EFFECT OF DRUGS ON DEVELOPMENT OF CARDIAC FAILURE

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The mechanisms by which hypertension leads to adverse cardiac effects, including heart failure and other serious diseases, are unclear. The long-term objectives of this proposal are to identify and explain the electrophysiologic changes which occur in pressure-overloaded myocardium during chronic hypertension and resulting cardiac hypertrophy and congestive heart failure, and to distinguish the mechanisms of action of new and old drugs which limit the progression and severity of these diseases. Areas of interest will encompass gradually-developing left or right ventricular overload. Four projects are proposed concerning these areas as follows: 1) to establish a model of gradually-developing chronic pressure overload of the left ventricle via systemic hypertension in the cat, and to determine the magnitude of left ventricular hypertrophy, the incidence of heart failure, and the alterations in myocardial cellular electrophysiology brought about by the overload; 2) to produce gradually-developing right ventricular hypertension in the cat in order to distinguish ionic currents, contractile properties and drug responsiveness of hypertrophied and failed myocardium; 3) to monitor Ca++ fluxes across the sarcolemma and to evaluate Ca++ channel function and Ca++i activity in the pressure-overloaded heart; and 4) to characterize arrhythmogenic activity and assess pharmacologic responsiveness during coronary ligation-induced acute myocardial ischemia superimposed on preexisting disease, i.e., "predisposing" chronic hypertension. The methodology includes production of renovascular hypertension and gradual pulmonary artery coarctation; intracellular microelectrode, patch and voltage clamp procedures; isometric contraction and K+ contracture measurements; pharmacologic intervention; isolation and characterization of single cardiac myocytes, 45Ca++ flux measurements and Ca++ selective microelectrodes. Each of these techniques will help identify cellular mechanisms by which hypertension leads to or predisposes the heart for more serious disease, and mechanisms whereby drugs ameliorate or influence aberrant electrical and contractile behavior in the myocardium.