ET-1 Regulates Hypoxia-induced ANP Secretion By Activation Of PI3K/Akt Signaling Pathway

Aim:Hypoxia promotes atrial ET-1 production and contributes to regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion. However, the mechanism by which hypoxia-induced endogenous ET-1 regulates ANP secretion is remains to be define. The purpose of the present study was to investigate the mechanism that the endogenous ET-1 regulates atrial ANP secretion.Methods:Isolated perfused acute hypoxic rabbit atrial model was used in this study. The levels of ET-1 and ANP in the atrial perfusates were measured by radioimmunoassay, and the protein levels of ET receptors, phosphorylated protein kinase B (pAkt) and GATA-4 protein in atrial tissue were determined by Western blot.Results:1. Acute hypoxia significantly enhanced ET-1 release and up regulated both of its type A and type B receptors (ETRA and ETRB) (n=5, P＜0.001 and P<0.01vs. control group) concomitantly with markedly increased atrial ANP secretion and inhibition of stroke volume as well as pulse pressure (n=6, P＜0.001 vs. control period).2. Hypoxia-induced ANP secretion was dramatically attenuated either by an ETRA antagonist BQ123 (0.3 μmol/L) or by BQ788 (0.3 μmol/L), an ETRB antagonist (n=6, P<0.01 vs. control period).3. Moreover, BQ123 as well as BQ788 or together of them significantly attenuated the levels of hypoxia-increased atrial pAkt (n=5, P＜0.001 vs. hypoxia).4. Inhibitor of Akt, LY294002 (30 μmol/L), were mimicked the roles of ET receptors antagonists on the hypoxia-induced ANP secretion (n=5, P＜0.001 vs. hypoxia).5. ET receptors antagonists significantly attenuated the level of hypoxia-induced atrial GATA-4 protein in beating rabbit atria (n=5. P<0.01, P＜0.001 vs. control; P＜0.001 vs. hypoxia).Conclusion:Acute hypoxia-promoted atrial endogenous ET-1 was contributed to the regulation of hypoxia-induced ANP secretion through activation of PI3K/Akt/GATA4 signaling pathways.