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

Abstract

INTRODUCTION:

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).

CONCLUSION:

Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury.

• Authors: D Uhlmann, H Witzigmann, N Senninger, J Hauss, H U Spiegel
• Journal: Microvascular research (Microvasc Res) Vol. 62 Issue 1 Pg. 43-54 (Jul 2001) ISSN: 0026-2862 [Print] United States
• PMID: 11421659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Endothelin-1
• Tetracyclines
• WS 79089B
• Aspartic Acid Endopeptidases
• Metalloendopeptidases
• Oxygen

Topics

• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Endothelin-1 (blood, metabolism)
• Female
• Hemodynamics
• Laser-Doppler Flowmetry
• Liver (blood supply, physiopathology)
• Liver Circulation
• Metalloendopeptidases (antagonists & inhibitors)
• Oxygen (metabolism)
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy)
• Tetracyclines (therapeutic use)