Antagonism of antidiuretic hormone in domestic pigs ( Sus scrofa)

Abstract

1. 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 V 2 receptors and vasopressin stimulation of adenylate cyclase activity in renomedullary membranes from both species. 2. 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. 3. During water diuresis (U osm < 230 mOsm/kg H 2O), administration of SK&F 101926 (100 μg/kg, i.v.) produced a maximal U osm of 192 ± 18 mOsm/kg H 2O, a concentration not significantly different from that in vehicle-treated pigs. 4. 4. In hydropenia, SK&F 101926 produced a modest decrease in U osm, from 945 to 629 mOsm/kg H 2O ( P < 0.05). 5. 5. In in vitro studies subsequently performed using renomedullary tissue from the same pigs, SK&F 101926 displayed high affinity for V 2 receptors ( K bind = 11.8 nM) and high potency to inhibit vasopressinstimulation of adenylate cyclase ( K i = 3.9 nM). 6. 6. No activity of SK&F 101926 to stimulate adenylate cyclase activity was detected. 7. 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. 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.