Chou T C, Li C Y, Lee A R, Wu T M
Graduate Institute of Medical Sciences, Tri-Service General Hospital, National Defense Medical Center, National Taiwan Normal University, Taipei, Taiwan.
Eur J Pharmacol. 2000 Jan 10;387(2):125-31. doi: 10.1016/s0014-2999(99)00812-2.
The antiplatelet effect of the pyridazinone analogue, 4, 5-dihydro-6-[4-[2-hydroxy-3-(3,4 dimethoxybenzylamino)propoxy]naphth-1-yl]-3(2H)-pyridazinone (HCL-31D), was investigated in vitro with rabbit platelets. HCL-31D dose-dependently inhibited the platelet aggregation and ATP release induced by collagen (10 microg/ml), arachidonic acid (100 microM) or thrombin (0.1 U/ml) with an IC(50) of about 0.95-5.41 microM. HCL-31D (0.5-5 microM) increased the platelet cyclic AMP level in a dose-dependent manner. Furthermore, HCL-31D potentiated cyclic AMP formation caused by prostaglandin E(1) but not that caused by 3-isobutyl-1-methylxanthine (IBMX). HCL-31D also attenuated phosphoinositide breakdown and intracellular Ca(2+) elevation induced by collagen, arachidonic acid or thrombin. HCL-31D inhibited the formation of thromboxane B(2) induced by collagen or thrombin but not by arachidonic acid. In addition, HCL-31D did not affect platelet cylooxygenase and thromboxane synthase activity. These data indicate that HCL-31D is an inhibitor of phosphodiesterase and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
在体外对兔血小板研究了哒嗪酮类似物4,5-二氢-6-[4-[2-羟基-3-(3,4-二甲氧基苄氨基)丙氧基]萘-1-基]-3(2H)-哒嗪酮（HCL-31D）的抗血小板作用。HCL-31D剂量依赖性地抑制胶原（10微克/毫升）、花生四烯酸（100微摩尔）或凝血酶（0.1单位/毫升）诱导的血小板聚集和ATP释放，其半数抑制浓度（IC50）约为0.95 - 5.41微摩尔。HCL-31D（0.5 - 5微摩尔）以剂量依赖性方式增加血小板环磷酸腺苷（cAMP）水平。此外，HCL-31D增强前列腺素E1引起的cAMP生成，但不增强3-异丁基-1-甲基黄嘌呤（IBMX）引起的cAMP生成。HCL-31D还减弱胶原、花生四烯酸或凝血酶诱导的磷酸肌醇分解和细胞内钙离子升高。HCL-31D抑制胶原或凝血酶诱导的血栓素B2生成，但不抑制花生四烯酸诱导的血栓素B2生成。此外，HCL-31D不影响血小板环氧化酶和血栓素合酶活性。这些数据表明HCL-31D是一种磷酸二酯酶抑制剂，其抗血小板作用主要由cAMP水平升高介导。
