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

BackgroundTolvaptan 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).MethodsNineteen 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).ResultsDuring 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.ConclusionDuring 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.

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

“…Surprisingly, u-AQP2 did not change after oral administration of tolvaptan, not even in response to the highest dose of tolvaptan. We measured a similar response in our previous study of tolvaptan 15 mg [12]. Most likely, this could be explained by the measured 3-fold increase in plasma AVP.…”

“…The present study is a continuation and expansion of a previous randomized, double-blinded, placebo-controlled crossover, single-dose study conducted by our laboratory [12]. …”

“…PRC was determined by immunoradiometric assay as previously described [12]. Aldo was determined by RIA as previously described [12].…”

“…Central BP, PWA and carotid-femoral PWV were measured using applanation tonometry (SphygmoCor® CPV system®, AtCor Medical, Sydney, Australia) as previously described [12]. …”

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

“…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.…”