DETERMINANTS OF VASODILATOR RESPONSE IN HEART FAILURE

When heart failure develops following an insult to the myocardium, a number of neurohormonal mechanisms are activated in an attempt to preserve circulatory homeostasis. Previous work has characterized the nature of these reactions, but little work has been done to determine how these mechanisms interact in specific target organs or how tissue agonist sensitivity may be altered in response to prolonged neurohormonal activation. The goal of this research proposal is (1) to determine if abnormalities of the beta- receptor/adenylate cyclase complex modulate neuro-hormonal responsiveness in heart failure, and thus may explain the pharmacologic resistance to inotropic drugs seen in these patients; and (2) to elucidate whether neurohormonal activation may modify the response to exogenous and endogenous vasodilators in heart failure, and thus may contribute to the development of tolerance to nitroglycerin and resistance to atrial natriuretic peptide. In a series of hemodynamic investigations in patients with heart failure undergoing right heart catheterization, tolerance will be induced to intravenous nitroglycerin to determine if its occurrence is the result of sulfhydryl depletion in vascular smooth muscle (by use of the sulfhydryl donors, N-acetylcysteine and methionine) or due to neurohormonal activation (by monitoring circulating neurohormones and attenuating their effects by the use of the neurohormonal antagonist, captopril). Abnormalities of the receptor-cyclase complex in circulating lymphocytes will be characterized (with particular emphasis on the guanine nucleotide binding proteins) and correlated with the responsiveness of patients of cyclic A MP-dependent inotropic drugs (dobutamine, glucagon and amrinone). Serial measurements of the receptor- cyclase complex will be made to determine if its components may change in response to prolonged neurohormonal stimulation, produced either by a sustained infusion of dobutamine or as a result of progression of the underlying disease. These serial measurements will be used to determine if changes in receptor-cyclase complex can predict survival in heart failure and if its prognostic utility compares favorably with conventional hemodynamic and hormonal variables. To determine the importance of neurohormonal activation in limiting the effects of atrial natriuretic peptide, the natriuretic effects of an infusion of the peptide will be assessed before and after the administration of indomethacin and captopril. By elucidating the biochemical and physiologic mechanisms by which the circulation reacts and adapts to pharmacologic interventions in chronic heart failure, this proposal should help to explain the heterogenous effects of treatment in these patients and should assist in the development of specific strategies designed to enhance the efficacy of a variety of therapeutic agents.