Abstract
BackgroundTolvaptan 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).MethodsIn 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).ResultsDuring 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.ConclusionsDuring 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 registrationClinical Trial no: NCT02078973. Registered 1 March 2014.
Highlights
Tolvaptan is a selective vasopressin receptor antagonist
We showed that Nitric Oxide (NO) promotes water excretion by a partly AVP dependent mechanism [12]
We demonstrated a clear effect of tolvaptan 15 mg at baseline and during tolvaptan with NO-inhibition on renal water excretion and the activity in ENaC, but no knowledge is available about the effect of different doses regarding interaction between tolvaptan and NO-inhibition
Summary
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 NOinhibition with L-NMMA (L-NG-monomethyl-arginine). Several studies have documented the effect of selective V2 receptor antagonism on renal sodium and water excretion, but whether NO is involved in the response of the V2 receptors in the renal tubular and vascular function is not clarified. Based on a most likely wide spread use of tolvaptan in the future, an in-depth knowledge is necessary regarding the effect of the tolvaptan on renal tubular function, vasoactive hormones and blood pressure. We demonstrated a clear effect of tolvaptan 15 mg at baseline and during tolvaptan with NO-inhibition on renal water excretion and the activity in ENaC, but no knowledge is available about the effect of different doses regarding interaction between tolvaptan and NO-inhibition
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
