Aquaretic and hormonal effects of a vasopressin V2 receptor antagonist after acute and long-term treatment in rats

A single oral administration of 1-[4-( N-tert-butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethoxy)cyclohexane]indol-2-one SR121463 (0.3-3 mg/kg), a vasopressin non-peptide V-2 receptor antagonist, to rats induced dose-dependent aquaresis which was accompanied by Na+, K+, aldosterone and arginine vasopressin excretion over 6 h after dosing. However, no solute excretion was observed over 24 h. As a result of aquaresis, hemoconcentration and increases in plasma angiotensin II and adenocorticotrophin hormone were seen with 3 mg/kg at 2 h after dosing. Chronic treatment with SR121463 (3 mg/kg/day x 28 days) induced a marked aquaresis associated with aldosterone and vasopressin excretion. After a week of treatment, urine volume and aldosterone excretion were reduced (similar to 40%) and then stabilised, while urine vasopressin excretion remained almost constant throughout the study. There were no changes in arterial pressure, plasma osmolality, plasma sodium concentration, or in number and affinity of liver vasopressin V-1A and kidney V-2 receptors 24 h after the last treatment. These results indicate that SR121463 is a potent aquaretic agent and might he useful for the chronic management of water-retaining diseases in humans. (C) 2000 Elsevier Science B.V. All rights reserved.