Effect of vasopressin antagonism on renal handling of sodium and water and central and brachial blood pressure during inhibition of the nitric oxide system in healthy subjects

Abstract

Background: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic hemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA).

Methods: Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a bolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP).

Results: During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was unchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after placebo (-54 vs.-42% and -34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaCγ decreased after placebo and increased after tolvaptan. CBP and bBP were unchanged.

Conclusion: During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more pronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal cells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained by a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests that NO interferes with the transport via ENaC by an AVP-dependent mechanism.

Figure 1

Relative changes in GFR (A), C_H2O(B), UO (C) and u-AQP₂(D) during NO-inhibition. Values are mean ± SEM. General linear model (GLM) with repeated measurements was performed for comparison within the group (δ) and interventions as between (∆) subject factor. Paired t-test or Wilcoxon signed rank test (#) was performed for comparison within treatment group at baseline vs during infusion period 90–150 min, and baseline vs post infusion 150–210 min. #/∆ p < 0.05; δδδ p < 0.0001.

Figure 2

Relative changes in FE_Na(E) and u-ENaCγ (F) during inhibition of the NO system. Values are mean ± SEM. General linear model (GLM) with repeated measurements was performed for comparison within the group (δ) and interventions as between (∆) subject factor. Paired t-test or Wilcoxon signed rank test (#) was performed for comparison within treatment group at baseline vs during infusion period 90–150 min, and baseline vs post infusion 150–210 min. # p < 0.05; ## p < 0.001.

Figure 3

Effect of tolvaptan on bBP during inhibition of the NO system. Values are mean ± SEM. Baseline brachial blood pressure (bBP) was defined as a mean of the four measurements 30 min prior to L-NMMA infusion. A stable bBP was achieved for the last 40 min of L-NMMA infusion. A mean of the six measurements from last 40 minutes of L-NMMA infusion was used to calculate changes from baseline. Post-hoc Bonferoni test was used for comparison of the mean of the last 40 min of infusion vs. baseline (p = 0.011 in placebo vs p < 0.0001 in tolvaptan). Paired t-test was performed for comparison of the last 40 min of infusion vs. baseline between treatment groups.