysates, PDGF-beta receptor tyrosine phosphorylation was temporally correlated with hypoxic ventilatory roll-off formation. Increased PDGF-B chain mRNA expression was induced by hypoxia in the nucleus of the solitary tract, and PDGF-B chain immunoreactivity colocalized with approximately 40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-beta receptor activation in the nucleus of the solitary tract are critical components of hypoxic ventilatory roll-off and may have important functional implications in processes underlying survival and acclimatization to hypoxic environments.     

Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep

Although the influence of altitude acclimatization on respiration has been carefully studied, the associated changes in hypoxic and hypercapnic ventilatory responses are the subject of controversy with neither response being previously evaluated during sleep at altitude. Therefore, six healthy males were studied at sea level and on nights 1, 4, and 7 after arrival at altitude (14,110 ft). During wakefulness, ventilation and the ventilatory responses to hypoxia and hypercapnia were determined on each occasion. During both non-rapid-eye-movement and rapid-eye-movement sleep, ventilation, ventilatory pattern, and the hypercapnic ventilatory response (measured at ambient arterial O2 saturation) were determined. There were four primary observations from this study: 1) the hypoxic ventilatory response, although similar to sea level values on arrival at altitude, increased steadily with acclimatization up to 7 days; 2) the slope of the hypercapnic ventilatory response increased on initial exposure to a hypoxic environment (altitude) but did not increase further with acclimatization, although the position of this response shifted steadily to the left (lower PCO2 values); 3) the sleep-induced decrements in both ventilation and hypercapnic responsiveness at altitude were equivalent to those observed at sea level with similar acclimatization occurring during wakefulness and sleep; and 4) the quantity of periodic breathing during sleep at altitude was highly variable and tended to occur more frequently in individuals with higher ventilatory responses to both hypoxia and hypercapnia.     

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)     

Ventilatory chemosensitivity of the 1-day-old chicken hatchling after embryonic hypoxia

We investigated the effects of sustained embryonic hypoxia on the neonatal ventilatory chemosensitivity. White Leghorn chicken eggs were incubated at 38 degrees C either in 21% O(2) throughout incubation (normoxia, Nx) or in 15% O(2) from embryonic day 5 (hypoxia, Hx), hatching time included. Hx embryos hatched approximately 11 h later than Nx, with similar body weights. Measurements of gaseous metabolism (oxygen consumption, Vo(2)) and pulmonary ventilation (Ve) were conducted either within the first 8 h (early) or later hours (late) of the first posthatching day. In resting conditions, Hx had similar Vo(2) and body temperature (Tb) and slightly higher Ve and ventilatory equivalent (Ve/Vo(2)) than Nx. Ventilatory chemosensitivity was evaluated from the degree of hyperpnea (increase in Ve) and of hyperventilation (increase in Ve/Vo(2)) during acute hypoxia (15 and 10% O(2), 20 min each) and acute hypercapnia (2 and 4% CO(2), 20 min each). The chemosensitivity differed between the early and late hours, and at either time the responses to hypoxia and hypercapnia were less in Hx than in Nx because of a lower increase in Ve and a lower hypoxic hypometabolism. In a second group of Nx and Hx hatchlings, the Ve response to 10% O(2) was tested in the same hatchlings at the early and late hours. The results confirmed the lower hypoxic chemosensitivity of Hx. We conclude that hypoxic incubation affected the development of respiratory control, resulting in a blunted ventilatory chemosensitivity.     

Hypoxic ventilatory response during light and dark periods and the involvement of histamine H1 receptor in mice

Ventilation oscillates throughout a day in parallel with oscillations in metabolic rate. Histamine affects ventilation and the balance of the energy metabolism via H1 receptors in the brain. We tested the hypothesis that the ventilatory response to hypoxia varies between light and dark periods and that histamine H1 receptors are required for the circadian variation, using wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice. Mice were exposed to hypoxic gas (7% O(2) + 3% CO(2) in N(2)) during light and dark periods. Ventilation initially increased and then declined. In WT mice, minute ventilation (.Ve) during hypoxia was higher in the dark period than in the light period, which was an upward shift along with the baseline ventilation. Hypoxia decreased the metabolic rate, whereas O2 consumption (.VO(2)) and CO(2) excretion were higher in the dark period than in the light period. However, in H1RKO mice, changes in Ve during hypoxia between light and dark periods were minimal, because .Ve was increased relative to .VO(2), particularly in the light period. In H1RKO mice, the HCO(3)(-) concentration and base excess values were increased in arterial blood, and the level of ketone bodies was increased in the serum, indicating that metabolic acidosis occurred. Respiratory compensation takes part in the .Ve increase relative to .VO(2) during hypoxia. These results suggested that changes in .Ve during hypoxia vary between light and dark periods and that H1 receptors play a role in circadian variation in .Ve through control of the acid-base status and metabolism in mice.     

Women at altitude: ventilatory acclimatization at 4,300 m.

Women living at low altitudes or acclimatized to high altitudes have greater effective ventilation in the luteal (L) compared with follicular (F) menstrual cycle phase and compared with men. We hypothesized that ventilatory acclimatization to high altitude would occur more quickly and to a greater degree in 1) women in their L compared with women in their F menstrual cycle phase, and 2) in women compared with men. Studies were conducted on 22 eumenorrheic, unacclimatized, sea-level (SL) residents. Indexes of ventilatory acclimatization [resting ventilatory parameters, hypoxic ventilatory response, hypercapnic ventilatory response (HCVR)] were measured in 14 women in the F phase and in 8 other women in the L phase of their menstrual cycle, both at SL and again during a 12-day residence at 4,300 m. At SL only, ventilatory studies were also completed in both menstrual cycle phases in 12 subjects (i.e., within-subject comparison). In these subjects, SL alveolar ventilation (expressed as end-tidal PCO(2)) was greater in the L vs. F phase. Yet the comparison between L- and F-phase groups found similar levels of resting end-tidal PCO(2), hypoxic ventilatory response parameter A, HCVR slope, and HCVR parameter B, both at SL and 4,300 m. Moreover, these indexes of ventilatory acclimatization were not significantly different from those previously measured in men. Thus female lowlanders rapidly ascending to 4,300 m in either the L or F menstrual cycle phase have similar levels of alveolar ventilation and a time course for ventilatory acclimatization that is nearly identical to that reported in male lowlanders.     

Ventilatory effects of substance P-saporin lesions in the nucleus tractus solitarii of chronically hypoxic rats

During ventilatory acclimatization to hypoxia (VAH), time-dependent increases in ventilation lower Pco(2) levels, and this persists on return to normoxia. We hypothesized that plasticity in the caudal nucleus tractus solitarii (NTS) contributes to VAH, as the NTS receives the first synapse from the carotid body chemoreceptor afferents and also contains CO(2)-sensitive neurons. We lesioned cells in the caudal NTS containing the neurokinin-1 receptor by microinjecting the neurotoxin saporin conjugated to substance P and measured ventilatory responses in awake, unrestrained rats 18 days later. Lesions did not affect hypoxic or hypercapnic ventilatory responses in normoxic control rats, in contrast to published reports for similar lesions in other central chemosensitive areas. Also, lesions did not affect the hypercapnic ventilatory response in chronically hypoxic rats (inspired Po(2) = 90 Torr for 7 days). These results suggest functional differences between central chemoreceptor sites. However, lesions significantly increased ventilation in normoxia or acute hypoxia in chronically hypoxic rats. Hence, chronic hypoxia increases an inhibitory effect of neurokinin-1 receptor neurons in the NTS on ventilatory drive, indicating that these neurons contribute to plasticity during chronic hypoxia, although such plasticity does not explain VAH.     

Ventilatory response to severe acute hypoxia in guinea-pigs and rats with high hemoglobin-oxygen affinity induced by cyanate

Baseline ventilation, hemoglobin concentration (Hb) and P50 were significantly lower in guinea-pigs than in rats. Chronic sodium cyanate (NaOCN) administration did not significantly increase hemoglobin concentration in either guinea-pigs or rats. It decreased the P50 significantly less in guinea-pigs than in rats. The high Hb-O₂ affinity experimentally induced did not modify the hypoxic ventilatory response (HVR) of guinea-pigs and rats. At the same level of acute hypoxia, HVR was significantly lower in NaOCN guinea-pigs than in NaOCN rats. Guinea-pigs, genotypically adapted animals to high altitude, displayed relatively minor ventilatory and Hb-O₂ affinity changes to NaOCN, and a relatively minor HVR to acute hypoxia. They probably use tissue and biochemical adaptive mechanisms, in addition to their limited extracellular responses to successfully tolerate ambient hypoxia.     

Abnormal control of ventilation in high-altitude pulmonary edema

We wished to determine the role of hypoxic chemosensitivity in high-altitude pulmonary edema (HAPE) by studying persons when ill and upon recovery. We studied seven males with HAPE and seventeen controls at 4,400 m on Mt. McKinley. We measured ventilatory responses to both O2 breathing and progressive poikilocapnic hypoxia. Hypoxic ventilatory response (HVR) was described by the slope relating minute ventilation to percent arterial O2 saturation (delta VE/delta SaO2%). HAPE subjects were quite hypoxemic (SaO2% 59 +/- 6 vs. 85 +/- 1, P less than 0.01) and showed a high-frequency, low-tidal-volume pattern of breathing. O2 decreased ventilation in controls (-20%, P less than 0.01) but not in HAPE subjects. The HAPE group had low HVR values (0.15 +/- 0.07 vs. 0.54 +/- 0.08, P less than 0.01), although six controls had values in the same range. The three HAPE subjects with the lowest HVR values were the most hypoxemic and had a paradoxical increase in ventilation when breathing O2. We conclude that a low HVR plays a permissive rather than causative role in the pathogenesis of HAPE and that the combination of extreme hypoxemia and low HVR may result in hypoxic depression of ventilation.     

Ventilatory responses to acute and chronic hypoxia are altered in female but not male Paskin-deficient mice

Proteins harboring a Per-Arnt-Sim (PAS) domain are versatile and allow archaea, bacteria, and plants to sense oxygen partial pressure, as well as light intensity and redox potential. A PAS domain associated with a histidine kinase domain is found in FixL, the oxygen sensor molecule of Rhizobium species. PASKIN is the mammalian homolog of FixL, but its function is far from being understood. Using whole body plethysmography, we evaluated the ventilatory response to acute and chronic hypoxia of homozygous deficient male and female PASKIN mice (Paskin-/-). Although only slight ventilatory differences were found in males, female Paskin-/- mice increased ventilatory response to acute hypoxia. Unexpectedly, females had an impaired ability to reach ventilatory acclimatization in response to chronic hypoxia. Central control of ventilation occurs in the brain stem respiratory centers and is modulated by catecholamines via tyrosine hydroxylase (TH) activity. We observed that TH activity was altered in male and female Paskin-/- mice. Peripheral chemoreceptor effects on ventilation were evaluated by exposing animals to hyperoxia (Dejours test) and domperidone, a peripheral ventilatory stimulant drug directly affecting the carotid sinus nerve discharge. Male and female Paskin-/- had normal peripheral chemosensory (carotid bodies) responses. In summary, our observations suggest that PASKIN is involved in the central control of hypoxic ventilation, modulating ventilation in a gender-dependent manner.