Prostaglandin E1 increases cGMP levels via NO‐sGC signaling: compartmentalized role of cyclic nucleotides in the cardiac atrium

Abstract

Members of prostaglandin (PG) E-series elicit cellular effects mainly through adenylyl cyclase-cAMP signaling. The role of PGE2-induced increase in cAMP has been shown to be compartmentalized in the cardiac myocytes: PGE2-induced increase in cAMP is not involved in the control of cardiomyocytic contraction. In the present study, we have found an alternative signaling pathway for PGE1. Experiments were performed in perfused beating rabbit atria allowing measurement of atrial contractile response, cGMP and cAMP efflux, and atrial natriuretic peptide (ANP) release. PGE1 increased cGMP as well as cAMP efflux in a concentration-dependent manner, in which no significant changes in atrial secretory and contractile responses were observed. Isoproterenol increased atrial cAMP efflux and atrial dynamics, and decreased ANP release. PGE1-induced increase in cGMP efflux showed a bell-shaped concentration-response curve. PGE1-induced increase in cGMP efflux was not observed in the presence of L-NAME, an inhibitor of nitric oxide (NO) synthase, or ODQ, an inhibitor of NO-sensitive guanylyl cyclase (GC). PG EP4 receptor antagonist, AH23848, blocked PGE1-induced increase in cGMP production. These data indicate that PGE1 increases cGMP production via NO-GC signaling through activation of EP4 receptor. The present study also suggests that PGE1-induced increase in cGMP and cAMP is not involved in the regulation of atrial secretory and contractile functions. Supported by KOSEF (R01-2003-000-10507-0).