Protective role of an endothelin-converting enzyme inhibitor (FR901533) inhepatic ischemia/reperfusion injury

Introduction. There is evidence that endothelin (ET) contributes to disturb ances of the hepatic microcirculation after warm ischemia/reperfusion (I/R) by causing vasoconstriction and by enhancing leukocyte endothelium interac tions. The aim of this study was to investigate a possible protective role of the endothelin converting enzyme (ECE) inhibitor FR901533 in this settin g. Methods. In an in vivo model (42 Wistar rats), hepatic ischemia was induced for 30 min by Pringle's maneuver. Sham operated (I), untreated ischemic (I I), and treatment (III) groups with FR901533 (1 mg/kg bw iv) were investiga ted. The effect of FR901533 in I/R was assessed by in vivo microscopy (30 - 90 min after reperfusion), measurement of local tissue pO(2) (30 and 60 min after reperfusion), and determination of AST/ALT levels (2 h, 6 h, and 2, 6, and 14 days after reperfusion). Results. In the untreated ischemic group (II) sinusoidal constriction to 76 .3 +/- 4.2% of basic diameters was observed, leading to significant decreas es in perfusion rate (2.3 +/- 3.6% of sham group) and in liver tissue pO(2) (43.5 +/- 3.2% of sham group) (P < 0.05). In addition, we found an increas ed percentage of stagnant leukocytes in sinusoids (138.3 <plus/minus> 9.8) and sticking leukocytes in postsinusoidal venules (155.2 +/- 3.3% of sham g roup) (P < 0.05). Hepatocellular damage (AST/ALT increase to 430.6 <plus/mi nus> 47.7 U/L/200.2 +/- 23.8 U/L, pre: 27.4 +/- 2.7 U/L/28.1 +/- 2.7 U/L) w as detected 6 h after reperfusion (P < 0.05). Administration of the ECE inh ibitor before ischemia significantly reduced I/R injury. Sinusoidal diamete rs were maintained (102.2 <plus/minus> 1.7%), while perfusion rate (93.1 +/ - 1.8%) and tissue pO(2) (105.3 +/- 2.7%) increased significantly (P < 0.05 ). Hepatocellular damage was decreased (AST/ALT levels after 6 h of reperfu sion: 166.6 <plus/minus> 26.3 U/L/132.4 +/- 22.5 U/L, P < 0.05) and leukocy te sticking and rolling were significantly reduced (P < 0.05). Conclusion. Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury. (C) 2001 Academic Press.