title: 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: BACKGROUND
  Tolvaptan 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).
  
  
  METHODS
  Nineteen 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).
  
  
  RESULTS
  During 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.
  
  
  CONCLUSIONS
  During 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.
authors: University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital and Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500 Holstebro, Denmark. safatherwani@hotmail.com.
authors: Safa
authors: S
authors: Al Therwani
authors: Frank Holden
authors: FH
authors: Mose
authors: Janni Majgaard
authors: JM
authors: Jensen
authors: Jesper Nørgaard
authors: JN
authors: Bech
authors: Erling Bjerregaard
authors: EB
authors: Pedersen
mesh_terms: D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage*; D001552:Benzazepines / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001834:Body Water / Q000378:metabolism; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D015990:Placebo Effect; D012016:Reference Values; D012964:Sodium / Q000652:urine*; D000077602:Tolvaptan; D014667:Vasopressins / Q000378:metabolism*; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D014667:Vasopressins; D000077602:Tolvaptan; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D012964:Sodium