title: New insights into the elucidation of angiotensin-(1-7) in vivo antiarrhythmic effects and its related cellular mechanisms.
abstract: What is the central question of this study? Recently, there have been many studies exploring the biological effects of angiotensin-(1-7), which has been proved to have cardioprotective actions. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. What is the main finding and its importance? We investigated protective effects of angiotensin-(1-7) on cardiac arrhythmias in vivo, which were not properly explored in terms of cellular mechanisms. To verify effects of angiotensin-(1-7), we used different but complementary experimental approaches. Our data provide new evidence on the cellular mechanism and an in vivo demonstration of the acute antiarrhythmic effect of angiotensin-(1-7). Angiotensin-(1-7) [Ang-(1-7)] has been proved to have cardioprotective effects. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. The aim of this study was to investigate the protective effects of Ang-(1-7) against cardiac arrhythmias, its in vivo effects and cellular mechanism of action. We analysed the ECG upon inducement of arrhythmias in vivo in rats using a combination of halothane and adrenaline. To analyse the effects of Ang-(1-7) on cells, fresh mouse ventricular cardiomyocytes were isolated. The cardiomyocytes were superfused with a solution containing halothane and isoprenaline as a model to induce arrhythmias and used in three different approaches, namely a contractility assay, patch-clamp technique and confocal microscopy. The in vivo ECG showed that the injection of Ang-(1-7) (4 nm i.v.) significantly reduced cardiac arrhythmias [before, 49 ± 43 arrhythmic events versus after Ang-(1-7), 16 ± 14 arrhythmic events]. This effect was blocked by injection of A-779 and l-NAME, without changes in haemodynamic parameters. In addition, contractility experiments showed that Ang-(1-7) significantly decreased the number of arrhythmic events without changing the fractional shortening. This protection was associated with a reduction of the action potential repolarization and membrane hyperpolarization. Moreover, Ang-(1-7) decreased the number of calcium waves without any changes in the amplitude of the calcium transient, despite a significant reduction in the decay rate. Our data provide new evidence on the cellular mechanism together with an in vivo demonstration of the antiarrhythmic effects of Ang-(1-7).
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Julliane Vasconcelos
authors.initials: JV
authors.lastname: Joviano-Santos
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Artur
authors.initials: A
authors.lastname: Santos-Miranda
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Humberto Cavalcante
authors.initials: HC
authors.lastname: Joca
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Jader Santos
authors.initials: JS
authors.lastname: Cruz
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Anderson José
authors.initials: AJ
authors.lastname: Ferreira
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7); D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester
keywords: angiotensin-(1-7); cardiac arrhythmias; renin-angiotensin system