The online version of this article (doi:10.1186/s12882-017-0501-1) contains supplementary material, which is available to authorized users.
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 (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP).
During baseline, FENa was unchanged. Tolvaptan decreased u-ENaCγ dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and CH2O decreased dose-dependently. FENa decreased dose-independently and u-ENaCγ 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.
Additional file 1: Table S1. Urine output, free water clearance (CH2O), urinary AQP2 excretion per minute (u-AQP2), urinary sodium excretion (u-Na) and urinary potassium excretion (u-K) during 24-h urine collection in a randomised, placebo-controlled, double-blind, crossover, dose-response study of 15 healthy subjects. Values are means with ± SD. One-way ANOVA was used for comparison between groups. (PDF 9 kb)12882_2017_501_MOESM1_ESM.pdf
Additional file 2: Table S2. Effect of tolvaptan 15, 30 and 45 mg at baseline, during and after NO-inhibition on plasma concentration of sodium and plasma osmolality in a randomized, placebo-controlled, double-blind, crossover, dose-response study of 15 healthy subjects. Data are presented as mean ± SD. General linear model (GLM) with repeated measurements 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 was performed for comparison of infusion period (90–150 min) vs baseline period (0–90 min), and post infusion period (150–210 min) vs baseline period. (PDF 84 kb)12882_2017_501_MOESM2_ESM.pdf
Additional file 3: Table S3. Effect of tolvaptan 15, 30 and 45 mg at baseline, during and after NO-inhibition on plasma concentrations of renin (PRC), angiotensin II (P-AngII) and aldosterone (P-aldo) in a randomized, placebo-controlled, double-blind, crossover, dose-response study of 15 healthy subjects. Data are presented as mean ± SD. General linear model (GLM) with repeated measures was performed for comparison within and between groups. Paired t-test was used for comparison between L-NMMA infusion period (at the end of L-NMMA infusion period) vs baseline (prior to L-NMMA infusion period) and at baseline vs post infusion period (1 h after L-NMMA infusion period) vs baseline period. One-way ANOVA was performed to test differences between treatment groups. (PDF 14 kb)12882_2017_501_MOESM3_ESM.pdf
Additional file 4: Table S4. Effect of tolvaptan 15, 30 and 45 mg at baseline, during and after NO-inhibition on brachial systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate in a randomized, placebo-controlled, double-blind, crossover, dose-response study of 15 healthy subjects. Data are presented as mean ± SD. General linear model (GLM) with repeated measures was performed for comparison within and between treatment groups. Paired t-test was used for comparison of infusion period (at the beginning of LNMMA infusion period/at the end of LNMMA infusion period) vs baseline (prior to LNMMA infusion period) and LNMMA infusion period vs post infusion period (30 min after the end of LMMMA infusion period/60 min after the end of LNMMA infusion period). * p < 0.05. One-way ANOVA was performed to test differences between treatment groups. (PDF 356 kb)12882_2017_501_MOESM4_ESM.pdf
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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
Safa Al Therwani
Jeppe Bakkestrøm Rosenbæk
Frank Holden Mose
Jesper Nørgaard Bech
Erling Bjerregaard Pedersen
- BioMed Central
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