Vasopressin's role as a vasoconstrictor in chronic heart failure, was examined in rabbits with adriamycin cardiomyopathic congestive heart failure. Chronic adriamycin treatment resulted in a decrease in cardiac output (829 +/- 38-610 +/- 36 ml/min, P less than 0.005) and blood pressure (83 +/- 2-76 +/- 3 mmHg, P less than 0.01), and an increase in peripheral resistance (8,377 +/- 381-10,170 +/- 657 dyn-s-cm-5, P less than 0.05). Plasma renin activity (4.7 +/- 0.6-10.9 +/- 2.8 ng angiotensin I/ml X h) and norepinephrine (0.7 +/- 0.1-1.3 +/- 0.2 pmol/ml, P less than 0.05) increased while plasma vasopressin levels did not change. Vasopressin infusion, however, produced significantly greater increases in peripheral resistance in animals with heart failure than in controls. Moreover, a specific vasopressin vascular antagonist reduced blood pressure (7 +/- 3%) and peripheral resistance (14 +/- 4%) and increased cardiac output (10 +/- 3%) in animals with heart failure but had no cardiovascular effects in normal rabbits. These results suggest that vascular sensitivity to vasopressin is increased in heart failure, and that it contributes significantly to the increased afterload in heart failure despite normal plasma levels. In this model of severe, chronic heart failure the sympathetic, renin-angiotensin, and vasopressin systems all appear to be activated.