Graft preconditioning with low-dose tacrolimus (FK506) and nitric oxide inhibitor aminoguanidine (AGH) reduces ischemia/reperfusion injury after liver transplantation in the rat

Abstract

Ischemia/reperfusion (I/R) injury is a main cause of primary dysfunction or non-function after liver transplantation (LTx). Recent evidence indicates that an increase in nitric oxide (NO) production after LTx is associated with I/R injury. The aim of this study was to demonstrate that low-dose FK506 in combination with aminoguanidine (AGH), which leads to a reduction of NO levels, has a protective effect by reducing I/R associated injury after LTx. Fortyone DA-(RT1av1) rats served as donors and recipients for syngenic orthotopic arterialised LTx. They were divided into 4 groups: controls without pre-/treatment (I), pre-/treatment with high-dose FK506 (II), pre-/treatment with AGH only (III), and pre-/treatment with low-dose FK506 in combination with AGH (IV). After LTx the laboratory parameters and liver biopsy were performed. The levels of transaminase (ALT) in groups I, II and III were significantly higher on day 3 after LTx compared to group IV (p = 0.001, p = 0.001, p = 0.000). In group IV the I/R-associated liver necrosis rate was reduced significantly. Our results demonstrated that a combined dual pharmacological pretreatment (group IV) reduced I/R injury of the graft after LTx in a rat model.

Experimental Studies on Protective Effects of FK506 Against Hepatic Ischemia-Reperfusion Injury

“…However, large amounts of NO may in turn paradoxically damage liver tissue by forming nitrogen peroxide (40). Husser N. reported that low-dose FK506 in combination with aminoguanidine, which leads to a reduction of NO levels, reduced IRI of the graft after liver transplantation in a rat model (41).…”

Tacrolimus Preconditioning of Rat Liver Allografts Impacts Glutathione Homeostasis and Early Reperfusion Injury

“…Because pharmaceutical preconditioning of liver grafts is more feasible in the clinical setting than donor preconditioning [32][33][34][35] or post-ischemic treatment [11,36], we studied the addition of a calcineurin inhibitor (tacrolimus; FK506) to the rinse solution. We chose tacrolimus because of recent work demonstrating beneficial effects of this immunosuppressant on reperfusion injury in human liver transplantation [19].…”

“…This suggests that ROS, either released intracellulary or in the sinusoidal space, might be a target for tacrolimus action [32,40]. Currently, the most important clinical use of tacrolimus is as an immunosuppressant, based on its ability to inactivate T-cells [41].…”

“…Currently, the most important clinical use of tacrolimus is as an immunosuppressant, based on its ability to inactivate T-cells [41]. However, additional effects of tacrolimus have been documented [32], in particular its ability to prevent ischemic damage in tissues when administered intravenously before ischemia, although the mechanisms underlying these effects are not known [42,43]. Other investigators were able to demonstrate the preservation of microvascular perfusion following liver ischemia and reperfusion [44], and a substantial decrease in free radical production in association with improvement of IRI when tacrolimus is administered before ischemia [18,45,46].…”

Portal and Arterial Flushing with HTK and Tacrolimus Can Attenuate the Incidence of Early Liver Allograft Dysfunction

“…Experimental data point to a possible role of calcineurin inhibitor Tacrolimus in IRI attenuation and liver protection during LT (10,11,12). Tacrolimus was shown to be able to inhibit inflammation and immune response in the transplanted liver at the genomic level; the available data on protective function of calcineurin inhibitors in cardiac IRI indicate organ-nonspecific possible mechanism of action (13,14).…”