EP receptor-mediated inhibition by prostaglandin E1 of cardiac L-type Ca2+ current of rabbits.

Prostaglandin E1(PGE1) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE1 on myocardium, we examined the effect of PGE1 on the L-type Ca2+ current ( I Ca) using single atrial cells from rabbits. PGE1 did not show a significant effect on basal I Ca but inhibited the I Caprestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC50 = 0.027 μM). Both sulprostone, a specific PGE receptor subtype (EP1 and EP3) agonist, and 11-deoxy-PGE1, an EP3 agonist, inhibited the Iso-stimulated I Ca, similar to PGE1. Pretreatment with pertussis toxin (PTX) abolished the PGE1inhibition of I Ca. Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE1. PGE1 did not show any further inhibition of I Cawhen the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE1. These findings suggest that 1) PGE1 inhibits Iso-stimulated I Ca by binding to the EP3 receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE1 inhibition of I Ca, but the nitric oxide-cGMP-dependent pathway is not. The PGE1-induced antiadrenergic effect shown in this study may contribute to the PGE1 protection of myocardium against ischemia.