title: Hemodynamic Effects of the Non-Peptidic Angiotensin-(1-7) Agonist AVE0991 in Liver Cirrhosis.
abstract: OBJECTIVE
  Although in cirrhosis with portal hypertension levels of the vasoconstrictor angiotensin II are increased, this is accompanied by increased production of angiotensin (Ang)-(1-7), the endogenous ligand of the Mas receptor (MasR), which blunts hepatic fibrosis and decreases hepatic vascular resistance. Therefore, we investigated the effects of the non-peptidic Ang-(1-7) agonist, AVE0991, in experimental cirrhosis.
  
  
  METHODS
  Cirrhosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) intoxication. The coloured microsphere technique assessed portal and systemic hemodynamic effects of AVE0991 in vivo. Hepatic expression of eNOS, p-eNOS, iNOS, JAK2, ROCK and p-Moesin were analyzed by western blots. Activities of ACE and ACE2 were investigated fluorometrically. Moreover, fibrosis was assessed in BDL rats receiving AVE0991.
  
  
  RESULTS
  In vivo, AVE0991 decreased portal pressure (PP) in both rat models of cirrhosis. Importantly, systemic effects were not observed. The hepatic effects of AVE0991 were based on upregulation of vasodilating pathways involving p-eNOS and iNOS, as well as by downregulation of the vasoconstrictive pathways (ROCK, p-Moesin). Short-term treatment with AVE0991 decreased the activity of ACE2, long-term treatment did not affect hepatic fibrosis in BDL rats.
  
  
  CONCLUSIONS
  The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure. Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Josephine
authors.initials: J
authors.lastname: Grace
authors.affiliation: Department of Obstetrics, Centre for Perinatal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Haltenhof
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Uschner
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Department of Obstetrics, Centre for Perinatal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany; Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.affiliation: Department of Gastronenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000503:physiopathology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects*; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: C469726:AVE 0991; D007093:Imidazoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D007703:Peptidyl-Dipeptidase A