AMPA Receptor-Dependent Glutamatergic Signaling is Present in the Carotid Chemoreceptor.

Exposure to both sustained and intermittent hypoxia for as little as a day produces sustained augmentation of carotid chemoreceptor sensitivity; however, the molecular basis for this chemoreflex plasticity remains uncertain. We previously reported that NMDA receptor-dependent glutamatergic signaling in rat carotid body played a role in altered hypoxic sensitivity after exposure to cyclic intermittent hypoxia (CIH). Here we found that mRNAs of multiple AMPA and Kainate glutamate receptors were expressed in rat carotid body. The AMPA receptor subunit GluR1 showed intense immunoreactivity in the carotid body, co-localizing with tyrosine hydroxylase in type I cells. Treatment of rat carotid body-derived primary cells with AMPA activated ERK1/2 in a time-dependent manner. Exposing Sprague-Dawley rats to CIH for 8 h/day for 3 weeks significantly enhanced the expression level of GluA1 mRNA as well as GluR1 protein in the carotid body. In addition, our results showed that multiple of vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters (EAATs) were expressed in the rat carotid body, indicating that glutamate might be as a neurotransmitter stored, released and uptake in the carotid body. Finally, we found that mRNAs of GluA1, GluA2 and GluA3 as well as PSD-95-like membrane-associated granulate kinase family members, PSD-95, PSD-93, and SAP97, were expressed in human carotid body. Our data suggest AMPA receptor-dependent glutamatergic signaling is present in the carotid body and might be involved in the carotid chemoreceptor response to hypoxia.

Sleep biology updates: Hemodynamic and autonomic control in sleep disorders.

Sleep disorders like obstructive sleep apnea syndrome, periodic limb movements in sleep syndrome, insomnia and narcolepsy-cataplexy are all associated with an increased risk of cardiovascular diseases. These disorders share an impaired autonomic nervous system regulation that leads to increased cardiovascular sympathetic tone. This increased cardiovascular sympathetic tone is, in turn, likely to play a major role in the increased risk of cardiovascular disease. Different stimuli, such as intermittent hypoxia, sleep fragmentation, decrease in sleep duration, increased respiratory effort, and transient hypercapnia may all initiate the pathophysiological cascade leading to sympathetic overactivity and some or all of these are encountered in these different sleep disorders. In this manuscript, we outline the different pathways leading to sympathetic over-activity in different sleep conditions. This augmented sympathetic tone is likely to play an important role in the development of cardiovascular disease in patients with sleep disorders, and it is further hypothesized to that sympathoexcitation contributes to the metabolic dysregulation associated with these sleep disorders.

Sympathoexcitation and arterial hypertension associated with obstructive sleep apnea and cyclic intermittent hypoxia.

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction during sleep. These obstructive episodes are characterized by cyclic intermittent hypoxia (CIH), by sleep fragmentation, and by hemodynamic instability, and they result in sustained sympathoexcitation and elevated arterial pressure that persist during waking, after restoration of normoxia. Early studies established that 1) CIH, rather than sleep disruption, accounts for the increase in arterial pressure; 2) the increase in arterial pressure is a consequence of the sympathoactivation; and 3) arterial hypertension after CIH exposure requires an intact peripheral chemoreflex. More recently, however, evidence has accumulated that sympathoactivation and hypertension after CIH are also dependent on altered central sympathoregulation. Furthermore, although many molecular pathways are activated in both the carotid chemoreceptor and in the central nervous system by CIH exposure, two specific neuromodulators-endothelin-1 and angiotensin II-appear to play crucial roles in mediating the sympathetic and hemodynamic response to intermittent hypoxia.

Effect of endothelin antagonism on apnea frequency following chronic intermittent hypoxia.

Chronic hypoxia increases the hypoxic ventilatory response (HVR). Augmented HVR contributes to central apneas seen in heart failure and complex sleep apnea. Endothelin receptor (ETR) antagonism decreases carotid body afferent activity following chronic intermittent hypoxia (CIH). We speculated ETR antagonism would reduce HVR and apneas following CIH. HVR and apneas were measured after exposure to CIH and room air sham (SHAM). ETR blocker Ambrisentan was administered via the chow of CIH-exposed animals from days 1 to 12 of CIH (CIH/AMB). A separate crossover group was exposed to CIH and fed normal chow (placebo) days 1-6, and Ambrisentan days 7-12 (CIH/PLA-AMB). SHAM and CIH/PLA animals were fed placebo days 1-12. The CIH/AMB and CIH/PLA-AMB rats had reduced HVR compared to CIH/PLA, similar HVR compared to sham exposed animals, and reduced apnea frequency compared to CIH/PLA animals. The reduced HVR and post-hypoxic apneas resulting from Ambrisentan administration suggests ETR antagonists may have utility in reducing central apneas following CIH.

Endothelin receptors in augmented vasoconstrictor responses to endothelin-1 in chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) contributes to the development of cardiovascular diseases in patients with obstructive sleep apnoea. Many studies have shown an association between increased circulating endothelin (ET)-1 levels and CIH. The aim of the present study was to determine the role of ET receptors in altered aortic function in an animal model of CIH. Rats were subjected to CIH (Fi o2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/week) for 3 weeks. After 3 weeks, the rats were killed and their aortas retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry and western blotting. Aortas from rats subjected to CIH exhibited marked endothelial dysfunction and increased responsiveness to ET-1. Furthermore, CIH induced increased ET-1 and ETA receptor expression, whereas ETB receptor expression was decreased. Aortic contractile responses to ET-1 were inhibited by the ETA and ETB receptor antagonists BQ-123 and BQ-788, respectively. Acetylcholine-induced relaxation responses were significantly attenuated in aortas from rats subjected to CIH, whereas CIH had no significant effect on aortic responses to sodium nitroprusside. The results of the present study suggest that increased expression of ETA receptors, which mediate a potent vasoconstrictor response, plays an important role in the pathogenesis of CIH. In addition, decreased endothelial ETB receptor expression, which is associated with the functional decline of endothelium-dependent vasodilation, also contributes to the pathogenesis of CIH. It appears that the ETB receptor-induced buffering of ET-1 responsiveness is mediated via a nitric oxide-dependent mechanism.

Effects of cyclic intermittent hypoxia on ET-1 responsiveness and endothelial dysfunction of pulmonary arteries in rats.

Obstructive sleep apnoea (OSA) is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH) to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk), and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1) and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.

Nitric oxide and obstructive sleep apnea.

Obstructive sleep apnea is a common disease, affecting 16% of the working age population. Although sleep apnea has a well-established connection to daytime sleepiness presumably mediated through repetitive sleep disruption, some other consequences are less well understood. Clinical, epidemiological, and physiological investigations have demonstrated a connection between sleep apnea and daytime hypertension. The elevation of arterial pressure is evident during waking, when patients are not hypoxic, and is mediated by sustained sympathoexcitation and by altered peripheral vascular reactivity. This review summarizes data suggesting that both the sympathoexcitation and the altered vascular reactivity are, at least in part, a consequence of reduced expression of nitric oxide synthase, in neural tissue and in endothelium. Reduced nitric oxide generation in central and peripheral sites of sympathoregulation and in endothelium together may, in part, explain the elevations in waking pressures observed in sleep apnea patients.

Long-term administration of fasudil improves cardiomyopathy in streptozotocin-induced diabetic rats.

Inhibition of Rho kinase (ROCK) has been shown to improve diabetic-related disorders. In this study, the cardio-protective effects and potential mechanisms of fasudil, a selective ROCK inhibitor, on diabetic cardiomyopathy were investigated in a streptozotocin (STZ)-induced diabetic rat model. Eight weeks after diabetes was induced by a single tail vein injection of 60 mg/kg STZ, rats were administered long-term fasudil or captopril as a control over a four-week period. Similar to the effect of captopril, fasudil treatment significantly protected against STZ-induced hemodynamic, histopathologic changes and decreased serum lactate dehydrogenase and creatine phosphokinase. Moreover, fasudil significantly down-regulated ROCK I mRNA expression and ROCK activity, reduced cardiac collagen deposition, and decreased the incidence of apoptosis and ratio of Bax/Bcl-2 protein expression. Additionally, fasudil potently elevated superoxide dismutase activity and suppressed the extent of lipid peroxidation in sera and hearts of diabetic rats. Our findings indicated that long-term treatment with fasudil could improve cardiac dysfunction, attenuate myocardial injury and prevent pathological changes in a rat model of diabetic cardiomyopathy. These effects could be attributed to regulation of antioxidative activities, suppression of myocardial hypertrophy, apoptosis, fibrosis and subsequent cardiac remodeling. These results may help to expand the clinical application of fasudil for diabetic cardiomyopathy.

Cyclic intermittent hypoxia enhances renal sympathetic response to ICV ET-1 in conscious rats.

To test the hypothesis that central changes in sympathoregulation might contribute to sympathoexcitation after cyclic intermittent hypoxia (CIH) we exposed male Sprague-Dawley rats to CIH or to room air sham (Sham) for 8h/d for 3 weeks. After completion of the exposure we assessed heart rate, mean arterial pressure and renal sympathetic nerve activity in conscious animals before and after intracerebroventricular (i.c.v.) administration of endothelin-1 (ET-1, 3 pmol). CIH-exposed animals had a significantly greater sympathetic response to ET-1 than did Sham-exposed animals (CIH 137.8+/-15.6% of baseline; Sham 112.2+/-10.0% of baseline; CIH vs. Sham, P=0.0373). This enhanced sympathetic response to i.c.v. ET-1 was associated with greater expression of endothelin receptor A (ETA) protein in the subfornical organs of CIH-exposed relative to Sham-exposed rats. We conclude that 3-week CIH exposure enhances central ET-1 receptor expression and the sympathetic response to i.c.v. ET-1 suggesting central endothelin may contribute to the sympathetic and hemodynamic response to cyclic intermittent hypoxia.

Treatment of positive airway pressure treatment-associated respiratory instability with enhanced expiratory rebreathing space (EERS).

STUDY OBJECTIVES: Hypocapnia is an important mediator of sleep-dependent respiratory instability. Positive pressure-associated ventilatory control instability results in poor control of sleep apnea and persistent sleep fragmentation. We tested the adjunctive efficacy of low volumes of dead space (enhanced expiratory rebreathing space [EERS]) using a non-vented mask to minimize sleep hypocapnia. DESIGN: Retrospective chart review. SETTING: American Academy of Sleep Medicine accredited sleep center and laboratory. INTERVENTION: Enhanced expiratory rebreathing space MEASUREMENTS AND RESULTS: 204 patients diagnosed with continuous positive pressure (CPAP)-refractory sleep apnea between 1/1/04 and 7/1/06 were included in this retrospective review. All patients had in-lab attended polysomnography for diagnosis, conventional CPAP titration, and further assessments of added EERS. EERS volume was titrated to control of disease, which was typically obtained when end-tidal (ET) CO2 during sleep was 1-2 mm Hg above wake eupneic CO2 levels. The clinic records were reviewed for clinical outcomes. Poor laboratory response to, and initial clinical abandonment of CPAP, was very common (89.2%) in this group of patients, who as a group demonstrated mild resting wake hypocapnia (ETCO2 = 38.1 ± 3.1 mm Hg). Minimizing sleep hypocapnia by adding 100-150 mL EERS (mean ETCO2) at optimal therapy 38.6 ± 2.9 mm Hg) markedly improved polysomnographic control of sleep apnea, without inducing tachypnea or tachycardia. Follow-up (range 30-1872 days) showed improved clinical tolerance, compliance, and sustained clinical improvement. Leak and sleep fragmentation modified clinical outcomes. CONCLUSIONS: EERS is a potentially useful adjunctive therapy for positive pressure-associated respiratory instability and salvage of some CPAP treatment failures.

Design and measurement of quality improvement indicators in ambulatory pulmonary care: creating a "culture of quality" in an academic pulmonary division.

BACKGROUND: Quality improvement (QI) measures often are cited as goals for individual practices and medical centers and may someday form a component of reimbursement guidelines. Relatively few QI metrics relevant to ambulatory pulmonary medicine have been published. We describe the development and implementation of a QI program in an academic pulmonary division, including progress to date and lessons learned. METHODS: Metrics for the pulmonary QI Dashboard were developed based on an extensive literature review. Patients were identified through International Classification of Diseases-based billing databases, and results data were obtained from a manual and automated review of the electronic medical record. The performance of the division was monitored and presented in regular faculty meetings. Quarterly, confidential, individual scorecards gave each clinician feedback about his or her performance and compared the feedback to that of the faculty of the entire division. RESULTS: Significant improvements were found in many QI measures during a 2-year period. The number of patients with asthma who received appropriately prescribed inhaled corticosteroids increased from a baseline of 76 to 92% to 98%. Flu shot and pneumococcal vaccine administration documentation for patients with COPD increased from baseline values of 11 to 32% and 11 to 34%, respectively, to 90% and 93%, respectively. The COPD Global Initiative for Obstructive Lung Disease pharmacotherapy guidelines adherence increased substantially for patients with all disease stages. Chest CT scan results notification documentation improved from a baseline of 67 to 76% to 98%. Comparison between baseline and QI periods yielded statistically significant increases for these indicators. CONCLUSIONS: QI measures for an ambulatory pulmonary practice can be designed, implemented, and monitored. Key components include a well-structured electronic medical record, measurable outcomes, strong QI leadership, and specific interventions, such as providing feedback through QI review meetings and individual "report cards."

Sympathetic response to chemostimulation in conscious rats exposed to chronic intermittent hypoxia.

Exposure to cyclic intermittent hypoxia (CIH) is associated with elevated arterial pressure and sustained sympathoexcitation, but the causes of the augmented sympathetic activity remain poorly understood. We recorded arterial pressure, heart rate, and renal sympathetic nerve (RSN) activity in conscious rats previously exposed to either CIH or Sham for 3 weeks during acute exposure to hypoxia (15% and 10% O(2)) or hypercapnia (7% CO(2)). Hemodynamic responses to both hypercapnia and hypoxia were similar between CIH-exposed and Sham-exposed rats, although the pattern of response was different for hypoxia (tachycardia with no change in arterial pressure) and hypercapnia (bradycardia and increased arterial pressure). RSN responses as a percent of the baseline were, however, significantly greater in CIH-exposed animals (CIH-exposed: 15% O(2) - 123.4+/-0.06%; 10% O(2) - 136.7+/-0.12%; 7% CO(2) - 138.3+/-0.18%; Sham-exposed: 15% O(2) - 106.6+/-0.03%; 10% O(2) - 107.6+/-0.01%; 7% CO(2) - 103.0+/-0.14% P<0.01 for all conditions). These data indicate that in conscious rats exposure to CIH enhances sympathetic responses to both hypoxia and hypercapnia.

A pilot study of sleep, cognition, and respiration under 4 weeks of intermittent nocturnal hypoxia in adult humans.

STUDY OBJECTIVES: A pilot study to examine the effects of intermittent nocturnal hypoxia on sleep, respiration and cognition in healthy adult humans. METHODS: Participants were eight healthy, non-smoking subjects (four male, four female), mean age of 26.4+/-5.2 years, and BMI 22.3+/-2.6 kg/m(2), exposed to 9h of intermittent hypoxia between the hours of 10 P.M. and 7 A.M. for 28 consecutive nights. At a simulated altitude of 13,000 feet (FIO(2) 0.13), intermittent hypoxia was achieved by administering nasal nitrogen, alternating with brief (approximately 5s) boluses of nasal oxygen. Pre- and post-exposure assessments included polysomnography, attention (20-min Psychomotor Vigilance Test), working memory (10-min verbal 2 and 3-back), Multiple Sleep Latency Test, and the Rey Auditory Verbal Learning Test. Obstructive and non-obstructive respiratory events were scored. RESULTS: Overall sleep quality showed worsening trends but no statistically significant change following exposure. There was no difference after hypoxia in sleepiness, encoding, attention or working memory. Hyperoxic central apneas and post-hyperoxic respiratory instability were noted as special features of disturbed respiratory control induced by intermittent nocturnal hypoxia. CONCLUSIONS: In this model, exposure to nocturnal intermittent hypoxia for 4 weeks caused no significant deficits in subjective or objective alertness, vigilance, or working memory.

Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body.

Although large quantities of glutamate are found in the carotid body, to date this excitatory neurotransmitter has not been assigned a role in chemoreception. To examine the possibility that glutamate and its N-methyl-d-aspartate (NMDA) receptors play a role in acclimatization after exposure to cyclic intermittent hypoxia (CIH), we exposed male Sprague-Dawley rats to cyclic hypoxia or to room air sham (Sham) for 8 h/day for 3 wk. Using RT-PCR, Western blot analysis, and immunohistochemistry, we found that ionotropic NMDA receptors, including NMDAR1, NMDAR2A, NMDAR2A/2B, are strongly expressed in the carotid body and colocalize with tyrosine hydroxylase in glomus cells. CIH exposure enhanced the expression of NMDAR1 and NMDAR2A/2B but did not substantially change the level of NMDAR2A. We assessed in vivo carotid sinus nerve activity (CSNA) at baseline, in response to acute hypoxia, in response to infused NMDA, and in response to infused endothelin-1 (ET-1) with and without MK-801, an NMDA receptor blocker. Infusion of NMDA augmented CSNA in CIH rats (124.61 +/- 2.64% of baseline) but not in sham-exposed rats. Administration of MK-801 did not alter baseline activity or response to acute hypoxia, in either CIH or sham animals but did reduce the effect of ET-1 infusion on CSNA (CSNA after ET-1 = 160.96 +/- 8.05% of baseline; ET-1 after MK-801 = 118.56 +/- 9.12%). We conclude that 3-wk CIH exposure increases expression of NMDA functional receptors in rats, suggesting glutamate and its receptors may play a role in hypoxic acclimatization to CIH.

Baroreflex responsiveness during ventilatory acclimatization in humans.

We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n=2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA (DeltaSNA)/change of diastolic blood pressure (DeltaDBP)], mechanical (Deltadiastolic diameter/DeltaDBP), and neural (DeltaSNA/Deltadiastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, -8.3+/-1.2; 1-h Hx, -7.2+/-1.0; 7-h Hx, -4.9+/-1.0; and post-Hx: -4.1+/-0.9 arbitrary integrated units (AIU) x min(-1) x mmHg(-1); P<0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, -2.70+/-0.53; 1-h Hx, -2.59+/-0.53; 7-h Hx, -1.60+/-0.34; and post-Hx, -1.34+/-0.27 AIU x min(-1) x microm(-1); P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans.

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.

Nocturnal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans.

STUDY OBJECTIVES: To assess the effect of 2 weeks of nocturnal hypoxia exposure using simulated altitude on attention and working memory in healthy adult humans. DESIGN: Prospective experimental physiological assessment. SETTING: General Clinical Research Center. PARTICIPANTS: Eleven healthy, nonsmoking, subjects (7 men, 4 women). The subjects had a mean age of 27 +/- 1.5 years and body mass index of 23 +/- 0.9 kg/m2. INTERVENTIONS: Subjects were exposed to 9 hours of continuous hypoxia from 2200 to 0700 hours in an altitude tent. Acclimatization was accomplished by graded increases in "altitude" over 3 nights (7700, 10,000 and 13,000 feet), followed by 13,000 feet for 13 consecutive days (FIO2 0.13). MEASUREMENTS AND RESULTS: Polysomnography that included airflow measurements with a nasal cannula were done at baseline and during 3 time points across the protocol (nights 3, 7, and 14). Attention (10-minute Psychomotor Vigilance Task) and working memory (10-minute verbal 2-back) were assessed at baseline and on day 4, 8, 9, and 15. Nocturnal hypoxia was documented using endpoints of minimum oxygen saturation, oxygen desaturation index, and percentage of total sleep time under 90% and 80%. Total sleep time was reduced, stage 1 sleep was increased, and both obstructive and nonobstructive respiratory events were induced by altitude exposure. There was no difference in subjective mood, attention, or working memory. CONCLUSIONS: Two weeks of nocturnal continuous hypoxia in an altitude tent did not induce subjective sleepiness or impair objective vigilance and working memory. Caution is recommended in the extrapolation to humans the effects of hypoxia in animal models.

Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans.

Hemodynamics, muscle sympathetic nerve activity (MSNA), and forearm blood flow were evaluated in 12 normal subjects before, during (1 and 7 h), and after ventilatory acclimatization to hypoxia achieved with 8 h of continuous poikilocapnic hypoxia. All results are means +/- SD. Subjects experienced mean oxygen saturation of 84.3 +/- 2.3% during exposure. The exposure resulted in hypoxic acclimatization as suggested by end-tidal CO(2) [44.7 +/- 2.7 (pre) vs. 39.5 +/- 2.2 mmHg (post), P < 0.001] and by ventilatory response to hypoxia [1.2 +/- 0.8 (pre) vs. 2.3 +/- 1.3 l x min(-1).1% fall in saturation(-1) (post), P < 0.05]. Subjects exhibited a significant increase in heart rate across the exposure that remained elevated even upon return to room air breathing compared with preexposure (67.3 +/- 15.9 vs. 59.8 +/- 12.1 beats/min, P < 0.008). Although arterial pressure exhibited a trend toward an increase across the exposure, this did not reach significance. MSNA initially increased from room air to poikilocapnic hypoxia (26.2 +/- 10.3 to 32.0 +/- 10.3 bursts/100 beats, not significant at 1 h of exposure); however, MSNA then decreased below the normoxic baseline despite continued poikilocapnic hypoxia (20.9 +/- 8.0 bursts/100 beats, 7 h Hx vs. 1 h Hx; P < 0.008 at 7 h). MSNA decreased further after subjects returned to room air (16.6 +/- 6.0 bursts/100 beats; P < 0.008 compared with baseline). Forearm conductance increased after exposure from 2.9 +/- 1.5 to 4.3 +/- 1.6 conductance units (P < 0.01). These findings indicate alterations of cardiovascular and respiratory control following 8 h of sustained hypoxia producing not only acclimatization but sympathoinhibition.