EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits.
Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when 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 PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
Yamamoto
T
T
Department of Laboratory Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan.
Habuchi
Y
Y
Tanaka
H
H
Suto
F
F
Morikawa
J
J
Kashima
K
K
Yoshimura
M
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000527:Alprostadil / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000502:physiology; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D018078:Receptors, Prostaglandin E; D000527:Alprostadil; D007545:Isoproterenol