Perucca Julie, Bichet Daniel G, Bardoux Pascale, Bouby Nadine, Bankir Lise
INSERM U 872, Université Paris Descartes, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France.
J Am Soc Nephrol. 2008 Sep;19(9):1721-31. doi: 10.1681/ASN.2008010021. Epub 2008 Jul 2.
The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However,for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 mug/kg but increased it at doses >5 umg/kg,an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma,renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.
精氨酸加压素（AVP）分别通过激活V2和V1a受体发挥其抗利尿和升压作用的机制已得到较好理解，但对钠代谢可能产生的相关影响仍存在争议。在本研究中，对正常清醒的Wistar大鼠急性给予不同剂量的AVP、去氨加压素（V2激动剂）、呋塞米或以下选择性非肽类受体拮抗剂SR121463A（V2拮抗剂）或SR49059（V1a拮抗剂）。将接下来6小时的尿流率和钠排泄率与前一天给予赋形剂处理后获得的基础值进行比较，以每只大鼠自身作为对照。钠排泄率随V2激动作用而降低，随V2拮抗作用呈剂量依赖性增加。然而，对于尿流率的可比增加，V2拮抗剂诱导的利钠作用比呋塞米小7倍。加压素在1μg/kg时降低钠排泄，但在剂量>5μg/kg时增加钠排泄，V1a拮抗剂可消除该作用。内源性加压素的V2和V1a联合作用预计会因血浆、肾髓质（作用于间质细胞）和尿液（作用于V1a管腔受体）中加压素各自的水平而有很大差异。在通常的调节范围内，加压素的抗利尿作用可能与不同程度的钠潴留有关。尽管V2拮抗剂主要是利水的，但其对钠排泄的可能影响不应被忽视。鉴于它们在几种人类疾病中的应用前景，选择性（V2）或混合（V1a/V2）受体拮抗剂对人类钠代谢的各自影响需要重新评估。
