title: Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats.
abstract: Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a -AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30-minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice-daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose-dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a -AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a -AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta.
  
  
  CONCLUSIONS
  FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a -AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis.
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.|Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernández-Varo
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Denise
authors.initials: D
authors.lastname: Oró
authors.affiliation: Ferring Research Institute Inc., San Diego, CA.
authors.forename: Edward Earl
authors.initials: EE
authors.lastname: Cable
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Reichenbach
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvajal
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Bernardino González
authors.initials: BG
authors.lastname: de la Presa
authors.affiliation: Ferring Research Institute Inc., San Diego, CA.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wiśniewski
authors.affiliation: Liver Unit, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Ginés
authors.affiliation: Ferring Research Institute Inc., San Diego, CA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Harris
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.|Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain.
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D001201:Ascites / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000819:agonists*; D012964:Sodium / Q000378:metabolism*
chemical_list: D017483:Receptors, Vasopressin; D012964:Sodium