Molecular mechanisms of novel antidiuretic antagonists: analysis of the effects on vasopressin binding and adenylate cyclase activation in animal and human kidney

Abstract

These studies describe the molecular mechanisms of a potential new class of diuretic agents, vasopressin antagonists. The inhibition of the antidiuretic response to antidiuretic hormone (ADH) by the novel vasopressin analogs d(CH2)5Tyr(Me)VAVP, d(CH2)5Tyr(Et)VAVP, d(CH2)5Tyr(Et)VDAVP and d(CH2)5D-TyrVAVP was studied using medullary membranes of pig kidney. These analogs were competitive inhibitors of vasopressin binding and adenylate cyclase activation by vasopressin with potencies that were 5- to 7-fold higher than those of d(CH2)5VDAVP (Kbind was 6.7 x 10(-7) M; Ki was 2.3 x 10(-7) M), an analog with no in vivo anti-ADH activity. The antagonists were judged selective for vasopressin receptors because the activation of renal adenylate cyclase by beta adrenergic agonists and prostaglandins E1, E2 and I2 was not affected by d(CH2)5D-TyrVAVP. Furthermore, blockade of the vasopressin receptors with this analog did not impair the other components of the adenylate cyclase system since basal enzyme activity and activity stimulated by guanyl-5'-yl imidodiphosphate and NaF were not diminished. In addition, d(CH2)5D-TyrVAVP was a potent inhibitor of vasopressin activation of adenylate cyclase in pig, rat and dog kidney, and also in human kidney (Ki was 1.9 x 10(-8) M). The possibility that these or similar agents could be useful therapeutic agents in man as novel diuretics must now be considered.