Background: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We\nwanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic\nhemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine\n(L-NMMA).\nMethods: Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover\nstudy of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a\nbolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance\n(CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels\n(u-ENaC?), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP).\nResults: During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was\nunchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after\nplacebo (?54 vs.-42% and ?34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaC?\ndecreased after placebo and increased after tolvaptan. CBP and bBP were unchanged.\nConclusion: During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more\npronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal\ncells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained\nby a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests\nthat NO interferes with the transport via ENaC by an AVP-dependent mechanism.
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