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Effect of endothelin receptor antagonist on the liver graft

内皮素受体拮抗剂对移植肝的影响

基本信息

批准号：
08671496
负责人：
YAMANAKA Naoki
金额：
$ 1.47万
依托单位：
First Department of Surgery, Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

One of the vasoconstrictive substances is endothelin-l (ET-l) that was isolated from the culture supernatant of vascular endothelial cells. First, dynamics of ET-l and its implication in the pathogenesis of liver ischemia-reperfusion injury was investigated. As a result, the ET-i released from the vascular endothelium, including the liver and the portal bed, was found to be a possible factor of ischemia-reperfusion injury (Ref. 1). Second, hepatoprotective effect of the endothelin receptor antagonist, TAK-044, against ischemia-reperfusion injury was investigated in the canine partial liver ischemic model. This study demonstrated that hepatic microcirculatory disturbance, tissue injury and elevation of portal pressure during and after inflow occlusion was significantly suppressed in the TAK-044 treated group (2). Better stability of the intracellular elements (Ca, Na, Cl, K) and better preservation of morphologic architecture after reperfusion was also obtained in the treated group (2, 3). This hepatoprotective effect was revealed not only in the normal rat liver but also in the cirrhotic liver (4). Third, a similar study was conducted using a liver transplanted graft. Rat transplantation model showed that optimal administration route of endothelin receptor antagonist for the graft protection was not intravenous injection but intraportal injection along with rinse solution.In reality, in a porcine transplantation model, better graft protection after recirculation was obtained in the treated animals in the aspect of the liver functions, microcirculation and intracellular elemental dynamics (5). These studies lead to the conclusion that ET-1 plays an important role in the pathogenesis of ischemia-reperfusion injury, and that supplementary use of the endothelin receptor antagonist prior to ischemia may contribute to hepatoprotection in a clinical setting of hepatic inflow occlusion during hepatectomy or liver transplantation.

从血管内皮细胞培养上清液中分离得到的内皮素-L(ET-L)是其中一种收缩血管的物质。首先，研究了ET-L的动态变化及其在肝脏缺血再灌注损伤发病机制中的意义。结果发现，血管内皮细胞(包括肝脏和门脉床)释放的ET-I可能是缺血再灌注损伤的一个因素。1)。其次，在犬部分肝缺血模型上观察了内皮素受体拮抗剂TAK-044对缺血再灌注损伤的保护作用。本研究表明，TAK-044治疗组在血流阻断过程中和阻断后的肝脏微循环障碍、组织损伤和门静脉压力升高均显著受到抑制(2)。治疗组(2、3)再灌注后细胞内元素(Ca、Na、Cl、K)稳定性较好，形态结构保存较好。这种保肝作用不仅在正常大鼠肝脏中表现出来，在肝硬变中也表现出来(4)。第三，使用肝移植进行了一项类似的研究。在大鼠移植模型中，内皮素受体拮抗剂的最佳给药途径不是静脉注射，而是门静脉注射加冲洗液。在猪移植模型中，在肝功能、微循环和细胞内元素动力学方面，处理动物在再循环后获得了更好的移植物保护。这些研究得出结论：ET-1在肝缺血再灌注损伤的发病机制中起重要作用，在肝切除或肝移植期间，在肝血流阻断的临床情况下，在缺血前补充内皮素受体拮抗剂可能有助于保护肝脏。