Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]

Jose R. López, Jaime Contreras, Nancy Linares, Paul D. Allen

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods: We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-selective microelectrodes before and after K+-induced partial depolarization. Results: [Ca2+](i) in untreated MHN fibers was 123 ± 8 nM versus 342 ± 33 nM in MHS fibers. Caffeine (2 mM) caused an increase in [Ca2+](i) in both groups (296 ± 41 nM MHN vs. 1,159 ± 235 nM MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 ± 22 nM in MHN and 967 ± 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+](i) was elevated induced an increment in [Ca2+](i) to 940 ± 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to control levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2+](i) returned to control, despite continued partial membrane depolarization. Conclusions: These results suggest that the increased 'sensitivity' to caffeine of MHS swine muscle fibers is a nonspecific response related, at least in part, to the high resting [Ca2+](i) and not an increased caffeine sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.

Original languageEnglish (US)
Pages (from-to)1799-1806
Number of pages8
JournalAnesthesiology
Volume92
Issue number6
StatePublished - Jun 2000
Externally publishedYes

Keywords

  • Hyperpyrexia
  • Potassium
  • Xanthine

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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