PROTECTION FROM CARDIAC REPERFUSION INJURY BY ETHANOL

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APPLICANT'S ABSTRACT: Moderate ethanol use is associated with protection against fatal coronary events. However, in addition to a decreased incidence of coronary events, improved recovery following an event may be important in ethanol's prevention of fatal outcomes due to coronary artery disease. Attenuation of post-ischemic reperfusion injury is a mechanism by which myocardial recovery, and thereby survival, may be improved following a coronary event. Pilot studies suggest that moderate ethanol use attenuates reperfusion injury through activation of adenosine receptors in guinea pig hearts. Hypotheses I and II will be tested addressing questions #1-5: I. Moderate ethanol use protects against myocardial post-ischemic reperfusion injury. 1. Does moderate ethanol use improve functional and metabolic recovery during reperfusion? 2. Following post-ischemic reperfusion, does moderate ethanol use decrease the amount of myocyte necrosis in perfused hearts and infarct size in vivo? 3. Does moderate ethanol use protect against Ca2+ overload during post-ischemic reperfusion? II. The protective effect of moderate ethanol use against reperfusion injury is the result of adenosine receptor mediated protein kinase C translocation. 4. Is ethanol's protective effect abolished by adenosine A1, A2, and/or A3 receptor antagonists? 5. Are delta and epsilon PKC translocated in myocytes from ethanol exposed hearts versus controls? Isolated guinea pig hearts (fed 10% ethanol for 6 weeks) will undergo ischemia - reperfusion. Energy depletion and recovery will be assessed with 31P-MRS; myocyte necrosis by creatine kinase release; cytosolic CA2+ by indo-1 fluorescence; and PKC isozyme translocation by immunofluorescence localization and western blot analysis. In vivo, infarct size will be measured after occlusion-reperfusion of the left coronary artery. The ultimate goals of this research are 1) to establish the mechanisms underlying the positive association between moderate alcohol use and cardiac health and 2) aid in the development of therapeutic interventions which mimic this effect in patients at risk for fatal coronary events who require elective or emergent reperfusion.