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

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

Breathing during sleep with mild hypoxia

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

Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat

We aimed to investigate whether newborn rats respond to acute hypoxia with a biphasic pattern as other newborn species, the characteristics of their ventilatory response to hypercapnia, and the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that newborn unanesthetized rats (2-4 days old) exposed to 10% O2 respond as other species. Their ventilation (VE), measured by flow plethysmography, immediately increased by 30%, then dropped and remained around normoxic values within 5 min. The drop was due to a decrease in tidal volume, while frequency remained elevated. Hence, alveolar ventilation was about 10% below normoxic value. At the same time O2 consumption, measured manometrically, dropped (-23%), possibly indicating a mechanism to protect vital organs. Ten percent CO2 in O2 breathing determined a substantial increase in VE (+47%), indicating that the respiratory pump is capable of a marked sustained hyperventilation. When CO2 was added to the hypoxic mixture, VE increased by about 85%, significantly more than without the concurrent hypoxic stimulus. Thus, even during the drop in VE of the biphasic response to hypoxia, the respiratory control system can respond with excitation to a further increase in chemical drive. Analysis of the breathing patterns suggests that in the newborn rat in hypoxia the inspiratory drive is decreased but the inspiratory on-switch mechanism is stimulated, hypercapnia increases ventilation mainly through an increase in respiratory drive, and moderate asphyxia induces the most powerful ventilatory response by combining the stimulatory action of hypercapnia and hypoxia.     

Increased chemoreceptor output and ventilatory response to sustained hypoxia

In adult humans the ventilatory response to sustained hypoxia (VRSH) is biphasic, characterized by an initial brisk increase, due to peripheral chemoreceptor (PC) stimulation, followed by a decline attributed to central depressant action of hypoxia. To study the effects of selective stimulation of PC on the ventilatory response pattern to hypoxia, the VRSH was evaluated after pretreatment with almitrine (A), a PC stimulant. Eight subjects were pretreated with A (75 mg po) or placebo (P) on 2 days in a single-blind manner. Two hours after drug administration, they breathed, in succession, room air (10 min), O2 (5 min), room air (5 min), hypoxia [25 min, arterial O2 saturation (SaO2) = 80%], O2 (5 min), and room air (5 min). End-tidal CO2 was kept constant at the normoxic base-line values. Inspiratory minute ventilation (VI) and breathing patterns were measured over the last 2 min of each period and during minutes 3-5 of hypoxia, and nadirs in VI were assessed just before and after O2 exposure. Independent of the day, the VRSH was biphasic. With P and A pretreatment, early hypoxia increased VI 4.6 +/- 1 and 14.2 +/- 1 (SE) l/min, respectively, from values obtained during the preceding room-air period. On A day the hypoxic ventilatory decline was significantly larger than that on P day, and on both days the decline was a constant fraction of the acute hypoxic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium/calmodulin-dependent kinase II mediates critical components of the hypoxic ventilatory response within the nucleus of the solitary tract in adult rats

Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-D-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O(2)-balance N(2) for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.     

Effect of a synthetic progestin on ventilatory response to hypoxia in anesthetized rats

Effects on ventilatory responses to progressive isocapnic hypoxia of a synthetic potent progestin, chlormadinone acetate (CMA), were determined in the halothane-anesthetized male rat. Ventilation during the breathing of hyperoxic gas was largely unaffected by treatment with CMA when carotid chemoreceptor afferents were kept intact. The sensitivity to hypoxia evaluated by hyperbolic regression analysis of the response curve did not differ between the control and CMA groups. The reduction of ventilation after bilateral section of the carotid sinus nerve (CSN) in hyperoxia was less severe in CMA-treated than in untreated animals. Furthermore, the CMA-treated rats showed a larger increase in ventilation during the hypoxia test and a lower PO2 break point for ventilatory depression. Inhibition of hypoxic ventilatory depression by CMA persisted even after the denervation of CSN. We conclude that exogenous progestin likely protects regulatory mechanism(s) for respiration against hypoxic depression through a stimulating action independent of carotid chemoreceptor afferents and without a change in the sensitivity of the ventilatory response to hypoxia.     

Effect of body position on ventilatory responses in anaesthetised mice

The effects of body position on ventilatory responses to chemical stimuli have rarely been studied in experimental animals, despite evidence that position may be a factor in respiratory results. The purpose of this study was to test whether body position could affect acute ventilatory responses to 4-min periods of moderate hypercapnia (5% CO(2) in O(2)) and poikilocapnic hypoxia (15% O(2) in N(2)) in the urethane-anaesthetised mouse. Respiratory measurements were conducted with mice in the prone and supine positions with a whole-body, single-chamber plethysmograph. During hypoxia, the time course of minute ventilation (V (E)) was similar in the two positions, but the breathing pattern was different. After the response peak, V (E) depended on respiratory frequency (f) and tidal volume (V(T)) in the prone position but mainly on V(T) in the supine position. In the supine position, f declined below the baseline values toward the end of hypoxic exposure. During hypercapnia, there were no ventilatory differences between the prone and supine positions. Brief hypoxic exposure elicited f depression in the supine position in the anaesthetised mouse. The depressive effect on f suggests that the supine position may not be optimal for sustaining ventilation, particularly during hypoxia.     

Enkephalin-induced changes in ventilation and ventilatory pattern in adult dogs

We studied the changes in ventilation induced by intracisternal administration of enkephalins in four unanesthetized adult dogs. Instantaneous minute ventilation (VT/TT) decreased markedly after D-Ala-Met-enkephalinamide (DAME). Mean VT/TT decreased maximally by 20-50 min after DAME and lasted an additional 15-60 min; by 2 h, VT/TT had returned to base line. Four doses (5, 25, 60, and 125 micrograms/kg) of DAME were used, and the ventilatory response depended on the dose. Mean inspiratory time decreased but mean expiratory time and mean TT showed a marked prolongation. Periodic breathing (2-3 breaths separated by long apneic pauses) occurred in every study and the frequency of sighs increased considerably. All these ventilatory changes were reversed by low doses of naloxone or naltrexone; in addition, VT/TT increased well above base line after the administration of these antagonists. However, naloxone did not increase VT/TT when injected without prior administration of DAME. We conclude that 1) the decrease in VT/TT is due to a decrease in respiratory duty cycle; 2) periodic breathing and increased frequency of sighs constitute part of the changes in the ventilatory pattern induced by DAME; 3) a ventilatory withdrawal reaction may occur after a receptor-agonist interaction of short duration; and 4) although enkephalins can modulate ventilation and the breathing pattern in a major way, these data provide no evidence suggesting that this modulation is tonic.     

Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness

Persons with acute altitude sickness hypoventilate at high altitude compared with persons without symptoms. We hypothesized that their hypoventilation was due to low initial hypoxic ventilatory responsiveness, combined with subsequent blunting of ventilation by hypocapnia and/or prolonged hypoxia. To test this hypothesis, we compared eight subjects with histories of acute altitude sickness with four subjects who had been asymptomatic during prior altitude exposure. At a simulated altitude of 4,800 m, the eight susceptible subjects developed symptoms of altitude sickness and had lower minute ventilations and higher end-tidal PCO2's than the four asymptomatic subjects. In measurements made prior to altitude exposure, ventilatory responsiveness to acute hypoxia was reduced in symptomatic compared to asymptomatic subjects, both when measured under isocapnic and poikolocapnic (no added CO2) conditions. Diminution of the poikilocapnic relative to the isocapnic hypoxic response was similar in the two groups. Ventilation fell, and end-tidal PCO2 rose in both groups during 30 min of steady-state hypoxia relative to values observed acutely. After 4.5 h at 4,800 m, ventilation was lower than values observed acutely at the same arterial O2 saturation. The reduction in ventilation in relation to the hypoxemia present was greater in symptomatic than in asymptomatic persons. Thus the hypoventilation in symptomatic compared to asymptomatic subjects was attributable both to a lower acute hypoxic response and a subsequent greater blunting of ventilation at high altitude.     

中枢β—内啡肽和5—羟色胺在低氧通气调控中的关系

实验在去双侧外周化学感受器传入的麻醉雄性家兔上进行。给动物吸低氧混合气(10%O_2于N_2中)导致通气抑制后,从动物侧脑室注入β-内啡肽拮抗剂纳洛酮使抑制的通气被“翻转”;注入拟似剂羟甲芬太尼则使抑制更加深化。此时中枢5-羟色胺含量均较给药前明显升高。给动物注入外源性5-羟色胺后,中枢β-内啡肽含量较给药前明显下降,此时通气回复至对照水平。结果提示:中枢β-内啡肽系统是引起低氧通气抑制的基本和直接因素,而5-羟色胺系统则是作为一种神经调质,通过调制其β-内啡肽活动而间接对低氧通气反应产生影响。     

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.     

Respiratory adaptation to chronic hypoxia in newborn rats

Newborn rats were maintained in an hypoxic chamber (10% O2 in N2) from the day of birth up to 2 wk of postnatal life. Body weight (BW) and nose-tail length were less in the hypoxic exposed (H) rats than in control (C) animals growing in air. Hematocrit rose from about 37% to about 51%. Oxygen consumption (VO2), measured with a manometric method, was lower in H than in C rats; the difference remained at 5-7 days even after normalization by BW. At 5-7 days ventilation, measured with an airflow plethysmograph, was much more elevated in H rats (whether breathing 10% O2 or air) than in C rats, with an increase in both tidal volume and frequency. This indicates that the biphasic ventilatory response, characterized by an initial rise and then a fall of ventilation toward normoxic values, commonly observed in newborns during acute hypoxic challenge is an immediate but only transient response. The dry lung weight-to-BW ratio and alveolar size were larger in H than in C rats. Lung volumes at 20 cmH2O were similar, despite the smaller BW of the H rats. Hence, in the rat, chronic hypoxia in the immediate postnatal period increases O2-carrying capacity, decreases metabolic demands, increases alveolar O2 availability, and promotes structural changes in the lung that protect the gas exchange area and optimize the structure-function relationship of the lung. These results may also suggest that the lung structural alterations with chronic hypoxia should not be attributed to changes in VO2 but, eventually, to the ventilatory action of the organ.     

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.     

Ventilatory response of intact cats to carbon monoxide hypoxia

Adult intact conscious or anesthetized cats have been exposed to either hypoxia or low concentrations of CO in air. In addition, the ventilatory response to CO2 was studied in air, hypoxic hypoxia, and CO hypoxia. The results show that 1) in conscious cats, low concentrations of CO (0.15%) induce a slight decrease in ventilation and higher concentrations of CO (0.20%) induce first a small decrease in ventilation and then a characteristic tachypnea similar to the hypoxic tachypnea described in carotid-denervated cats; 2) in anesthetized cats, CO hypoxia induces only mild changes in ventilation; and 3) the ventilatory response to CO2 is increased in CO hypoxia in both conscious and anesthetized animals but differs from the increase observed during hypoxia. It is concluded that the initial decrease in ventilation may be caused by some brain stem depression of the respiratory centers with CO hypoxia, whereas the tachypnea originates probably at some suprapontine level. Conversely, the possible central acidosis may account for the potentiation of the ventilatory response to CO2 observed in either conscious or anesthetized animals.     

成人急性低氧通气压抑中的内啡肽作用

本工作设想,内啡肽参与了成人急性低氧通气压抑机制。受试者均为健康成年男子。6名受试者吸入中度低氧混合气(12.8％O_2)30min;7名吸入重度低氧混合气(10.8％O_2)20min,其中6名并在重度低氧下吸入三口纯氮气。吸入低氧气前先由静脉注入生理盐水(对照)或纳洛酮(中度低氧5mg,重度低氧10mg)。观察低氧时的通气反应、终末潮气二氧化碳分压(P_(ETCO2)、动脉血氧饱和度和外周低氧通气敏感性以及纳洛酮对上述测定的影响。结果表明,纳洛酮使重度低氧下的通气压抑明显减弱,低氧第3～15分钟的通气水平明显高于对照实验;而P_(ETCO2)明显低于对照值。但纳洛酮对中度低氧下的通气压抑无明显作用。此外,纳洛酮显著增强外周低氧敏感性。结果提示,在重度低氧下,内啡肽参与了成人低氧通气压抑机制,并对外周低氧敏感性有抑制作用。     

Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.     

The affinity of hemoglobin for oxygen affects ventilatory responses in mutant mice with Presbyterian hemoglobinopathy

The purpose of this study was to test whether chronically enhanced O2 delivery to tissues, without arterial hyperoxia, can change acute ventilatory responses to hypercapnia and hypoxia. The effects of decreased hemoglobin (Hb)-O2 affinity on ventilatory responses during hypercapnia (0, 5, 7, and 9% CO2 in O2) and hypoxia (10 and 15% O2 in N2) were assessed in mutant mice expressing Hb Presbyterian (mutation in the beta-globin gene, beta108 Asn --> Lys). O2 consumption during normoxia, measured via open-circuit methods, was significantly higher in the mutant mice than in wild-type mice. Respiratory measurements were conducted with a whole body, unrestrained, single-chamber plethysmograph under conscious conditions. During hypercapnia, there was no difference between the slopes of the hypercapnic ventilatory responses, whereas minute ventilation at the same levels of arterial PCO2 was lower in the Presbyterian mice than in the wild-type mice. During both hypoxic exposures, ventilatory responses were blunted in the mutant mice compared with responses in the wild-type mice. The effects of brief hyperoxia exposure (100% O2) after 10% hypoxia on ventilation were examined in anesthetized, spontaneously breathing mice with a double-chamber plethysmograph. No significant difference was found in ventilatory responses to brief hypoxia between both groups of mice, indicating possible involvement of central mechanisms in blunted ventilatory responses to hypoxia in Presbyterian mice. We conclude that chronically enhanced O2 delivery to peripheral tissues can reduce ventilation during acute hypercapnic and hypoxic exposures.     

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.     

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.