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Platelet lipoxygenase inhibitors attenuate thrombin- and thromboxane mimetic-induced intracellular calcium mobilization and platelet aggregation

MD Nyby, M Sasaki, Y Ideguchi, HE Wynne, MT Hori, ME Berger, MS Golub, AS Brickman and ML Tuck

Department of Endocrinolgy, Veterans Affairs Medical Center, Sepulveda, California, USA.

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygenase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known regarding the physiological significance of these products. We used three structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (ETI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of platelet intracellular calcium ([Ca++]i) in washed human platelets. LO inhibitors also reduced platelet aggregation induced by thrombin and U46619. The effect of ETI on reducing the thrombin-induced [Ca++]i elevation persisted even when cation channels were blocked, suggesting that LO inhibitors modify release of Ca from intracellular stores. Stimulating endogenous LO product formation potentiated thrombin-induced [Ca++]i responses and aggregation, and these effects were eliminated by ETI. ETI did not alter inositol 1,4,5-trisphosphate production in stimulated platelets, but increased platelet cyclic AMP production in thrombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++]i mobilization and aggregation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.

Volume 278, Issue 2, pp. 503-509, 08/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics.