These studies will focus on defining th nature of the cellular electrophysiological abnormalities of ischemic myocardium which causes arrhythmias after coronary occlusion in dogs. Because ischemic subepicardial myocardial cells have been shown to be critical links in the formation of reentrant ventricular arrhythmias after ligation of the left anterior descending coronary artery, epicardial preparations including ischemic and normal myocardium will be isolated in vitro. Conduction, refractoriness, and automaticity of ischemic cells will be assessed by means of multiple intracellular and extracellular recordings and program stimulation. The ionic mechanisms for maintenance of resting potential and for excitation will be evaluated by the determination of intracellular activities of sodium and potassium, the manipulation of the ionic composition of the superfusate, and the use of blockers of fast and slow current. The effects of pharmacologic agents, autonomic mediators, and metabolic factors will be noted in order to clarify the mechanism of action of antiarrhythmic agents, evaluate the role of the autonomic nervous system in ischemic arrhythmias, and to explore metabolic means to alter ischemic electrophysiologic abnormalities. In addition, chronically ischemic tissues will be studied in animal models with multiple coronary occlusions with or without aneurysms with a view toward uncovering the nature and location of the cellular electrophysiological arrangements that generate arrhythmias chronically. The overridding objective of these studies is the development of understanding and rational therapy of lethal arrhythmias in ischemic heart disease in man.