CYTOSOLIC CA2+ INCREASE AND CELL-DAMAGE IN L6 RAT MYOBLASTS BY HMG-COA REDUCTASE INHIBITORS

Acute rhabdomyolysis is caused by HMG-CoA reductase (HCR) inhibitors clinically and experimentally. To study the mechanism of muscle cell damage, we investigated the change in the cytosolic free Ca2+ concentration ([Ca2+](i)) in L6 rat myoblasts stimulated with three kinds of HCR inhibitors: simvastatin, simvastatin-acid form and pravastatin. Simvastatin and simvastatin-acid form induced an increase in [Ca2+](i) through two different pathways, namely, the Ca2+ release from intracellular stores and the Ca2+ influx from extracellular solution. They also caused cell puncture either in the presence or absence of extracellular Ca2+. Pravastatin induced little or no change in [Ca2+](i) and no cell damage resulted. Simvastatin was 10-fold more potent than simvastatin-acid form. These results suggest that the mechanism of cell damage may relate to the [Ca2+](i) elevation by these drugs and may be dependent on the lipophilicity of the inhibitors. (C) 1994 Academic Press, Inc.