ATP-stimulated ANP release through P1 receptor subtype

Extracellular ATP acts as a local regulator of physiological functions in the cardiovascular system via P1 and P2 receptors. However, little is known about the effect of ATP on the release of atrial natriuretic peptide (ANP) secretion. The purpose of this study was to investigate the effects of extracellular ATP on atrial hemodynamics and ANP release and to identify their receptor-mediated mechanism. ATP was infused into isolated perfused beating rat atria in the absence and presence of various receptor antagonists. ATP (from 0.1 to 30 μM) increased the ANP release with negative inotropism in a dose-dependent manner. ADP (30 μM ) also caused an increase in ANP release with similarity to ATP, but α,β-methylene ATP (α,β-MeATP, P2X1 receptor agonist) and 2-methylthioADP (2-MesADP, P2Y1 receptor agonist) did not. The rank order of potency for the increment of ANP release was adenosine>ATP=ADP>2-MesADP>α,β-MeATP. In contrast, UTP, an agonist for P2Y2,4,6 receptor, caused a decrease in ANP release without changes in contractility. Extracellular ATP-induced increase in ANP release and negative inotropism were completely blocked by the pretreatment of 8-cyclopentyl-1,3-dipropylxanthine (P1 receptor antagonist), but not by pyridoxal phosphate-6-azobenzene-2,4-disulfonic acid (P2X1 receptor antagonist) and suramin (P2XY receptor antagonist). Reactive Blue 2 (P2Y receptor antagonist) caused an augmentation of ATP-induced increase in ANP release without affecting negative inotropism. Adenosine 5′-(α,β-methylene) diphosphate, an ectonucleotidase inhibitor, did not affect ATP-induced augmentation of ANP release with negative inotropy. These results suggest that extracellular ATP-induced increase in ANP release and negative inotropism are mediated mainly by P1 receptor, and UTP decreases ANP release. Therefore, we suggest that extracellular ATP and UTP may have opposite actions on the regulation of ANP secretion.