Cardioprotective effects of 17 beta-estradiol produced by activation of mitochondrial ATP-sensitive K+ channels in canine hearts

Mic have previously demonstrated the effects of estrogen on modulation of m yocardial ATP-sensitive K+ (K-ATP) channel, previous studies have demonstra ted that activation of mitochondrial K-An channel is a major contributor of ischemic cardioprotection. The purpose of the present study was to investi gate the role of K-ATP channel in estrogen-induced myocardial protection af ter ischemia/reperfusion in dogs. Anaesthetized dogs were subjected to 60 m in of left anterior descending coronary artery occlusion followed by 2 h of reperfusion. In a fil st study to characterize effects of sex and the dose -response profile of estrogen on infarct size, the drug was intravenously a dministered at 10 or 20 mu g/kg. In a second study to investigate the cardi oprotective mechanisms of estrogen, vehicle, preconditioning or 17 beta-est radiol (10 mu g/kg) was given, beginning 15 min prior to the 60 min occlusi on period in the presence or absence of 5-hydroxydecanoate (5-HD), In the f irst study, administration of 17 beta-estradiol resulted in a significant, dose-dependent limitation of infarct size. Estrogen administration provided myocardial protection of similar magnitude in both males and females. In t he second study, infarct size in control animals averaged 39 +/- 5% of the risk region, compared with 14+/-5% of the risk region in estrogen-treated d ogs and 6 +/- 5% of the risk region in preconditioning dogs (both P<0.0001 v controls). Pretreatment with 5-HD completely abolished preconditioning- a nd estrogen-induced cardioprotrection. Estrogen limits myocardial infarctio n size resulting from coronary artery occlusion and reperfusion in a dose-d ependent fashion, irrespective of gender difference, The infarct size-limit ing effect of estroge was abolished by 5-HD, suggesting that the cardioprot ective effect of estrogen mag result from activation of myocardial mitochon drial K-ATP channels. (C) 2000 Academic Press.