Antiaggregatory activity of 8-epi-prostaglandin F(2α) and other F-series prostanoids and their binding to thromboxane A2/prostaglandin H2 receptors in human platelets

K. Yin, P. V. Halushka, Y. T. Yan, P. Y.K. Wong

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8-Epi-prostaglandin F(2α) (8-epi-PGF(2α)) is a nonenzymatic, free radical-catalyzed peroxidation product of arachidonic acid that has potent biological activity, including contraction of vasculature and inhibition of aggregation induced by thromboxane (TX) A2 mimetics. In the present study, we demonstrate that 8-epi-PGF(2α) could inhibit platelet aggregation induced by the TX mimetics U46619 and I-BOP as well as low-dose collagen but not thrombin or the primary wave of aggregation caused by high-dose ADP. The secondary (TX-dependent) wave of aggregation induced by high-dose ADP, however, was not affected. This suppression was dose dependent where 3.6 and 3.3 μM of 8-epi-PGF(2α) caused 50% inhibition of platelet aggregation induced by U46619 and I-BOP, respectively, whereas 10 μM caused approximately 72% inhibition of collagen-induced aggregation. In contrast, 8- epi-PGF(2α) significantly potentiated reversible platelet aggregation in response to low-dose ADP. These results indicate that 8-epi-PGF(2α) has partial agonist activity. 9α, 11β-PGF2, a structural isomer of 8-epi- PGF(2α), inhibited platelet aggregation induced by collagen, high- and low- dose ADP and thrombin, demonstrating marked differences between structural isomers where 9α, 11β-PGF2 inhibited platelet aggregation induced by TX- dependent as well as TX-independent stimuli. In addition to platelet aggregation, we performed competition-binding assays on washed human platelets using [125I]BOP to further investigate the interaction of 8- epi-PGF(2α) and 9α,11β-PGF2 with TXA2/PGH2 receptors. We found that 8- epi-PGF(2α) was a relatively poor competitor of TX receptor binding sites compared with unlabeled I-BOP, SQ 29548 or U46619. The IC50 for 8-epi- PGF(2α) and 9α,11β-PGF2 to displace 0.05 nM [125I]BOP was 3.3 and 14 μM, respectively, which was approximately 1000 times less effective than unlabeled I-BOP (IC50 = 2.2 nM) and SQ 29548 (IC50 = 2.9 nM). A similar result was observed using a platelet membrane preparation. Our results suggest that 8-epi-PGF(2α) is a partial agonist of TXA2/PGH2 platelet receptors. Its structural isomer, 9α,11β-PGF2, is an antiaggregatory compound that works through a mechanism other than antagonism of TXA2/PGH2 receptors.

Original languageEnglish (US)
Pages (from-to)1192-1196
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1994

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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