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

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 B₂ receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro7-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-Pro⁷-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-Pro⁷-Ang-(1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways.