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

Abstract

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.

• Authors: A Katoh, H Ikeda, T Murohara, N Haramaki, H Ito, T Imaizumi
• Journal: Circulation (Circulation) 1998 Dec 22-29 Vol. 98 Issue 25 Pg. 2891-8 ISSN: 0009-7322 [Print] United States
• PMID: 9860792 (Publication Type: Journal Article)

Chemical References

• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• Thromboxane A2
• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid

Topics

• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid (antagonists & inhibitors, metabolism, physiology)
• Animals
• Aorta (drug effects, physiology)
• Blood Platelets (metabolism)
• Blood Pressure (drug effects)
• Coronary Thrombosis (etiology, metabolism)
• Dogs
• Heart Rate (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Thromboxane A2 (metabolism)