Although all peripheral vasodilator drugs produce acute improvement in cardiac performance in patients with severe chronic heart failure, the hemodynamic and clinical responses to long-term therapy vary greatly. Present evidence suggests that these varied effects are the result of interpatient differences in the magnitude of vasodilation achieved acutely and in the extent to which these vasodilator responses are sustained. Unfortunately, the mechanisms by which vasodilator drugs mediate their acute and chronic effects have not been examined. Cyclic nucleotides and prostaglandins appear to play important roles in the actions of these drugs in vitro and in patients with coronary artery disease or hypertension, but the significance of these vosoactive intermediates in the responses in patients with heart failure remain unknown. In a series of hemadynamic investigations in patients with heart failure undergoing right heart catheterization, we will determine the changes in plasma and urinary levels of cyclic nucleotides and prostaglandins produced by nitroglycerin and captopril and will correlate these changes with the observed hemodynamic effects of these drugs. We will determine which prostaglandins (PG1-2 or PGE-2) are most important and from what sources they are derived (i.e., renal or vascular). By repeating the humoral and hemodynamic studies during sustained nitrate or captopril therapy, we will determine whether the acute changes in prostaglandins and cyclic nucleotides persist during long-term treatment. We will determine whether the acute and chronic hemodynamic and humoral effects of these vasodilators can be attenuated by drugs that inhibit prostaglandin synthesis (i.e., indomethacin and aspirin). We will correlate pretreatment measurements of vasoactive substances with the acute and long-term hemodynamic effects of therapy. We will induce tolerance to nitroglycerin and determine whether this tolerance is the result of a reduction in active sulfhydryl groups (by administration of N-acetylcysteine, a sulfhydryl donor), due to a reduced ability to generate vasoactive intermediates or due to the opposition of direct vasodilator effects by enhanced activity of the sympathetic nervous and renin-angiotensin systems. We will examine treatment modifications (i.e., low-dose or intermittent therapy) to determine whether the pathophysiologic factors underlying the development of tolerance can be altered. By elucidating the means by which the vasodilator responses are mediated, we may be able to explain some of the heterogeneity observed in the hemodynamic and clinical effects of therapy and may be able to select those patients most likely to respond to a specific drug. We will also be able to clarify those mechanisms underlying the development of tolerance to vasodilator therapy in an effort to prevent it occurrence and/or to reverse its development once it is observed.
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