Role of adenosine uptake and metabolism by blood cells in the antiplatelet actions of dipyridamole, dilazep and nitrobenzylthioinosine.
Role of adenosine uptake and metabolism by blood cells in the antiplatelet actions of dipyridamole, dilazep and nitrobenzylthioinosine.
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血细胞腺苷摄取和代谢在双嘧达莫、地拉西普和硝基苄硫肌苷的抗血小板作用中的作用。
DOI：
10.1016/0006-2952(85)90373-9
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发表时间：
1985
影响因子：
5.8
通讯作者：
ParksJr,RE
中科院分区：
文献类型：
--
作者：
Dawicki,DD;Agarwal,KC;ParksJr,RE
腺苷（Ado，10 μM）不抑制ADP诱导的人全血血小板聚集。然而，如果血液与双嘧达莫（10 μM）（红细胞核苷转运系统（NTS）的强效抑制剂）预孵育，则Ado可作为血小板聚集的强效抑制剂。同样地，Ado在其他有效的NTS抑制剂地拉卓（1 μM）和对硝基苄硫肌苷（NBMPR，1 μM）存在下抑制全血中的血小板聚集。RA 233（10 μM）是双嘧达莫的类似物，是血小板cAMP磷酸二酯酶（PDE）的有效抑制剂，在全血中不引起Ado效应。然而，在富血小板血浆（PRP）中，RA 233增强了强烈的抑制作用，而潘生丁，地拉卓和NBMPR没有活性。Ado受体拮抗剂5 '-甲基硫代腺苷（MTA）可逆转核苷转运系统抑制剂与Ado合用对全血细胞的抑制作用。双嘧达莫（10 μM）、地拉卓（1 μM）或NBMPR（1 μM）阻断全血中血细胞摄取[14 C]Ado（10 μM），而RA 233（10 μM）则无效。腺苷脱氨酶（ADA）的紧密结合抑制剂2 '-脱氧共形霉素（dCF，5 μM）与腺苷激酶（Ado激酶）的强效抑制剂5-碘杀结核菌素（ITu，10 μM）联合使用，对全血中血小板聚集的抑制作用与用地拉卓预处理血液时相当。这些研究表明，药物如双嘧达莫和地拉卓的体内抗血小板作用是由于它们能够阻断红细胞对Ado的摄取和随后的代谢，从而提高生理上存在的抗血小板剂Ado的细胞外稳态浓度。
Adenosine (Ado, 10 μM) did not inhibit ADP-induced human platelet aggregation in whole blood. However, if the blood was preincubated with dipyridamole (10 μM), a potent inhibitor of the erythrocytic nucleoside transport system (NTS), Ado acted as a strong inhibitor of platelet aggregation. Similarly, Ado inhibited platelet aggregation in whole blood in the presence of other potent NTS inhibitors, dilazep (1 μM) andp-nitrobenzylthioinosine (NBMPR, 1 μM). RA 233 (10 μM), an analog of dipyridamole which is a potent inhibitor of platelet cAMP phosphodiesterase (PDE), did not evoke the Ado effect in whole blood. However, in platelet-rich plasma (PRP), RA 233 potentiated strongly Ado-mediated inhibition, whereas dipyridamole, dilazep and NBMPR were without activity. 5'-Methyl-thioadenosine (MTA), an Ado receptor antagonist, reversed the inhibition produced by a nucleoside transport system inhibitor plus Ado in whole blood. Dipyridamole (10 μM), dilazep (1 μM) or NBMPR (1 μM) blocked [14C]Ado (10 μM) uptake by blood cells in whole blood, whereas RA 233 (10 μM) was not effective. The combination of 2'-deoxycoformycin (dCF, 5 μM), a tight-binding inhibitor of adenosine deaminase (ADA), plus 5-iodotubercidin (ITu, 10 μM), a potent inhibitor of adenosine kinase (Ado kinase), gave comparable Ado-mediated inhibition of platelet aggregation in whole blood as was obtained when the blood was pretreated with dilazep. These studies suggest that thein vivoantiplatelet actions of drugs such as dipyridamole and dilazep result from their abilities to block erythrocytic Ado uptake and subsequent metabolism, thus elevating the extracellular steady-state concentration of the physiologically occurring, antiplatelet agent, Ado.