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.

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 However, when AVP was withdrawn from chronically AVP-treated DI rats, water intake increased to values higher than those observed after the antagonist.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.

Contribution of vascular and tubular effects of arginine-vasopressin to the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats.

The role of arginine-vasopressin (AVP) in the pathogenesis of deoxycorticosterone acetate (DOCA) salt hypertension in rats was studied with AVP receptor antagonists for its tubular (V2) and/or vascular (V1) actions. When chronic (six weeks) infusion of the antagonists was started concomitantly with DOCA-salt treatment the development of hypertension was attenuated by the V1-antagonist and prevented by the V1V2-antagonist. However, the V1V2-antagonist induced severe and persistent hypernatraemia in all rats. When chronic (two weeks) infusion of the antagonists was started in rats with established hypertension after five weeks of DOCA-salt treatment blood pressure was not influenced by the V1-antagonist. The rats which received the V1V2-antagonist died from hypernatraemia within four days. These results suggest that in DOCA-salt treated rats AVP is essential for the prevention of severe and life-threatening hypernatraemia. AVP appears to contribute significantly to the development of this form of hypertension through both its vascular and tubular effects.