Scommotau S, Uhlmann D, Löffler B M, Breu V, Spiegel H U
University of Leipzig, Department of Ophthalmology, Germany.
Langenbecks Arch Surg. 1999 Feb;384(1):65-70. doi: 10.1007/s004230050176.
Endothelin (ET) and nitric oxide (NO) act as opponents in the regulation of the hepatic microcirculation. During ischemia/reperfusion (I/R) ET levels are increased, whereas no rise in NO levels is observed. This imbalance may be responsible for microcirculatory disturbances. The aim of this study was to restore the delicate ET/NO balance to maintain the integrity of the hepatic microcirculation and to reduce I/R injury.
Ischemia was induced by crossclamping of the hepatoduodenal ligament for 30 min with portal decompression using a splenocaval shunt (56 Wistar rats, 200-250 g). Sham operation, ischemia and treatment groups with the endothelin receptor antagonist (ERA) bosentan (1 mg/kg body weight i.v.) and the NO donor L-arginine (400 mg/kg body weight i.v.) were performed. For assessment of the microcirculation, sinusoidal perfusion rate, diameters of sinusoids and postsinusoidal venules, leukocyte endothelium interactions and velocity of free-flowing leukocytes were investigated by means of in vivo microscopy 30-90 min after reperfusion. Local hepatic tissue PO2 was measured prior to ischemia, 30 min and 60 min after reperfusion and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels were investigated 2 h and 6 h after reperfusion.
After ischemia, sinusoidal and venular diameters were reduced to 76% and 85%, respectively, of sham operation group values (P<0.05), but were maintained at baseline in ERA (98/102%) and NO (102/105%) groups (P<0.05). Increased postischemic leukocyte sticking in sinusoids (144%) and venules (435%) was reduced by therapy to 110/253% (ERA) and 111/ 324% (NO), respectively (P<0.05). Perfusion rate was increased to 93% and 94% compared with 82% in the ischemia group (P<0.05). Concomitant with the improved microcirculation in therapy groups, local hepatic tissue pO2 was improved 30 min after reperfusion in the ERA (11.0 mmHg) and the L-arginine group (11.5 mmHg) relative to the ischemic group (6.9 mmHg) (P<0.05). In addition, postischemic AST/ALT increase was reduced by therapy.
Our results indicate that maintenance of ET/NO balance by blocking ET receptors, as well as providing a NO donor, protects the liver microcirculation and reduces hepatic I/R injury.
内皮素（ET）和一氧化氮（NO）在肝微循环调节中起拮抗作用。在缺血/再灌注（I/R）期间，ET水平升高，而未观察到NO水平升高。这种失衡可能是微循环障碍的原因。本研究的目的是恢复ET/NO的微妙平衡，以维持肝微循环的完整性并减少I/R损伤。
通过夹闭肝十二指肠韧带30分钟诱导缺血，并使用脾肾分流术进行门静脉减压（56只体重200 - 250克的Wistar大鼠）。进行假手术、缺血以及使用内皮素受体拮抗剂（ERA）波生坦（静脉注射1毫克/千克体重）和NO供体L-精氨酸（静脉注射400毫克/千克体重）的治疗组。为评估微循环，在再灌注后30 - 90分钟通过体内显微镜检查研究窦状隙灌注率、窦状隙和窦后小静脉直径、白细胞与内皮细胞相互作用以及自由流动白细胞的速度。在缺血前、再灌注后30分钟和60分钟测量局部肝组织PO2，并在再灌注后2小时和6小时研究天冬氨酸转氨酶（AST）/丙氨酸转氨酶（ALT）水平。
缺血后，窦状隙和小静脉直径分别降至假手术组值的76%和85%（P<0.05），但在ERA组（98/102%）和NO组（102/105%）中维持在基线水平（P<0.05）。缺血后窦状隙（144%）和小静脉（435%）中白细胞黏附增加，经治疗分别降至110/253%（ERA）和111/324%（NO）（P<0.05）。灌注率与缺血组的82%相比分别提高到93%和94%（P<0.05）。与治疗组微循环改善相伴，再灌注后30分钟，ERA组（11.0 mmHg）和L-精氨酸组（11.5 mmHg）的局部肝组织pO2相对于缺血组（6.9 mmHg）有所改善（P<0.05）。此外，治疗减轻了缺血后AST/ALT的升高。
我们的结果表明，通过阻断ET受体以及提供NO供体来维持ET/NO平衡可保护肝微循环并减少肝I/R损伤。
