title: The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE-0991 attenuates heart failure induced by myocardial infarction.
abstract: The nonpeptide AVE-0991, which has been reported as a selective ligand for the angiotensin-(1-7) [ANG-(1-7)] receptor Mas, has actions similar to those attributed to the cardioprotective product of the renin-angiotensin system, ANG-(1-7). In this study, we evaluated the cardiac effects of AVE-0991 in normal and infarcted male Wistar rats. Myocardial infarction was induced by left coronary artery ligation. At the end of the treatment, the Langendorff technique was used to analyze cardiac function. Left ventricle serial sections were dyed with Gomori trichrome stain to quantify the infarcted area. In normal hearts, AVE-0991 produced a significant decrease in perfusion pressure and an increase in systolic tension, rate of tension rise and fall (+/-dT/dt), and heart rate. These effects were completely blocked by the perfusion of the hearts with a solution containing the selective ANG-(1-7) antagonist A-779. N(G)-nitro-l-arginine methyl ester treatment abolished the AVE-0991-induced vasodilation in isolated hearts. AVE-0991 significantly attenuated the decrease in systolic tension (sham operated, 13.00 +/- 1.02 g; infarction, 7.18 +/- 0.66 g; AVE treated, 9.23 +/- 1.05 g, n = 5), +dT/dt, -dT/dt, and heart rate induced by myocardial infarction. Infarction-induced vasoconstriction was completely prevented by AVE-0991 treatment. Furthermore, AVE-0991 significantly decreased the infarcted area (6.98 +/- 1.01 vs. 3.94 +/- 1.04 mm(2) in AVE-treated rats). These data indicate that the compound AVE-0991 produces beneficial effects in isolated perfused rat hearts involving the ANG-(1-7) receptor Mas and the release of nitric oxide. In addition, our results indicate that AVE-0991 attenuates postischemic heart failure.
authors.affiliation: Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Jacoby
authors.forename: Cícero A A
authors.initials: CA
authors.lastname: Araújo
authors.forename: Filipe A F F
authors.initials: FA
authors.lastname: Macedo
authors.forename: Gerluza A B
authors.initials: GA
authors.lastname: Silva
authors.forename: Alvair P
authors.initials: AP
authors.lastname: Almeida
authors.forename: Marcelo V
authors.initials: MV
authors.lastname: Caliari
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002303:Cardiac Output, Low / Q000209:etiology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C092006:7-Ala-angiotensin (1-7); C469726:AVE 0991; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014665:Vasodilator Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester