title: Angiotensin-(1-7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger.
abstract: Angiotensin-(1-7) [ANG-(1-7)], one of the bioactive peptides produced in the renin-angiotensin system, plays a pivotal role in cardiovascular physiology by providing a counterbalance to the function of ANG II. Recently, it has been considered as a potential candidate for therapeutic use in the treatment of various types of cardiovascular diseases. The aim of the present study is to explain the modulatory role of ANG-(1-7) in atrial natriuretic peptide (ANP) secretion and investigate the functional relationship between two peptides to induce cardiovascular effects using isolated perfused beating rat atria and a cardiac hypertrophied rat model. ANG-(1-7) (0.01, 0.1, and 1 muM) increased ANP secretion and ANP concentration in a dose-dependent manner at high atrial pacing (6.0 Hz) with increased cGMP production. However, at low atrial pacing (1.2 Hz), ANG-(1-7) did not cause changes in atrial parameters. Pretreatment with an antagonist of the Mas receptor or with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), or nitric oxide synthase blocked the augmentation of high atrial pacing-induced ANP secretion by ANG-(1-7). A similar result was observed with the inhibition of the Na(+)/H(+) exchanger-1 and Ca(2+)/calmodulin-dependent kinase II (CaMKII). ANG-(1-7) did not show basal intracellular Ca(2+) signaling in quiescent atrial myocytes. In an in vivo study using an isoproterenol-induced cardiac hypertrophy animal model, an acute infusion of ANG-(1-7) increased the plasma concentration of ANP by twofold without changes in blood pressure and heart rate. A chronic administration of ANG-(1-7) increased the plasma ANP level and attenuated isoproterenol-induced cardiac hypertrophy. The antihypertrophic effect was abrogated by a cotreatment with the natriuretic peptide receptor-A antagonist. These results suggest that 1) ANG-(1-7) increased ANP secretion at high atrial pacing via the Mas/PI3K/Akt pathway and the activation of Na(+)/H(+) exchanger-1 and CaMKII and 2) ANG-(1-7) decreased cardiac hypertrophy which might be mediated by ANP.
authors.affiliation: Department of Physiology, Chonbuk National University Medical School, 2-20 Keum-Am-Dong-San, Jeonju, Korea. shkim@chonbuk.ac.kr
authors.forename: Amin
authors.initials: A
authors.lastname: Shah
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Gul
authors.forename: Kuichang
authors.initials: K
authors.lastname: Yuan
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.forename: Young-Bin
authors.initials: YB
authors.lastname: Oh
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000803:Angiotensin I; D009320:Atrial Natriuretic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002316:Cardiotonic Agents; D006152:Cyclic GMP; D007545:Isoproterenol; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017461:Receptors, Atrial Natriuretic Factor; D043562:Receptors, G-Protein-Coupled; D017923:Sodium-Hydrogen Exchangers; C118790:angiotensin I (1-7)