Hypersensitive response of malignant hyperthermia-susceptible skeletal muscle to inositol 1,4,5-trisphosphate induced release of calcium |
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Authors: | J. R. López C. Pérez N. Linares P. Allen A. Terzic |
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Affiliation: | (1) Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela;(2) Division of Cardiovascular Diseases, Departments of Internal Medicine and Pharmacology, Guggenheim 7, Mayo Clinic, Mayo Foundation, 55905 Rochester, MN, USA;(3) Department of Anesthesiology, Brigham and Women Hospital, Harvard Medical School, Boston, MA, USA |
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Abstract: | 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-trisphosphate (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 M) 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+. |
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Keywords: | Inositol 1,4,5-trisphosphate Malignant hyperthermia Calcium Skeletal muscle Dantrolene Ca2+ microelectrode Nitrendipine |
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