Angiotensin IV stimulates high atrial stretch-induced ANP secretion via insulin regulated aminopeptidase

Angiotensin IV (Ang IV) is formed by aminopeptidase N (APN) from angiotensin III (Ang III) by removing the first N-terminal amino acid. Previouslt, we reported that angiotensin II (Ang II) inhibits atrial natriuretic peptide (ANP) secretion via angiotensin II type 1 receptor (AT1R). In contrast, angiotensin-(1-7) [Ang-(1-7)] and Ang III stimulate ANP secretion via Mas receptor (Mas R) and angiotensin II type 2 receptor (AT2R), respectively. However, it is not known whether there is any relationship between Ang IV and ANP secretion. Therefore, the aim of the present study was to determine the effect of Ang IV on ANP secretion and to find its downstream signaling pathway using in isolated perfused beating atria. Ang IV (0.1, 1 and 10 μM) stimulated high atrial stretch-induced ANP secretion and ANP concentration in a dose-dependent manner. The augmented effect of Ang IV (1 μM) on high atrial stretch-induced ANP secretion and concentration was attenuated by pretreatment with insulin-regulated aminopeptidase (IRAP) antagonist but not by AT1R or AT2R antagonist. Pretreatment with inhibitors of downstream signaling pathway including phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) blocked Ang IV-induced ANP secretion and concentration. Therefore, these results suggest that Ang IV stimulates ANP secretion and concentration via IRAP and PI3K-Akt-mTOR pathway.