title: Vascular, hemodynamic and renal effects of low-dose losartan in rats with secondary biliary cirrhosis.
abstract: BACKGROUND
  In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to alpha1-adrenoceptor agonists. Recently, the angiotensin II type 1-receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to alpha1-adrenoceptor agonists.
  
  
  METHODS
  We studied, in rats with secondary biliary cirrhosis and sham-operated rats, the effect of 0.5 and 10 mg losartan/kg x day on aortic responsiveness to alpha1-adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function.
  
  
  RESULTS
  In cirrhotic rats, 10 mg losartan/kg x day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg x day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis.
  
  
  CONCLUSIONS
  In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to alpha1-adrenoceptor agonists.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany. jheller@uni-bonn.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Heller
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.forename: Thomas
authors.initials: T
authors.lastname: Shiozawa
authors.forename: Michael
authors.initials: M
authors.lastname: Schepke
authors.forename: Markus
authors.initials: M
authors.lastname: Neef
authors.forename: Martin
authors.initials: M
authors.lastname: Hennenberg
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000502:physiology; D008102:Liver Circulation / Q000187:drug effects*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D018340:Receptors, Adrenergic, alpha-1; D008729:Methoxamine; D019808:Losartan; D009638:Norepinephrine