PLATELET LIPOXYGENASE INHIBITORS ATTENUATE THROMBIN-INDUCED AND THROMBOXANE MIMETIC-INDUCED INTRACELLULAR CALCIUM MOBILIZATION AND PLATELET-AGGREGATION

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygen ase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known re garding the physiological significance of these products. We used thre e structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (E TI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of plat elet intracellular calcium ([Ca++](i)) in washed human platelets. LO i nhibitors also reduced platelet aggregation induced by thrombin and U4 6619. The effect of ETI on reducing the thrombin-induced [Ca++](i) ele vation persisted even when cation channels were blocked, suggesting th at LO inhibitors modify release of Ca from intracellular stores. Stimu lating endogenous LO product formation potentiated thrombin-induced [C a++](i) responses and aggregation, and these effects were eliminated b y ETI. ETI did not alter inositol 1,4,5-trisphosphate production in st imulated platelets, but increased platelet cyclic AMP production in th rombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++](i) mobilization and aggr egation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.