Important Role for Endothelins in Acute Hepatic Ischemia/Reperfusion Injury

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Abstract
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.