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

【背景】选择性内皮素受体拮抗剂TAK-O44经静脉给药后，其与白蛋白的连接作用减弱。为保持TAK-O44的有效性，需要持续输注。采用内皮素非肽抑制剂SB20670对缺血再灌注肝损伤的保护作用进行研究。SB的半衰期超过2小时，比单独使用TAK-O44效果更持久。【结果】与夹持前相比，无缺血组的灌注率保持稳定，在整个实验时间内没有变化，假手术后60 min为97.5%，120 min为97.6%。与非缺血组相比，NaCl给药后缺血组在去钳后60 min和120 min的灌注率分别为65.8±5.4和70.2±6.5。而缺血组在去钳后60 min和120 min的灌流率分别为去钳前的92.0±2.7%和93.3±1.6%。经SB治疗的缺血组与未缺血组在这些比值上无显著差异。无缺血组开腹后每腺泡黏附白细胞数为0.91±0.3个，60 min时为0.84±0.2个，120 min时为1.07±0.3个。两组间黏附细胞数目无显著性差异。相比之下，在NaCl处理的缺血组中，每个腺泡的数量从夹钳前的1.07±0.2个显著增加到60 min时的4.31±0.8个，并在去钳后120 min时达到最大值5.12±1.0个。另一方面，与NaCl处理的缺血组相比，SB组在60和120 min时粘附的白细胞数量显著减少（分别为1.10±0.2、1.54±0.2）；白细胞数量减少与未缺血组相同。假手术后窦后小静脉，即使在无缺血组，每平方毫米切口表面黏附白细胞的平均数量也有增加的趋势，分别为60min时的87.4±28个和120min时的69.9±20个。与未缺血组相比，缺血组在I-R后60 min和120 min时，NaCl处理的粘附白细胞数量分别为228±51和340±62，随时间的推移，粘附白细胞数量显著增加，而SB组在去断路后60 min的平均粘附白细胞数量为47.3±13，与未缺血组的相应值87.4±28无显著差异；然而，在接下来的连续60分钟内，它显著增加，与未缺血组的相应值相比，它达到了208±79的平均值。也就是说，在I-R后120 min， SB组和NaCl组在60min时观察到的粘附白细胞数量的显著差异已经消失。[结论]SB对鼻窦区I-R微血流动力学有拮抗作用。另一方面，在窦后小静脉中，它不能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