Selective activation of the prostaglandin E2 receptor subtype EP2 or EP4 leads to inhibition of platelet aggregation

Shuhko Kuriyama; Hitoshi Kashiwagi; Koh-ichi Yuhki; Fumiaki Kojima; Takehiro Yamada; Takayuki Fujino; Akiyoshi Hara; Koji Takayama; Takayuki Maruyama; Akitoshi Yoshida; Shuh Narumiya; Fumitaka Ushikubi

doi:10.1160/TH10-01-0043

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(04): 796-803
DOI: 10.1160/TH10-01-0043

Platelets and blood cells

Schattauer GmbH

Selective activation of the prostaglandin E₂ receptor subtype EP₂ or EP₄ leads to inhibition of platelet aggregation

Shuhko Kuriyama^*

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

²Department of Ophthalmology, Asahikawa Medical College, Asahikawa, Japan

,

Hitoshi Kashiwagi^*

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Koh-ichi Yuhki

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Fumiaki Kojima

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Takehiro Yamada

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Takayuki Fujino

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Akiyoshi Hara

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Koji Takayama

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

,

Takayuki Maruyama

³Minase Research Institute, Ono Pharmaceutical Company, Osaka, Japan

,

Akitoshi Yoshida

²Department of Ophthalmology, Asahikawa Medical College, Asahikawa, Japan

,

Shuh Narumiya

⁴Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan

,

Fumitaka Ushikubi

¹Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan

› Author Affiliations

Abstract

Summary

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.

Keywords

Platelet aggregation - prostaglandin E₂ - EP₂ - EP₄ - anti-platelet agent

Full Text

References

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