| Co-Investigator(Kenkyū-buntansha) |
SASAKI Sadao Associated Professor, 医学部, 助教授 (20104276)
YAMANAKA Junichi Assistant Professor, 医学部, 助手 (90289083)
YASUI Chiaki Assistant Professor, 医学部, 助手 (10291816)
TANAKA Tsuneo Assistant Professor, 医学部, 助手 (80248137)
OKAMOTO Eizo Professor, 医学部, 教授 (50068425)
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| Research Abstract |
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.
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