title: Angiotensin II type 1 receptor blockade restores angiotensin-(1-7)-induced coronary vasodilation in hypertrophic rat hearts.
abstract: The aim of the present study was to investigate the coronary effects of Ang-(1-7) [angiotensin-(1-7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (N(G)-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1-7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.
authors.affiliation: Department of Physiological Sciences, Federal University of Goiás, Goiânia 74001-970, Brazil.
authors.forename: Álvaro P S
authors.initials: ÁP
authors.lastname: Souza
authors.forename: Deny B S
authors.initials: DB
authors.lastname: Sobrinho
authors.forename: Jônathas F Q
authors.initials: JF
authors.lastname: Almeida
authors.forename: Gisele M M
authors.initials: GM
authors.lastname: Alves
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Macedo
authors.forename: Juliana E
authors.initials: JE
authors.lastname: Porto
authors.forename: Eneida F
authors.initials: EF
authors.lastname: Vêncio
authors.forename: Diego B
authors.initials: DB
authors.lastname: Colugnati
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Mendes
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Castro
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C469726:AVE 0991; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; C073402:PD 123319; D000803:Angiotensin I; C118790:angiotensin I (1-7); D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester