Antagonism of antidiuretic hormone in domestic pigs (Sus scrofa).
1. Morphological and physiological aspects of renal function are shared by humans and swine. SK&F 101926 is a potent antagonist of vasopressin binding to V2 receptors and vasopressin stimulation of adenylate cyclase activity in renomedullary membranes from both species. 2. Unexpectedly, SK&F 101926 proved to be an antidiuretic agonist in humans. Hence, we evaluated SK&F 101926 for antidiuretic agonist and antagonist activities in conscious domestic pigs. 3. During water diuresis (Uosm < 230 mOsm/kg H2O), administration of SK&F 101926 (100 micrograms/kg, i.v.) produced a maximal Uosm of 192 +/- 18 mOsm/kg H2O, a concentration not significantly different from that in vehicle-treated pigs. 4. In hydropenia, SK&F 101926 produced a modest decrease in Uosm, from 945 to 629 mOsm/kg H2O (P < 0.05). 5. In in vitro studies subsequently performed using renomedullary tissue from the same pigs, SK&F 101926 displayed high affinity for V2 receptors (Kbind = 11.8 nM) and high potency to inhibit vasopressin-stimulation of adenylate cyclase (Ki = 3.9 nM). 6. No activity of SK&F 101926 to stimulate adenylate cyclase activity was detected. 7. We conclude that, in spite of its activity in in vitro assays, SK&F 101926 is a weak antidiuretic antagonist in domestic pigs. 8. These results underscore the limited utility of assessments of vasopressin receptor binding and vasopressin-stimulated adenylate cyclase activities in vitro to predict functional antidiuretic activities in vivo.
Monaghan
M L
ML
University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Kennett Square, PA 19348.
Divers
T
T
Huffman
W F
WF
Kinter
L B
LB
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004327:Drinking Behavior / Q000187:drug effects; D004573:Electrolytes / Q000097:blood; D005260:Female; D066298:In Vitro Techniques; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008236:Lypressin / Q000494:pharmacology; D009994:Osmolar Concentration; D013552:Swine; D014667:Vasopressins / Q000037:antagonists & inhibitors* / Q000097:blood
D004573:Electrolytes; D014667:Vasopressins; D001127:Arginine Vasopressin; D008236:Lypressin; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin; D000262:Adenylyl Cyclases