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

Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MBS) 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 us. 1,159 +/- 235 nM MHS) with no change in resting membrane potential. When either MHN or MBS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 +/- 22 nar in MHN and 967 +/- 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+], was elevated induced an increment in [Ca2+](i) to 340 +/- 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.