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.

The role of PGE2 in human atherosclerotic plaque on platelet EP3 and EP4 receptor activation and platelet function in whole blood

“…Values are mean of duplicate determinations of one experiment influence platelet function in human blood [25]. Another difference of murine and human platelets has been observed recently by Kuriyama et al, who found a much higher inhibitory potency of a selective EP 4 -receptor-agonist in human platelets as compared to murine platelets [16]. Those disparities draw attention to the limits of comparison of mouse and human platelets.…”

“…It is often propagated that PGE 2 shows a biphasic effect on platelets: low PGE 2 concentrations potentiate platelet aggregation via EP 3 activation, whereas higher lM concentrations inhibit platelet aggregation via EP 2 /EP 4 activation [13,14,16,17,24,26,31,32]. The biphasic effect is apparently more pronounced in mice platelets [13,14,16,17], whereas studies with human platelets show less consistent results [26,29,32,33]. Our recent investigation of the effect of PGE 2 on platelets in human blood clearly showed no potentiation of platelet aggregation by low PGE 2 concentrations, and only a slight inhibition at high concentrations (5 lM) [25].…”

“…The EP 2 and EP 4 receptors are coupled via G s to the stimulation of adenylyl cyclase and mediate platelet inhibition [15]. Very recently, it was reported that a selective EP 4 -receptor agonist inhibits human platelet aggregation with very high potency and might therefore be a promising new antiplatelet agent [16].…”

Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease

“…Iloprost is an EP1 agonist, but is poorly selective [57]. Newer synthetic EP receptor agonists include ONO-DI-004 (EP1) [58], ONO-AE1-259 (EP2) [58, 59], ONO-AE-248 (EP3) [60], and ONO-AE1-329 (EP4) [60]. Novel EP receptor antagonists include ONO-8713 (EP1) [58], ONO-AE3-240 (EP3) [61], DG-041 (EP3) [62], ONO-AE208 (EP4) [63], and MF-191 (EP4) [56].…”

“…Thus, EP2 stimulation leads to inhibition of platelet aggregation. The selective EP2 agonist ONO-AE1-259 inhibits platelet aggregation [58, 59]. This inhibitory effect is also seen with the EP2 agonist butaprost [56].…”