title: Angiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide-mediated pathway in cirrhotic rat liver.
abstract: Recent studies have shown that, in cirrhosis, portal angiotensin-(1-7) [Ang-(1-7)] levels are increased and hepatic expression of angiotensin converting enzyme 2 (ACE2) and the Mas receptor are upregulated, but the effects of Ang-(1-7) on hepatic hemodynamics in cirrhosis have not been studied. This study investigated the effects of Ang-(1-7) on vasoconstrictor-induced perfusion pressure increases in cirrhotic rat livers. Ang II or the alpha 1 agonist methoxamine (MTX) were injected in the presence or absence of Ang-(1-7), and the perfusion pressure response was recorded. Denudation of vascular endothelial cells with sodium deoxycholate was used to investigate the contribution of endothelium to the effects of Ang-(1-7). Ang-(1-7) alone had no effect on perfusion pressure. However, it reduced the maximal vasoconstriction response and area under the pressure response curve to Ang II and MTX by >50% (P < 0.05). This effect of Ang-(1-7) was not blocked by Mas receptor inhibition with A779 or by Ang II type 1 and type 2 receptor and bradykinin B(2) receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro(7)-Ang-(1-7), a novel Ang-(1-7) receptor antagonist, completely abolished the vasodilatory effects of Ang-(1-7), as did inhibition of endothelial nitric oxide synthase (eNOS) with N(G)-nitro-L-arginine methyl-ester, guanylate cyclase blockade with ODQ and endothelium denudation. The functional inhibition by D-Pro(7)-Ang-(1-7) was accompanied by significant (P < 0.05) inhibition of eNOS phosphorylation. This study shows that Ang-(1-7) significantly inhibits intrahepatic vasoconstriction in response to key mediators of increased vascular and sinusoidal tone in cirrhosis via a receptor population present on the vascular endothelium that is sensitive to D-Pro(7)-Ang-(1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Victoria, Australia. cherath@unimelb.edu.au
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
authors.forename: Kai
authors.initials: K
authors.lastname: Mak
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008729:Methoxamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects; D043782:Receptor, Bradykinin B2 / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; D052250:Nitric Oxide Synthase Type III; D008729:Methoxamine; C118790:angiotensin I (1-7)