Biologic response to chronic blockade of vasopressin receptors in Sprague-Dawley rats

The renal tubular arginine vasopressin receptor antagonist, d-(CH2)5-D-Tyr(Et)VAVP, is a potent inhibitor of the vasopressin-induced stimulation of adenylate cyclase in rat renal medullary homogenates in vitro. In acute experiments in vivo, this antagonist increased urine volume and decreased urine osmolality after i.v. or s.c. administration in normally hydrated or dehydrated Sprague-Dawley rats. It did not show any effects in water-loaded rats. The duration of action of the antagonist was between 3 to 4 hr. Chronic i.v. infusion or repeated s.c. injections did not result in a persistent diabetes insipidus. A transient rise in water excretion was followed by a progressive normalization. The marked initial water loss was fully compensated for by an increased water intake so that plasma volume and extracellular fluid volume remained unchanged. After 1 week of treatment with the antagonist, glomerular filtration rate and plasma renin activity were not significantly different from base-line values. Only small functional deficits in renal concentrating capacity became manifest when drinking water was withheld. It is possible that the activation of endogenous compensatory mechanisms restored water balance during chronic arginine vasopressin receptor blockade. An intrinsic agonism of this antagonist, which was not detectable in acute experiments, might have contributed to the normalization of water balance by limiting the maximum anti-antidiuretic effects of renal tubular arginine vasopressin receptor blockade.