The administration of dopamine (DA) to patients with heart failure results in improved cardiac performance and a natriuresis. The efficacy of an oral formulation of DA in heart failure was evaluated by the principal investigator, who demonstrated that orally administered levodopa, which is decarboxylated endogenously to DA, produced an improvement in cardiac function. Thus, the overall goal of this proposal is to define the pharmacological actions of DA that influence cardiac performance and sodium excretion in heart failure and the role of these actions in determining the efficacy of sustained therapy with levodopa. The proposal consists of 4 protocols. In Prototol #1, the effect of long-term ingestion of levodopa on exercise tolerance in patients with heart failure will be evaluated. A randomized, double-blind, placebo-controlled design will be utilized and exercise capacity will be assessed by measuring oxygen uptake at the anaerobic threshold and maximum exercise. Protocol #2 will evaluate changes in left ventricular contractile state and afterload induced by DA generated from levodopa. Changes in the left ventricular endsystolic wall stress-velocity of fiber shortening (rate-corrected) relation will be monitored during long-term ingestion of levodopa. Desensitization of the beta1-adrenoceptor during chronic levodopa therapy will also be assessed by examining the positive inotropic response to a selective beta1-adrenoceptor agonist. Protocol #3 will determine whether oral levodopa ingestion will result in improved renal function in heart failure. Changes in renal plasma flow (p-aminohippurate clearance), glomerular filtration rate (inulin clearance), and urinary sodium excretion will be determined after the patients achieve metabolic balance. In Protocol #4, the neuroendocrine effects of levodopa that influence cardiac function and sodium excretion will be evaluated in heart failure. Activation of DA2 receptors will be monitored by measuring plasma norepinephrine levels, peripheral vascular resistance, and plasma prolactin levels. Also, the role of DA in modulating aldosterone secretion will be examined by measuring aldosterone levels after administration of metoclopramide and levodopa, while monitoring serum potassium, plasma adrenocorticotropic hormone (ACTH) concentration, and plasma renin activity. Plasma norepinephrine levels will be assayed by high performance liquid chromatography. Plasma renin activity and plasma prolactin, aldosterone, and ACTH levels will be measured by radioimmunoassay. Vascular resistance will be determined as the quotient of mean arterial pressure and limb blood flow (measured by plethysmography).
