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 language | English (US) |
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Pages (from-to) | 442-446 |
Number of pages | 5 |
Journal | Naunyn-Schmiedeberg's Archives of Pharmacology |
Volume | 352 |
Issue number | 4 |
DOIs | |
State | Published - Oct 1995 |
Keywords
- Ca microelectrode
- Calcium
- Dantrolene
- Inositol 1,4,5-trisphosphate
- Malignant hyperthermia
- Nitrendipine
- Skeletal muscle
ASJC Scopus subject areas
- Pharmacology