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Open Access 01-12-2017 | Research article

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

Authors: Safa Al Therwani, Jeppe Bakkestrøm Rosenbæk, Frank Holden Mose, Jesper Nørgaard Bech, Erling Bjerregaard Pedersen

Published in: BMC Nephrology | Issue 1/2017

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.

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Title: Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects
Authors: Safa Al Therwani
Jeppe Bakkestrøm Rosenbæk
Frank Holden Mose
Jesper Nørgaard Bech
Erling Bjerregaard Pedersen
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Nephrology / Issue 1/2017
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-017-0501-1

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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

Methods

Results

Conclusions

Trial registration

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Abstract

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Conclusions

Trial registration

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