Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i.
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(2+) concentration ([Ca(2+)](i)) using double-barreled, Ca(2+)-selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca(2+)](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 (4-CmC) produced an elevation in [Ca(2+)](i) in both groups; however, the concentration required to cause a rise in [Ca(2+)](i) elevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca(2+) buffer BAPTA reduced [Ca(2+)](i), raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca(2+)](i), and reduced the amount of Ca(2+) 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(2+)](i) levels in these cells.
López
José R
JR
Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela. lopez@zeus.bwh.harvard.edu
Linares
Nancy
N
Pessah
Isaac N
IN
Allen
Paul D
PD
D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002614:Chelating Agents / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D004594:Electrophysiology; D005659:Fungicides, Industrial / Q000494:pharmacology; D008305:Malignant Hyperthermia / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D008839:Microelectrodes; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D013552:Swine
D000697:Central Nervous System Stimulants; D002614:Chelating Agents; D003408:Cresols; D005659:Fungicides, Industrial; C006984:chlorocresol; D002110:Caffeine; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium