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: Amin Shah, Rukhsana Gul, Kuichang Yuan, Shan Gao, Young-Bin Oh, Uh-Hyun Kim, Suhn Hee Kim
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 298 Issue 5 Pg. H1365-74 (May 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20190099 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Peptide Fragments
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• Receptors, G-Protein-Coupled
• Sodium-Hydrogen Exchangers
• Atrial Natriuretic Factor
• Angiotensin I
• Proto-Oncogene Proteins c-akt
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Receptors, Atrial Natriuretic Factor
• Cyclic GMP
• angiotensin I (1-7)
• Isoproterenol

Topics

• Angiotensin I (pharmacology)
• Animals
• Atrial Natriuretic Factor (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cardiac Pacing, Artificial
• Cardiotonic Agents (pharmacology)
• Cyclic GMP (metabolism)
• In Vitro Techniques
• Isoproterenol (pharmacology)
• Male
• Myocytes, Cardiac (drug effects, metabolism)
• Peptide Fragments (pharmacology)
• Phosphatidylinositol 3-Kinases (physiology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Radioimmunoassay
• Rats
• Rats, Sprague-Dawley
• Receptors, Atrial Natriuretic Factor (antagonists & inhibitors)
• Receptors, G-Protein-Coupled (physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Sodium-Hydrogen Exchangers (drug effects, metabolism)