emia/reperfusion injury in clinical liver transplanta-Angiotensin-converting enzyme (ACE) inhibitors
tion. (HEPATOLOGY 1997; 25:648-651.) 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
After more than 20 years of clinical experience, liver transyet been investigated. Therefore, we studied in a plantation is an established treatment modality for end-stage model of syngeneic liver transplantation in the rat liver disease, acute liver failure, and selected hepatic maligthe effect of recipient enalapril treatment on postnancies. 1,2 The timing of transplantation and selection of suitischemic liver injury. Untreated animals served as able donors and recipients are crucial cornerstones for a sucthe control group. Treatment with enalapril was cessful outcome of the costly procedure. In up to 22% of cases, started 5 minutes before reperfusion by intravenous primary graft dysfunction after transplantation is observed, infusion of enalapril at a dosage of 5 mg/kg/h. By initiating a cascade of severe postoperative complications means of in vivo microscopy, the sinusoidal perfusion with considerable impact on morbidity and mortality. 3 Pathorate and leukocyte adherence in sinusoids and postphysiologically, graft dysfunction is based on preexisting dosinusoidal venules were analyzed during 45 to 60 minnor liver damage and insults from cold/warm ischemia and utes of reperfusion. Liver function was monitored by reperfusion. measuring bile output over a period of 60 minutes.
In recent years, many attempts have been made to improve Analysis of coagulation factors (prothrombin time, organ preservation, e.g., to prolong the tolerable ischemic factor V, fibrinogen) and liver enzymes (alanine time, and to better protect the graft from both anoxic and transaminase [ALT], aspartate transaminase [AST]) oxygen free radical-mediated damage. Therapeutic strateserved for the evaluation of organ dysfunction and gies in recipients were aimed particularly at the reduction of damage secondary to ischemia/reperfusion injury. reperfusion injury mediated by oxygen free radicals, which The sinusoidal perfusion rate was significantly imare generated with reoxygenation of the liver. Results in aniproved by enalapril treatment (94.7% [1.0] vs. 75.3% mal studies of myocardial ischemia showed cardioprotective [3.8]; mean [SEM]; P ร
.005). In addition, leukocyteproperties of angiotensin-converting enzyme (ACE) inhibisticking in both liver sinusoids and postsinusoidal vetors, 4-6 perhaps related to favorable effects of these drugs on nules was remarkably reduced in enalapril-treated vasomotor tone and bradykinin-prostacyclin metabolism. 7 In animals as compared with controls (stickers/lobule: the present work, using a model of syngeneic liver trans-21.0 [3.3] vs. 59.2 [2.1]; P ร
.0004; stickers/mm 2 venular plantation in rats, we tested whether similar beneficial efsurface: 20.5 [4.7] vs. 110.3 [18.1]; P ร
.0004). Moreover, fects of ACE-inhibitor enalapril occur following hepatic isbile output was increased (1.13 [0.35] vs. 0.43 [0.18] g chemia and reperfusion. bile/60 minr100 g liver; P ร
.06). Values for PT (22.5% [2.1] vs. 9.7% [1.8]; P ร
.005), factor V 99.4% [9.5] vs. MATERIALS AND METHODS 49.5% [8.5]; P ร
.007), and fibrinogen (64.1% [7.7] vs. All experiments were performed with the permission of the Gov-12.8% [3.2]; P ร
.001) were significantly improved, parernment Authorities and in accordance with the German Legislation alleled by a remarkable reduction in serum ALT (1,428 on Laboratory Animal Experiments.