Hypersensitive response of malignant hyperthermia-susceptible skeletal muscle to inositol 1,4,5-trisphosphate inducers release of calcium

J. R. Lopez, C. Perez, N. Linares, P. Allen, A. Terzic

Research output: Contribution to journalArticle

16 Scopus citations

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 μM) 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+.

Original languageEnglish (US)
Pages (from-to)442-446
Number of pages5
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume352
Issue number4
StatePublished - 1995
Externally publishedYes

Keywords

  • 1,4,5-trisphosphate
  • Calcium
  • Dantrolene Ca microelectrode
  • Inositol
  • Malignant hyperthermia
  • Nitrendipine
  • Skeletal muscle

ASJC Scopus subject areas

  • Pharmacology

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