Yu S M, Tsai S Y, Kuo S C, Ou J T
Department of Pharmacology, Chang Gung College of Medicine and Technology, Tao-Yuan, Taiwan.
Blood. 1996 May 1;87(9):3758-67.
The effect of A02131-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl thieno (3,2-c)pyrazole], a cGMP-specific phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and adenosine triphosphate (ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), adenosine diphosphate (ADP) and A23187, and the inhibitory effect was concentration-dependent. A02131-1 also disaggregated the performed platelet aggregates induced by these inducers. Thromboxane B2 (TXB2) formations caused by collagen, PAF, ADP, and A23187 were inhibited by A02131-1 at concentrations that did not affect the AA-induced formation of TXB2 and prostaglandin D2 (PGD2). A02131-1 suppressed both the generation of inositol 1,4,5-triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers. A02131-1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time. A02131-1 increased the cAMP level much more slowly than the cGMP level. Activities of adenylate cyclase, guanylate cyclase, and PDEs (type I and III) were not altered by A02131-1. However, the activity of cGMP-specific PDE (type V) was inhibited by A02131-1. The antiplatelet aggregation activity and the effect on raising cAMP level of A02131-1 were both potentiated by prostaglandin E1 (PGE1). In the mouse tail bleeding test, A02131-1 was clearly shown to be more effective than dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that A02131-1 is a cGMP-specific PDE (type V) inhibitor in human platelets.
研究了cGMP特异性磷酸二酯酶（PDE）抑制剂A02131-1[3-(5'-羟甲基-2'-呋喃基)-1-苄基噻吩并(3,2-c)吡唑]对血小板功能的影响。发现该化合物可抑制花生四烯酸（AA）、胶原、U46619、血小板活化因子（PAF）、二磷酸腺苷（ADP）和A23187等聚集诱导药物诱导的富含人血小板血浆和洗涤血小板的聚集以及三磷酸腺苷（ATP）释放，且抑制作用呈浓度依赖性。A02131-1还可使这些诱导剂诱导形成的已形成血小板聚集体解聚。A02131-1在不影响AA诱导的血栓素B2（TXB2）和前列腺素D2（PGD2）形成的浓度下，抑制胶原、PAF、ADP和A23187诱导的TXB2形成。A02131-1抑制这些聚集诱导剂刺激的肌醇1,4,5-三磷酸（IP3）生成和细胞内Ca2+浓度升高。结果表明，A02131-1可提高血小板中的cAMP和cGMP水平，且其程度也取决于浓度和时间。A02131-1升高cAMP水平的速度比cGMP水平慢得多。A02131-1未改变腺苷酸环化酶、鸟苷酸环化酶和PDEs（I型和III型）的活性。然而，A02131-1抑制cGMP特异性PDE（V型）的活性。前列腺素E1（PGE1）增强了A02131-1的抗血小板聚集活性和提高cAMP水平的作用。在小鼠尾部出血试验中，A02131-1在延长清醒小鼠尾部出血时间方面明显比双嘧达莫更有效。这些数据表明，A02131-1是人类血小板中的cGMP特异性PDE（V型）抑制剂。
