Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC275

Poster Communications

Chronic intermittent hypoxia-induced respiratory muscle fatigue is mediated by reactive oxygen species

C. Shortt1, A. Bradford2, K. O'Halloran1

1. University College Dublin, Dublin, Ireland. 2. Royal College of Surgeons, Dublin, Ireland.

Obstructive sleep apnoea syndrome (OSAS) is characterized by recurrent collapse of the upper airway during sleep. The disorder is very common and is associated with significant cardiovascular morbidity. Respiratory muscle dysfunction is documented in OSAS patients and it is speculated that this, and other key morbidities, may be a result of oxidative stress which is secondary to the repeated hypoxia/re-oxygenation events characteristic of the condition due to apnoea. We sought to explore the effects of chronic intermittent hypoxia (CIH) on respiratory muscle function in a rodent model 1, and to test the efficacy of antioxidant agents in preventing CIH-induced respiratory muscle impairment. Adult male Wistar rats were exposed to CIH (n=8) consisting of 90s normoxia/ 90s hypoxia [5% oxygen at the nadir; SaO2 ~ 80%]) for 8h/day or to sham treatment (air/air, n=8) for 2 weeks. Three additional groups of CIH-treated rats had free access to water containing N-acetyl cysteine (1% NAC, n=8), tempol (1mM, n=8) or apocynin (2mM, n=8). Following gas treatments, diaphragm and sternohyoid (pharyngeal dilator) muscle contractile and endurance properties were examined in vitro at 35°C. Additionally, muscle was snap frozen and stored for structural analysis. CIH increased sternohyoid muscle fatigue (63±7 vs. 47±7%, sham vs. CIH, mean±SEM, % of initial force after 2 min of repeated stimulation, p=0.08, ANOVA). NAC (60±6%) and tempol (62±4%) reversed the effects of CIH on sternohyoid muscle fatigue (p<0.05, ANOVA), but apocynin treatment during CIH exposure only partially recovered muscle endurance (56±5%). All three drugs reversed the deleterious effects of CIH on diaphragm endurance (52±5 vs. 38±3%, sham vs. CIH, p<0.05); 62±6%, 67±6% and 58±6% NAC, tempol and apocynin respectively). There was no significant effect of CIH treatment on respiratory muscle MHC fibre type, relative area of fibres expressing SERCA 1 and 2 protein or Na+-K+-ATPase pump content. We conclude that the deleterious effect of CIH on respiratory muscle endurance is due to oxidative stress since, for the most part, antioxidants reversed CIH-induced respiratory muscle fatigue. Pharmacological blockade of the superoxide generating NADPH oxidase (NOx) enzyme with apocynin improved diaphragm muscle endurance, suggesting that cytosolic oxidases may be a source of increased ROS production in CIH. Our results suggest that respiratory muscle dysfunction in OSAS may be the result of oxidative stress, and as such antioxidant treatment could prove a useful adjunct therapy in the treatment of OSAS.

Where applicable, experiments conform with Society ethical requirements