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(Circulation. 1998;98:2891-2898.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Platelet-Derived 12-Hydroxyeicosatetraenoic Acid Plays an Important Role in Mediating Canine Coronary Thrombosis by Regulating Platelet Glycoprotein IIb/IIIa Activation

Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 10–13, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-722).

Atsushi Katoh, MD; Hisao Ikeda, MD; Toyoaki Murohara, MD; Nobuya Haramaki, MD; Hideki Ito, MS; Tsutomu Imaizumi, MD

From the Department of Internal Medicine III, Kurume University School of Medicine (A.K., H. Ikeda, T.M., N.H., T.I.), and the Third Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co (H. Ito), Japan.

Correspondence to Hisao Ikeda, MD, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan. E-mail ikeikeda{at}med.kurume-u.ac.jp

Background—In the thrombotic process of acute coronary syndromes, the pathophysiological role of thromboxane A₂ via cyclooxygenase is well established; however, the role of 12-HETE via 12-lipoxygenase is little known. Therefore, 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-injured canine coronary arteries.

Methods and Results—After developing CFVs, dogs received a vehicle or OPC-29030 intravenously. Plasma and intraplatelet 12-HETE levels increased after CFVs. OPC-29030 but not vehicle reduced CFVs, which was associated with decreases 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 increases in ex vivo platelet 12-HETE production and aggregation were inhibited significantly. Platelet aggregation was linearly correlated with platelet 12-HETE production. OPC-29030 suppressed activation of human platelet glycoprotein IIb/IIIa.

Conclusions—OPC-29030 reduced intraplatelet 12-HETE levels, resulting in the inhibition of coronary thrombosis in vivo in dogs. OPC-29030 inhibited human platelet glycoprotein IIb/IIIa activation in vitro. Thus, platelet-derived 12-HETE may play an important role in mediating thrombotic process.

Key Words: platelets • hydroxyeicosatetraenoic acid • platelet aggregation • glycoproteins • thrombosis

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