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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-017-0501-1) contains supplementary material, which is available to authorized users.

Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study

“…As expected, tolvaptan increased renal water excretion during baseline conditions. This result is in accordance with our previous RCT in healthy subjects [ 15 , 16 ]. Both studies proved increased renal water excretion following tolvaptan administration.…”

“…Several studies have shown that tolvaptan’s diuretic action is caused by preventing AVP to bind to the V2 receptors, and thus to activate AQP2 by the second messenger cAMP. In the present study, we measured a similar level of u-AQP2 after placebo and tolvaptan, which is in agreement with our previous studies [ 15 , 16 ]. This response could be explained by the 3-fold increase in p-AVP after tolvaptan.…”

“…In our single-dose study, tolvaptan 15 mg promoted renal water excretion [ 15 ]. In the dose-response study, tolvaptan antagonized the antidiuretic action of L-NMMA, in part via an AVP-dependent mechanism consistent with the present study [ 16 ]. This apparent discrepancy could be explained by a difference in the administration time of the study drug, since tolvaptan was given at 6:00 AM in the single-dose study compared with 8:00 AM in the dose-response study and the present study.…”

“…No increase was measured in the components in the renin-angiotensin-aldosterone system, which could have been expected after mild dehydration, but the very large increase in p-AVP seemed to have been a sufficient vasoconstrictor response during tolvaptan treatment. In our previous RCTs with tolvaptan, we did not measure a decrease in 51 Cr-EDTA clearance [ 15 , 16 ]. However, in these trials, we studied healthy control subjects, and the dosis of tolvaptan used was 15–45 mg in contrast to a dosis of 60 mg in the present study.…”

“…NO is synthesized from L-arginine, a NO synthase-catalyzed process competitively inhibited by L-NMMA [ 13 ]. Previous clinical studies conducted by our laboratory demonstrated that NO promoted natriuresis and diuresis in healthy subject [ 15 , 16 ]. Although these results support that NO is involved in the V2R response in the tubular function, it is unknown whether the response is similar in ADPKD patients.…”