Respiratory muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased sternohyoid muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy.

The effects of chronic hypoxia (CH) on respiratory muscle are poorly understood. The aim of the present study was to examine the effects of CH on respiratory muscle structure and function, and to determine whether nitric oxide is implicated in respiratory muscle adaptation to CH.Male Wistar rats were exposed to CH for 1-6 weeks. Sternohyoid and diaphragm muscle contractile properties, muscle fibre type and size, the density of fibres expressing sarco/ endoplasmic reticulum calcium-ATPase (SERCA) 2 and sodium-potassium ATPase (Na + ,K + -ATPase) pump content were determined. Muscle succinate dehydrogenase (SDH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase activities were also assessed. Acute and chronic blockade of nitric oxide synthase (NOS) was employed to determine whether or not NO is critically involved in functional remodelling in CH muscles. CH improved diaphragm, but not sternohyoid, fatigue tolerance in a time-dependent fashion. This adaptation was not attributable to increased SDH or NADPH dehydrogenase activities. The areal density of muscle fibres and relative area of fibres expressing SERCA2 were unchanged. Na + ,K + -ATPase pump content was significantly increased in CH diaphragm. Chronic NOS inhibition decreased diaphragm Na + ,K + -ATPase pump content and prevented CH-induced increase in muscle endurance. This study provides novel insight into the mechanisms involved in CH-induced muscle plasticity. The results may be of relevance to respiratory disorders characterised by CH, such as chronic obstructive pulmonary disease.KEYWORDS: Chronic obstructive pulmonary disease, fatigue, myosin heavy chain isoforms, nitric oxide synthase, sarco/endoplasmic reticulum calcium-ATPase 2 S keletal muscle has enormous capacity for remodelling, as evident in various physiological and pathophysiological settings. Chronic hypoxia (CH), a feature of respiratory disease, is known to affect skeletal muscle structure and function. Alterations include changes in capillarity [1,2], fibre size and distribution [3][4][5][6][7][8][9][10], oxidative capacity [5,6,11,12] and contractile performance [5,9,[13][14][15][16]. CH induces reflex hyperventilation. Thus respiratory muscles are unique in that they must increase their workload in the face of a reduction in oxygen availability, necessary for aerobic metabolism. Respiratory muscle remodelling is a feature of chronic obstructive pulmonary disease (COPD) [17][18][19][20][21][22][23][24][25][26][27], which may be the result of hypoxic adaptation. Surprisingly, there is a general paucity of information concerning the effects of CH on respiratory muscle structure and function despite the clinical relevance. Translational animal models permit examination of the effects of CH on skeletal muscle independent of other confounding factors that are present in disease. Furthermore, they permit a thorough exploration of the molecular mechanisms that underpin muscle adaptation. As such, the major aim of the present study was to conduct a compreh...

Background-Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia. Methods and Results-Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1Ϯ3.2 versus 17.2Ϯ3.1 mm Hg; nϭ8, PϽ0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8Ϯ5.9 mm Hg; nϭ8, PϽ0.05), an effect that was attenuated by the thromboxane (TX) A 2 /prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB 2 increased during hypoxia (5.9Ϯ0.9 versus 1.2Ϯ0.2 ng/mg creatinine; nϭ6, PϽ0.01) and was further increased by COX-2 inhibition (8.5Ϯ0.7 ng/mg creatinine; nϭ6, PϽ0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F 1␣ decreased with COX-2 inhibition (8.6Ϯ3.0 versus 27.0Ϯ4.8 ng/mg creatinine; nϭ6, PϽ0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the COX-2 gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of COX-1 had no effect. Conclusions-COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxiainduced pulmonary hypertension.

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New Findings r What is the central question of this study?The effects of chronic intermittent hypoxia (CIH) on respiratory muscles are relatively underexplored. It is speculated that muscle dysfunction and other key morbidities associated with sleep apnoea are the result of CIH-induced oxidative stress. We sought to investigate the putative role of CIH-induced reactive oxygen species in the development of respiratory muscle dysfunction. r What is the main finding and its importance?The CIH-induced diaphragm muscle fatigue is time and intensity dependent and is associated with a modest oxidative stress. Supplementation with N-acetyl cysteine prevents CIH-induced diaphragm muscle dysfunction, suggesting that antioxidant supplementation may have therapeutic value in respiratory muscle disorders characterized by CIH, such as obstructive sleep apnoea.Respiratory muscle dysfunction documented in sleep apnoea patients is perhaps due to oxidative stress secondary to chronic intermittent hypoxia (CIH). We sought to explore the effects of different CIH protocols on respiratory muscle form and function in a rodent model. Adult male Wistar rats were exposed to CIH (n = 32) consisting of 90 s normoxia-90 s hypoxia (either 10 or 5% oxygen at the nadir; arterial O 2 saturation ß90 or 80%, respectively] for 8 h per day or to sham treatment (air-air, n = 32) for 1 or 2 weeks. Three additional groups of CIH-treated rats (5% O 2 for 2 weeks) had free access to water containing N-acetyl cysteine (1% NAC, n = 8), tempol (1 mm, n = 8) or apocynin (2 mm, n = 8). Functional properties of the diaphragm muscle were examined ex vivo at 35°C. The myosin heavy chain and sarco(endo)plasmic reticulum Ca 2+ -ATPase isoform distribution, succinate dehydrogenase and glyercol phosphate dehydrogenase enzyme activities, Na + -K + -ATPase pump content, concentration of thiobarbituric acid reactive substances, DNA oxidation and antioxidant capacity were determined. Chronic intermittent hypoxia (5% oxygen at the nadir; 2 weeks) decreased diaphragm muscle force and endurance. All three drugs reversed the deleterious effects of CIH on diaphragm endurance, but only NAC prevented CIH-induced diaphragm weakness. Chronic intermittent hypoxia increased diaphragm muscle myosin heavy chain 2B areal density and oxidized glutathione/reduced glutathione (GSSG/GSH) ratio. We conclude that CIH-induced diaphragm dysfunction is reactive oxygen species dependent. N-Acetyl cysteine was most effective in reversing CIH-induced effects on diaphragm. Our results suggest that respiratory muscle dysfunction in sleep apnoea may be the result of oxidative stress and, as such, antioxidant treatment could prove a useful adjunctive therapy for the disorder. DOI