title: Selective activation of the prostaglandin E2 receptor subtype EP2 or EP4 leads to inhibition of platelet aggregation.
abstract: The effect of selective activation of platelet prostaglandin (PG) E2 receptor subtype EP2 or EP4 on platelet aggregation remains to be determined. In platelets prepared from wild-type mice (WT platelets), high concentrations of PGE2 inhibited platelet aggregation induced by U-46619, a thromboxane receptor agonist. However, there was no significant change in the inhibitory effect of PGE2 on platelets lacking EP2 (EP2-/- platelets) and EP4 (EP4-/- platelets) compared with the inhibitory effect on WT platelets. On the other hand, AE1-259 and AE1-329, agonists for EP2 and EP4, respectively, potently inhibited U-46619 -induced aggregation with respective IC50 values of 590 ± 14 and 100 ± 4.9 nM in WT platelets, while the inhibition was significantly blunted in EP2-/- and EP4-/- platelets. In human platelets, AE1-259 and AE1-329 inhibited U-46619-induced aggregation with respective IC50 values of 640 ± 16 and 2.3 ± 0.3 nM. Notably, the inhibitory potency of AE1-329 in human platelets was much higher than that in murine platelets, while such a difference was not observed in the inhibitory potency of AE1-259. AE1-329 also inhibited adenosine diphosphate-induced platelet aggregation, and the inhibition was almost completely blocked by AE3-208, an EP4 antagonist. In addition, AE1-329 increased intracellular cAMP concentrations in a concentration- and EP4-dependent manner in human platelets. These results indicate that selective activation of EP2 or EP4 can inhibit platelet aggregation and that EP4 agonists are particularly promising as novel anti-platelet agents.
authors.affiliation: Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Shuhko
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kashiwagi
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Yuhki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kojima
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujino
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hara
authors.forename: Koji
authors.initials: K
authors.lastname: Takayama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Yoshida
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ushikubi
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000235:genetics; D017482:Receptors, Thromboxane / Q000819:agonists
chemical_list: D010975:Platelet Aggregation Inhibitors; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015232:Dinoprostone