title: Vascular hyporesponsiveness to angiotensin II in rats with CCl(4)-induced liver cirrhosis.
abstract: BACKGROUND
  Portal hypertension is triggered by vasodilation due to impaired contraction of extrahepatic vessels. Angiotensin II type 1 (AT(1)) receptor-induced vasocontraction is mediated by G proteins and may be desensitized by recruitment of beta-arrestin-2 to the receptor. In this study, we analysed the interaction of AT(1) receptors with beta-arrestin-2 in the context of vascular hypocontractility in rats with CCl(4)-induced cirrhosis.
  
  
  METHODS
  Micronodular liver cirrhosis in rats (n = 15) was induced by regular CCl(4) exposure. Age-matched rats (n = 15) served as controls. Contractility of aortic rings was measured by myography. Protein expressions and phosphorylations were assessed by Western blot analysis, and AT(1) receptor interaction with beta-arrestin-2 by co-immunoprecipitation.
  
  
  RESULTS
  Aortic rings from CCl(4) rats were hypocontractile to angiotensin II independent of nitric oxide synthases (Nomega-nitro-l-arginine methyl ester 200 microM). Expression of the AT(1) receptor, Galpha(q/11) and the contraction-mediating effector Rho kinase was similar in aortas from both groups. Expression and AT(1) receptor binding of beta-arrestin-2 were up-regulated in aortas from CCl(4) rats. Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats, but no further interaction of AT(1) receptors with beta-arrestin-2 was found in aortas from CCl(4) rats. While angiotensin II stimulation resulted in Rho kinase activation in aortas from noncirrhotic rats but not in aortas from CCl(4) rats, extracellular signal-regulated kinase activation in response to angiotensin II was observed in aortas from both groups.
  
  
  CONCLUSIONS
  Vascular hyporesponsiveness to angiotensin II in CCl(4) rats is due to enhanced interaction of the AT(1) receptor with beta-arrestin-2 and consecutively changed receptor function.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany. martin.hennenberg@med.uni-muenchen.de
authors.forename: M
authors.initials: M
authors.lastname: Hennenberg
authors.forename: J
authors.initials: J
authors.lastname: Trebicka
authors.forename: A Z
authors.initials: AZ
authors.lastname: Kohistani
authors.forename: J
authors.initials: J
authors.lastname: Heller
authors.forename: T
authors.initials: T
authors.lastname: Sauerbruch
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D006975:Hypertension, Portal / Q000378:metabolism* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D002251:Carbon Tetrachloride