Article ID Journal Published Year Pages File Type
2192521 Journal of Molecular and Cellular Cardiology 2006 10 Pages PDF
Abstract

Nicorandil has been shown to inhibit myocyte apoptosis by opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels and nitrate-like effect against oxidative stress. However, the detailed mechanism of nicorandil-mediated cardioprotection under hypoxic conditions remains to be largely unknown. The present study examined whether nicorandil can inhibit apoptosis via regulation of Bcl-2 family proteins in hypoxic myocytes. Neonatal rat cardiac myocytes were exposed to hypoxia for 7 hours. Hypoxia-induced myocyte apoptosis (13.9 ± 0.9%) under glucose-rich conditions. Myocyte apoptosis was accompanied by loss of mitochondrial membrane potential (Δψm), cytochrome c release from mitochondria into cytosol, and activation of caspase-3. Hypoxia also significantly increased Bax and decreased Bcl-2 mRNA and protein expression, thereby increasing Bax/Bcl-2 ratio. Nicorandil 100 μmol/l significantly decreased the percentage of apoptotic myocytes (7.2 ± 0.5%) by inhibiting loss of Δψm and translocation of cytochrome c. These effects of nicorandil were partially but significantly inhibited by cotreatment of either 500 μmol/l 5-hydroxydecanoate, a selective mitoKATP channel antagonist, or 10 μmol/l 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Moreover, nicorandil significantly inhibited the hypoxia-induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria. These effects of nicorandil in Bax and Bcl-2 expression were significantly blunted by cotreatment of ODQ and 5-HD, respectively. Cotreatment of KT5823, an inhibitor of protein kinase G, significantly blocked the effect of nicorandil on Bax expression and 8-bromo-cyclic guanosine 3′,5′ monophosphate (8-bromo-cGMP), a cGMP analog, mimicked the effect of nicorandil on Bax expression. The present study demonstrates that nicorandil regulates Bcl-2 family proteins via opening of mitoKATP channels and nitric oxide-cGMP signaling and inhibits hypoxia-induced mitochondrial death pathway.

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