Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i

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Abstract
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic syndrome caused by exposure to halogenated volatile anesthetics and/or depolarizing muscle relaxants. We have measured intracellular Ca2+concentration ([Ca2+]i) using double-barreled, Ca2+-selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca2+]iwas approximately twofold in MHS compared with MHN quiescent myoballs (232 ± 35 vs. 112 ± 11 nM). Treatment of myoballs with caffeine or 4-chloro- m-cresol (4-CmC) produced an elevation in [Ca2+]iin both groups; however, the concentration required to cause a rise in [Ca2+]ielevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca2+buffer BAPTA reduced [Ca2+]i, raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca2+]i, and reduced the amount of Ca2+release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC may be mediated at least in part by the chronic high resting [Ca2+]ilevels in these cells.

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