The effect of TAK-O44 combined with SOD-DIVEMA on ischemia reperfusion liver injury.

[背景]内皮素受体拮抗剂选择性抑制剂TAK-O 44经静脉给药后，与白蛋白联用后，其作用减弱。为了保持TAK-O 44的有效性，需要持续输注。采用内皮素非肽类抑制剂SB 20670，观察其对肝缺血再灌注损伤的保护作用。SB的半衰期长于2小时，这显示出比单独的TAK-O 44更长的效果。[结果]非缺血组大鼠肝窦血流灌注率在整个实验过程中保持稳定，假手术后60 min和120 min分别为97.5%和97.6%。与非缺血组相比，缺血组给予氯化钠后60 min和120 min的灌注率明显降低至65.8±5.4和70.2±6.5。然而，在SB治疗的缺血组中，灌注率仍然显著高 ...更多信息 松夹后60 min和120 min分别为松夹前的92.0± 2.7%和93.3± 1.6%。非缺血组的贴壁白细胞数为0.91±0.3个/腺泡，60 min时为0.84±0.2个/腺泡，120 min时为1.07±0.3个/腺泡，非缺血组的贴壁白细胞数无显著性差异。与此相反，在缺血组中，给予NaCl的每个腺泡的数量从夹闭前的1.07±0.2显著增加到60 min时的4.31±0.8，并在120 min时达到最大值5.12±1.0。另一方面，SB给药的缺血组中粘附的白细胞数量在60和120 min时显著减少与氯化钠缺血组相比分别为（1.10± 0.2）、（1.54 ± 0.2）;白细胞数量的减少与非缺血组相同。就窦后小静脉而言，在假手术后60分钟和120分钟，即使在无缺血组中，每平方毫米切割表面的粘附白细胞的平均数也表现出增加的趋势，分别为87.4±28和69.9±20。在缺血组中，随着时间的推移，NaCl处理沿着粘附的白细胞数量显著增加，在I-R后60和120 min分别为228±51和340±62，与非缺血组相比。SB组开放后60 min贴壁白细胞数为47.3±13，与非缺血组的87.4±28无显著性差异;但在接下来的连续60 min内，它显著增加，与无缺血组的相应值相比，平均值达到208±79。也就是说，SB组和NaCl组在60分钟时观察到的粘附白细胞数量方面的显著差异在I-R后120分钟消失。[结论]SB可拮抗窦状隙I-R微血流动力学。而在肝窦后微静脉则不拮抗血管收缩和白细胞粘附，导致I-R肝损伤。少

[Background]TAK-O44,selective inhibitor of endothelin receptor antagonist, loose its efficacy connecting to albumin after administrated into the vein. To keep the effectiveness of TAK-O44,continuous infusion is needed. Using SB20670,non-peptide inhibitor of endothelin, we estimated its protective effect on the ischemia-reperfusion liver injury. The half life of SB is longer than 2 hours, which shows prolonged effects rather than TAK-O44 alone.[Result]The sinusoidal perfusion rate in the no-ischemia group remained stable and did not alter throughout the experimental time period as the level of 97.5% at 60 min after sham operation and 97.6% at 120 min, as compared to the perfusion rate prior to clamping. As opposed to the no-ischemia group, the perfusion rates in the ischemia group with NaCl administration were significantly reduced to 65.8±5.4 and 70.2±6.5 at 60 min and 120 min after declamping. However, in the ischemia group treated by SB the perfusion rates remained significantly high … More , as 92.0±2.7 % and 93.3±1.6 % of the rate before clamping at 60 min and 120 min after declamping, respectively. There is no significant difference in those ratios between the ischemia group with SB treatment and the no-ischemia group.The number of sticking leukocytes per acini in the sinusoid of the no-ischemia group was 0.91±0.3 after the laparotomy, 0.84±0.2 at 60 min and 1.07±0.3 at 120 min. There were no significant differences among the number of sticking leykocytes in no-ischemia group. In contrast, within the ischemia group with NaCl administration that number per acini increased significantly from 1.07±0.2 (before clamping) to 4.31±0.8 at 60 min and reached maximum 5.12±1.0 at 120 min after declamping. On the other hand, the number of leukocytes adhering in the ischemia group with SB administration reduced significantly at 60 and 120 min (1.10±0.2,1.54±0.2,respectively) in comparison to that of the ischemia group treated by NaCl ; the reduced number of leukocytes was the same as that noted in the no-ischemia group.In terms of the postsinusoidal venule, the mean number of adhering leukocytes per square millimeter of the cut surface demonstrated the tendency to increase even in the no-ischemia group as 87.4±28 at 60min and 69.9±20 at 120 min after sham operation, respectively. In the ischemia group, the number of sticking leukocytes increased significantly by NaCl treatment along with the passage of time as 228±51 and 340±62 at 60 and 120 min after I-R, respectively, in comparison to those in the no-ischemic group, On the other hand, in the SB group the mean number of sticking leukocytes 60 min after declamping was 47.3±13 and it was not significantly different from the corresponding value of 87.4±28 in the no-ischemia group ; however, it significantly increased during the next continuous 60 min and reached a mean value of 208±79 in comparison to the corresponding value of the no-ischemia group. That is, the significant difference between the SB and NaCl groups in terms of the number of sticking leukocytes observed at 60min had disappeared 120 min after I-R.[Conclusion]SB antagonized the I-R microhemodynamics in the sinusoid. On the other hand, in the postsinusoidal venule it did not antagonize the vasoconstriction and leukocyte sticking and resulted in I-R liver injury. Less