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

Abstract

As in other organs, oxidative stress-induced injury and cell death may result from free oxygen radical-dependent mechanisms and alterations in signal transduction pathways leading to apoptosis. Among the new suggested therapies for 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 adenosine triphosphate-dependent potassium (mitoK ATP ) channels and nitric oxide (NO). In 50 anesthetized rats, liver ischemia/reperfusion (I/R) was performed via nontraumatic portal occlusion. In some animals, levosimendan was infused into the portal vein at the onset of reperfusion, whereas other rats received the vehicle only. Moreover, in some rats, levosimendan was given after the intraportal administration of L-Nx-nitro-arginine methyl ester (L-NAME) or 5-hydroxydecanoate (5HD). The portal vein blood flow was measured, and blood samples were taken for the determination of transaminases, thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH); liver biopsy samples were used for B cell lymphoma 2-associated X protein, caspase-9, Akt, and endothelial nitric oxide synthase (eNOS) activation through western blotting. Also, caspase-3 activity was measured. In rats, I/R caused an increase in apoptotic markers, transaminases, and TBARS and a decrease in GSH and Akt activation. Levosimendan administration was able to counteract oxidative damage and apoptosis in a dose-dependent way and to increase GSH, Akt, and eNOS activation. All effects of levosimendan were abolished by pretreatment with L-NAME and 5HD. In conclusion, the results of the present study show that levosimendan can exert protection against ischemic liver damage through mechanisms related to NO production and mitoK ATP channel function. These data provide interesting perspectives into the use of levosimendan in hepatic surgery and transplantation. Liver Transpl 20:361-375, 2014. V C 2013 AASLD.Received August 1, 2013; accepted November 9, 2013.Oxidative stress has been implicated as a mechanism of liver injury due to ischemia/reperfusion (I/R) and can occur in a variety of clinical contexts, including hepatectomy, transplantation, hypovolemic shock, cardiogenic shock, and low-output syndrome.1-5 The precise mechanisms of I/R-induced liver injury have Abbreviations: 5HD, 5-hydroxydecanoate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bax, B cell lymphoma 2-associated X protein; eNOS, endothelial nitric oxide synthase; GSH, reduced glutathione; H&E, hematoxylin and eosin; I/R, ischemia/reperfusion; L-NAME, L-Nx-nitro-arginine methyl ester; MDA, malondialdehyde; mitoK ATP , mitochondrial adenosine triphosphate-dependent potassium; NO, nitric oxide; p-Akt, phosphorylated Akt; p-Bax, phosphorylated B cell lymphoma 2-associated X protein; p-caspase-9, phosphorylated caspase-9; p-eNOS, phosphorylated endotheli...

Protective effect of proanthocyanidins on anoxia-reoxygenation injury of myocardial cells mediated by the PI3K/Akt/GSK-3β pathway and mitochondrial ATP-sensitive potassium channel

“…The mitoKATP channel has a protective role in anoxia-reoxygenation injury; however, the precise location of interference with the process remains to be identified. A number of studies have hypothesized that the mitoKATP channel is the initiating factor in the protection mechanism of ischemia-reperfusion injury, while others consider it to be the final effector (26)(27)(28).…”

Paeoniflorin attenuates hepatic ischemia/reperfusion injury via anti-oxidative, anti-inflammatory and anti-apoptotic pathways

“…In liver surgery, hepatic blood flow is typically blocked in order to reduce bleeding; however, this inevitably results in hepatic ischemia/reperfusion injury (HI/R) (1). HI/R injury does not only cause significant direct damage to liver cells; but also alters the regenerative ability of these cells, which is a critical factor influencing the success rate of liver surgery and the postoperative survival rate of patients (2).…”

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

“…RCSs from lipid peroxidation cascade are quite heterogeneous and can be divided into three main classes, namely: (1) the a,b-unsaturated aldehydes, including 4-hydroxy-2-nonenal (HNE) and acrolein (ACR); (2) di-aldehydes, including the well-known lipid peroxidation by product malondialdehyde and glyoxal; (3) keto-aldehydes, such as methylglyoxal [13]. Several studies, both in animal models and in humans, have reported the increase of RCSs such as free aldehydes or protein adducts in the liver under I/R damage [15][16][17][18][19]. The usual analytical methods give an overall measure of RCS/advanced glycation and lipoxidation end-products (AGEs/ALEs) content, but do not identify the specific RCSs or protein substrates involved in the damaging reaction.…”