The inhibitory effect of 2-thienyl 2'-hydroxyphenyl ketone (C85) on platelet thromboxane formation.
A new synthetic compound, 2-thienyl 2'-hydroxyphenyl ketone (C85), was demonstrated as an antiplatelet agent. In rabbit washed platelets, C85 dose-dependently inhibited arachidonic acid(AA), collagen and platelet activating factor(PAF)-induced platelet aggregation and ATP release with IC50 values of 0.6 +/- 0.2, 20.5 +/- 8.3 and 145.6 +/- 28.6 microM respectively. In human platelet rich plasma(PRP), C85 selectively inhibited the second phase of platelet aggregation and ATP release induced by epinephrine. The formation of platelet thromboxane B2 (TXB2) caused by AA, collagen and thrombin was completely inhibited by C85(10 microM). C85 could significantly reduce cyclooxygenase activity as reflected by attenuation of prostaglandin E2(PGE2) formation. C85 also possess weakly inhibitory effect on thromboxane synthase as reflected by slightly inhibition of prostaglandin H2 (PGH2)-induced TXB2 formation. In Fura-2/AM loaded platelets, the rise of intracellular calcium level challenged by AA, collagen and thrombin were inhibited by C85. The C85(10 microM) also significantly suppressed the phosphoinositide breakdown induced by AA and collagen. In vivo, C85(50 micrograms/Kg i.p.) produced a marked prolongation of tail bleeding time than that treated by indomethacin in mice. In summary, the antiplatelet mechanism of C85 is mainly inhibition of platelet cyclooxygenase activity and partly inhibition of thromboxane synthase activity and lead to diminution of TXA2 formation.
Graduate Institute of Life Science, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China.
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Chou
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Hsu
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Yen
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Ding
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D016257:Fura-2; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis*
C104197:2-thienyl 2'-hydroxyphenyl ketone; D007659:Ketones; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D013929:Thromboxane B2; D000255:Adenosine Triphosphate; D015232:Dinoprostone; D002118:Calcium; D016257:Fura-2