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Received for publication July 8, 2004.
Revised August 16, 2004.
Accepted for publication August 17, 2004.
We previously reported that 2-chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone (J78), 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 antiplatelet 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 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.
Key words:
1,4-naphthoquinone, J78, TXA2 receptor, TXA2 synthase, [Ca2+]i mobilization, antiplatelet
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