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

Abstract

emia/reperfusion injury in clinical liver transplantaAngiotensin-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 post-nancies. 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 post-physiologically, graft dysfunction is based on preexisting dosinusoidal venules were analyzed during 45 to 60 min-nor 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 im-are generated with reoxygenation of the liver. Results in ani- first time that ACE inhibition in the liver recipient g body weight; recipients: 190-250 g) underwent orthotopic liver by enalapril attenuates hepatic ischemia/reperfusion transplantation according to the cuff technique described by Kamada damage after experimental liver transplantation. Our and Calne. 8 In contrast to Kamada's original technique, grafts were results may offer a novel approach to reduce isch-rearterialized and simultaneously reperfused by the portal and arterial route as described by Post et al. 9 Livers were preserved by retrograde aortal flush with University of Wisconsin solution and stored at 4ЊC for 24 hours. Before reperfusion, the grafts were flushed with 10 mL of Ringer's lactat...

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

“…Because ACEIs increase the level of bradykinin, our findings emphasize the importance of using ACEIs in situations in which I/R injury is likely to occur. Pretransplant treatment of the donor with ACEIs, as well as posttransplant treatment of the recipient, merits consideration (5).…”

“…Angiotensin-I-converting enzyme (ACE) inhibitors (ACEIs) reduce not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by I/R in the heart (3), lung (4), liver (5), and kidneys (6,7). Several observations indicate that the beneficial effects of ACEIs in the acute phase are mainly due to activation of the bradykinin nitric oxide (NO) cascade as a result of inhibition of the inactivation of bradykinin, rather than due to suppression of angiotensin II formation.…”

Effects of Vasodilatory Antihypertensive Agents on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure.

“…It is well established that ACE inhibitors prevent not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by ischemia/reperfusion in the heart, lung, liver and kidneys (23)(24)(25)(26)(27). Interestingly, it has been demonstrated that the beneficial effects of ACE inhibitors in the acute phase are mainly due to the activation of bradykinin-NO or of the bradykinin-prostacyclin cascade, rather than to the suppression of angiotensin II, because angiotensin type 1 receptor antagonists have been clearly shown to be less beneficial than ACE inhibitors in previous studies (28,29), and because addition of bradykinin type 2 receptor antagonists has been shown to abolish the effects of ACE inhibitors (28)(29)(30).…”

Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor

“…Ultimately, Ang II causes vascular injury and organ damage. In fact, several lines of evidence have implicated that inhibition of Ang II may protect against ischemia-reperfusion-induced tissue injury in the heart, brain, liver, kidney, and small intestine (1,5,17,42). Previous studies have shown that the increase in Ang II is more prominent in the splanchnic circulation than in the systemic circulation during major aortic surgery and hypovolemia (44).…”