Selective blockade of vasopressin V-2 receptors reveals significant V-2-mediated water reabsorption in Brattleboro rats with diabetes insipidus

Background. In a previous study we observed that acute administration of th e selective antagonist of vasopressin (AVP) V-2 receptors, SR 121463A (SR), aggravated the symptoms of diabetes insipidus (DI) in homozygous Brattlebo ro rats (an AVP-deficient strain). The present study investigates in more d etails the acute and chronic effects of SR in DI rats. Methods and results. In experiment A, different groups of rats received acu te i.p. injections of SR (0.001-10 mg/kg) or vehicle alone, and urine was c ollected for the next 24 h. SR dose-dependently increased urine flow rate a nd decreased urine osmolality with no significant change in solute excretio n, thus confirming a pure 'aquaretic' effect. In experiments B and C, the c hronic effects of orally administered SR were evaluated over 8 days in Brat tleboro DI rats (experiment B, 1 mg/kg/day) and in adult Sprague-Dawley rat s with normal AVP secretion (experiment C, 3 mg/kg/day). In DI rats, the aq uaretic effects of SR persisted with the same intensity over the 8 days. In Sprague-Dawley rats, SR induced a sustained, stable aquaretic effect and a lso increased non-renal water losses, suggesting an effect of AVP on water conservation in extrarenal sites. Because oxytocin (OT) synthesis is elevat ed in DI rats and OT is known to bind to V-2 receptors, we evaluated the an tidiuretic effects of OT in DI rats in experiment D. Chronic infusion of OT (3 mug/kg/h, i.p.) induced a marked antidiuresis, and acute SR(1 mg:kg) in OT-treated DI rats completely abolished this antidiuretic effect, thus ind icating that it was due to binding of OT to V-2 receptors. Conclusion. (i) SR is a potent orally active aquaretic and induces stable e ffects during 1 week in rats with or without endogenous AVP secretion. (ii) Significant Vt receptor-mediated water reabsorption occurs in collecting d ucts of Brattleboro DI rats because their usual urine osmolality is about t wofold higher than the minimum observed during SR-induced maximum diuresis. (iii) This V-2 agonism could be mediated in part by OT binding to V-2 rece ptors. Small amounts of endogenous AVP, known to be produced by adrenal and testis in DI rats, could also contribute to this V-2 agonism, as well as a possible constitutive activation of the V-2 receptors. (iv) In normal rats , AVP probably reduces water losses through extrarenal sites, probably the lungs.