Hypersensitive response of malignant hyperthermia-susceptible skeletal muscle to inositol 1,4,5-triphosphate 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-triphosphate (InsP3) levels could be a possible candidate for the abnormal regulation of intracellular calcium. However, the effect of InsP3 on [Ca2+]i in MH is not known. Microinjection of InsP3 increased intracellular Ca2+ in intact skeletal muscle from malignant hyperthermia susceptible swines (MHS) with a higher potency and efficacy than in muscles from nonsusceptible (MHN) swines. Omission of extracellular Ca2+ or incubation of muscle fibers with Ca2+ channel blockers did not modify the response to InsP3. However, dantrolene (50 microM) a known blocker of intracellular Ca2+ release, decreased resting intracellular Ca2+ concentration and prevented the InsP3-induced increase in intracellular Ca2+. This suggests (i) that MHS skeletal muscles exhibit a higher responsiveness to InsP3-induced release of Ca2+, which could implicate InsP3 in the pathophysiology of MH, and (ii) that the beneficial effect of dantrolene in MHS could be related to its ability to prevent the InsP3-induced release of Ca2+.
Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
J R
JR
López
C
C
Pérez
N
N
Linares
P
P
Allen
A
A
Terzic
D002118:Calcium / Q000378:metabolism*; D003620:Dantrolene / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D008305:Malignant Hyperthermia / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*
D015544:Inositol 1,4,5-Trisphosphate; D003620:Dantrolene; D002118:Calcium