Model Of Obstructive Sleep Apnea Research Articles

A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries

Obstructive sleep apnea (OSA), a condition in which the upper airway collapses during sleep, is strongly associated with metabolic and cardiovascular diseases. Little is known how OSA affects the cerebral circulation. The goals of this study were 1) to develop a rat model of chronic OSA that involved apnea and 2) to test the hypothesis that 4 wk of apneas during the sleep cycle alters endothelium-mediated dilations in middle cerebral arteries (MCAs). An obstruction device, which was chronically implanted into the trachea of rats, inflated to obstruct the airway 30 times/h for 8 h during the sleep cycle. After 4 wk of apneas, MCAs were isolated, pressurized, and exposed to luminally applied ATP, an endothelial P2Y2 receptor agonist that dilates through endothelial-derived nitric oxide (NO) and endothelial-dependent hyperpolarization (EDH). Dilations to ATP were attenuated ~30% in MCAs from rats undergoing apneas compared with those from a sham control group (P < 0.04 group effect; n = 7 and 10, respectively). When the NO component of the dilation was blocked to isolate the EDH component, the response to ATP in MCAs from the sham and apnea groups was similar. This finding suggests that the attenuated dilation to ATP must occur through reduced NO. In summary, we have successfully developed a novel rat model for chronic OSA that incorporates apnea during the sleep cycle. Using this model, we demonstrate that endothelial dysfunction occurred by 4 wk of apnea, likely increasing the vulnerability of the brain to cerebrovascular related accidents.

Antioxidant vitamins prevent oxidative and carbonyl stress in an animal model of obstructive sleep apnea

The aim of our study was to analyze the effects of an antioxidant treatment on markers of oxidative and carbonyl stress in a rat model of obstructive sleep apnea. Wistar rats were randomized into six groups-according to gender and intervention-sham, intermittent hypoxia, and intermittent hypoxia with treatment by vitamins C and E. Rats underwent tracheostomy. The tracheal cannula was closed for 12 s every minute for 1 h to simulate obstructive sleep apnea-related intermittent hypoxia. In the treatment group, rats received vitamin C and E 24 h prior to surgery. The intervention had a significant effect on advanced oxidation protein products (p = 0.008) and advanced glycation end products-specific fluorescence (p = 0.006) but no effect on malondialdehyde. Oxidation and glycation protein products were higher in intermittent hypoxia groups than in sham and in treated groups. Antioxidants alleviate oxidative and carbonyl stress in an experimental model of obstructive sleep apnea. Future studies will show whether such treatment has any clinical value regarding cardiovascular complications of sleep apnea syndrome, preferably in patients with low compliance to continuous positive airway pressure.

Renal Sympathetic Denervation Suppresses Postapneic Blood Pressure Rises and Atrial Fibrillation in a Model for Sleep Apnea

The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at -80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline; P=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27±5 versus 43±3 ms after atenolol; P=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by high-frequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events.

A New Animal Model of Obstructive Sleep Apnea Responding to Continuous Positive Airway Pressure

An improved animal model of obstructive sleep apnea (OSA) is needed for the development of effective pharmacotherapies. In humans, flexion of the neck and a supine position, two main pathogenic factors during human sleep, are associated with substantially greater OSA severity. We postulated that these two factors might generate OSA in animals. We developed a restraining device for conditioning to investigate the effect of the combination of 2 body positions-prone (P) or supine (S)-and 2 head positions-with the neck flexed at right angles to the body (90°) or in extension in line with the body (180°)-during sleep in 6 cats. Polysomnography was performed twice on each cat in each of the 4 sleeping positions-P180, S180, P90, or S90. The effect of continuous positive airway pressure (CPAP) treatment was then investigated in 2 cats under the most pathogenic condition. NA. NA. NA. Positions P180 and, S90 resulted, respectively, in the lowest and highest apnea-hypopnea index (AHI) (3 ± 1 vs 25 ± 2, P < 0.001), while P90 (18 ± 3, P<0.001) and S180 (13 ± 5, P<0.01) gave intermediate values. In position S90, an increase in slow wave sleep stage 1 (28% ± 3% vs 22% ± 3%, P<0.05) and a decrease in REM sleep (10% ± 2% vs 18% ± 2%, P<0.001) were also observed. CPAP resulted in a reduction in the AHI (8 ± 1 vs 27 ± 3, P<0.01), with the added benefit of sleep consolidation. By mimicking human pathogenic sleep conditions, we have developed a new reversible animal model of OSA.

Reactive oxygen species and the brain in sleep apnea

Rodents exposed to intermittent hypoxia (IH), a model of obstructive sleep apnea (OSA), manifest impaired learning and memory and somnolence. Increased levels of reactive oxygen species (ROS), oxidative tissue damage, and apoptotic neuronal cell death are associated with the presence of IH-induced CNS dysfunction. Furthermore, treatment with antioxidants or overexpression of antioxidant enzymes is neuroprotective during IH. These findings mimic clinical cases of OSA and suggest that ROS may play a key causal role in OSA-induced neuropathology. Controlled production of ROS occurs in multiple subcellular compartments of normal cells and de-regulation of such processes may result in excessive ROS production. The mitochondrial electron transport chain, especially complexes I and III, and the NADPH oxidase in the cellular membrane are the two main sources of ROS in brain cells, although other systems, including xanthine oxidase, phospholipase A2, lipoxygenase, cyclooxygenase, and cytochrome P450, may all play a role. The initial evidence for NADPH oxidase and mitochondrial involvement in IH-induced ROS production and neuronal injury unquestionably warrants future research efforts.

Mesenchymal stem cells reduce inflammation in a rat model of obstructive sleep apnea

The aim was to test the hypothesis that mesenchymal stem cells (MSC) could reduce the inflammation induced by recurrent airway occlusions in an animal model of obstructive sleep apnea (OSA). A nasal mask was applied to 30 anesthetized rats. Twenty rats were subjected to a pattern of recurrent obstructive apneas mimicking OSA (60/h, lasting 15 s each) for 5h. MSC (5x10(6) cells) were intravenously injected into 10 of these rats. Ten rats not subjected to apneas or MSC injection were used as controls. The rat blood serum concentrations of pro-inflammatory cytokine IL-1beta were measured by ELISA. IL-1beta was significantly greater in the rats subjected to recurrent apneas (66.7+/-41.2 pg/mL; m+/-SEM) than in controls (1.9+/-1.0 pg/mL; p<0.05). In the group of apneic rats subjected to MSC injection, IL-1beta was significantly reduced (6.1+/-3.8 pg/mL; p<0.05). In conclusion, MSC triggered an early anti-inflammatory response in rats subjected to recurrent obstructive apneas, suggesting that these stem cells could play a role in the physiological response to counterbalance inflammation in OSA.

Diagnostic characteristics of clinical prediction models for obstructive sleep apnea in different clinic populations

As predictive factors and their diagnostic values are affected by the characteristics of the population studied, clinical prediction model for obstructive sleep apnea (OSA) may exhibit different diagnostic characteristics in different populations. We aimed to compare the diagnostic characteristics of clinical prediction models developed in two different populations. One hundred seventeen consecutive clinic patients (group 1) were evaluated to develop a clinical prediction model for OSA (local model). The diagnostic characteristics of this local model were compared with those of a foreign model by applying both models to another group of 52 patients who were referred to the same clinic (group 2). All patients underwent overnight polysomnography. The local model had an area under receiver operator characteristics curve of 79%. A cutoff of 0.6 was associated with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 77.9%, 72.5%, 84.5%, and 63.0%, respectively. The overall diagnostic accuracy, sensitivity, specificity, PPV, and NPV of the local model using data from patients in group 2 were 69.0%, 78.1%, 45.0%, 69.4%, and 56.3%, respectively. The foreign model had an overall diagnostic accuracy of 64.0% when applied to data from patients in group 2. At the optimal cutoff of 17, the foreign model was associated with sensitivity of 38.2%, specificity of 83.3%, NPV of 41.7% and PPV of 81.3%. Clinical prediction model for OSA derived from a foreign population exhibits markedly different diagnostic characteristics from one that is developed locally, even though the overall accuracy is similar. Our findings challenge the predictive usefulness and the external validity of clinical prediction models.

Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea

Obstructive sleep apnea is primarily characterized by hypoxemia due to frequent apneic episodes and fragmentation of sleep due to the brief arousals that terminate the apneic episodes. Though neurobehavioral deficits frequently accompany sleep apnea, the relative roles of hypoxia versus sleep fragmentation are difficult to separate in apneic patients. Here, we assessed cognitive function as measured by water maze in the Fischer/Brown Norway (FBN) rat, comparing 24 h of sleep interruption (SI) to 24 h of intermittent hypoxia (IH), in order to dissociate their relative contributions to cognitive impairment. For SI, automated treadmills were used to induce brief ambulation in rats every 2 min, either prior to, or after, initial water maze acquisition training. IH was simulated by cycling environmental oxygen levels between 6% and 19% every 2 min, again either prior to, or after, acquisition. Twenty-four hours of IH exposure had no significant effect on either acquisition or retention, irrespective of whether IH occurred prior to, or after, acquisition. To replicate previous work, another group of rats, exposed to 3 days of IH (10 h/day) prior to acquisition, had impaired performance during acquisition. A comparison of the 24 h IH and 3 day IH findings suggests that a minimum amount of IH exposure is necessary to produce detectable spatial memory impairments. Although SI before acquisition had no effect on acquisition or later retention of the hidden platform location, SI after acquisition robustly impaired retention, indicating that spatial memory consolidation is more susceptible to the effects of sleep disruption than is the acquisition (learning) of spatial information.

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Biological consequences of oxygen desaturation and respiratory effort in an acute animal model of obstructive sleep apnea (OSA)

Background An animal model mimicking all the factors involved in obstructive sleep apnea (OSA) is useful for investigating mechanisms because the associated comorbidity usually present in such patients is an important limitation. Aim To test the hypothesis that hypoxia/normoxia and respiratory effort have different effects on the induction of inflammatory response and endothelial dysfunction in an acute rat model of OSA. Methods Four groups of anesthetized rats were studied ( n = 8): (1) sham; (2) apnea: obstructions (15 s each, 60/h, for 3 h); (3) apnea + O 2: obstructions and breathing oxygen-enriched air to avoid hypoxia and (4) intermittent hypoxia/normoxia. Inflammatory and endothelial mediators were measured as outcomes along with NF-κB in the lung and diaphragm. Results TNF-α and IL-1β significantly increased in all groups compared with sham. NF-κB in the lung was increased in apnea and hypoxia/normoxia groups, but not in apnea + O 2 group. In diaphragm tissue, NF-κB was only significant in apnea compared to sham. Significant differences were found in the ratio thromboxane-B2/6-keto-Prostaglandin-F1α between apnea and hypoxia/normoxia compared to sham but not in apnea + O 2. Conclusions Oxygen desaturations and respiratory efforts play a role in the induction of systemic inflammation but only hypoxia/normoxia induces endothelial dysfunction. These data suggest a potential role for oxygen therapy in patients with OSA.

Major Role for Hypoxia Inducible Factor-1 and the Endothelin System in Promoting Myocardial Infarction and Hypertension in an Animal Model of Obstructive Sleep Apnea

Our aim was to investigate the involvement of the endothelin (ET) system in the cardiovascular consequences of intermittent hypoxia (IH). Obstructive sleep apnea (OSA) syndrome is an important risk factor for cardiovascular morbidity. Chronic IH, a major component of OSA, is thought to be responsible for most of the cardiovascular complications occurring during OSA, but the underlying mechanisms remain to be determined. Chronic IH was applied in rats genetically prone to develop hypertension (spontaneous hypertensive rats [SHR]) and their normotensive controls. The cardiovascular effects were assessed in vivo and in Langendorff perfused hearts. Hypoxia inducible factor (HIF)-1 activity and targeting of the myocardial ET-1 gene and activation of the ET system were investigated using tissue chromatin immunoprecipitation, enzyme-linked immunoadsorbent assay, immunostaining, and Western blotting. Chronic IH enhanced hypertension development and infarct size in SHR compared with that seen in control rats. This was accompanied by an increase in myocardial big ET-1, ET-1, and ET-A receptor expression and by an enhanced coronary vascular reactivity to ET-1 in SHR only. Myocardial HIF-1 activity was increased, and HIF-1 was shown to be linked to the promoter of the myocardial ET-1 gene after chronic IH only. Moreover, administration of bosentan, a mixed ET receptor antagonist, during chronic IH prevented both the increase in blood pressure and in infarct size. In SHR, activation of the ET system, mediated by HIF-1 activity, is responsible for the enhanced susceptibility to chronic IH and for its associated cardiovascular consequences leading to hypertension and ischemic injury. Furthermore, the beneficial effects of bosentan suggest exploring ET antagonists as possible therapeutic tools in OSA.

Obstructive Apneas Induce Early Release of Mesenchymal Stem Cells into Circulating Blood

To investigate whether noninvasive application of recurrent airway obstructions induces early release of mesenchymal stem cells into the circulating blood in a rat model of obstructive sleep apnea. Prospective controlled animal study. University laboratory. Twenty male Sprague-Dawley rats (250-300 g). A specially designed nasal mask was applied to the anesthetized rats. Ten rats were subjected to a pattern of recurrent obstructive apneas (60 per hour, lasting 15 seconds each) for 5 hours. Ten anesthetized rats were used as controls. Mesenchymal stem cells from the blood and bone marrow samples were isolated and cultured to count the total number of colony-forming unit fibroblasts (CFU-F) of adherent cells after 9 days in culture. The number of CFU-F from circulating blood was significantly (P = 0.02) higher in the rats subjected to recurrent obstructive apneas (5.00 +/- 1.16; mean +/- SEM) than in controls (1.70 +/- 0.72). No significant (P = 0.54) differences were observed in CFU-F from bone marrow. Application of a pattern of airway obstructions similar to those experienced by patients with sleep apnea induced an early mobilization of mesenchymal stem cells into circulating blood.

P443 Rat model of obstructive sleep apnea (OSA) that reproduce SAHS respiratory events

Aim: To setup a rat model of apneas able to reproduce the major respiratory events that characterize SAHS and to know whether the rat is able to be in model during at least 6 h a day during 4 weeks. Material and methods: The model consists of a cylindrical restraint box able to keep the rat head in a special cone where different respiratory events can be applied by using and specific valve [Farre et al. Respiratory Physiology and Neurobiology, 2003]. The restrainer with a specific membrane around the rat neck preserve the head of the rat inside the cone space without leaks. Three groups of Sprague–Dawley rats were studied: (1) Four rats inside the box in which obstructive events were applied (respiratory rate 60, length 5 s) during 4 weeks, (2) Four as Sham (inside of the box but without intervention),and finally (3) four naive rats. Results: (1) The model reproduced the major respiratory events that mimic SAHS being capable to consistently measure among others, the degree of respiratory effort. (2) The rats tolerate well periods of 6 hs in the box with repetitive occlusion during 4 weeks. Rats with OSA did gain less weight (11%). Conclusions: The model reproduces obstructive events, consistently measures the different variables implicated in SAHS and rats become adapted to the setup. Supported: (SAF2002-03616 and SAF 2004-00684); SEPAR, FUCAP.

Extraluminal tissue pressure: what does it mean?

In this issue of the Journal of Applied Physiology , Kairaitis et al. ([9][1]) examine the control of pharyngeal extraluminal tissue pressure by mandibular advancement and jaw position. Utilizing a novel approach for measuring peripharyngeal tissue pressures, they demonstrated that mandibular

The effects of ondansetron on sleep-disordered breathing in the English bulldog.

Serotonin and serotoninergic drugs have significant effects on respiration, at many sites throughout the nervous system, and serotonin has been implicated in the pathogenesis of obstructive sleep apnea. Thus, understanding the serotoninergic mechanisms underlying respiratory control may help discover novel pharmacotherapies for sleep-disordered breathing. Ondansetron, a serotonin (5-HT) antagonist selective for the 5-HT3 receptor subtype has recently been shown to suppress sleep-related central apneas in rats, particularly in rapid-eye-movement (REM) sleep. To evaluate the potential of ondansetron in the treatment of obstructive sleep-disordered breathing, we have performed randomized trials of two doses of ondansetron (20 and 40 mg orally) and placebo (4 studies for each of the 3 conditions) in our animal model of obstructive sleep apnea, the English Bulldog. Ondansetron significantly reduced the respiratory disturbance index (RDI) in REM sleep from 24.15+/-4.85 events/hour at placebo to 11.01+/-1.56 events/hour with high dose treatment, n=4, p<0.05. In contrast, the effects of drug on the RDI in non-rapid-eye-movement (NREM) sleep (5.23+/-1.30 events/hour, placebo; 4.31+/-1.36, with 20 mg ondansetron and 2.89+/-1.30 with 40 mg ondansetron, n=4) were not significant. Ondansetron, however, had no effect on either sleep efficiency or sleep architecture, and there were no effects on either oxyhemoglobin saturation nadirs or on the sleep time with saturations <90%. Although a trend towards reduction in the latter measure of oxygenation was seen at the higher dose of ondansetron. These data suggest a therapeutic potential for ondansetron in obstructive sleep-disordered breathing, particularly REM sleep apnea.

A model of obstructive sleep apnea in normal humans. Role of the upper airway.

We determined whether upper airway obstruction in normal individuals with intact reflexes could produce the syndrome of obstructive sleep apnea. Upper airway obstruction was produced in 12 normal individuals by lowering nasal pressure to -10 cm H(2)O during sleep. Full night polysomnography was performed during two consecutive nights of sleep with subatmospheric nasal pressure and compared with control nights before and after the negative pressure nights. We found that the application of negative pressure was associated with the development of recurrent obstructive apneas (non-REM-disordered breathing rate, 32.6 +/- 34.8 and 37.8 +/- 29.1 events/h during each of two negative pressure nights; p < 0.001) that were associated with oxyhemoglobin desaturation, arousals from sleep, and alterations in sleep stage distribution. Moreover, the median daytime sleep latency after two nights of sleep with subatmospheric pressure fell from 6.9 +/- 1.1 to 3.4 +/- 0.6 min, and rose significantly again to 8.1 +/- 1.5 min (p < 0.03) after the control night following subatmospheric pressure nights. Our findings suggest that a decrease in the pharyngeal transmural pressure alone is a sufficient condition for the production of the sleep apnea syndrome in normal individuals.

Baroreflex control of heart rate in a canine model of obstructive sleep apnea.

We have recently demonstrated the development of systemic hypertension in a canine model of obstructive sleep apnea (OSA), but the underlying physiological mechanisms were not identified. Therefore, the purpose of this study was to examine the effect of OSA on arterial baroreceptor control of heart rate (HR) in this canine model. OSA was produced in three dogs for 1 to 3 mo. Baroreflex control of HR was determined with graded infusions of vasoactive agents (phenylephrine and nitroprusside) administered over 30 to 60 s, during which steady-state systolic blood pressure (BP) and cardiac R-R interval responses were recorded. BP was measured with a permanently implanted arterial catheter and a telemetry system. Although, as previously reported, OSA resulted in increases in daytime (awake) mean BP of 6.0 to 26.8 mm Hg, there was no change in daytime baseline HR or in the slope of the systolic BP-R-R interval curve (p > 0.2). The findings demonstrate that OSA in the dog is associated with resetting of the baroreceptors to a higher pressure, but no change in baroreflex sensitivity.

Sleep Architecture in a Canine Model of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) causes recurrent sleep disruption that is thought to contribute to excessive daytime sleepiness in patients with this disorder. The purpose of this study was to determine the specific effects of OSA on overall sleep architecture in a canine model of OSA. The advantage of this model is that sleep during long-term OSA can be compared to both normal sleep before OSA and recovery sleep after OSA. Studies were performed in four dogs in which sleep-wake state was monitored continuously by a computer that received telemetered EEG and EMG signals. Whenever sleep was detected, the computer sent a signal to close a valve through which the dog breathed; when the dog awoke the occlusion was released. In each dog, data were analyzed from 4 consecutive nights in three phases: a control phase before induction of OSA, a phase during long-term OSA (mean = 85 days, apnea index = 59/hour), and a recovery phase after cessation of OSA. During recovery there was a significant increase in the amount of rapid-eye-movement (REM) sleep compared to the OSA phase (p < 0.01), as well as significant increases in sleep efficiency and decreases in wakefulness (p < 0.01), similar to that reported in OSA patients. The REM rebound during recovery, however, could not be attributed to overall REM deprivation since the amount of REM sleep during the OSA phase was not different from the control phase (p = 0.708). This finding suggests that REM rebound during recovery from OSA is not the result of an overall REM sleep deficit per se. Rather, repeated sleep disruption due to the effects of repetitive apneas and hypoxia may lead to an increased REM sleep drive that manifests itself as a REM sleep rebound during recovery sleep after OSA.

Systemic and pulmonary hemodynamic responses to normal and obstructed breathing during sleep

We examined the hemodynamic responses to normal breathing and induced upper airway obstructions during sleep in a canine model of obstructive sleep apnea. During normal breathing, cardiac output decreased (12.9 +/- 3.5%, P < 0.025) from wakefulness to non-rapid-eye-movement sleep (NREM) but did not change from NREM to rapid-eye-movement (REM) sleep. There was a decrease (P < 0.05) in systemic (7.2 +/- 2.1 mmHg) and pulmonary (2.0 +/- 0.6 mmHg) arterial pressures from wakefulness to NREM sleep. In contrast, systemic (8.1 +/- 1.0 mmHg, P < 0.025), but not pulmonary, arterial pressures decreased from NREM to REM sleep. During repetitive airway obstructions (56.0 +/- 4.7 events/h) in NREM sleep, cardiac output (17.9 +/- 3.1%) and heart rate (16.2 +/- 2.5%) increased (P < 0.05), without a change in stroke volume, compared with normal breathing during NREM sleep. During single obstructive events, left (7.8 +/- 3.0%, P < 0.05) and right (7.1 +/- 0.7%, P < 0.01) ventricular outputs decreased during the apneic period. However, left (20.7 +/- 1.6%, P < 0.01) and right (24.0 +/- 4.2%, P < 0.05) ventricular outputs increased in the post-apneic period because of an increase in heart rate. Thus 1) the systemic, but not the pulmonary, circulation vasodilates during REM sleep with normal breathing; 2) heart rate, rather than stroke volume, is the dominant factor modulating ventricular output in response to apnea; and 3) left and right ventricular outputs oscillate markedly and in phase throughout the apnea cycle.

Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea.

We have previously described a canine model of obstructive sleep apnea (OSA) in which sleep-wake state is monitored continuously by a computer that produces tracheal occlusion when sleep occurs. Our aim was to assess the effects of long-term application of this model on resting ventilation and on the ventilatory and arousal responses to hypercapnia and hypoxia. Five dogs were maintained on the model for 15.5 +/- 1.7 (mean +/- SE) wk, with a mean apnea index of 57.5 +/- 4.5 occlusions/h of sleep. Resting ventilation and the ventilatory and arousal responses to progressive hypoxic and hypercapnic rebreathing were assessed during wakefulness (W) and both slow-wave (SWS) and rapid-eye-movement (REM) sleep at baseline prior to intervention, at the end of the OSA phase, and following a 1 to 3-mo recovery period. During the period of OSA there were small changes in respiratory timing at rest, but no significant changes in PCO2 or SaO2. As compared with baseline, the ventilatory response to hypoxia during OSA was strikingly reduced during W, and significantly although less markedly reduced during SWS and REM. The reduction was due to a decreased breathing frequency response to hypoxia. In addition, during OSA there was a significant decrease from baseline in SaO2 at arousal during hypoxic rebreathing in both SWS and REM. All responses returned to normal during recovery. In contrast to hypoxia, hypercapnic ventilatory responses during OSA were slightly increased over their baseline values both in W and SWS, owing to a leftward shift of the ventilation-versus-PCO2 relationship. During recovery, these responses reverted partly to baseline for W and reverted completely to baseline for SWS. There were no significant changes in arousal PCO2 during hypercapnic rebreathing in either SWS or REM across the pre-OSA baseline, OSA, and post-OSA recovery periods. We conclude that long-term application of the OSA model is associated with a selective, reversible decrease in ventilatory and arousal responses to hypoxia.