Platelet-derived 12-hydroxyeicosatetraenoic acid plays an important role in mediating canine coronary thrombosis by regulating platelet glycoprotein IIb/IIIa activation

Background-In the thrombotic process of acute coronary syndromes, the patho physiological role of thromboxane A, via cyclooxygenase is well established ; however, the role of 12-HETE via 12-lipoxygenase is little known. Therefo re, we used OPC-29030, a novel specific inhibitor of 12-HETE synthesis, to test whether platelet-derived 12-HETE is involved in mediating cyclic flow variations (CFVs) and platelet aggregation in stenosed and endothelium-inju red canine coronary arteries. Methods and Results-After developing CFVs, dogs received a vehicle or OPC-2 9030 intravenously. Plasma and intraplatelet 12-HETE levels increased after CFVs, OPC-29030 but not vehicle reduced CFVs, which was associated with de creases in plasma and intraplatelet 12-HETE levels, Cessation of OPC-29030 restored CFVs in association with increases in plasma and intraplatelet 12- HETE levels. ADP and U46619 induced ex vivo platelet 12-HETE production and aggregation. After OPC-29030 administration, the ADP- and U46619-induced i ncreases in ex vivo platelet 12-HETE production and aggregation were inhibi ted significantly. Platelet aggregation was linearly correlated with platel et 12-HETE production. OPC-29030 suppressed activation of human platelet gl ycoprotein IIb/IIIa. Conclusions-OPC-29030 reduced intraplatelet 12-HETE levels, resulting in th e inhibition of coronary thrombosis in vivo in dogs, OPC-29030 inhibited hu man platelet glycoprotein IIb/IIIa activation in vitro. Thus, platelet-deri ved 12-HETE may play an important role in mediating thrombotic process.