title: Differential effects of sarcolemmal and mitochondrial K(ATP) channels activated by 17 beta-estradiol on reperfusion arrhythmias and infarct sizes in canine hearts.
abstract: 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.
authors.affiliation: Department of Surgery, Cardiology Section, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan. tmlee@ha.mc.ntu.edu.tw
authors.forename: Chang-Her
authors.initials: CH
authors.lastname: Tsai
authors.forename: Sheng-Fang
authors.initials: SF
authors.lastname: Su
authors.forename: Tsai-Fwu
authors.initials: TF
authors.lastname: Chou
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
mesh_terms: D000208:Acute Disease; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology* / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D015221:Potassium Channels; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D001549:Benzamides; D003652:Decanoic Acids; D004965:Estrogen Antagonists; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000077267:Fulvestrant; D004958:Estradiol; C052853:5-hydroxydecanoic acid; C410297:HMR 1098