Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure

We investigated the effects of intravenously administered conivaptan hydrochloride, a dual vasopressin V-1A and V-2 receptor antagonist, on cardiac function in rats with congestive heart failure following myocardial infarction. and compared results with those for the selective vasopressin V-2 receptor antagonist SR121463A. Rats were subjected to left coronary artery occlusion to induce myocardial infarction.,which in turn led to congestive heart failure. At 4 weeks after coronary occlusion. conivaptan (0.03, 0.1 and 0.3 mg/kg i.v.) dose-dependently increased urine volume and reduced urine osmolality in both myocardial infarction and sham-operated rats. SR121463A (0.3 mg/kg i.v.) also increased urine volume and decreased urine osmolality in myocardial infarction rats, to a degree comparable to that by conivaptan (0.3 mg/kg i.v.). At 6 weeks after surgery, myocardial infarction rats showed increases in right ventricular systolic pressure, right atria] pressure, left ventricular end-diastolic pressure and relative weights of the heart and the lungs, and a decrease in first derivative of left ventricular pressure (dP/d/(max))/left ventricular pressure, showing that congestive heart failure was well established. Conivaptan (0.3 mg/kg i.v.) significantly reduced fight ventricular systolic pressure, left ventricular end-diastolic pressure, lung/body weight and fight atrial pressure in myocardial infarction rats. Moreover, conivaptan (0.3 mg/kg i.v.) significantly increased dP/d/(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and fight atrial pressure, and tended to decrease fight ventricular systolic pressure and relative lung weight in myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR1214163A were similar to those of conivaptan, SR121463A failed to improve dP/d/(max)/left ventricular pressure. These results suggest that dual vasopressin V-1A and V-2 receptor antagonists provide greater benefit than selective vasopressin V-2, receptor antagonists in the treatment of congestive heart failure. (C) 2004 Elsevier B.V. All rights reserved.