We investigated the effects of intravenously administered
conivaptan hydrochloride, a dual
vasopressin V1A and
V2 receptor antagonist, on cardiac function in rats with
congestive heart failure following
myocardial infarction, and compared results with those for the selective
vasopressin V2 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 atrial 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/dt(max))/left ventricular pressure, showing that
congestive heart failure was well established.
Conivaptan (0.3 mg/kg i.v.) significantly reduced right ventricular systolic pressure, left ventricular end-diastolic pressure, lung/
body weight and right atrial pressure in
myocardial infarction rats. Moreover,
conivaptan (0.3 mg/kg i.v.) significantly increased dP/dt(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and right atrial pressure, and tended to decrease right ventricular systolic pressure and relative lung weight in
myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR121463A were similar to those of
conivaptan, SR121463A failed to improve dP/dt(max)/left ventricular pressure. These results suggest that dual
vasopressin V1A and
V2 receptor antagonists provide greater benefit than selective
vasopressin V2 receptor antagonists in the treatment of
congestive heart failure.