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Abstract
We examined whether nicorandil, a clinically useful drug for the treatment of ischemic
syndromes, inhibits myocardial apoptosis.
Nicorandil has been reported to have a cardioprotective action through activation
of mitochondrial ATP-sensitive potassium (mitoK(ATP)) 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.
Cultured neonatal rat cardiac myocytes were exposed to hydrogen peroxide to induce
apoptosis. Effects of nicorandil were evaluated using a number of apoptotic markers.
Exposure to 100 microM 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 (Delta(Psi)(m)). Nicorandil (100 microM)
suppressed all of these markers of apoptosis. Notably, nicorandil prevented Delta(Psi)(m)
depolarization in a concentration-dependent manner (EC(50) approximately 40 microM,
with saturation by 100 microM), as shown by fluorescence-activated cell sorter analysis
of cells stained with a fluorescent Delta(Psi)(m)-indicator, tetramethylrhodamine
ethyl ester (TMRE). Time-lapse confocal microscopy of individual cells loaded with
TMRE shows that nicorandil suppresses Delta(Psi)(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.
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.