Relative effects of flurbiprofen on platelet 12-hydroxy-eicosatetraenoic acid and thromboxane A2 production: influence on collagen-induced platelet aggregation and adhesion.
Flurbiprofen has been shown to inhibit cyclo-oxygenase metabolism of arachidonic acid to thromboxane A2 (TxA2), resulting in the inhibition of platelet aggregation. Recently, our laboratory reported that the "irreversible" phase of platelet aggregation and adhesion were regulated, in part, by the lipoxygenase metabolism of arachidonic acid to 12-hydroxy-eicosatetraenoic acid (12-HETE) in platelets, and that selective inhibition of one enzyme i.e. either cyclo-oxygenase or lipoxygenase, resulted in paradoxical effects on the metabolism of arachidonic acid and platelet response related to the other pathway. Therefore, we performed experiments to assess the relative effects of flurbiprofen on TxA2 and 12-HETE synthesis, and on collagen-induced platelet aggregation and platelet adhesion to collagen-coated surfaces. "Irreversible" collagen-induced platelet aggregation was only partially inhibited by pre-incubation with 1 x 10(-6) M flurbiprofen, while TxA2 production was elevated and 12-HETE production was maximally inhibited in these platelets. At this concentration of flurbiprofen (1 x 10(-6)M), collagen-induced platelet adhesion was also reduced by 50%. At higher concentrations of flurbiprofen, both platelet aggregation and adhesion were further reduced, with a corresponding inhibition of TxA2 production. Thus it appears that the lipoxygenase pathway of arachidonic acid metabolism in platelets is not only inhibited by flurbiprofen, but is more sensitive to inhibition by flurbiprofen than the cyclo-oxygenase pathway. This differential effect of flurbiprofen on arachidonic acid metabolism in the platelet is related to differential effects on platelet function.
Department of Pathology, McMaster University Hamilton, Ontario, Canada.
J
J
Van Ryan-McKenna
M R
MR
Buchanan
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000037:antagonists & inhibitors; D005480:Flurbiprofen / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D066298:In Vitro Techniques; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D011422:Propionates / Q000494:pharmacology*; D011863:Radioimmunoassay; D013928:Thromboxane A2 / Q000096:biosynthesis*
D006893:Hydroxyeicosatetraenoic Acids; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D013928:Thromboxane A2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D005480:Flurbiprofen; D003094:Collagen