Chronic blockade of vasopressin receptors in rats

Chronic i.v. administration of a competitive antagonist of arginine-vasopressin (AVP), d(CH2)5-D-Tyr(Et)-VAVP, in Sprague-Dawley rats induced only a transient diabetes insipidus (DI)-like state. Water excretion and intake were markedly increased on the first day of administration but subsequently reverted to normal. A similar response to the antagonist was observed upon continuous i.v. infusion in Brattleboro rats, homozygous for hereditary hypothalamic DI, which had been substituted with exogenous AVP. This excludes the possibility that increased secretion of endogenous AVP had overcome the blocking effect of the competitive antagonist in Sprague-Dawley rats. However, when AVP was withdrawn from chronically AVP-treated DI rats, water intake increased to values higher than those observed after the antagonist. Subsequently, water intake also decreased but remained elevated compared to that of AVP-substituted rats receiving the antagonist. This suggests that the antagonist might have AVP-like agonistic properties that limit its efficacy and allow compensatory mechanisms to restore normal water balance despite continuous blockade of AVP receptors. The agonistic properties of d(CH2)5-D-Tyr(Et)VAVP were verified upon chronic i.v. administration in nonpretreated DI rats. Thus, the normalization of water balance in Sprague-Dawley rats chronically receiving d(CH2)5-D-Tyr(Et)VAVP is probably due to the activation of compensatory mechanisms and to the agonistic effects of d(CH2)5-D-Tyr(Et)VAVP.