title: The endothelium-dependent vasodilator effect of the nonpeptide Ang(1-7) mimic AVE 0991 is abolished in the aorta of mas-knockout mice.
abstract: Recently, we demonstrated that the endothelium-dependent vasodilator effect of angiotensin(1-7) in the mouse aorta is abolished by genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene. To circumvent the limitations posed by the possible metabolism of Ang(1-7) in this vessel, in this work we studied the mechanism underlying the vasorelaxant effect of AVE 0991, a nonpeptide mimic of the effects of Ang(1-7), using wild-type and Mas-deficient mice. Ang(1-7) and AVE 0991 induced an equipotent concentration-dependent vasodilator effect in aortic rings from wild-type mice that was dependent on the presence of endothelium. The vasodilator effect of Ang(1-7) and AVE 0991 was completely blocked by 2 specific Ang(1-7) receptor antagonists, A-779 and D-Pro-Ang(1-7), and by inhibition of NO synthase with L-NAME. Moreover, in aortic rings from Mas-deficient mice, the vasodilator effect of both Ang(1-7) and AVE 0991 was abolished. In contrast, the vasodilator effect of acetylcholine and substance P were preserved in Mas-null mice. In addition, the vasoconstriction effect induced by Ang II was slightly increased, and the vasodilation induced by the AT2 agonist CGP 42112A was not altered in Mas-deficient mice. Our results show that Ang(1-7) and AVE 0991 produced an NO-dependent vasodilator effect in the mouse aorta that is mediated by the G protein-coupled receptor Mas.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil, and Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University, Berlin, Germany.
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Lemos
authors.forename: Denise M R
authors.initials: DM
authors.lastname: Silva
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C469726:AVE 0991; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009842:Oligopeptides; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; C060894:CGP 42112A; D000803:Angiotensin I; D052250:Nitric Oxide Synthase Type III; C118790:angiotensin I (1-7); D019331:NG-Nitroarginine Methyl Ester