Chen X S, Zeng H W, Jiang Y Y, Wan W Q, Long K
Department of Pharmacology and Medicinal Chemistry, Second Military Medical University, Shanghai, China.
Zhongguo Yao Li Xue Bao. 1990 Jul;11(4):338-43.
In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.
在兔富血小板血浆中，4,5-二氢-6-[4-(1H-咪唑-1-基)苯基]-5-甲基-3(2H)-哒嗪酮（CI-930）抑制由花生四烯酸（AA）、U-46619、二磷酸腺苷（ADP）、胶原和血小板活化因子（PAF）引发的血小板聚集，其半数抑制浓度（IC50）值分别为0.91、0.73、2.12、2.35和7.15μmol/L。CI-930对AA诱导的聚集的抑制作用被腺苷酸环化酶激活剂前列腺素E1（PGE1）增强，并被腺苷酸环化酶抑制剂SQ-22536拮抗。5-50μmol/L的CI-930可增加洗涤过的兔血小板中cAMP的含量。在0.5-500μmol/L的浓度范围内，CI-930可减少洗涤过的大鼠或兔血小板或大鼠胸膜中性粒细胞中血栓素B2（TXB2）的合成。同时，CI-930可诱导大鼠血小板中前列腺素E2（PGE2）、前列腺素F2α（PGF2α）和前列腺素D2（PGD2）生物合成呈剂量依赖性增加，且对中性粒细胞中前列环素F1α（6-酮-PGF1α）的形成无显著影响。结果表明，CI-930是一种具有广谱活性的抗血小板药物，其抗聚集作用可能通过增加cAMP含量和选择性抑制血小板中血栓素A2（TXA2）合成这两种机制来发挥。
