内皮素1在内毒素所致肝损伤中的作用

目的 观察内皮素－１（ＥＴ－１）在内毒素所致肝损伤中的作用。方法 应用原位灌注肝脏模型，观察肝组织中ＥＴ－１，乳酸脱氢酶（ＬＤＨ），丙二醛（ＭＤＡ）和三磷酸腺苷（ＡＴＰ）含量的变化，以及肝组织学的变化。结果 内毒素能使ＥＴ－１含量增加，ＥＴ－１和内毒素使肝细胞脂质过氧化物形成和酶的漏出，肝细胞浊肿变性。ＥＴ－１抗体能部分拮抗内毒素所致肝损伤。结论 ＥＴ－１参与内毒素所致的肝损伤作用。     

内皮素对肝血流量影响的实验研究

选用Ｗｉｓｔａｒ大鼠２０只，随机分为对照组、内皮素１（ＥＴ１）组、ＥＴ１＋硝基左旋精氨酸组和ＥＴ１＋前列环素＋消炎痛组，每组５只。采用氢气清除法观察ＥＴ１对肝血流量的影响以及一氧化氮（ＮＯ）和前列环素（ＰＧＩ２）对ＥＴ１生物学效应的调节作用。结果显示：ＥＴ１能使肝血流量迅速降低，并且持续时间较长；ＮＯ及ＰＧＩ２可部分拮抗ＥＴ１的生物学效应。表明内皮细胞源性血管因子对肝血流量有一定调节作用     

抗肿瘤坏死因子抗体和头孢噻甲羧肟对急性胆道感染肝损害的保…

在急性胆道感染大鼠模型上检测血浆肿瘤坏死因子（ＴＮＦ）、内毒素（ＥＴ）水平及血清谷丙转氨酶（ＡＬＴ）活性；观察肝组织结构和超微结构，抗ＴＮＦ单克隆抗体（ＴＮＦ－ＭＡｂ）和头孢噻甲羧肟的保护作用，结果显示：急性胆道感染组血浆ＴＮＦ、ＥＴ水平显著升高，血清ＡＬＴ活性也显著升高，肝组织病理变化明显：ＴＮＦ－ＭＡｂ与头孢噻甲羧肟保护组血浆ＴＮＦ、ＥＴ水平及血清ＡＬＴ活性显著下降，肝组织病理变化较轻，结果提     

抗肿瘤坏死因子抗体和头孢噻甲羧肟对急性胆道感染肝损害的保护作用

在急性胆道感染大鼠模型上检测血浆肿瘤坏死因子（ＴＮＦ）、内毒素（ＥＴ）水平及血清谷丙转氨酶（ＡＬＴ）活性；观察肝组织结构和超微结构，抗ＴＮＦ单克隆抗体（ＴＮＦ－ＭＡｂ）和头孢噻甲羧肟的保护作用，结果显示：急性胆道感染组血浆ＴＮＦ、ＥＴ水平显著升高，血清ＡＬＴ活性也显著升高，肝组织病理变化明显；ＴＮＦ－ＭＡｂ与头孢噻甲羧肟保护组血浆ＴＮＦ，ＥＴ水平及血清ＡＬＴ活性显著下降，肝组织病理变化较轻，结果提示ＴＮＦ是急性胆道感染肝损害的重要介质；ＴＮＦ－ＭＡｂ和头孢噻甲羧肟对胆道感染肝损害有保护作用。     

内毒素对血管内皮细胞分泌功能的影响

目的　探讨内毒素对脐静脉内皮细胞分泌功能的影响。方法　选择体外培养的人脐静脉血管内皮细胞（ＨＵＶＥＣ）为研究对象,分别用内毒素、Ｌ左旋精氨酸和硝基左旋精氨酸进行处理,并检测上清液中内皮素１（ＥＴ１）和一氧化氮（ＮＯ） 含量。结果　内毒素使ＥＴ１ 和ＮＯ 含量增加;ＮＯ 则使ＥＴ１的含量降低。结论　内毒素能导致人脐静脉内皮细胞损伤,使ＥＴ１ 和ＮＯ的合成和释放增加;ＮＯ则抑制ＥＴ１ 的合成和释放。     

缺血再灌流肾组织内皮素—1及其受体基因表达的实验研究

为了探究内皮素１（ＥＴ１）对肾功能的影响和作用方式，采用斑点杂交和原位杂交方法对大鼠缺血６０分钟再灌注肾组织ＥＴ１及其受体亚型（ＥＴＡ、ＥＴＢ）的基因表达进行了研究。结果发现：再灌流１小时，ＥＴ１、ＥＴＡ、ＥＴＢｍＲＮＡ均明显升高；再灌流２４小时仍维持较高水平。ＥＴ１和ＥＴＡｍＲＮＡ杂交信号再灌流３小时达高峰。ＥＴ１ｍＲＮＡ主要分布肾皮质小血管内皮细胞、髓质肾小管和集合管，ＥＴＡ受体ｍＲＮＡ则分布于上述小血管的平滑肌细胞。ＥＴＢ受体ｍＲＮＡ于再灌流６小时达高峰，主要分布髓质肾小管、集合管。说明缺血再灌流肾内皮素受体亚型上调在皮质以ＥＴＡ为主，在髓质以ＥＴＢ为主，分别与增强表达的ＥＴ１结合导致肾皮质缺血和水钠代谢异常。     

黄芪对胆道梗阻后心肌损伤保护作用的实验研究

目的：观察胆道梗阻后心肌损害及黄芪（ＡＭ）的保护作用。方法：动脉观测心肌组织丙二醛（ＭＤＡ）和超氧化物歧化酶（ＳＯＤ）、血清Ｔ－ＢｉＩ、ＴＢＡ、内毒素（ＥＴ）、肿瘤坏死因子（ＴＮＦα）含量;取左室心肌行光电镜检查,应用ＡＢＣ免疫组化染色法,定位ＴＮＦα在心肌组织中的表达和分布。结果：胆道梗阻后,血清Ｔ－ＢｉＩ、ＴＢＡ、ＥＴ、ＴＮＦα水平逐渐升高,心肌组织ＭＤＡ含量逐渐升高,ＳＯＤ逐渐减少;各ＡＭ治疗且与同时相梗阻组比较,血清ＥＴ、ＴＮＦα、心肌组织ＭＤＡ含量减少,ＳＯＤ含量升高;心肌组织ＭＤＡ含量与血清ＴＮＦα含量变化呈正相关;光电镜下可见随胆道梗阻时间延长,心肌组织细胞损害加重,各ＡＭ治疗组与同时相梗阻组比较组织细胞损害减轻。结论;ＡＭ通过对抗自由基损伤、内毒素血症、ＴＮＦα的综合作用,对胆道梗阻所致心肌损伤     

急性胆管炎时肝微循环的变化及其细胞间粘附分子-1和E-选择素的作用

为探讨细胞间粘附分子１ （ Ｉ Ｃ Ａ Ｍ１） 和 Ｅ选择素 （ Ｅｓｅｌｅｃｔｉｎ） 在急性胆管炎肝微循环变化中的作用, 对急性胆管炎时肝脏组织学、肝脏血流量及肝组织伊文思蓝 （ Ｅ Ｂ） 含量的变化, 以及 Ｉ Ｃ Ａ Ｍ１ 和 Ｅ选择素单抗预处理对以上变化的影响进行了观察。结果： 急性胆管炎时肝窦内皮细胞及肝细胞出现变性和结构破坏, 肝窦及肝细胞周围多形核粒细胞 （ Ｐ Ｍ Ｎ） 数量显著增多, 肝微血管血流量明显减少, 肝组织 Ｅ Ｂ含量显著增高, 肝窦通透性增高; 而抗 Ｉ Ｃ Ａ Ｍ１ 及 Ｅ选择素单抗预处理使以上损害均明显减轻。由此表明, Ｉ Ｃ Ａ Ｍ １ 及 Ｅ选择素在肝脏微循环障碍的发生发展中起重要作用。     

梗阻性黄疸兔血浆内毒素和内皮素1含量与血流动力学改变的关系

研究梗阻性黄疸内毒素血症对血管内皮细胞产生内皮素１（ＥＴ－１）的作用及ＥＴ－１与梗阻性黄应时血流动力学改变的关系。方法用肝总管结扎法建立梗阻性黄疸（ＯＪ）兔模型,偶氮显色法定量测定血内毒素含量,特异性放射免疫分析法测定血浆ＥＴ－１,生理记录仪和电磁血流计测定心率（ＨＲ）、平均动脉压（ＭＡＰ）、心输出量（ＣＯ）、肝动脉血流量（ＨＡＢＦ）、门静脉血流量（ＰＶＢＦ）、门静脉压力（ＰＶＰ）及内脏血管阻力（ＳＡＲ）。结果ＯＪ组血浆内毒素含量明显高于正常对照（ＮＣ）组;血浆ＥＴ－１低于ＮＣ组。ＯＪ组血浆内毒素与血浆ＥＴ－１含量呈负相关;ＯＪ组血浆ＥＴ－１含量与ＭＡＰ、ＨＡＢＦ、ＰＶＢＦ及ＳＡＲ呈正相关。结论梗阻性黄疽时血浆ＥＴ－１水平降低,内毒素血症不能刺激血管内皮细胞产生ＥＴ－１,血浆ＥＴ－１水平下降在系统血流动力学改变中起一定的作用。     

己酮可可碱对内毒素肺损伤肺组织TNFmRNA表达的影响

目的：观察己酮可可碱对内毒素血症引起的肺组织ＴＮＦｍＲＮＡ表达及血浆ＴＮＦ的影响。方法：选用ＳＤ大鼠６３只，分三组：①生理盐水组（Ｃ组）；②内毒素组（Ｅ组），大肠杆菌Ｏ５５Ｂ５内毒素１５ｍｇ／ｋｇ静注；③内毒素＋己酮可可碱组（Ｅ＋Ｐ组），１５ｍｇ／ｋｇ内毒素加２０ｍｇ／ｋｇ己酮可可碱静注，６ｍｇ／ｋｇ己酮可可碱维持。每组分１、３、６小时三个时间点，用差别聚合酶链反应测定肺组织ＴＮＦｍＲＮＡ的变化，双抗体夹心法测定血浆ＴＮＦ的变化。结果：内毒素组血浆ＴＮＦ在１小时达高峰，３小时仍升高，６小时接近生理盐水组水平，己酮可可碱组１小时和３小时血浆ＴＮＦ与相应内毒素组比明显下降（Ｐ分别＜０．０１，０．０５）；ＴＮＦｍＲＮＡ表达在内毒素组１小时和３小时明显升高，己酮可可碱治疗后ＴＮＦｍＲＮＡ表达和内毒素组比明显下降（Ｐ＜０．０１），己酮可可碱组病理损害明显减轻。结论：ＴＮＦ是一个早期的重要炎症介质，己酮可可碱能抑制ＴＮＦ的产生，通过抑制其转录而产生作用，己酮可可碱对内毒素肺损伤具有保护作用。     

一氧化氮、内皮素-1在内毒质所致肝脏损伤中的作用机制研究

目的 探讨一氧化氮（NO）和内皮素-1（ET-1）在内毒素所致肝脏损伤中的作用机制。方法 Waster大鼠40只随机分成对照组，内毒素组、内毒素组、内皮素受体拮抗剂组和左旋精氨酸组，观察各组大鼠血浆NO和ET-1水平，肝脏功能变化，在光镜下观察肝细胞损伤程度，在电镜下观察肝脏超微结构改变。结果 大鼠投予内毒素12h后，血浆NO和ET-1水平明显下升，血浆转氨酶水平增加，肝细胞明显水肿，变性和坏死，肝筛的数量和直径明显减少，左旋精氨酸和内皮素受体损坏抗剂均能明显减轻肝脏功能和结构的损伤，结论 在内毒素所致肝损伤中，NO起保护性作用，而ET-1则起促进作用，二者在肝脏中的作用可能是通过作用于肝筛而引起的。     

山莨菪碱对大鼠肝脏缺血再灌注损伤保护作用的实验研究

目的 探索山莨菪碱对大鼠肝脏缺血再灌注损伤的保护作用。方法 选雄性Wistar大鼠160只,分为正常对照组、缺血再灌注组、生理盐水组和山莨菪碱组,观察了肝脏缺血60分钟及再灌注1、3、6、12及24小时后血浆内皮素－1（ET－1）、透明质酸（HA）和谷丙转氨酶（ALT）含量变化及肝组织病理学变化。结果 肝脏缺血再灌注后,血浆ET－1、HA和ALT含量均明显增高,同时肝脏瘀血很明显,肝脏缺血再灌注前用山莨菪碱后,血浆HA和ALT含量明显降低,同时肝组织瘀血减轻。结论 山莨菪碱可改善再灌注后的肝脏微循环障碍,对大鼠肝脏缺血再灌注损伤有保护作用。     

Extracorporeal liver perfusion system for successful hepatic support pending liver regeneration or liver transplantation: a pre-clinical controlled trial.

BACKGROUND: There is a well recognized need for a system capable of providing effective support for patients with hepatic failure pending liver regeneration or liver transplantation. Recent attempts of using bioartificial liver containing encapsulated porcine hepatocytes, the deployment of emergency whole liver, or hepatocyte transplantation are complex and not consistently successful. The technique of ex vivo hepatic perfusion developed and used clinically by Abouna in the 1970s, has now been redesigned in a perfusion circuitry that mimics the physiological conditions of a normal liver. Before clinical application of this system, a preclinical trial was carried out in dogs with induced hepatic failure. METHODS: Acute hepatic failure was induced in dogs by an end-to-side porto caval shunt, followed 24 hr later, by a 2-hr occlusion of the hepatic artery. All animals (n=18) were medically supported and were divided into three groups. In the control group (n=6) only medical support was used. In the experimental group (n=12) the animals were connected to the ex vivo liver support apparatus during acute hepatic failure via an AV shunt using a dog liver (n=6) or calf liver (n=6) (after a temporary extracorporeal bovine kidney transplant to remove preformed xeno antibody). Hepatic perfusion was carried out at 37 degrees C through the hepatic artery and portal vein at physiological pressures, and blood flow rate for 6-8 hr. RESULTS: All control animals died of progressive hepatic failure at 14-19 hr after clamping the hepatic artery. The animals treated with ex vivo liver showed remarkable clinical and biochemical improvement. Five animals survived for 36-60 hr. Another seven animals recovered completely and became long-term survivors with biochemical and histological evidence of regeneration of their own liver. Biopsy of the allogeneic ex vivo liver at the end of perfusion showed some interstitial edema. Similar biopsy of the xenogeneic calf liver showed only mild and delayed xenograft rejection, which was most likely due to removal of preformed xeno antibody by temporary transplantation of the calf kidney before liver perfusion. CONCLUSIONS: The observations and results obtained in this trial strongly confirm that extracorporeal perfusion through a whole liver, using the system described, is very successful and cost effective for the treatment of acute, but reversible hepatic failure, as well as serving as a bridge to liver transplantation. The time has come for this form of liver support technology to be reintroduced and widely used.     

内皮素-1与肝脏缺血再灌注损伤的实验研究

目的：探索内皮素－1（ET－1）在肝脏血再灌注损伤中的作用。方法：选择雄性Wistar大鼠80只,分为正常对照组、缺血再灌注组1生理盐水组和ET－1抗体组、观察肝脏缺血60min再灌注3h后血浆ET－1、丙氨酸转氨酶（ALT）、透明质本酸（HA）、以及肝组织中ET－1和丙二醛（MDA）含量的变化,并观察肝组织病理学变化,同时,在缺血再灌注组选择第1、3、6、12和24h时相点观察ET－1的变化规律。结果：肝脏缺血再灌注后,血浆和肝组织中ET－1,血浆HA`ALT肝组织中MDA显著升高,而ET－1抗体组血浆ET－1、HA、ALT与缺血再灌注组相比显著降低（P＜0．01,P＜0．05）,同时,肝组织的瘀血程度和损伤程度显著改善。结论ET－1参与了肝脏缺血再灌注损伤,这种损伤与肝脏微循环障碍有关。     

重组杀菌／通透性增加蛋白对内毒素休克中肝脏一氧化氮合酶的 …

目的：探讨重组杀菌／通透性增加蛋白（ｒＢＰＩ２１）对内毒素休克中肝组织一氧化氮合酶（ＮＯＳ）的影响及其意义。方法 大鼠腹腔注射大肠杆菌内毒素（１５．０ｍｇ／ｋｇ）复制内毒素休克模型，动物随机分成正常对照组、内毒素休克组和ｒＢＰＩ２１治疗组。检测肝组织ＮＯＳ活性、三磷酸鸟苷环水解酶Ｉ（ＧＴＰ－ＣＨＩ）活性及生物喋呤含量，同时还观察肝脏微循环血流灌注量的改变。结果 内毒素攻击后肝组织诱生型ＮＯＳ（ｉＮ     

Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models.

The liver function and perfusion following brain death is mainly influenced by the sympathetic nerves and hormones. We examined the specific influence of surgical liver denervation on systemic and hepatic perfusion parameters, bowel ischemia and oxidative stress in hemodynamically stable BD and control (living donor [LD]) pigs. Brain death was induced in 8 pigs via saline infusion into the balloon of an epidural Tieman-catheter (1 mL/15 minutes) and compared to the control group (n = 6) over 4 hours. At 2 hours postoperatively, complete liver denervation was initiated. We analyzed systemic cardiocirculatory parameters (mean arterial pressure, aortic flow, bowel ischemia (endotoxin, and endotoxin-neutralizing capacity) and oxidative stress (total glutathione in erythrocytes [tGSH(E)]) and compared them to local/hepatic perfusion parameters (hepatic artery and portal venous flow, liver blood flow index, and microperfusion), local bowel ischemia (intramucosal pH [pHi] of stomach [pHi(S)]/colon[pHi(C)]), and liver oxidative stress (glutathione [rGSH(L), GSSG(L)]). Following brain death, the parameters including mean arterial pressure, aortic flow, pHi, endotoxin, and tGSH(E) showed no significant changes at 2 hours. Portal venous flow and microperfusion were decreased significantly and hepatic arterial buffer response was ineffective. Hepatic oxidative stress was increased in BD animals (decrease rGSH(L), increase GSSG(L)). Surgical denervation/manipulation increased portal venous flow significantly, hepatic arterial buffer response became effective, and stomach pHi decreased (BD and LD groups). Hepatic oxidative stress was reduced in the BD group (increase rGSH(L)/GSSG(L); P < 0.001) while it was increased in the LD group (decrease rGSH(L)/GSSG(L); P < 0.001). In conclusion, denervation reduces hepatic oxidative stress in BD only in contrast to the LD. The reciprocal effect of denervation depends on the state of neural activation and postulates a potential benefit of surgical denervation before organ harvesting in brain death.     

Effects of hemodynamic instability on brain death-induced prepreservation liver damage

BACKGROUND: Brain death (BD) is an important multifactorial variable contributing to donor-specific liver damage. Our study aimed at assessing the specific effects of hemodynamic instability on systemic and hepatic parameters of perfusion, bowel ischemia, and oxidative stress in a porcine model of BD. METHODS: BD was induced in 16 pigs (German Landrace, 18-28 kg) in two groups (hypotension-BD [HYPO-BD], n=8; normotension-BD [NORM-BD], n=8), which were compared with control animals/living donors (n=6) for a period of 2 hr. We analyzed systemic hemodynamic parameters, bowel ischemia (intramucosal pH in the stomach and colon, plasma endotoxin levels, and endotoxin-neutralizing capacity [ENC]), and oxidative stress (total glutathione levels in erythrocytes) and compared the findings with hepatic parameters of perfusion (hepatic arterial flow, portal venous flow, and microperfusion) and liver oxidative stress (reduced glutathione and oxidized glutathione levels in the liver). RESULTS: Independent of the hemodynamic stability, liver macrocirculation and microcirculation decreased (HYPO-BD, 79+/-6 to 69+/-10 mL/100 g/min; NORM-BD, 81+/-10 to 73+/-7 mL/100 g/min; P<0.05). Hepatocellular damage (aspartate aminotransferase: NORM-BD, 49+/-20 units/L; HYPO-BD, 170+/-140 units/L; P<0.01) and hepatic oxidative stress (reduced glutathione in the liver/oxidized glutathione in the liver: NORM-BD, 29.4+/-2.3 to 13.0+/-1.3; HYPO-BD, 29.4+/-2.3 to 9.05+/-0.81; P<0.001) increased in both BD groups. With dependence on systemic hemodynamic parameters, bowel ischemia increased (intramucosal pH in the colon, 7.22+/-0.01, P<0.01; ENC, 75+/-14 endotoxin-neutralizing units/mL, P<0.01; endotoxin levels, 7+/-2 to 43+/-10 pg/mL, P<0.01) in the HYPO-BD group but not in the NORM-BD group or the living donor group. Furthermore, systemic oxidative stress was increased in the HYPO-BD group only (total glutathione levels in erythrocytes, 2.65+/-0.25 to 0.15+/-0.25 mM; P<0.01). CONCLUSIONS: During BD, liver-specific parameters (portal venous flow, microperfusion, aspartate aminotransferase activity, ENC, and hepatic oxidative stress) were compromised, independent of the hemodynamic status. Therefore, the systemic hemodynamic status does not reflect the functional status of the liver during BD.     

Beta-glucan reflects liver injury after preservation and transplantation in dogs.

Graft failure and extrahepatic organ complications, which frequently develop after transplantation, may be related to inflammatory mediators stimulated by endotoxin (ET). The role of endotoxemia after liver transplantation is controversial and may depend upon differences in the ET assay method used in the various contradicting studies. While the standard Limulus amebocyte lysate (LAL) is reactive for ET and beta-glucan, a novel turbidimetric assay method enables separate determinations of ET and beta-glucan. Beagle dogs undergoing orthotopic liver transplantation were divided into two groups. In Group I (n = 6) the grafts were transplanted immediately and in Group II (n = 6) grafts were preserved for 48 h in University of Wisconsin (UW) solution. Animals received cyclosporine immunosuppression and were followed for 14 days. Daily measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were performed. Samples for ET and beta-glucan measurement were collected serially and processed using the turbidimetric assay method. While no graft failure was seen in Group I, three of six Group II animals died from graft failure within 1 day after transplantation. Preservation and reperfusion injury was much more severe in the Group II grafts than in Group I grafts. While endotoxemia could not be detected, postoperative beta-glucan levels (undetectable pretransplant) were seen in both groups. Beta-glucan levels were much higher in Group II grafts than in Group I grafts, and correlated with the severity of liver damage. In conclusion, this study shows that beta-glucan, instead of ET, appears during the early posttransplant period. We believe that posttransplant elevation of beta-glucan is related to liver damage, especially endothelial damage by preservation and reperfusion.     

Influence of oxygen-derived free radical scavengers on ischemic livers

It has been hypothesized that the formation of oxygen-derived free radicals may play an important part in ischemically induced tissue injury. Using a canine ischemic liver model, we have assessed the role of two oxygen-free radical scavengers, catalase (CAT) and superoxide dismutase (SOD), used alone and in combination, on the recovery of ischemic livers. Liver ischemia was induced in adult mongrel dogs by cross-clamping of the portal vein and hepatic artery for 40 min. Hepatectomy was then performed, and livers were tested in an isolated perfusion model with 500 ml of an albumin-mannitol solution at 37 degrees C for 3 hr. Liver function tests were performed hourly during the perfusion period. Biopsies and 99m-Tc-HIDA scans were also done at the end of perfusion. Livers in group 1 (n = 6) served as controls and were not pretreated prior to ischemic injury. Livers in group 2 (n = 6), group 3 (n = 6), and group 4 (n = 6) were pretreated, respectively, with CAT (5000 U/kg), SOD (5000 U/kg), and SOD and CAT in combination (5000 U/kg) each. The results indicated that the oxygen-derived free radical scavengers, CAT and SOD, were able to provide partial protection against the free radicals accumulated during ischemic damage. These studies offer some potential avenues for the protection of livers prior to and after transplantation.     

Important role for endothelins in acute hepatic ischemia/reperfusion injury.

The aim of this study was to explore the complex role of endothelins (ETs) in hepatic ischemia-reperfusion injury and to minimize this type of injury by nonselective ET receptor blockade. In an in vivo rat model, hepatic ischemia was induced for 30 min. The rats were divided into three groups: (1) sham operated, (2) untreated ischemic, and (3) group treated with the nonselective ET receptor antagonist bosentan (1 mg/kg body weight iv). Blockage of the ET system during ischemia-reperfusion was assessed by: (1) in vivo microscopic analysis, (2) measurement of local tissue PO2, (3) laser Doppler flowmetry, (4) transaminases, and (5) tumor necrosis factor (TNF)- serum levels. During liver ischemia, anoxia (mean liver pO2 decreased from 14.7 to 1.5 mm Hg) and TNF- (levels rose from 0 pg/mL to 145.3 pg/mL at the end ofischemia) were associated with the release of ETs. Immunoreactive ET-1 (ir-ET-1) plasma levels (basal levels: 12.1+/-1.8 pg/mL) went up by 2.6-fold (32.1+/-6.8 pg/mL) after 15 min and by 11.7-fold (142.1+/-32.6 pg/mL) after 120 min of reperfusion. Increased plasma levels of ir-ET-1 were associated with sinusoidal constriction to 77.6+/-7.1% of basal diameters. This constriction led to significant decreases in perfusion rate (77+/-3%), local tissue PO2 (6.9+/-2.7 mm Hg), and erythrocyte flux (61.7+/-13.8% of basal values). Hepatocellular damage, evaluated via the serum level of aspartate aminotransferase (AST, increase to 393.5+/-68.3 U/L, preoperative 23.9+/-2.0 U/L) was detectable 6 h after reperfusion (p < .05). Administration of bosentan before 30 min of ischemia significantly reduced ischemia-reperfusion injury and was associated with an increase of ir-ET-1 levels to 110.8+/-12.0 pg/mL and 94.1+/-25.0 pg/mL after 15 and 120 min of reperfusion. Sinusoidal diameters were maintained at nearly 100% in the treatment group instead of 77%, while perfusion rate (88+/-2%) and tissue PO2 (12.1+/-1.0 mm Hg) rose significantly in contrast with the nontreatment group (p < .05). Hepatocellular damage was reduced (AST levels after 6 h of reperfusion 244.0+/-34.4 U/L, p <.05), and leukocyte sticking and rolling were diminished (p < .01). In the treatment group, bosentan values of 5.6+/-0.7 and 2.9+/-0.4 ng/mL after 15 and 120 min of reperfusion were measured. In conclusion the release of endothelins is combined with microcirculatory disturbances and local hypoxia, thereby causing liver damage. By protecting the liver microcirculation, ET receptor blockade of both receptors at a low dose increased blood and oxygen supply to the liver and reduced hepatocellular injury. These results constitute the bases for further studies and transfer into clinical practice.