Angiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide-mediated pathway in cirrhotic rat liver

Am J Physiol Gastrointest Liver Physiol. 2013 Jan 1;304(1):G99-108. doi: 10.1152/ajpgi.00163.2012. Epub 2012 Oct 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Angiotensin II / pharmacology*
  • Animals
  • Blood Pressure / drug effects*
  • Blotting, Western
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology*
  • In Situ Hybridization
  • Liver / metabolism
  • Liver / pathology
  • Liver Circulation / drug effects*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / physiopathology*
  • Male
  • Methoxamine / antagonists & inhibitors*
  • Methoxamine / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase Type III / metabolism*
  • Peptide Fragments / pharmacology*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / drug effects
  • Receptor, Angiotensin, Type 2 / drug effects
  • Receptor, Bradykinin B2 / drug effects
  • Vasoconstrictor Agents / antagonists & inhibitors*
  • Vasoconstrictor Agents / pharmacology


  • Peptide Fragments
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptor, Bradykinin B2
  • Vasoconstrictor Agents
  • Angiotensin II
  • Nitric Oxide
  • Angiotensin I
  • Nitric Oxide Synthase Type III
  • Methoxamine
  • angiotensin I (1-7)