Simvastatin-sodium delays cell death of anoxic cardiomyocytes by inhibition of the Na+/Ca2+ exchanger.
When incubated under anoxic conditions, cultured neonatal cardiomyocytes undergo cell necrosis. Simvastatin-sodium, the bioactive metabolite of simvastatin (a potent serum cholesterol-lowering drug), delayed the anoxia-induced myocyte necrosis in a dose-dependent manner. This beneficial effect of simvastatin-sodium could not be attributed to its cholesterol-lowering properties. We found that simvastatin-sodium, at concentrations of 20 and 50 microM, attenuated the rise in intracellular Ca2+ concentration ([Ca2+]i) measured with Fura-2 in anoxic cardiomyocytes. In a test of sarcolemmal Na+/Ca2+ exchange activity, simvastatin-sodium attenuated the rise of [Ca2+]i upon incubation in sodium-free buffer, which normally causes a reversal of Na+/Ca2+ exchange and cellular calcium overload. The inhibitory action of simvastatin-sodium on the sarcolemmal Na+/Ca2+ exchanger could well explain the cardioprotective effect of the drug on myocytes subjected to anoxia.
Bastiaanse
E M
EM
Department of Cardiology, University Hospital Leiden, The Netherlands.
Atsma
D E
DE
Kuijpers
M M
MM
Van der Laarse
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D051381:Rats; D019821:Simvastatin; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D008148:Lovastatin; D012964:Sodium; D019821:Simvastatin; D007770:L-Lactate Dehydrogenase; D002118:Calcium