Cyclooxygenase inhibition unmasks the full antidiuretic agonist activity of the vasopressin antagonist, SK&F 101926, in dogs.

The vasopressin (AVP) antagonist, SK&F 101926 (beta-mercapto-beta beta-cyclopentamethylene propionic acid1, D-Tyr(Et)2, Phe3, Val4, Asn5, Cys6, Pro7, Arg8-NH2), is an antidiuretic antagonist in rats and squirrel monkeys in vivo. In rat, dog, pig, squirrel monkey and human in vitro studies, SK&F 101926 is an AVP antagonist with no discernable agonist activity. Not predicted by these studies was the discovery that SK&F 101926 is an antidiuretic agonist in humans. The purpose of these studies was to show that indomethacin, which potentiates the antidiuretic activity of AVP in hydrated dogs, also potentiates the antidiuretic agonist activity of SK&F 101926, and to determine what structural modifications of this AVP antagonist would confer diminished agonist activity. Treatment of dogs with i.v. indomethacin (2 mg/kg bolus + 3 mg/kg/hr infusion, a dose which inhibited 80-90% of the urinary prostaglandin E2 excretion) unmasked the full antidiuretic activity of SK&F 101926. SK&F 104146 (Arg7-D-Arg8-NH2 peptide tail modification of SK&F 101926) in the presence of indomethacin caused a partial antidiuretic response. Replacement of the 1 to 6 disulfide bridge of SK&F 104146 with methylene groups to form a "dicarba bridge" resulted in SK&F 105494, a compound lacking antidiuretic agonist activity. Using the indomethacin-treated dog model, we have unmasked the full antidiuretic agonist activity of SK&F 101926 in nonhumans. In addition, both SK&F 104146 and 105494 blocked the antidiuretic agonist activity of SK&F 101926, suggesting that the agonist effect seen in the presence of indomethacin treatment is receptor mediated.