Effects of an Epoxymethano Stable Analogue of Prostaglandin Endoperoxides (U-46619) on Human Platelets

Summary

U-46619 is a stable epoxymethano analogue of cyclic endoperoxide PGH₂. We studied platelet aggregation, ¹⁴C-5HT release, LDH extrusion and prostaglandin and thromboxane production induced by this compound in platelet-rich plasma samples from 15 healthy volunteers. Each subject was tested both before and 90 min after aspirin (500 mg) ingestion. The threshold aggregating concentration (TAC) of U-46619 ranged between 0.18 and 0.90 µM. Aggregation was maximal between 40 and 60 min after venipuncture and was concentration-dependent. At concentrations below the TAC, U-46619 induced primary reversible aggregation with minimal ¹⁴C-5HT release. At TAC or higher concentrations aggregation and release proceded as parallel events. Neither prostaglandin or thromboxane production nor LDH loss could be detected in any of the situations tested. Aspirin ingestion did not modify the pattern of platelet responses. In unstirred, not aggregated platelet samples ¹⁴C-5HT release by U-46619 occurred to a similar extent as in stirred, aggregated platelet samples. Addition to citrated PRP of 0.3 mM Na₂ EDTA blocked both aggregation and release induced by U-46619. This compound, however, aggregated washed platelets resuspended in Ca⁺⁺-free-tyrode-albumin containing fibrinogen. The mechanism by which U-46619 activates platelets differs from that of all other common aggregating agents.

Keywords

Prostaglandin endoperoxides - Platelet aggregation - Release reaction - Washed platelets

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