Effects of hypoxia on diaphragm relaxation rate during fatigue

Skeletal muscle fatigue is associated with a slowing of relaxation rate. Hypoxia may increase the rate at which fatigue occurs, but, surprisingly, mild to moderate hypoxia has not been found to augment the degree of slowing of relaxation during fatigue. The present study tested the hypothesis that severe hypoxia interacts with fatigue in slowing the rate of muscle relaxation and that this can be modulated by altering membranous ionic conductances. Rat diaphragm muscle strips were studied in vitro while aerated with 95% O2-5% CO2 (normoxia) or 95% N2-5% CO2 (hypoxia). During continuous 0.1-Hz stimulation, relaxation rate and force remained stable over time, and relaxation rate was not slowed by hypoxia. Hypoxia accelerated force decline during continuous 5-Hz but not intermittent 20-Hz stimulation. During both 5- and 20-Hz stimulation, relaxation rate became slower over time as force declined, the extent of which was increased significantly by hypoxia. The extent of hypoxia-augmented slowing of relaxation rate during fatigue increased over time and was greater than expected for a given degree of force loss. 4-Aminopyridine did not attenuate or partially attenuated, whereas lowering extracellular Cl-concentration fully attenuated, the hypoxia-induced prolongation of relaxation rate during repetitive stimulation. Thus hypoxia slows relaxation rate to a greater extent than expected for a given degree of force decline, an effect that increases over time, is at most partially attenuated by lowering K+ conductance, and is fully attenuated by lowering membranous Cl-conductance.