The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3':5'-cyclic monophosphate in platelets.
The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3':5'-cyclic monophosphate in platelets.
复制标题
影响血小板中腺苷3:5-环单磷酸积累的药物对血小板聚集的影响。
作者：
D. C. B. Mills;J. B. Smith
1.用放射化学技术研究了前列腺素E（1）、异丙肾上腺素和腺苷抑制血小板聚集时细胞内3 '：5'-环腺苷酸的参与。将富血小板血浆与放射性腺嘌呤孵育，以将（14）C放射性掺入血小板核苷酸中。取两对相同处理的样品，一个用于ADP诱导的血小板聚集的光度测量，另一个用于估计3 '：5'-环AMP的放射性。2.茶碱、罂粟碱、双嘧达莫和2，6-二-（二乙醇氨基）-4-哌啶基嘧啶并[5，4 d]嘧啶（化合物RA 233）对血小板3 '：5'-环腺苷酸磷酸二酯酶有抑制作用。当3 '：5'-环AMP浓度大于50 μ m时，最具活性的抑制剂是双嘧达莫;当3 '：5'-环AMP浓度小于19 μ m时，罂粟碱和化合物RA 233的活性高于双嘧达莫。3.在化合物RA 233（50 μ m）的存在下，前列腺素E（1）作为血小板聚集抑制剂的有效性增加了10倍。化合物RA 233还增加前列腺素E（1）对放射性掺入3 '：5'-环AMP的刺激。4.化合物RA 233（50 μ m）将腺苷和2-氯腺苷作为聚集抑制剂的有效性提高了70-100倍，并且在化合物RA 233存在下，腺苷和2-氯腺苷都刺激放射性掺入3 ′：5 ′-环AMP中;刺激的程度与核苷浓度的对数成比例。5.化合物RA 233（100- 500 μ m）本身抑制血小板聚集，并引起3 '：5'-环AMP放射性的小幅增加。在加入聚集剂（ADP）时测得的血小板中3 '：5'-环AMP的放射性与聚集被抑制的程度之间存在部分正相关。6.结果表明腺苷、2-氯腺苷、异丙肾上腺素、前列腺素E（1）和抑制血小板3 '：5'-环AMP磷酸二酯酶的药物均通过涉及细胞内3 '：5'-环AMP的共同机制抑制聚集。
1. The involvement of intracellular 3':5'-cyclic AMP in the inhibition of platelet aggregation by prostaglandin E(1), isoprenaline and adenosine has been examined by a radiochemical technique. Platelet-rich plasma was incubated with radioactive adenine to incorporate (14)C radioactivity into platelet nucleotides. Pairs of identically treated samples were taken, one for the photometric measurement of platelet aggregation induced by ADP, the other for estimation of the radioactivity of 3':5'-cyclic AMP. 2. Theophylline, papaverine, dipyridamole and 2,6-bis-(diethanolamino)-4-piperidinopyrimido[5,4d]pyrimidine (compound RA233) were found to inhibit 3':5'-cyclic AMP phosphodiesterase from platelets. At concentrations of 3':5'-cyclic AMP greater than 50mum the most active inhibitor was dipyridamole; at 3':5'-cyclic AMP concentrations less than 19mum, papaverine and compound RA233 were more active than dipyridamole. 3. In the presence of compound RA233 (50mum), the effectiveness of prostaglandin E(1) as an inhibitor of platelet aggregation was increased tenfold. Compound RA233 also increased the stimulation by prostaglandin E(1) of the incorporation of radioactivity into 3':5'-cyclic AMP. 4. Compound RA233 (50mum) increased the effectiveness of both adenosine and 2-chloroadenosine as inhibitors of aggregation by 70-100-fold, and in the presence of compound RA233 both adenosine and 2-chloroadenosine stimulated the incorporation of radioactivity into 3':5'-cyclic AMP; the extent of the stimulation was proportional to the logarithm of the nucleoside concentration. 5. Compound RA233 (100-500mum) inhibited platelet aggregation by itself and caused small increases in the radioactivity of 3':5'-cyclic AMP. Partial positive correlations were found between the radioactivity of 3':5'-cyclic AMP in platelets measured at the time of addition of the aggregating agent (ADP) and the extent to which the aggregation was inhibited. 6. The results are interpreted as indicating that adenosine, 2-chloroadenosine, isoprenaline, prostaglandin E(1) and drugs that inhibit platelet 3':5'-cyclic AMP phosphodiesterase all inhibit aggregation by a common mechanism involving intracellular 3':5'-cyclic AMP.