hmr-1098 and Acute-Disease

We have demonstrated the effects of estrogen on modulation of ATP-sensitive K(+) channels; however, the subcellular location of these channels is unknown. The purpose of the present study was to investigate the role of the sarcolemmal and mitochondrial ATP-sensitive K(+) channels in a canine model of myocardial infarction after stimulation with 17 beta-estradiol. Anesthetized dogs were subjected to 60 min of the left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Infarct size was markedly reduced in estradiol-treated dogs compared with controls (14 +/- 6 versus 42 +/- 6%, P < 0.0001), indicating the effective dose of estradiol administrated. Pretreatment with the mitochondrial ATP-sensitive K(+) channel antagonist 5-hydroxydecanoate completely abolished estradiol-induced cardioprotection. The sarcolemmal ATP-sensitive K(+) channel antagonist 1-15-12-(5-chloro-o-anisamido)ethyl-methoxyphenyl)sulfonyl-3-methylthiourea (HMR 1098) did not significantly attenuate estradiol-induced infarct size limitation. In addition, estradiol administration significantly reduced the incidence and duration of reperfusion-induced ventricular tachycardia and ventricular fibrillation. Although 5-hydroxydecanoate alone caused no significant effect on the incidence of reperfusion arrhythmias in the presence or absence of estradiol, the administration of HMR 1098 abolished estrogen-induced improvement of reperfusion arrhythmias. Pretreatment with the estrogen-receptor antagonist faslodex (ICI 182,780) did not alter estrogen-induced infarct-limiting and antiarrhythmic effects. These results demonstrate that estrogen is cardioprotective against infarct sizes and fatal reperfusion arrhythmias by different ATP-sensitive K(+) channels for an estrogen receptor-independent mechanism. The infarct size-limiting and antiarrhythmic effects of estrogen were abolished by 5-hydroxydecanoate and HMR 1098, suggesting that the effects may result from activation of the mitochondrial and sarcolemmal ATP-sensitive K(+) channels, respectively.

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Decanoic Acids; Dogs; Electrocardiography; Estradiol; Estrogen Antagonists; Fulvestrant; Hydroxy Acids; Male; Membrane Proteins; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Potassium Channels; Sarcolemma; Ventricular Function, Left