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Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm

¹The Dorothy M. Davis Heart and Lung Research Institute, and Departments of ²Internal Medicine (Division of Pulmonary, Critical Care and Sleep Medicine), ³Emergency Medicine, and ⁴Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio

Submitted 16 September 2004 ; accepted in final form 17 December 2004

Acute exposure to severe hypoxia depresses contractile function and induces adaptations in skeletal muscle that are only partially understood. Previous studies have demonstrated that antioxidants (AOXs) given during hypoxia partially protect contractile function, but this has not been a universal finding. This study confirms that specific AOXs, known to act primarily as superoxide scavengers, protect contractile function in severe hypoxia. Furthermore, the hypothesis is tested that the mechanism of protection involves preservation of high-energy phosphates (ATP, creatine phosphate) and reductions of P_i. Rat diaphragm muscle strips were treated with AOXs and subjected to 30 min of hypoxia. Contractile function was examined by using twitch and tetanic stimulations and the degree of elevation in passive force occurring during hypoxia (contracture). High-energy phosphates were measured at the end of 30-min hypoxia exposure. Treatment with the superoxide scavengers 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron, 10 mM) or Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (50 µM) suppressed contracture during hypoxia and protected maximum tetanic force. N-acetylcysteine (10 or 18 mM) had no influence on tetanic force production. Contracture during hypoxia without AOXs was also shown to be dependent on the extracellular Ca²⁺ concentration. Although hypoxia resulted in only small reductions in ATP concentration, creatine phosphate concentration was decreased to 10% of control. There were no consistent influences of the AOX treatments on high-energy phosphates during hypoxia. The results demonstrate that superoxide scavengers can protect contractile function and reduce contracture in hypoxia through a mechanism that does not involve preservation of high-energy phosphates.

skeletal muscle; 4,5-dihydroxy-1,3-benzenedisulfonic acid; N-acetylcysteine; Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride; calcium regulation

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