Angiotensin-converting enzyme inhibition by enalapril: a novel approach to reduce ischemia/reperfusion damage after experimental liver transplantation.

Abstract

Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective in the reduction of ischemia/reperfusion damage after myocardial ischemia. Whether this favorable effect can be related to other models of ischemia and reperfusion has not yet been investigated. Therefore, we studied in a model of syngeneic liver transplantation in the rat the effect of recipient enalapril treatment on postischemic liver injury. Untreated animals served as the control group. Treatment with enalapril was started 5 minutes before reperfusion by intravenous infusion of enalapril at a dosage of 5 mg/kg/h. By means of in vivo microscopy, the sinusoidal perfusion rate and leukocyte adherence in sinusoids and postsinusoidal venules were analyzed during 45 to 60 minutes of reperfusion. Liver function was monitored by measuring bile output over a period of 60 minutes. Analysis of coagulation factors (prothrombin time, factor V, fibrinogen) and liver enzymes (alanine transaminase [ALT], aspartate transaminase [AST]) served for the evaluation of organ dysfunction and damage secondary to ischemia/reperfusion injury. The sinusoidal perfusion rate was significantly improved by enalapril treatment (94.7% [1.0] vs. 75.3% [3.8]; mean [SEM]; P = .005). In addition, leukocyte-sticking in both liver sinusoids and postsinusoidal venules was remarkably reduced in enalapril-treated animals as compared with controls (stickers/lobule: 21.0 [3.3] vs. 59.2 [2.1]; P = .0004; stickers/mm2 venular surface: 20.5 [4.7] vs. 110.3 [18.1]; P = .0004). Moreover, bile output was increased (1.13 [0.35] vs. 0.43 [0.18] g bile/60 min x 100 g liver; P = .06). Values for PT (22.5% [2.1] vs. 9.7% [1.8]; P = .005), factor V 99.4% [9.5] vs. 49.5% [8.5]; P = .007), and fibrinogen (64.1% [7.7] vs. 12.8% [3.2]; P = .001) were significantly improved, paralleled by a remarkable reduction in serum ALT (1,428 U/L [190] vs. 2,315 [248]; P = .02). Our data show for the first time that ACE inhibition in the liver recipient by enalapril attenuates hepatic ischemia/reperfusion damage after experimental liver transplantation. Our results may offer a novel approach to reduce ischemia/reperfusion injury in clinical liver transplantation.