Interactions between prostaglandin E 2 and inhibitors of platelet aggregation which act through cyclic AMP

Abstract

Prostaglandin (PG) E 2 potentiates platelet aggregation at low concentrations (10 −8−10 −6 M). It also inhibits aggregation at a higher concentration (10 −5 M), probably by acting through cyclic adenosine 3′,5′-monophosphate (cyclic AMP). The mechanism of this biphasic effect of PGE 2 and its implications for thrombosis are not clearly understood. Using a sensitive cyclic AMP assay, in conjunction with platelet aggregation studies, we have examined the interactions between PGE 2 and other inhibitors of platelet aggregation which act through cyclic AMP. Low concentrations of PGE 2 reversed the inhibition of platelet aggregation and increase in cyclic AMP levels induced by PGI 2, PGD 2 and adenosine (which stimulate adenylate cyclase (AC) through separate and specific platelet receptors). In contrast, low concentrations of PGE 2 added to the inhibition of platelet aggregation and increase in cyclic AMP levels induced by forskolin (which stimulates AC directly) and AH-P 719 and DN-9693 (which inhibit cyclic AMP phosphodiesterase (PDE)). These results suggest that the biphasic effect of PGE 2 may be mediated by interaction with two separate platelet receptors. Low concentrations appear to potentiate aggregation by acting at a receptor which is directly coupled to an inhibitory guanine nucleotide-binding protein (G 1), possibly the putative PG endoperoxide receptor. High concentrations of PGE 2 appear to inhibit aggregation by acting at an additional receptor, probably the PGI 2 receptor. The ease with which PGE 2 reverses the effects of PGI 2, PGD 2 and adenosine, but adds to the effects of AH-P 719 and DN-9693, suggests that PDE inhibitors might offer greater potential then these AC stimulators as an anti-thrombotic strategy. This could be particularly true in the microcirculation (including the coronary and cerebral microcirculation) and in the intra-renal circulation, where PGE 2 is the major prostaglandin synthesised.