Ouabain stimulates atrial natriuretic peptide secretion via the endothelin-1/ETB receptor-mediated pathway in beating rabbit atria

Aims: Ouabain has been reported to increase the secretion of atrial natriuretic peptide (AMP) in vitro. However, the mechanism by which ouabain increases ANP secretion is not well known. Therefore, the purpose of the present study was to investigate the underlying mechanism of ouabain-stimulated AMP secretion. Main methods: A perfused beating rabbit atrial model was used. The ANP and ET-1 levels in the atrial perfusates were measured by radioimmunoassays. Key findings: Ouabain (1.0, 3.0 and 6.0 mu mol/L) significantly increased atrial AMP secretion in a dose-dependent manner, while the endothelin (ET)-1 levels were increased by the higher doses (3.0 and 6.0 mu mol/L) of ouabain. Ouabain-increased atrial ET-1 release was blocked by PD98059 (30.0 mu mol/L), an inhibitor of mitogen-activated protein kinase (MAPK). Nifedipine (1.0 mu mol/L), an inhibitor of L-type Ca2+ channels, completely abolished ouabain-increased ANP secretion without changing the ouabain-induced atrial dynamics. KB-R7943 (3.0 mu mol/L), an inhibitor of Na+-Ca2+ exchangers, completely blocked the effects of ouabain-increased atrial dynamics, but did not modulate ouabain-increased ANP secretion. ET-1 significantly stimulated atrial AMP release in a dose-dependent manner. The effects of ET-1 and ouabain on ANP secretion were completely blocked by BQ788 (0.3 mu mol/L), an inhibitor of ET-1 type B (ETB) receptors, but not by BQ123 (0.3 mu M), an inhibitor of ET-1 type A receptors. Ouabain-increased atrial ANP secretion was blocked by PD98059 and indomethacin (30.0 mu mol/L), an inhibitor of cyclooxygenase. Significance: Ouabain significantly stimulated atrial ANP secretion via an ET-1-T-B receptor-mediated pathway involving MAPK signaling pathway activation and prostaglandin formation. (C) 2012 Elsevier Inc. All rights reserved.