Actions of the E2-isoprostane, 8-ISO-PGE2, on the platelet thromboxane/endoperoxide receptor in humans and rats: additional evidence for the existence of a unique isoprostane receptor.
D2/E2-isoprostanes, are a recently discovered series of novel prostaglandin-like compounds that are produced in vivo as products of free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. One of the E-ring compounds expected to be produced in abundance by this mechanism, 8-iso-prostaglandin E2 (8-iso-PGE2), is a potent renal vasoconstrictor in the rat, and this effect can be abrogated by the thromboxane/endoperoxide (TxA2/PGH2) receptor antagonist SQ29548, suggesting that 8-iso-PGE2 exerts these effects by interaction with this receptor in the vasculature. Nonetheless, it has recently been suggested that 8-iso-PGE2 induces vasoconstriction by interaction with a unique receptor similar to, but distinct from, the TxA2/PGH2 receptor. Because this issue has not been resolved, we carried out studies to further examine the interaction of this compound with the TxA2/PGH2 receptor on human and rat platelets. Only at concentrations of 10(-5) M or greater did 8-iso-PGE2 induce human platelet aggregation. The aggregation was unaffected by indomethacin but was inhibited by the TxA2/PGH2 receptor antagonist SQ29548. Conversely, 8-iso-PGE2 inhibited the thromboxane receptor agonists U46619 (10(-6) M) and IBOP (3.3 x 10(-7) M) with an IC50 of 5 x 10(-7) M and 5 x 10(-6) M, respectively. 8-iso-PGE2 also inhibited platelet aggregation induced by arachidonic acid but not by ADP. Similarly in rat platelets, 8-iso-PGE2 alone.
Longmire
A W
AW
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
Roberts
L J
LJ
Morrow
J D
JD
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007536:Isomerism; D028421:Isoprostanes; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011463:Prostaglandins H; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000302:isolation & purification*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000187:drug effects*; D044244:Receptors, Thromboxane A2, Prostaglandin H2
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D028421:Isoprostanes; D010975:Platelet Aggregation Inhibitors; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C045749:SQ 29548; D015232:Dinoprostone; C011987:8-isoprostaglandin E2