Protective role of an endothelin-converting enzyme inhibitor (FR901533) in hepatic ischemia/reperfusion injury.
BACKGROUND
There is evidence that endothelin (ET) contributes to disturbances of the hepatic microcirculation after warm ischemia/reperfusion (I/R) by causing vasoconstriction and by enhancing leukocyte endothelium interactions. The aim of this study was to investigate a possible protective role of the endothelin converting enzyme (ECE) inhibitor FR901533 in this setting.


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 (II), and treatment (III) groups with FR901533 (1 mg/kg bw iv) were investigated. The effect of FR901533 in I/R was assessed by in vivo microscopy (30-90 min after reperfusion), measurement of local tissue pO2 (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 decreases in perfusion rate (82.3 +/- 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 increased percentage of stagnant leukocytes in sinusoids (138.3 +/- 9.8) and sticking leukocytes in postsinusoidal venules (155.2 +/- 3.3% of sham group) (P < 0.05). Hepatocellular damage (AST/ALT increase to 430.6 +/- 47.7 U/L/200.2 +/- 23.8 U/L, pre: 27.4 +/- 2.7 U/L/28.1 +/- 2.7 U/L) was detected 6 h after reperfusion (P < 0.05). Administration of the ECE inhibitor before ischemia significantly reduced I/R injury. Sinusoidal diameters were maintained (102.2 +/- 1.7%), while perfusion rate (93.1 +/- 1.8%) and tissue pO2 (105.3 +/- 2.7%) increased significantly (P < 0.05). Hepatocellular damage was decreased (AST/ALT levels after 6 h of reperfusion: 166.6 +/- 26.3 U/L/132.4 +/- 22.5 U/L, P < 0.05) and leukocyte sticking and rolling were significantly reduced (P < 0.05).


CONCLUSIONS
Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury.
Uhlmann
D
D
Second Department of Surgery, University of Leipzig, Leipzig, 04103, Germany.
Witzigmann
H
H
Senninger
N
N
Hauss
J
J
Spiegel
H U
HU
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D005260:Female; D006439:Hemodynamics; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000098:blood supply* / Q000503:physiopathology; D008102:Liver Circulation; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D013754:Tetracyclines / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D013754:Tetracyclines; C088494:WS 79089B; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D010100:Oxygen