Bradykinin and its metabolite, Arg-Pro-Pro-Gly. Phe, are selective inhibitors of alpha-thrombin-induced platelet activation
Bradykinin and its metabolite, Arg-Pro-Pro-Gly. Phe, are selective inhibitors of alpha-thrombin-induced platelet activation
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DOI：
10.1161/01.cir.94.3.517
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发表时间：
1996-08-01
期刊：
影响因子：
37.8
通讯作者：
Schmaier, AH
中科院分区：
文献类型：
--
作者：
Hasan, AAK;Amenta, S;Schmaier, AH
背景血浆激肽原是血小板和血管内皮细胞激活α-凝血酶的选择性抑制物。方法和结果缓激肽及其类似物MKRPPGFSPFRSSRIG抑制α-凝血酶诱导的血小板聚集和分泌，其IC50分别为0.25和1 mm ol/L和0.23和0.5 mm o l/L：。最小抑制肽为RPPGF。缓激肽及其类似物不抑制ADP、胶原、U46619或SFLLRN诱导的血小板激活，也不抑制α-凝血酶裂解发色底物、凝结纤维蛋白原或阻断α-凝血酶与血小板的结合。缓激肽、MKRPPGFSPFRSSRIG和RPPGF可阻断α-凝血酶诱导的(1nmol/L)钙动员。在流式细胞术中，缓激肽和MKRPPGFSPFRSSRIG阻止了α-凝血酶去除其在克隆的凝血酶受体上的裂解位点的表位。结论缓激肽及其代谢产物通过阻止α-凝血酶对克隆的凝血酶受体在精氨酸-41和丝氨酸-42之间的裂解而成为选择性抗凝血酶。这些新发现的抗凝血酶多肽，被称为血栓抑素，有助于激肽的心脏保护性质。
Background Plasma kininogens are selective inhibitors of alpha-thrombin activation of platelets and endothelial cells. In the present study, we localized the alpha-thrombin inhibitory sequence of kininogens and describe its mechanism of action.Methods and Results Bradykinin and an analogue, MKRPPGFSPFRSSRIG, inhibited alpha-thrombin-induced platelet aggregation and secretion with an IC50 of 0.25 and 1 mmol/L and of 0.23 and 0.5 mmol/L: respectively. The minimal inhibitory peptide was RPPGF. Bradykinin and its analogues did not inhibit ADP-, collagen-, U46619-, or SFLLRN-induced platelet activation or the ability of alpha-thrombin to cleave chromogenic substrates, clot fibrinogen, or block alpha-thrombin binding to platelets. Bradykinin, MKRPPGFSPFRSSRIG, and RPPGF abolished alpha-thrombin-induced (1 nmol/L) calcium mobilization. On flow cytometry, bradykinin and MKRPPGFSPFRSSRIG blocked alpha-thrombin from removing the epitope of its cleavage site on the cloned thrombin receptor. Furthermore, peptide RPPGF or high-molecular-weight kininogen prevented alpha-thrombin from cleaving the thrombin receptor peptide, NATLDPRSFLLR, between arginine and serine.Conclusions These results indicate that bradykinin and its metabolites are selective antithrombins by preventing alpha-thrombin cleavage of the cloned thrombin receptor between arginine-41 and serine-42. These newly recognized antithrombin peptides, which are termed thrombostatins, contribute to the cardioprotective nature of kinins.