Human hypoxic ventilatory response with blood dopamine content under intermittent hypoxic training

Adaptation to intermittent hypoxia can enhance a hypoxic ventilatory response (HVR) in healthy humans. Naturally occurring oscillations in blood dopamine (DA) level may modulate these responses. We have measured ventilatory response to hypoxia relative to blood DA concentration and its precursor DOPA before and after a 2-week course of intermittent hypoxic training (IHT). Eighteen healthy male subjects (mean 22.8+/-2.1 years old) participated in the study. HVRs to isocapnic, progressive, hypoxic rebreathing were recorded and analyzed using piecewise linear approximation. Rebreathing lasted for 5-6 min until inspired O2 reached 8 to 7%. IHT consisted of three identical daily rebreathing sessions separated by 5-min breaks for 14 consecutive days. Before and after the 2-week course of IHT, blood was sampled from the antecubital vein to measure DA and DOPA content. The investigation associated pretraining high blood DA and DOPA values with low HVR (r = -0.66 and -0.75, respectively), elevated tidal volume (r = 0.58 and 0.37) and vital capacity (r = 0.69 and 0.58), and reduced respiratory frequency (r = -0.89 and -0.82). IHT produced no significant change in ventilatory responses to mild hypoxic challenge (Peto2 from 110 to 70-80 mm Hg; 1 mm Hg = 133.3 Pa) but elicited a 96% increase in ventilatory response to severe hypoxia (from 70-80 to 45 mm Hg). Changes in HVRs were not accompanied by statistically significant shifts in blood DA content (24% change), although a twofold increase in DOPA concentration was observed. Individual subject's changes in DA and DOPA content were not correlated with HVR changes when these two parameters were evaluated in relation to the IHT. We hypothesize that DA flowing to the carotid body through the blood may provoke DA autoreceptor-mediated inhibition of endogenous DA synthesis-release, as shown in our baseline data.     

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.     

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.     

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.     

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.     

Effects of Hypoxia on the Activities of Noradrenergic and Dopaminergic Neurons in the Rat Brain

The effects of hypoxia (10% O2, 90% N2) on the content, biosynthesis, and turnover of noradrenaline (NA) and 3,4-dihydroxyphenylethylamine (dopamine, DA) in the rat brain were examined. Up to 24 h following exposure to hypoxia, NA content in the whole brain was decreased, whereas DA content remained unchanged. The accumulation of 3,4-dihydroxyphenylalanine (DOPA) after central decarboxylase inhibition was decreased. The turnover rate of DA after synthesis inhibition was markedly decreased up to 8 h and returned to the control level within 24 h. In contrast, the turnover rate of NA was all but unchanged, except for a 4-h exposure. The 2-h exposure to the hypoxic environment resulted in a significant decrease in NA content and DOPA accumulation in all brain regions tested, but no significant change was observed in DA content. The turnover rate of DA was remarkably decreased in all brain regions tested, whereas the rate of NA was slightly decreased only in the cerebral cortex and hippocampus. These results suggest that although hypoxia decreases the biosynthesis of both NA and DA, the effects of oxygen depletion on the functional activities of NA neurons differ considerably from those of DA neurons: Only in the cerebral cortex and hippocampus are the NA neurons slightly sensitive to hypoxia, whereas the DA neurons are most sensitive in all brain regions.     

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.     

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.     

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 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.     

Brain stem NO modulates ventilatory acclimatization to hypoxia in mice.

The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.     

Regional Blood Flow in the Upper Extremity during and after Exposure to Acute Normobaric Hypoxia

Cardiovascular indices were analyzed in young healthy males exposed to normobaric hypoxia (breathing a gas mixture containing 10% O₂ for 16 min). There was a marked variation in individual responses. A linear relationship was observed between the individual blood oxygen saturation at the end of exposure and the baseline muscle blood flow (MBF). Moreover, blood oxygen saturation decreased in subjects with an initially high forearm MBF and remained unchanged or even slightly increased in subjects with a low forearm MBF. After hypoxic exposure (10–15 min), the MBF continued to decrease, venous capacity increased, and postocclusion hyperemic response decreased. It is suggested that hypoxic exposure activates the neuroreflex mechanisms regulating the peripheral blood flow and that the peripheral vascular response to acute hypoxia depends largely on the baseline blood flow in skeletal muscles.     

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.     

Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats.

Episodic hypoxia induces a persistent augmentation of respiratory activity, termed long-term facilitation (LTF). Phrenic LTF saturates in anesthetized animals such that additional episodes of stimulation cause no further increase in LTF magnitude. The present study tested the hypothesis that 1) ventilatory LTF also saturates in awake rats and 2) more severe hypoxia and hypoxic episodes increase the effectiveness of eliciting ventilatory LTF. Minute ventilation was measured in awake, male Sprague-Dawley rats by plethysmography. LTF was elicited by five episodes of 10% O(2) poikilocapnic hypoxia (magnitude: 17.3 +/- 2.8% above baseline, between 15 and 45 min posthypoxia, duration: 45 min) but not 12 or 8% O(2). LTF was also elicited by 10, 20, and 72 episodes of 12% O(2) (19.1 +/- 2.2, 18.9 +/- 1.8, and 19.8 +/- 1.6%; 45, 60, and 75 min, respectively) but not by three or five episodes. These results show that there is a certain range of hypoxia that induces ventilatory LTF and that additional hypoxic episodes may increase the duration but not the magnitude of this response.     

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.     

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9–82 years of age and 542 Bolivian Aymara 13–94 years of age, native residents at 3,800–4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2–7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara. Am J Phys Anthropol 104:427–447, 1997. © 1997 Wiley-Liss, Inc.     

Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans.

We tested the hypothesis that intermittent hypoxia (IH) and/or continuous hypoxia (CH) would enhance the ventilatory response to acute hypoxia (HVR), thereby altering blood pressure (BP) and cerebral perfusion. Seven healthy volunteers were randomly selected to complete 10-12 days of IH (5-min hypoxia to 5-min normoxia repeated for 90 min) before ascending to mild CH (1,560 m) for 12 days. Seven other volunteers did not receive any IH before ascending to CH for the same 12 days. Before the IH and CH, following 12 days of CH and 12-13 days post-CH exposure, all subjects underwent a 20-min acute exposure to poikilocapnic hypoxia (inspired fraction of O(2), 0.12) in which ventilation, end-tidal gases, arterial O(2) saturation, BP, and middle cerebral artery blood flow velocity (MCAV) were measured continuously. Following the IH and CH exposures, the peak HVR was elevated and was related to the increase in BP (r = 0.66 to r = 0.88, respectively; P < 0.05) and to a reciprocal decrease in MCAV (r = 0.73 to r = 0.80 vs. preexposures; P < 0.05) during the hypoxic test. Following both IH and CH exposures, HVR, BP, and MCAV sensitivity to hypoxia were elevated compared with preexposure, with no between-group differences following the IH and/or CH conditions, or persistent effects following 12 days of sea level exposure. Our findings indicate that IH and/or mild CH can equally enhance the HVR, which, by either direct or indirect mechanisms, facilitates alterations in BP and MCAV.     

Tyrosine kinase inhibitors modulate the ventilatory response to hypoxia in the conscious rat.

Tyrosine kinases (TKs) exert multiple regulatory roles in neuronal activity and synaptic plasticity and could be involved in modulation of cardiovascular and respiratory control mechanisms within the dorsocaudal brain stem. To study this issue, the cardioventilatory responses to 1-microl microinjection within the dorsocaudal brain stem of either vehicle (Veh), the inactive TK inhibitor analog tyrphostin A1 (A1; 1 mM), or the active TK inhibitors genistein (Gen; 10 mM) and tyrphostin A25 (A25; 1 mM) were assessed by whole body plethysmography in unrestrained Sprague-Dawley adult rats. No changes in minute ventilation, heart rate, or mean arterial pressure occurred with Veh, A1, Gen, or A25 during room air breathing (P not significant). However, Gen and A25 attenuated the peak hypoxic ventilatory responses (HVR) to 10% O(2) (P < 0.006 vs. Veh), whereas A1 did not modify HVR (P not significant). HVR reductions by Gen and A25 were primarily due to diminished respiratory frequency enhancements (P < 0.002). No changes in heart rate or mean arterial pressure responses occurred during hypoxia with TK inhibition. In addition, increases in tyrosine phosphorylation of the NR2A/B subunits, but not of the NR2C subunit, of the N-methyl-D-aspartate receptor occurred at 5, 30, and 60 min of hypoxia in the dorsocaudal brain stem and returned to baseline values at 120 min. We conclude that hypoxia induces tyrosine phosphorylation of the N-methyl-D-aspartate glutamate receptor, and TK inhibition within the dorsocaudal brain stem attenuates components of HVR in conscious rats.     

Increased normoxic ventilation induced by repetitive hypoxia in conscious dogs.

To determine if a long-lasting increase in normoxic ventilatory drive is induced in conscious animals by repetitive hypoxia, we examined the normoxic [arterial O2 saturation (SaO2) > 93%] ventilatory response following successive episodes of 2-min eucapnic hypoxic challenges (SaO2 = 80%) in awake tracheotomized dogs. End-tidal CO2 was maintained at the resting level during and after repetitive hypoxia. The experimental protocol was performed twice in each of five dogs on separate days. To determine if changes in normoxic ventilation occurred between episodes of repetitive hypoxia, data were compared from six periods (epochs) for all experiments. The mean minute ventilation (VI) during three normoxic periods between episodes of intermittent hypoxia was 135, 154, and 169% of control (P < 0.05). VI during a 30-min recovery period was still higher at 183 and 172% of control (P < 0.05). Normoxic VI between hypoxic and recovery periods was significantly higher than the corresponding values in sham experiments. Our results indicate that a long-lasting increase in normoxic ventilation can be evoked in an awake unanesthetized dog by a short exposure to repetitive hypoxia.