N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA, receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure. An increase in cardiac index and decline in systemic vascular resistance was observed with each dose, and these hemodynamic effects persisted for 3 to 6 hr. Small transient increments in right atrial and pulmonary capillary wedge pressures occurred 0.5 hr after ingestion of 200 and 300 mg of ibopamine, but these pressures returned to baseline or lower levels within 30 min. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of epinine peaked 0.5 hr after administration of drug and then declined to minimal levels at 3 hr. Ten patients enrolled in a trial to evaluate the efficacy of long-term therapy with ibopamine; after 8 weeks of treatment, the initial hemodynamic responses to the drug were attenuated and no significant improvement in oxygen uptake at peak exercise was observed. A decline in plasma norepinephrine concentrations, which could be attributed to activation of a2-adrenoceptors and/or DA2 receptors on sympathetic nerves, was observed after initial administration of ibopamine and persisted after long-term drug ingestion; no long-term hemodynamic benefit could be ascribed to the reduction in sympathetic activity. Circulation 73, No. 4, 740-748, 1986. THE ADMINISTRATION of dopamine to patients with congestive heart failure may effect an improvement in the performance of the impaired myocardium, and thus an oral formulation of this drug would be desirable. 2 The beneficial actions of dopamine in patients with heart failure have been attributed not only to a positive inotropic effect that is mediated by activation of the 8,1-adrenoceptor, but also to its agonist activity at the dopamine vascular (DA1) receptor.3 Activation of the DA1 receptor in the renal vascular bed appears primarily responsible for the marked natriuresis produced by this drug. N-Methyldopamine (epinine) is one of the few modifications of the dopamine molecule that retains full agonist activity at the DA1 receptor.4 Ibopamine is the diisobutyric ester of epinine, and after ingestion, it is hydrolyzed by plasma esterases to yield epinine.5 Initial studies have demonstrated beneficial short-term hemodynamic responses to ibopamine in patients with heart failure.-9 This investigation was undertaken to evaluate the hemodynamic actions and bioavailability of ibopamine after short-and long-term administration to patients with chronic congestive heart failure, and to assess the role of the sympathetic nervous system in modulating the hemodynamic responses to the drug.

No abstract

Clinical trials in patients with dilated cardiomyopathy (DCM) have shown a wide disparity in the hemodynamic responses to positive inotropic therapy. In addition, the response of the failing left ventricle to positive inotropic agents reflects the net interaction of multiple factors, including the magnitude of contractile abnormality and compensatory mechanisms. In the current study, left ventricular geometry, loading conditions, and contractile state were assessed in 13 patients with nonischemic DCM with the use of simultaneous high-fidelity pressure measurements and echocardiographic recordings. Comparisons were made with echocardiographic and calibrated carotid pulse data acquired in nine age-matched normal subjects. The patients with DCM were divided according to the left ventricular end-diastolic wall thickness-to-dimension ratio into groups with "appropriate" hypertrophy (i.e., < 2 SDs from mean normal; n = 5; group 1) and "inadequate" hypertrophy (i.e

Among the positive inotropic drugs available to improve myocardial contractility in congestive heart failure, only digitalis glycosides are suitable for oral administration. In this study, we administered oral levodopa (1.5 to 2.0 g), which is decarboxylated to form dopamine, to 10 patients with severe congestive heart failure. Peak hemodynamic responses occurred one hour after the ingestion of levodopa, with the mean (+/- S.E.M.) cardiac index increasing from 1.8 +/- 0.1 to 2.4 +/- 0.2 liters per minute per square meter of body-surface area (P less than 0.01) and systemic vascular resistance declining from 1905 +/- 112 to 1513 +/- 121 dyn X sec X cm-5 (P less than 0.01). These effects persisted for four to six hours. Left ventricular filling pressure, heart rate, and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose to a peak level of 34 +/- 5 ng per milliliter one hour after drug ingestion and decreased toward base line over the ensuing five hours. A significant correlation was observed between plasma dopamine levels and changes in cardiac index (r = 0.8; P less than 0.02). Five patients enrolled in a trial to evaluate the effectiveness of long-term therapy with levodopa had similar hemodynamic responses to the drug after 6.8 +/- 1.7 months of treatment. Thus, oral administration of levodopa to patients with severe heart failure produced a sustained improvement in cardiac function. The hemodynamic responses observed can be attributed to the activation of beta 1-adrenergic, dopamine, and dopamine receptors by dopamine derived from levodopa.

No abstract