Renal effects of specific antagonists of arginine vasopressin in dogs.

Abstract

ABSTRACT-To investigate the effects on renal hemodynamics of specific antagonists of arginine vasopressin (AVP), CGP 29325 (d(CH2)5-D-Tyr(Et)VAVP), which has both anti-vasopressor and anti-antidiuretic activities against AVP, and CGP 25838E (d(CH2)5-Tyr(Me)AVP), which has only anti-vasopressor activity, were administered to normally hydrated anesthetized dogs, and the effects on renal function were examined. The pressor response and constriction of renal and mesenteric arteries induced by AVP were dose-dependently blocked by intravenous CGP 25838E. Following intrarenal arterial administration (i.r.a.) of CGP 29325 at 3,ug/min, water diuresis occurred and urine osmolality (Uosm) decreased to less than 250 mOsm/kg. Renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNaV) remained unchanged. A higher dose (10,ug/min, i.r.a.) of CGP 29325 further decreased Uosm to about 110 mOsm/kg. Although arterial blood pressure (BP), GFR and UNaV remained unchanged, RBF decreased from the control value 3.7 ± 0.35 to 2.4 ± 0.40 ml/g•min. CGP 25838E (10,ug/min, i.r.a.) had no effect on renal hemodynamics and urine formation. When administered into the mesenteric artery, CGP 25838E (10,ug/min) increased mesenteric blood flow (MBF) from 199 ± 34 to 240 ± 40 ml/min without any alteration in blood pressure. We tentatively conclude that CGP 29325, at a lower dose, exerted anti-antidiuretic effects through a specific inhibition of V2 receptors, while the higher dose of CGP 29325 altered RBF, through yet to be determined mechanisms. The vasoconstrictive activity of AVP may contribute to the regulation of mesenteric circulation, but not to renal hemodynamics, in anesthetized dogs. pressor activity, while the latter mediates antidiuretic activity. In in vitro experiments, a V2 antagonist has been shown to specifically inhibit the AVP-dependent adenylate cyclase of human and animal kidneys in a competitive manner (4). A V1 receptor antagonist inhibits AVP induced smooth muscle contraction of the rat uterus (2). Antagonists which have an in vitro high specificity for V1 and/or V2 receptors may be effective agents for treating