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.
Nakahara
K
K
Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan.
Yada
T
T
Kuriyama
M
M
Osame
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009132:Muscles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D019821:Simvastatin
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D002118:Calcium