Effect of endothelin receptor antagonist on the liver graft

血管收缩物质之一是内皮素- 1 (et - 1)，它是从血管内皮细胞培养上清中分离出来的。首先，研究et - 1的动态变化及其在肝缺血-再灌注损伤发病机制中的意义。因此，从血管内皮（包括肝脏和门静脉床）释放的ET-i被发现可能是缺血再灌注损伤的一个因素（文献1）。其次，在犬部分肝缺血模型中研究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治疗组在血流阻断期间和之后的肝脏微循环障碍、组织损伤和门静脉压力升高明显受到抑制(2)。治疗组细胞内元素（Ca, Na, Cl， K）的稳定性更好，再灌注后形态结构的保存也更好（2,3）。这种保护肝脏的作用不仅在正常大鼠肝脏中被发现，而且在肝硬化肝中也被发现(4)。第三，使用肝移植进行了类似的研究。大鼠移植模型显示，内皮素受体拮抗剂对移植物保护的最佳给药途径不是静脉注射，而是门静脉内与冲洗液一起给药。实际上，在猪移植模型中，在肝脏功能、微循环和细胞内元素动力学方面，治疗动物在再循环后获得了更好的移植物保护(5)。这些研究表明ET-1在缺血-再灌注损伤的发病机制中起重要作用，并且在缺血前补充使用内皮素受体拮抗剂可能有助于肝切除术或肝移植中肝流入阻塞的临床设置。

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.