The F 2-isoprostane, 8-epi-prostaglandin F2 α, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist

Abstract

F 2-isoprostanes are a recently discovered series of prostaglandin (PG)F 2-like compounds that are produced in vivo in humans by nonenzymatic free radical catalyzed peroxidation of arachidonic acid. One of the compounds that can be produced in abundance by this mechanism is 8-epi- PGF 2 α . 8-epi- PGF 2 α is a potent vasoconstrictor in the rat, an effect that has been shown to be mediated via interaction with vascular thromboxane (TxA 2)/ endoperoxide (PGH 2) receptors. In an effort to further understand the biological properties of this prostanoid in relation to its ability to interact with TxA 2/PGH 2 receptors, we examined its effects on human and rat platelets. At concentrations of 10 −6 M and 10 −5 M, 8-epi- PGF 2 α induced only a shape change in human platelets and at higher concentrations (10 −4 M) induced reversible but not irreversible aggregation. Both the shape change and reversible aggregation were unaffected by indomethacin but were inhibited by the TxA 2/PGH 2 receptor antagonist SQ29548. Conversely, 8-epi- PGF 2 α inhibited platelet aggregation induced by the TxA 2/PGH 2 receptor agonists U46619 (10 −6 M) and IBOP (3.3×10 −7 M) with an IC 50 of 1.6 × 10 −6 M and 1.8 × 10 −6 M, respectively. 8- epi- PGF 2 α also inhibited platelet aggregation induced by arachidonic acid. Similarly, in rat platelets, 8-epi- PGF 2 α alone induced only modest reversible aggregation but completely inhibited U46619-induced aggregation. Thus, whereas 8-epi- PGF 2 α is a potent agonist of TxA 2/PGH 2 receptors in rat vascular smooth muscle, it acts primarily as an antagonist of TxA 2/PGH 2 receptors in both rat and human platelets. Therefore, vasoconstriction induced by 8-epi- PGF 2 α would not be expected to be accompanied by platelet aggregation in vivo . These observations sustain the controversy that different TxA 2/PGH 2 receptor subtypes may exist in platelets and vascular smooth muscle.