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1 Department of Laboratory Medicine, Oita medical university, Oita, Japan
2 Department of Pharmacology, Chiba University Graduate School of Medicine, Tiba, Japan
* To whom correspondence should be addressed. E-mail: yonemo{at}oita-med.ac.jp.
Although mitochondrial ATP-sensitive potassium (mitoKATP) channels have been reported to reduce the extent of apoptosis, the critical timing of mitoKATP channel opening required to protect myocytes against apoptosis remains unclear. In the present study, we examined whether the mitoKATP channel serves as a trigger of cardioprotection against apoptosis induced by oxidative stress. Apoptosis of cultured neonatal rat cardiomyocytes was determined by flow cytometry (light scatter and propidium iodide/annexin V-FITC fluorescence) and by nuclear staining with Hoechst 33342. Mitochondrial membrane potential (
) was measured by flow cytometry of cells stained with rhodamine-123 (Rh-123). Exposure to H2O2 (500 µM) induced apoptosis and the percentage of apoptotic cells increased progressively and peaked at 2 hours.This H2O2-induced apoptosis was associated with the loss of , and the time-course of decrease in Rh-123 fluorescence paralleled that of apoptosis. Pretreatment of cardiomyocytes with diazoxide (100 µM), a putative mitoKATP channel opener, for 30 min prior to exposure to H2O2 elicited the transient and mild depolarization of , and consequently suppressed both apoptosis and loss after 2 hours exposure to H2O2. These protective effects of diazoxide were abrogated by the mitoKATP channel blocker 5-hydroxydecanoate (500 µM), but not by the sarcolemmal KATP channel blocker HMR 1098 (30 µM). Our results suggest for the first time that diazoxide-induced opening of mitoKATP channels triggers cardioprotection against apoptosis induced by oxidative stress in rat cardiomyocytes.
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