title: Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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).
  
  
  RESULTS
  During baseline, FENawas unchanged. Tolvaptan decreased u-ENaCγdose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and CH2Odecreased dose-dependently. FENadecreased dose-independently and u-ENaCγremained unchanged. Central BP increased equally after all treatments.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Clinical Trial no: NCT02078973 . Registered 1 March 2014.
authors.affiliation: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark. safatherwani@hotmail.com.
authors.forename: Safa
authors.initials: S
authors.lastname: Al Therwani
authors.affiliation: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
authors.forename: Jeppe Bakkestrøm
authors.initials: JB
authors.lastname: Rosenbæk
authors.affiliation: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
authors.forename: Frank Holden
authors.initials: FH
authors.lastname: Mose
authors.affiliation: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
authors.forename: Jesper Nørgaard
authors.initials: JN
authors.lastname: Bech
authors.affiliation: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
authors.forename: Erling Bjerregaard
authors.initials: EB
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001834:Body Water / Q000378:metabolism*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D015990:Placebo Effect; D012964:Sodium / Q000652:urine*; D000077602:Tolvaptan; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D001552:Benzazepines; D000077602:Tolvaptan; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D012964:Sodium
keywords: AQP2; Blood pressure; ENaC; Nitric oxide; Tolvaptan; Vasoactive hormones