Hepatoprotective effect of the endothelin receptor antagonist TAK‐044 against ischemia‐reperfusion injury in the canine liver
Hepatoprotective effect of the endothelin receptor antagonist TAK‐044 against ischemia‐reperfusion injury in the canine liver
复制标题
内皮素受体拮抗剂TAK-044对犬肝脏缺血再灌注损伤的保肝作用
作者：
Y. Kitayama;N. Yamanaka;E. Kawamura;N. Kuroda;E. Okamoto
本研究旨在研究TAK-044（一种新型内皮素（ET）ETA/ETB受体拮抗剂）是否抑制缺血再灌注肝损伤。初步研究显示，使用标记ET-1与ET异构体和TAK-044的特异性结合试验，犬肝膜组分中存在ETA和ETB受体。非选择性ETA/ETB受体拮抗剂TAK-044以浓度依赖性方式抑制ET-1与受体的特异性结合。在使用犬70%部分肝脏缺血模型（60分钟）的后续研究中，我们发现与对照组相比，缺血前静脉注射TAK-044（3 mg/kg）可显著抑制血清肝酶（天冬氨酸转氨酶、丙氨酸转氨酶、线粒体谷草转氨酶）的释放，并可显著抑制再灌注后吲哚菁绿色留存率的增加。在门静脉三联体闭塞期间，门静脉压力升高也受到显著抑制，并且在TAK-044给药组中观察到再灌注后肝组织中氧压的快速恢复。形态计量学分析显示，再灌注后1小时，治疗组的肝细胞肿胀和窦状收缩明显轻于对照组。在给药组中，窦腔中的红细胞淤积也极轻微。总之，在TAK-044给药组中显示了缺血再灌注后肝脏微循环障碍和组织损伤的显著抑制。这一结果表明，TAK-044预处理可用作肝脏保护剂，以防止缺血再灌注损伤，否则缺血再灌注损伤是通过ET-1途径产生的。
The present study was designed to investigate if TAK‐044, a novel endothelin (ET) ETA/ETB receptor antagonist, inhibits ischemia‐ reperfusion liver injury. The initial study showed the presence of both ETA and ETB receptors in canine hepatic membrane fractions using the specific binding assay of labeled ET‐1 with ET isomers and TAK‐044. The nonselective ETA/ETB receptor antagonist TAK‐044 inhibited the specific binding of ET‐1 to the receptors in a concentration‐dependent manner. In subsequent studies using a canine 70% partial liver ischemic model (60 minutes), we found that an intravenous injection of TAK‐044 (3 mg/kg) before ischemia significantly inhibited the release of serum liver enzymes (aspartate transaminase, alanine transaminase, mitochondrial glutamic oxaloacetic transaminase, and an increase of indocyanine green retention rate after reperfusion, compared with the control group. Elevation of the portal venous pressure was also suppressed significantly during the portal triad occlusion, and a rapid restoration of oxygen pressure in the liver tissue after reperfusion was observed in the TAK‐044‐treated group. Morphometric analysis revealed that the hepatocyte swelling and sinusoidal contraction 1 hour after reperfusion were significantly less severe in the treated group than in the control group. The sludging of erythrocytes in the sinusoidal lumens was also minimal in the treated group. In conclusion, the significant suppression of hepatic microcirculatory disturbance and tissue injury after ischemia‐reperfusion were shown in the TAK‐044‐treated group. This finding indicates that the pretreatment of TAK‐044 is useful as a hepatoprotective agent against ischemia‐reperfusion injury, which is otherwise produced by a pathway involving ET‐1.
内皮素-1 诱导肝窦直接收缩。
DOI：
10.1152/ajpgi.1994.266.4.g624
发表时间：
1994
期刊：
The American journal of physiology
影响因子：
--
作者：
Zhang,JX;PegoliJr,W;Clemens,MG
通讯作者：
Clemens,MG
内皮素，肝脏中的一种有效的肽激动剂。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Gandhi,CR;Stephenson,K;Olson,MS
通讯作者：
Olson,MS
影响因子：
4.1
作者：
GANDHI, CR;BEHAL, RH;OLSON, MS
通讯作者：
OLSON, MS