Pouzet B, Serradeil-Le Gal C, Bouby N, Maffrand J P, Le Fur G, Bankir L
INSERM Unité 367, 17 Rue du Fer à Moulin, Paris, France.
Nephrol Dial Transplant. 2001 Apr;16(4):725-34. doi: 10.1093/ndt/16.4.725.
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.
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.
(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.
在先前的一项研究中，我们观察到急性给予血管加压素（AVP）V2受体选择性拮抗剂SR 121463A（SR）会加重纯合布拉特洛维大鼠（一种AVP缺乏品系）的尿崩症（DI）症状。本研究更详细地调查了SR对DI大鼠的急性和慢性影响。
在实验A中，不同组的大鼠接受急性腹腔注射SR（0.001 - 10 mg/kg）或单独给予溶剂，随后收集24小时尿液。SR剂量依赖性地增加尿流率并降低尿渗透压，而溶质排泄无显著变化，从而证实了纯粹的“水利尿”作用。在实验B和C中，评估了口服SR对布拉特洛维DI大鼠（实验B，1 mg/kg/天）和成年具有正常AVP分泌的斯普拉格 - 道利大鼠（实验C，3 mg/kg/天）的8天慢性影响。在DI大鼠中，SR的水利尿作用在8天内以相同强度持续存在。在斯普拉格 - 道利大鼠中，SR诱导了持续、稳定的水利尿作用，并且还增加了非肾性水分丢失，表明AVP对肾外部位的水分保留有影响。由于DI大鼠中催产素（OT）合成增加且已知OT可与V2受体结合，我们在实验D中评估了OT对DI大鼠的抗利尿作用。慢性输注OT（3 μg/kg/h，腹腔注射）诱导了显著的抗利尿作用，而在接受OT治疗的DI大鼠中急性给予SR（1 mg/kg）完全消除了这种抗利尿作用，从而表明这是由于OT与V2受体结合所致。
（i）SR是一种有效的口服活性水利尿剂，在有或无内源性AVP分泌的大鼠中，1周内均可诱导稳定作用。（ii）在布拉特洛维DI大鼠的集合管中发生了显著的V2受体介导的水重吸收，因为它们通常的尿渗透压比SR诱导最大利尿时观察到的最小值高约两倍。（iii）这种V2激动作用可能部分由OT与V2受体结合介导。已知DI大鼠的肾上腺和睾丸会产生少量内源性AVP，这也可能导致这种V2激动作用，以及V2受体可能的组成性激活。（iv）在正常大鼠中，AVP可能通过肾外部位（可能是肺）减少水分丢失。
