咪苯嗪酮对TXA2和HHT生成的选择性抑制作用

咪苯嗪酮(CI-914)能抑制大鼠血小板环氧酶和TXA₂合成酶产物HHT的生成,而对脂氧酶产物12-HETE的生成仅高浓度药物才有弱的抑制作用,提示CI-914主要影响花生四烯酸(AA)环氧酶途径,而对脂氧酶途径影响较少。在大鼠血小板和中性白细胞CI-914能抑制TXA₂的生成,同时CI-914还可使白细胞6-keto-PGF_1a和血小板PGE₂的产生量显著增加,提示CI-914在这两种细胞引起了AA的转向合成。上述结果基本证实,CI-914在大鼠中性白细胞和血小板对TXA₂合成酶具有选择性抑制作用。

SELECTIVE INHIBITION OF CI-914 ON THE PRODUCTION OF TXA2 AND HHT

The effects of CI-914, a novel cardiotonic agent, on AA metabolism in rat neutrophils and platelets in vitro were investigated. Using washed rat platelets, the formation of HHT (measured by HPLC), a product of AA metabolism via cyclooxygenase and TXA2 synthetase, was found to be inhibited by the agent in a dose-dependent manner, with IC50 value of 78.6 mumol/L. Only at higher concentration (500 mumol/L) of CI-914, was the production of 12-HETE (measured by HPLC), a lipoxygenase product in platelets, shown to be inhibited. These indicate that CI-914 mainly inhibits the metabolism of AA via cyclooxygenase and TXA2 synthetase rather than via lipoxygenase. In rat platelets and A23187-stimulated pleural neutrophils, CI-914 caused a dose-related decrease of TXA2 production (measured by RIA), with IC50 values of 28.6 and 51.3 mumol/L, respectively. Meanwhile, significant increases of PGE2 synthesis in the platelets and 6-keto-PGF1 alpha synthesis in the pleural neutrophils were observed when CI-914 was preincubated with these cells. It is suggested that CI-914 might selectively inhibit the activity of TXA2 synthetase in rat platelets and pleural neutrophils.