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

López, José R., Nancy Linares, Isaac N. Pessah, and Paul D. Allen. Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca ]i. Am J Physiol Cell Physiol 288: C606– C612, 2005. First published November 10, 2004; doi:10.1152/ajpcell. 00297.2004.—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 Ca concentration ([Ca ]i) using double-barreled, Ca -selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca ]i was 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 (4CmC) produced an elevation in [Ca ]i in both groups; however, the concentration required to cause a rise in [Ca ]i elevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca buffer BAPTA reduced [Ca ]i, raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca ]i, and reduced the amount of Ca 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 [Ca ]i levels in these cells.