ANTAGONISM OF ANTIDIURETIC-HORMONE IN DOMESTIC PIGS (SUS-SCROFA)

1. Morphological and physiological aspects of renal function are share d by humans and swine. SK&F 101926 is a potent antagonist of vasopress in binding to V2 receptors and vasopressin stimulation of adenylate cy clase activity in renomedullary membranes from both species. 2. Unexpe ctedly, SK&F 101926 proved to be an antidiuretic agonist in humans. He nce, we evaluated SK&F 101926 for antidiuretic agonist and antagonist activities in conscious domestic pigs. 3. During water diuresis (U(osm ) < 230 mOsm/kg H2O), administration of SK&F 101926 (100 mug/kg, i.v.) produced a maximal U(osm) of 192 +/- 18 mOsm/kg H2O, a concentration not significantly different from that in vehicle-treated pigs. 4. In h ydropenia, SK&F 101926 produced a modest decrease in U(osm), from 945 to 629 mOsm/kg H2O (P < 0.05). 5. In in vitro studies subsequently per formed using renomedullary tissue from the same pigs, SK&F 101926 disp layed high affinity for V2 receptors (K(bind) = 11.8 nM) and high pote ncy to inhibit vasopressin-stimulation of adenylate cyclase (K(i) = 3. 9 nM). 6. No activity of SK&F 101926 to stimulate adenylate cyclase ac tivity was detected. 7. We conclude that, in spite of its activity in in vitro assays, SK&F 101926 is a weak antidiuretic antagonist in dome stic pigs. 8. These results underscore the limited utility of assessme nts of vasopressin receptor binding and vasopressin-stimulated adenyla te cyclase activities in vitro to predict functional antidiuretic acti vities in vivo.