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Unlabelled: Ischemia leads to profound endothelin-related constriction of the hepatic microcirculation with resulting disturbances in blood and oxygen supply. The aim of the study was to modulate hepatic microvascular diameters by blocking endothelin receptors with bosentan, and also to find the best possible vessel width (as produced by bosentan) for minimizing ischemia/reperfusion injury., Methods: In an in vivo rat model hepatic ischemia was induced for 30 minutes by crossclamping the hepatoduodenal ligament. The endothelin receptor antagonist (ERA) bosentan was administered before ischemia in stepwise dosages of 0.1, 1.0 and 10 mg/kg bw i.v. and 10 mg/kg bw intraportally (i.p.). Vasoactive effect was assessed by in vivo microscopy. The influence on hepatic oxygen supply and hepatocellular function was evaluated by measuring local tissue pO(2) and AST levels., Results: Because of ischemia sinusoidal diameters were reduced to 76.3 +/- 7.4% compared with values found in sham-operated animals. After administration of 0.1 mg/kg ERA (bosentan) the sinusoids remained constricted (89.7 +/- 9.9%). Blocking endothelin receptors with 1 mg/kg bosentan avoided sinusoidal constriction (99.0 +/- 8.8%, p<0.05) and led to the most effective reduction of AST level peak after 6 h of reperfusion (244.0 +/- 34.2 U/l vs 422.9 +/- 163.3 U/l in untreated ischemia). 10 mg/kg i.v. caused an increase in sinusoidal diameter to 109.1 +/- 6.4% and 10 mg/kg intraportally to 136.8 +/- 19.3% and even an increase in AST levels (618.9 +/- 209.3 U/l). Hepatic ischemia led to a significant decrease of local tissue pO(2) after reperfusion (9.4 +/- 1.2 mm Hg; p<0.05 vs sham: 16.8 +/- 1.8 mm Hg). The greatest improvement in postischemic oxygen supply was found in the 1.0 mg/kg group (12.9 +/- 1.0 mm Hg; p< 0.05 vs ischemia). Venular diameter changed almost to the same extent as sinusoidal diameter. Perfusion rate was significantly increased and sticking of leukocytes in sinusoids and venules was reduced after doses of 1 and 10 mg/kg bw bosentan i.v. (p<0.05)., Implications: In this model we were able to regulate the diameters of sinusoids and postsinusoidal venules incrementally. We conclude that the avoidance of constriction, without excessive vasodilatation gives increased perfusion rates with improved hepatic oxygen supply and hepatocellular function.

The aim of this study was to develop and establish a new system of laparoscopic fluorometry for the purpose of investigating the intestinal microcirculation. In 25 pigs (German Landrace, 16–25 kg body weight), ischemia was established in two segments (A, irreversible; B, reversible ischemia; C, internal control) of the small intestine by a laparoscopic technique. Microcirculation in the segments was assessed by laparoscopy at a second-look operation 24 h later by means of the fluorescence system Endoscan. The fluorescence of the three bowel segments was measured by arbitrary dye fluorescence units (DFU) 15 min after starting reperfusion, before and after injection of sodium fluorescein (NaFlu, 0.25 mg/kg body weight). The dividing line between viable and nonviable bowel tissue was established from the inflow and outflow rates of NaFlu with the aid of ROC (receiver operating characteristic) curves. The specificity and sensitivity of the new method were evaluated by correlating the results with the viability of each intestinal segment as predicted by three laparoscopically experienced surgeons and by histological examination. By means of the calculated separation sharpness (fluorescence index at 2 min >0.5, outflow factor of NaFlu at 10 min >20%), the overall predictions of intestinal viability in all 25 animals achieved a sensitivity of 93.5% and a specificity of 94.1% by laparoscopic fluorometry, versus a sensitivity of 70.8% and a specificity of 87.5% for the prediction of bowel viability by ordinary laparoscopic technique. Used as an adjunct to conventional laparoscopy, laparoscopic fluorometry brought significant gains in sensitivity and specificity in the distinction between reversible and irreversible intestinal ischemia. [ABSTRACT FROM AUTHOR]

Leukocyte emigration from blood to sites of inflammation involves sequential interaction of specific adhesion molecules expressed by both leukocytes and endothelial cells. The central steps in leukocyte-endothelial adhesive interactions are leukocyte rolling, sticking, and transmigration. This study investigated the effect of monoclonal antibodies against CD54 (ICAM-1) and CD11b (αM-chain of MAC-1) on intestinal inflammation. Anti-CD54 and anti-CD11b were tested in rats with indomethacin-induced chronic ileitis. Macroscopic changes were assessed by a modified version of the Wallace et al. score. Leukocyte rolling and sticking were investigated by intravital microscopy. Results show that indomethacin administration led to a chronic inflammatory response characterized by significant increase ( P<0.05) in rolling (from 5.41±2.87 to 32.41±15.03 100 µm–1 s–1) and sticking (from 0.16±0.18 to 9.11±5.3 100 µm–1 s–1) leukocytes. After antibody treatment only the anti-CD11b group showed significant ( P<0.05) reduction in rolling (from 32.41±15.03 to 6.6±2.7 100 µm–1 s–1) and sticking (from 9.11±5.3 to 0.07±0.09 100 µm–1 s–1) leukocytes. This was also the case for macroscopic changes. Indomethacin led to a rise in the Wallace score from 0 to 4.29±0.76 points ( P<0.05) and anti-CD11b to a reduction from 4.29±0.76 to 1.29±1.11 points ( P<0.05). Anti-CD54 and combined anti-CD11b/CD54 administration was not followed by significant changes. Therefore we suggest that leukocyte-based CD11b but not endothelial-based CD54 contributes most to leukocyte adhesion in the setting of indomethacin-induced ileitis in rats. [ABSTRACT FROM AUTHOR]

Hepatic ischemia followed by reperfusion evokes an imbalance between the vasoregulatory compounds endothelin and nitric oxide (NO) followed by constriction of the vascular bed, leading to microcirculatory disturbances and reduced blood flow, thereby causing hypoxia and liver damage. The aim of this study was to protect the liver microcirculation by maintaining this delicate balance. Material and Methods: In an in vivo ischemia/reperfusion model with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by Pringle’s maneuver. The effect of the NO donor L-arginine (400 mg/kg b.w. i.v.) was assessed by in vivo microscopy. Microhemodynamic studies, including the sinusoidal perfusion rate, diameters of hepatic sinusoids and postsinusoidal venules, leukocyte endothelium interactions and leukocyte velocity were performed. Microcirculatory data were compared with local tissue pO[sub 2] and serum transaminase levels. Results: After ischemia the diameters of sinusoids and postsinusoidal venules were significantly reduced to 76 ± 7 and 86 ± 10% respectively in the nontreatment group, but dilated to 102 ± 3 and 105 ± 7% in the group treated with L-arginine (p < 0.001). The percentage of permanently adherent leukocytes in sinusoids and venules was increased by ischemia, but L-arginine reversed this increase (p < 0.001). Perfusion rate was improved to 90 ± 2 compared with 83 ± 5% in the untreated group (p < 0.01). Systemic arterial blood pressure was not affected by administration of the NO donor. The postischemic increase in serum transaminase levels was diminished in the treatment group (ASAT: p < 0.05). Local postischemic hepatic tissue pO[sub 2] was significantly decreased to 45% of basal values after 30 min and to 55% after 60 min of reperfusion (p < 0.05). Administration of L-arginine results in a significant increase in local tissue pO[sub 2] to 86 and 106% of basal values respectively (p < 0.05). Conclusion: These data indicate that L-arginine improves hepatic microcirculation after warm ischemia by increasing sinusoidal perfusion rate and by diminishing leukocyte endothelium interactions. Maintained integrity of microcirculation is associated with sufficient oxygen supply and improved hepatocellular function. [ABSTRACT FROM AUTHOR]

Researchers studied a selective endothelin-A receptor antagonist for its potential influence on the microcirculation in the setting of partial liver transplantation. Ninetyeight isogeneic Lewis rats were divided into 4 groups: (I) partial liver transplantation, (II) partial liver transplantation treated with the Darusentan immediately before reperfusion, (III) full-size liver transplantation, (IV) sham operation. Subsequently, the liver microcirculation was evaluated by intravital microscopy, and survival, liver function, and morphology were followed up to the 14th day. Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan, group (I), showed a lower survival rate. These animals displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion. Disintegration of endothelium and increased recruitment of Kupffer cells were a frequent morphologic finding. The Darusentan-treated group (II) showed improved survival as well as improved parameters of microcirculatory function and morphology.