Effect of cyclo‐oxygenase blockade on the renal actions of vasopressin and SK&F 105494 in the rhesus monkey

Abstract

1 Vasopressin administration to pentobarbitone-anaesthetized, hydrated female rhesus monkeys resulted in dose-dependent increases in urine osmolality and decreases in urine flow. Treatment with indomethacin at a dose (5 mg kg-1, i.v.) that reduced urinary prostaglandin E2 (PGE2) excretion by at least 70% did not alter these responses. 2 The vasopressin antagonist, SK&F 105494 (Pas" 6D-Tyr(Et)2Val4Arg7D-Arg8desGly9 arginine vasopressin; l0pgkg-1), caused significant rightward shifts (P < 0.05) of both the vasopressin-urine osmolality and the vasopressin-urine flow dose-response curves. Treatment with indomethacin did not alter these responses.3 SK&F 105494 alone or after indomethacin treatment had minimal effects on urine osmolality and urine flow. 4 The data indicate that indomethacin does not alter the antidiuretic activity of vasopressin in the rhesus monkey and that SK&F 105494 is a potent antagonist of exogenous vasopressin with minimal agonist activity.

Novel Design of Nonpeptide AVP V2Receptor Agonists: Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Template

“…Another subtype of the AVP receptor was found in the pituitary as a V 1b receptor that is involved in the corticotropic response to stress through regulation of ACTH secretion and the potentiating effect on the corticotropin-releasing hormone (CRH). Although many attempts to develop a V 2 antagonist for treating diseases characterized by excess renal reabsorption of free water have been reported, because V 2 antagonists may correct the fluid retention and hyponatremia observed in congestive heart failure, liver cirrhosis, and nephrotic syndrome, marked species differences and inconsistencies have been revealed between the in vivo and in vitro assay systems as reported in the case of 1 (Figure ) . This compound showed antagonist activity in an in vitro study and in animal models including the rhesus monkey but showed full antidiuretic response in humans.…”