Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects

Abstract

Background: 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).

Methods: 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_H2O), fractional excretion of sodium (FE_Na), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP).

Results: During baseline, FE_Na was unchanged. Tolvaptan decreased u-ENaC_γ dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and C_H2O decreased dose-dependently. FE_Na decreased dose-independently and u-ENaC_γ remained unchanged. Central BP increased equally after all treatments.

Conclusions: 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.

Trial registration: Clinical Trial no: NCT02078973 . Registered 1 March 2014.

Keywords: AQP2; Blood pressure; ENaC; Nitric oxide; Tolvaptan; Vasoactive hormones.

Fig. 1

Effect of tolvaptan 15, 30 and 45 mg at baseline, during and after NO-inhibition on GFR (⁵¹ Cr-EDTA-clearance) (a), UO (b), C_H2O (c) and u-AQP2 (d). Data are presented as mean ± SEM. General linear model (GLM) with repeated measures was performed for comparison within and between groups. One-way ANOVA (*) was used to test differences between tolvaptan 15, 30 and 45 mg vs placebo. Paired t-test (α/β/γ) was used for comparison of infusion period (90–150 min) vs baseline period (0–90 min) and post infusion period (150–210 min) vs baseline period.† p<; 0.05; †† p < 0.001; */††† p < 0.0001. Paired t-test was used for comparison between the three tolvaptan doses at baseline period (0–90 min), L-NMMA infusion period (90–150 min) and post infusion period (150–210 min); the significance levels are listed under the result section

Fig. 2

Effect of tolvaptan 15, 30 and 45 mg at baseline, during and after NO-inhibition on FE_Na (e) and u-ENaCγ (f). Data are presented as mean ± SEM. General linear model (GLM) with repeated measures was performed for comparison within and between groups. One-way ANOVA (*) was used to test differences between tolvaptan 15, 30 and 45 mg vs placebo. Paired t-test (α/β/γ) was used for comparison of infusion period (90–150 min) vs baseline period (0–90 min) and post infusion period (150–210 min) vs baseline period. † p<; 0.05; †† p < 0.001; */††† p < 0.0001. Paired t-test was used for comparison between the three tolvaptan doses at baseline period (0–90 min), L-NMMA infusion period (90–150 min) and post infusion period (150–210 min); the significance levels are listed under the result section

Fig. 3

Effect of tolvaptan 15, 30 and 45 mg on p-AVP at baseline, during and after NO-inhibition. Data are depicted as mean ± SEM. Friedman test was used for comparison between treatment groups prior to L-NMMA infusion, at the end of L-NMMA infusion and 1 h after the end of L-NMMA infusion