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CARDIOVASCULAR

Antiplatelet Activity of J78 (2-Chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an Antithrombotic Agent, Is Mediated by Thromboxane (TX) A₂ Receptor Blockade with TXA₂ Synthase Inhibition and Suppression of Cytosolic Ca²+ Mobilization

College of Pharmacy, Chungbuk National University, Cheongju, Korea (Y.-R.J., M.-R.C., J.-T.H., K.-S.L., J.-J.L., Y.L., Y.-P.Y.); College of Pharmacy, Ewha Women's University, Seoul, Korea (C.-K.R.); College of Pharmacy, Seoul National University, Seoul, Korea (J.-H.C.); and Research Center for Bioresource and Health, Chungbuk National University, Cheongju, Korea (D.-Y.Y., M.-Y.L., Y.-P.Y.)

We previously reported that J78 (2-chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), a newly synthesized 1,4-naphthoquinone derivative, exhibited a potent antithrombotic effect, which might be due to antiplatelet rather than anticoagulation activity. In the present study, possible anti-platelet mechanism of J78 was investigated. J78 concentration-dependently inhibited rabbit platelet aggregation induced by collagen (10 µg/ml), thrombin (0.05 U/ml), arachidonic acid (100 µM), and U46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F₂; 1 µM), a thromboxane (TX) A₂ mimic, with IC₅₀ values of 0.32 ± 0.01, 0.44 ± 0.02, 0.50 ± 0.04, and 0.36 ± 0.02 µM, respectively. J78 also produced a shift to the right of the concentration-response curve of U46619, indicating an antagonistic effect on the TXA₂ receptor. J78 concentration-dependently inhibited collagen-induced arachidonic acid liberation. In addition, J78 potently suppressed TXA₂ formation by platelets that were exposed to arachidonic acid in a concentration-dependent manner but had no effect on the production of PGD₂, indicating an inhibitory effect on TXA₂ synthase. This was supported by a TXA₂ synthase activity assay that J78 concentration-dependently inhibited TXB₂ formation converted from PGH₂. Furthermore, J78 was also able to inhibit the [Ca²⁺]_i mobilization induced by collagen or thrombin at such a concentration that completely inhibited platelet aggregation. Taken together, these results suggest that the antiplatelet activity of J78 may be mediated by TXA₂ receptor blockade with TXA₂ synthase inhibition and suppression of cytosolic Ca²⁺ mobilization.

Address correspondence to: Dr. Yeo-Pyo Yun, College of Pharmacy, Chungbuk National University, 48 Gaesin-Dong, Heungduk-Gu, Cheongju, Chungbuk, 361-763, Korea. E-mail: ypyun{at}chungbuk.ac.kr

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