Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect.

摘要: The anti-anginal drug nicorandil has been shown to inhibit apoptosis by activating mitochondrial ATP-sensitive potassium (K(ATP)) channels. possible contribution of the nitrate moiety this its anti-apoptotic effect now investigated in neonatal rat ventricular myocytes subjected oxidative stress. Exposure cultured 100 micromol/l hydrogen peroxide (H(2)O(2)) increased number nuclei stained terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique as well induced internucleosomal DNA fragmentation, loss membrane potential, cytochrome c release into cytosol, and activation caspases-3 -9, all which are characteristics apoptosis. Pretreatment cells with (100 micromol/l) inhibited these effects H(2)O(2). Both K(ATP) channel antagonist 5-hydroxydecanoate (5-HD) 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor soluble guanylyl cyclase, attenuated concentration-dependent manners. Coapplication ODQ (10 5-HD (500 completely abolished nicorandil-induced cytoprotection. was also reduced cGMP-dependent protein kinase (KT5823, 1 micromol/l). nitric oxide donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 50 mimicked protective a manner sensitive but not 5-HD. A cell-permeable cGMP analog, 8-bromo-cGMP, H(2)O(2)-induced inhibition caspase-3, that caspase-9, presence or SNAP reversed addition dithiothreitol enzyme assay. Nicorandil inhibits stress-induced cardiac through oxide/cGMP-dependent mechanism