Agarwal K C, Buckley R S, Parks R E
Division of Biology and Medicine, Brown University, Providence, RI 02912.
Thromb Res. 1987 Jul 15;47(2):191-200. doi: 10.1016/0049-3848(87)90376-8.
The potent inhibitor of platelet cAMP phosphodiesterase (PDE) HL 725 (9,10-Dimethoxy-2-mesitylimino-3-methyl-3, 4,6,7-tetrahydro-2H-pyrimido(6,1-A)-isoquinoline-4-one-hydrochloride), was examined for its effects on human and rat platelet aggregation. Strong inhibitory effects are seen on collagen-induced platelet aggregation both in rat platelet-rich plasma (PRP) (IC50, 54 +/- 12 nM) and whole blood (IC50, 57 +/- 25 nM). Compared to the effects on rat platelets, HL 725 is about two-fold less inhibitory in human PRP (IC50, 94 +/- 29 nM) and whole blood (IC50, 126 +/- 50 nM). The inhibitory action of HL 725 can be reversed by washing and resuspension of the platelets, suggesting that HL 725 does not bind tightly to cAMP PDE. If human or rat PRP is pretreated with adenosine deaminase, an enzyme that degrades adenosine or 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, the inhibitory effect of HL 725 is reversed. Similar blockade of the inhibitory actions of several other inhibitors of cAMP PDE such as RA 233, RX-RA 69 (analogs of dipyridamole) and oxagrelate is seen by adenosine deaminase pretreatment. The nucleoside transport inhibitors, dilazep and dipyridamole which are non-inhibitory alone to platelet aggregation, strongly potentiate (about 10-fold) the inhibitory action of HL 725 on collagen-induced platelet aggregation in human whole blood. However, if the whole blood is pretreated with adenosine deaminase, no inhibitory effect of dipyridamole plus HL 725 is seen on platelet aggregation. These studies demonstrate that plasma adenosine plays a crucial role in the antiaggregatory actions of HL 725 and several other inhibitors of cAMP PDE both in human and rat blood.
研究了血小板环磷酸腺苷磷酸二酯酶（PDE）的强效抑制剂HL 725（9,10 - 二甲氧基 - 2 - 均三甲苯基亚氨基 - 3 - 甲基 - 3,4,6,7 - 四氢 - 2H - 嘧啶并[6,1 - A] - 异喹啉 - 4 - 酮盐酸盐）对人和大鼠血小板聚集的影响。在大鼠富含血小板血浆（PRP）（IC50，54±12 nM）和全血（IC50，57±25 nM）中，均观察到HL 725对胶原诱导的血小板聚集有强烈抑制作用。与对大鼠血小板的作用相比，HL 725对人PRP（IC50，94±29 nM）和全血（IC50，126±50 nM）的抑制作用约低两倍。通过洗涤和重悬血小板可逆转HL 725的抑制作用，这表明HL 725不与环磷酸腺苷磷酸二酯酶紧密结合。如果用人或大鼠PRP预先用腺苷脱氨酶处理，腺苷脱氨酶是一种降解腺苷或2',5'-二脱氧腺苷（腺苷酸环化酶的抑制剂）的酶，则HL 725的抑制作用会被逆转。腺苷脱氨酶预处理也能类似地阻断其他几种环磷酸腺苷磷酸二酯酶抑制剂（如RA 233、RX - RA 69（双嘧达莫类似物）和奥扎格雷）的抑制作用。核苷转运抑制剂双嘧达莫和地拉齐普单独对血小板聚集无抑制作用，但能强烈增强（约10倍）HL 725对人全血中胶原诱导的血小板聚集的抑制作用。然而，如果全血预先用腺苷脱氨酶处理，则双嘧达莫加HL 725对血小板聚集无抑制作用。这些研究表明，血浆腺苷在HL 725和其他几种环磷酸腺苷磷酸二酯酶抑制剂在人和大鼠血液中的抗聚集作用中起关键作用。
