Selective blockade of vasopressin V2 receptors reveals significant V2-mediated water reabsorption in Brattleboro rats with diabetes insipidus.
BACKGROUND
In a previous study we observed that acute administration of the selective antagonist of vasopressin (AVP) V2 receptors, SR 121463A (SR), aggravated the symptoms of diabetes insipidus (DI) in homozygous Brattleboro rats (an AVP-deficient strain). The present study investigates in more details the acute and chronic effects of SR in DI rats.


RESULTS
In experiment A, different groups of rats received acute i.p. injections of SR (0.001-10 mg/kg) or vehicle alone, and urine was collected for the next 24 h. SR dose-dependently increased urine flow rate and decreased urine osmolality with no significant change in solute excretion, thus confirming a pure 'aquaretic' effect. In experiments B and C, the chronic effects of orally administered SR were evaluated over 8 days in Brattleboro DI rats (experiment B, 1 mg/kg/day) and in adult Sprague-Dawley rats with normal AVP secretion (experiment C, 3 mg/kg/day). In DI rats, the aquaretic effects of SR persisted with the same intensity over the 8 days. In Sprague-Dawley rats, SR induced a sustained, stable aquaretic effect and also increased non-renal water losses, suggesting an effect of AVP on water conservation in extrarenal sites. Because oxytocin (OT) synthesis is elevated in DI rats and OT is known to bind to V2 receptors, we evaluated the antidiuretic effects of OT in DI rats in experiment D. Chronic infusion of OT (3 microg/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 indicating that it was due to binding of OT to V2 receptors.


CONCLUSIONS
(i) SR is a potent orally active aquaretic and induces stable effects during 1 week in rats with or without endogenous AVP secretion. (ii) Significant V2 receptor-mediated water reabsorption occurs in collecting ducts of Brattleboro DI rats because their usual urine osmolality is about twofold higher than the minimum observed during SR-induced maximum diuresis. (iii) This V2 agonism could be mediated in part by OT binding to V2 receptors. Small amounts of endogenous AVP, known to be produced by adrenal and testis in DI rats, could also contribute to this V2 agonism, as well as a possible constitutive activation of the V2 receptors. (iv) In normal rats, AVP probably reduces water losses through extrarenal sites, probably the lungs.
Pouzet
B
B
INSERM Unité 367, 17 Rue du Fer à Moulin, Paris, France.
Serradeil-Le Gal
C
C
Bouby
N
N
Maffrand
J P
JP
Le Fur
G
G
Bankir
L
L
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003919:Diabetes Insipidus / Q000652:urine*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D013141:Spiro Compounds / Q000494:pharmacology*; D014667:Vasopressins / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D009025:Morpholines; D013141:Spiro Compounds; D014867:Water; D014667:Vasopressins; C103281:satavaptan