Antiapoptotic Effect of nicorandil mediated by mitochondrial ATP-sensitive potassium channels in cultured cardiac myocytes

OBJECTIVES We examined whether nicorandil, a clinically useful drug for the treatment of ischemic syndromes, inhibits myocardial apoptosis. BACKGROUND Nicorandil has been reported to have a cardioprotective action through activation of mitochondrial. ATP-sensitive potassium (mitoKATP) channels. Based on our recent observation that mitoK(ATP) channel activation has a remarkable antiapoptotic effect in cultured cardiac cells, we hypothesized that the protective effects of nicorandil may be at least partially due to an antiapoptotic effect. METHODS Cultured neonatal rat cardiac myocytes were exposed to hydrogen peroxide to induce apoptosis. Effects of nicorandil were evaluated using a number of apoptotic markers. RESULTS Exposure to 100 muM hydrogen peroxide resulted in apoptotic cell death as shown by TUNEL positivity, cytochrome c translocation, caspase-3 activation and dissipation of mitochondrial inner membrane potential (Deltapsi(m)). Nicorandil (100 muM) suppressed an of these markers of apoptosis. Notably, nicorandil prevented Deltapsi(m) depolarization in a concentration-dependent manner (EC50 similar to 40 muM, with saturation by 100 muM), as shown by fluorescence-activated cell sorter analysis of cells stained with a fluorescent Deltapsi(m)-indicator, tetramethylrhodamine ethyl ester (TMRE). Time-lapse confocal microscopy of individual cells loaded with TMRE shows that nicorandil suppresses Deltapsi(m) loss. Subcellular calcein localization revealed inhibition of the mitochondrial permeability transition by nicorandil. These protective effects of nicorandil were blocked by the mitoK(ATP) channel antagonist 5-hydroxydecanoate. CONCLUSIONS Our findings identify nicorandil as an inhibitor of apoptosis induced by oxidative stress in cardiac myocytes, and confirm the critical role of mitoK(ATP) channels in inhibiting apoptosis. (C) 2002 by the American College of Cardiology Foundation.