Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats

As in other organs, oxidative stress-induced injury and cell death may result from free oxygen radicals-dependent mechanisms and alterations in signal transduction pathways leading to apoptosis. Among new suggested therapies against injuries caused by oxidative stress, the use of levosimendan has been reported to be quite promising. In the present study we aimed to examine the protective effects of levosimendan against liver oxidative stress in anesthetized rats and to analyze the involvement of mitochondrial ATP-dependent K (mitoKATP ) channels and nitric oxide (NO). In 50 anesthetized rats, liver ischemia/reperfusion was performed by non-traumatic portal occlusion. In some animals, levosimendan was infused into the portal vein at the onset of reperfusion whereas other rats received vehicle only. Moreover, in some rats, levosimendan was given after intra-portal L-N?-nitro-arginine-methyl-esthere (L-NAME), or 5-hydroxydecanoate (5HD). Portal vein blood flow was measured and blood samples were taken for transaminases, thiobarbituric acid reactive substances (TBARS) and gluthatione (GSH) determination, whereas liver biopsy samples were used for Bax, Caspase 9, Akt and endothelial NOS (eNOS) activation through Western blot. Also, Caspase 3 activity was measured. In rats, ischemia/reperfusion caused an increase of apoptotic markers, transaminases and TBARS, and a decrease of GSH and of Akt activation. Levosimendan administration was able to counteract oxidative damages and apoptosis in a dose-dependent way and to increase GSH, Akt and eNOS activation. All effects of levosimendan were abolished by pre-treatment with L-NAME and 5HD. The results of the present study have shown that levosimendan can exert protection against liver ischemic damages through mechanisms related to NO production and mitoKATP channels function. These data open interesting perspectives for the use of levosimendan in hepatic surgery and transplantation.