Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction.
Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V(1A) and V(2) receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V(1A) receptors and plays a major role in retaining free water through vasopressin V(2) receptors in this model of congestive heart failure. Additionally, conivaptan, with its dual vasopressin V(1A) and V(2) receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Koh-ichi
K
Wada
Atsuo
A
Tahara
Yukinori
Y
Arai
Motonori
M
Aoki
Yuichi
Y
Tomura
Junko
J
Tsukada
Takeyuki
T
Yatsu
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014667:Vasopressins / Q000097:blood
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C106389:conivaptan; D014667:Vasopressins