title: Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor.
abstract: OBJECTIVE
  Angiotensin-(1-9) [Ang-(1-9)] and Ang-(1-7) are cleaved by Ang converting enzyme 2 forming Ang I and Ang II, respectively, and the truncated Angs play a role in regulating atrial natriuretic peptide (ANP) secretion. Previously, we found that Ang-(1-7) stimulates ANP secretion via the Mas receptor. However, the effect of Ang-(1-9) on ANP secretion is still unknown. The aim of the present study is to determine whether Ang-(1-9) stimulates ANP secretion and to characterize the signaling pathway involved in stimulating secretion.
  
  
  METHODS
  We examined the effects of Ang-(1-9) on ANP secretion and atrial contractility with and without inhibitors in isolated perfused atria.
  
  
  RESULTS
  Ang-(1-9) stimulated ANP secretion and concentration without change in atrial contractility. Ang-(1-9)-induced-ANP secretion was increased from 5% to 60% by 3 μM Ang-(1-9) during the low-stretch state of the atrium. This stimulatory effect of Ang-(1-9) on ANP secretion was attenuated by pretreatment with an Ang II type 2 receptor (AT2R) antagonist but not by AT1R or Mas receptor antagonist. In addition, pretreatment with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) blocked Ang-(1-9)-induced ANP secretion. In the high-stretch atrial state, Ang-(1-9)-induced ANP secretion was increased more than in the low-stretch state following addition of 1 μM Ang-(1-9) (from 108% to 170%). In an in vivo experiment, acute infusion of Ang-(1-9) increased plasma ANP level without altering arterial blood pressure. This effect was attenuated by pretreatment with AT2R antagonist but not by Mas receptor antagonist.
  
  
  CONCLUSIONS
  These results suggest that Ang-(1-9) stimulates ANP secretion via the AT2R-PI3K-Akt-NO-cGMP pathway.
authors.affiliation: Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Cha
authors.forename: Byung Mun
authors.initials: BM
authors.lastname: Park
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000465:Algorithms; D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical
chemical_list: C092006:7-Ala-angiotensin (1-7); D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C506331:angiotensin I (1-9); D000804:Angiotensin II; C073402:PD 123319; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D006152:Cyclic GMP
keywords: AT(2) receptor; Angiotensin-(1-9); Atrial natriuretic peptide; Renin–angiotensin system