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

 

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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.

^* These authors contributed equally to this work.

• References

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