SK-AND-F-105494 - A POTENT ANTIDIURETIC-HORMONE ANTAGONIST DEVOID OF PARTIAL AGONIST ACTIVITY IN DOGS

  • 1 December 1988
    • journal article
    • research article
    • Vol. 247  (3) , 897-901
Abstract
Previous studies from our laboratory have shown that in vivo cyclooxygenase blockade in dogs unmasks the antidiuretic agonist activity associated with the vasopressin antagonist, SK and F 101926, and have revealed two new vasopressin analogs, SK and F 104146 and 105494, with greatly reduced antidiuretic agonist activity. The purpose of the present study was to characterize SK and F 104146 and SK and F 105494 for water diuretic activity (aquaretic activity) in hydropenic dogs and for fantagonism of vasopressin-stimulated antidiuresis in hydrated dogs. The vasopressin receptor affinity and inhibition of vasopressin-stimulated adenylate cyclase activity in renal membranes were also studied. When administered to hydropenic dogs, SK and F 101926 (3 or 30 .mu.g/kg) did not cause a water diuresis. Substitution of the dipeptide tial of SK and F 101926 with Arg7D-Arg8NH2 (SK and F 104146; 30 .mu.g/kg) was associated with a reduction of urine osmolality from 1876 .+-. 182 to 349 .+-. 94 mOsm/kg of H2O, and an increase in free water clearance (from -0.32 .+-. 0.09 to 0.06 .+-. 0.09 ml/min). Replacement of the 1 to 6 disulfide bridge of SK and F 104146 with at 1 to 6 dicarba bridge (SK and F 105494; 3 .mu.g/kg) was associated with a further reduction of urine osmolality (1709 .+-. 281 to 210 .+-. 79 mOsm/kg of H2O) and a net positive free water clearance (from -0.56 .+-. 0.02 to 0.6 .+-. 0.35 ml/min). In water diuretic dogs, SK and F 104146 and 105494 shifted the vasopressin dose-response for antidiuresis to the right. SK and F 105494 appeared to be 3 times more potent than SK and F 104146. In in vitro studies in dog renal plasma membranes, SK and F 105494, 104146 and 101926 were potent antagonists of vasopressin stimulation of adenylate cyclase and devoid of detectable agonist activity (up to 10-6 M). We conclude that, in dogs, SK and F 105494 is the most potent aquaretic agent identified to date and lacks detectable antidiuretic agonist activity.

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