Urodilatin [ANP-95-126] is a new natriuretic peptide of renal origin not subjected to tolerance in experimental congestive heart failure (CHF). To evaluate its therepeutic potentials in CHF, we investigated the efficacy of a prolonged infusion of urodilatin (15 ng/kg/min for 10 hours) in 12 patients with CHF (New York Heart Association functional classes II and III) in a randomized, double-blind, placebo-controlled study. Urodilatin elevated plasma cyclic guanosine monophosphate (cGMP) concentrations and increased urinary cGMP excretion. Systolic blood pressure (121 ± 9 mm Hg to 111 ± 7 mm Hg) and central venous pressure (7.4 ± 3.3 mm Hg to 5.2 ± 3.4 mm Hg) decreased significantly, and diastolic blood pressure and heart rate remained unchanged. Urine flow (0.7 ± 0.6 ml/min to 1.5 ± .6 ml/min) and urinary sodium excretion (48 ± 16 μmol/min to 180 ± 87 μmol/min) were significantly increased. Plasma norepinephrine, renin, aldosterone, and vasopressin were unaltered. the substance was well tolerated. Thus prolonged infusion of urodilatin lowers preload and increases diuresis sna natriuresis without neurohomoral activation or adverse side effects, demonstrating a profile of effects that may be beneficial in patients with CHF.