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 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.
Wada
Koh-ichi
K
Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. wada@yamanouchi.co.jp
Fujimori
Akira
A
Matsukawa
Utane
U
Arai
Yukinori
Y
Sudoh
Katsumi
K
Yatsu
Takeyuki
T
Sasamata
Masao
M
Miyata
Keiji
K
D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001552:Benzazepines; C106389:conivaptan