HYPERSENSITIVE RESPONSE OF MALIGNANT HYPERTHERMIA-SUSCEPTIBLE SKELETAL-MUSCLE TO INOSITOL 1,4,5-TRISPHOSPHATE INDUCED RELEASE OF CALCIUM

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Besides a mutation in the ryanodine receptor gene, an increase in inositol, 1,4,5-trisphosp hate (InsP(3)) levels could be a possible candidate for the abnormal r egulation of intracellular calcium. However, the effect of InsP(3) on [Ca2+]i in MH is not known. Microinjection of InsP(3) increased intrac ellular Ca2+ in intact skeletal muscle from malignant hyperthermia sus ceptible swines (MHS) with a higher potency and efficacy than in muscl es from nonsusceptible (MHN) swines, Omission of extracellular Ca2+ or incubation of muscle fibers with Ca2+ channel blockers did not modify the response to InsP(3). However, dantrolene (50 mu M) a known blocke r of intracellular Ca2+ release, decreased resting intracellular Ca2concentration and prevented the InsP(3)-induced increase in intracellu lar Ca2+. This suggests (i) that MHS skeletal muscles exhibit a higher responsiveness to InsP(3)-induced release of Ca2+, which could implic ate InsP(3) in the pathophysiology of MH, and (ii) that the beneficial effect of dantrolene in MHS could be related to its ability to preven t the InsP(3)-induced release of Ca2+.