Volume 9 Supplement 2

15th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access

Prostaglandin E2 acts via the EP4 receptor to inhibit platelet aggregation

  • Sonia Philipose1,
  • Martina Ofner1,
  • Ákos Heinemann1 and
  • Rufina Schuligoi1Email author
BMC Pharmacology20099(Suppl 2):A8

https://doi.org/10.1186/1471-2210-9-S2-A8

Published: 12 November 2009

Background

Platelets play a central role in haemostasis. Blood vessel injury leads to platelet aggregation and also invokes an inflammatory response leading to the formation of prostanoids like prostaglandin E2 (PGE2) and prostacyclin (PGI2). It is known that low concentrations of PGE2 enhance and high concentrations inhibit platelet aggregation. PGE2 mediates its effect through four receptors: EP1 (Gαq signalling), EP3 (three isoforms present; signals via Gi, Gs or Gq based on cell type), EP2 and EP4 (Gs signalling). PGI2 is known to inhibit platelet aggregation through its IP receptor (Gs signalling). The role of EP3 in exacerbating platelet aggregation has been well described. However, the role of EP4 which acts via the same G protein coupling like IP has not been explored in detail. The aim of this study was to investigate the role of EP4 in platelet aggregation.

Methods

Platelet aggregation assays were performed ex vivo using a platelet aggregation analyser (Aggregometer II). Blood from healthy human donors was used to obtain platelet-rich plasma. Aggregation was induced using ADP or collagen. Different agonists and antagonists were added to investigate their effects on platelet aggregation. Ca2+ flux changes caused by addition of agonists were also examined using a fluorescent Ca2+ dye (Fluo-3 AM) by flow cytometry.

Results

As expected, PGE2 (up to 300 nM) and an EP3 agonist (sulprostone) enhanced platelet aggregation, whereas an EP2-selective agonist (butaprost) seemed to have no effect on platelet aggregation. On the contrary, an EP4 agonist (ONO AE1-329) inhibited platelet aggregation in a concentration-dependent manner, and this effect could be reversed by using EP4 antagonists (ONO AE3-208 and GW627368x) but not an IP or a DP antagonist. Inhibition of protein kinase C prevented the inhibitory effect of the EP4 agonist, while inhibition of adenylate cyclase had no effect. The EP4 agonist ONO AE1-329 also attenuated Ca2+ flux in platelets that had been stimulated with ADP.

Conclusion

These results are suggestive of an exclusive EP4 effect on inhibition of platelet aggregation and EP4 could be a potential target of antithrombotic therapy.

Authors’ Affiliations

(1)
Institute of Experimental and Clinical Pharmacology, Medical University of Graz

Copyright

© Philipose et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

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