Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats
Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats
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DOI：
10.1016/j.ejphar.2011.05.034
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发表时间：
2011-09-01
影响因子：
5
通讯作者：
Hishinuma, Ieharu
中科院分区：
文献类型：
--
作者：
Kogushi, Motoji;Matsuoka, Toshiyuki;Hishinuma, Ieharu
凝血酶是一种强大的激动剂，可促进多种细胞反应，包括血小板聚集和血管平滑肌细胞(SMC)增殖。这些作用是由一种名为蛋白酶激活受体-1(PAR-1)的凝血酶受体介导的。最近我们发现氢溴酸1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5，6-diethoxy-7-fluoro-1-imino-1，3-dihydro-2H-isoindol-2-yl)ethanone(E5555，阿托紫杉醇)是一种有效的选择性凝血酶受体拮抗剂。本研究探讨了E5555对体外培养的SMC增殖和大鼠球囊损伤后内膜增厚的药理作用。E5555选择性地抑制凝血酶和凝血酶受体激活肽(TRAP)诱导的大鼠主动脉系膜细胞增殖，半数抑制浓度(IC_(50))分别为0.16和0.038 mU/L。E5555对碱性成纤维细胞生长因子和血小板衍化生长因子诱导的大鼠动脉系膜细胞增殖无明显抑制作用。E5555对凝血酶诱导的血管内皮细胞增殖有抑制作用，IC50值分别为0.028和0.079 mU M，而对碱性成纤维细胞生长因子诱导的增殖无明显影响。这些结果表明，PAR-1拮抗剂除了预防血栓形成外，还可以有效地治疗血管介入治疗后的再狭窄。因此，E5555可能对再狭窄和慢性动脉粥样硬化性血栓疾病具有治疗潜力。(C)2011爱思唯尔B.V.保留所有权利。
Thrombin is a powerful agonist for a variety of cellular responses including platelet aggregation and vascular smooth muscle cell (SMC) proliferation. These actions are mediated by a thrombin receptor known as protease-activated receptor-1 (PAR-1). Recently we discovered that 1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl)ethanone hydrobromide (E5555, atopaxar) is a potent and selective thrombin receptor antagonist. This study characterized the pharmacological effects of E5555 on SMC proliferation in vitro and in a rat model of intimal thickening after balloon injury in vivo. E5555 selectively inhibited rat aortic SMC proliferation induced by thrombin and thrombin receptor-activating peptide (TRAP) with half maximal inhibitory concentration (IC50) values of 0.16 and 0.038 mu M, respectively. E5555 did not inhibit rat SMC proliferation induced by basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) at concentrations up to 1 mu M. In addition, E5555 inhibited human aortic SMC proliferation induced by thrombin at concentrations of 0.3 and 3 units/ml with IC50 values of 0.028 and 0.079 mu M, respectively, whereas it did not affect bFGF-induced proliferation at concentrations up to 1 W. Repeated oral administration of 30 mg/kg E5555 (once daily for 16 days) significantly reduced neointimal formation in the balloon-injured rat arterial model. These results suggested that a PAR-1 antagonist could be effective for treating restenosis following vascular intervention in addition to preventing thrombus formation. E5555 could thus have therapeutic potential for restenosis and chronic atherothrombotic disease. (C) 2011 Elsevier B.V. All rights reserved.