Modification of levosimendan-induced suppression of atrial natriuretic peptide secretion in hypertrophied rat atria

Abstract This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion. Suppression of ANP secretion by 1 µM levosimendan was abolished by PDE3 inhibitor, but reversed by PDE4 inhibitor. Levosimendan-induced suppression of ANP secretion was potentiated by K ATP channel blocker, but blocked by K ATP channel opener. Levosimendan alone did not significantly change cyclic adenosine monophosphate (cAMP) efflux in the perfusate; however, levosimendan combined with PDE4 inhibitor markedly increased this efflux. The stimulation of ANP secretion induced by levosimendan combined with PDE4 inhibitor was blocked by the protein kinase A (PKA) inhibitor. In isoproterenol-treated atria, levosimendan augmented the positive inotropic effect and ANP secretion in response to an increased extracellular calcium concentration ([Ca + ] o ). These results suggests that levosimendan suppresses ANP secretion by both inhibiting PDE3 and opening K ATP channels and that levosimendan combined with PDE4 inhibitor stimulates ANP secretion by activating the cAMP–PKA pathway. Modification of the effects of levosimendan on [Ca + ] o -induced positive inotropic effects and ANP secretion in isoproterenol-treated rat atria might be related to a disturbance in calcium metabolism.