Al Therwani Safa, Rosenbæk Jeppe Bakkestrøm, Mose Frank Holden, Bech Jesper Nørgaard, Pedersen Erling Bjerregaard
University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
BMC Nephrol. 2017 Mar 13;18(1):86. doi: 10.1186/s12882-017-0501-1.
Tolvaptan is a selective vasopressin receptor antagonist. Nitric Oxide (NO) promotes renal water and sodium excretion, but the effect is unknown in the nephron's principal cells. In a dose-response study, we measured the effect of tolvaptan on renal handling of water and sodium and systemic hemodynamics, during baseline and NO-inhibition with L-NMMA (L-NG-monomethyl-arginine).
In a randomized, placebo-controlled, double blind, cross over study, 15 healthy subjects received tolvaptan 15, 30 and 45 mg or placebo. L-NMMA was given as a bolus followed by continuous infusion during 60 min. We measured urine output (UO), free water clearance (C), fractional excretion of sodium (FE), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP).
During baseline, FE was unchanged. Tolvaptan decreased u-ENaC dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and C decreased dose-dependently. FE decreased dose-independently and u-ENaC remained unchanged. Central BP increased equally after all treatments.
During baseline, fractional excretion of sodium was unchanged. During tolvaptan with NO-inhibition, renal water excretion was reduced dose dependently, and renal sodium excretion was reduced unrelated to the dose, partly via an AVP dependent mechanism. Thus, tolvaptan antagonized the reduction in renal water and sodium excretion during NO-inhibition. Most likely, the lack of decrease in AQP2 excretion by tolvaptan could be attributed to a counteracting effect of the high level of p-AVP.
Clinical Trial no: NCT02078973 . Registered 1 March 2014.
托伐普坦是一种选择性血管加压素受体拮抗剂。一氧化氮（NO）可促进肾脏水和钠的排泄，但在肾单位主细胞中的作用尚不清楚。在一项剂量反应研究中，我们测量了在基线状态以及用L-NMMA（L-NG-单甲基精氨酸）抑制NO期间，托伐普坦对肾脏水和钠处理及全身血流动力学的影响。
在一项随机、安慰剂对照、双盲、交叉研究中，15名健康受试者接受15、30和45毫克托伐普坦或安慰剂。给予L-NMMA推注，随后在60分钟内持续输注。我们测量了尿量（UO）、自由水清除率（C）、钠排泄分数（FE）、尿水通道蛋白-2通道（u-AQP2）和上皮钠通道（u-ENaCγ）、血浆血管加压素（p-AVP）和中心血压（cBP）。
在基线状态下，FE未发生变化。托伐普坦剂量依赖性地降低u-ENaC并使p-AVP增加三倍，而u-AQP2未发生变化。在用L-NMMA抑制NO的情况下给予托伐普坦时，UO和C剂量依赖性降低。FE与剂量无关地降低，u-ENaC保持不变。所有治疗后中心血压均同等升高。
在基线状态下，钠排泄分数未发生变化。在用L-NMMA抑制NO的情况下给予托伐普坦时，肾脏水排泄呈剂量依赖性减少，肾脏钠排泄减少与剂量无关，部分通过AVP依赖性机制。因此，托伐普坦拮抗了在抑制NO期间肾脏水和钠排泄的减少。很可能，托伐普坦未能使AQP2排泄减少可归因于高水平p-AVP的抵消作用。
临床试验编号：NCT0207897 . 于2014年3月1日注册。
