Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats
Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats
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DOI：
10.1002/lt.23799
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发表时间：
2014-03-01
影响因子：
4.6
通讯作者：
Vacca, Giovanni
中科院分区：
文献类型：
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作者：
Grossini, Elena;Pollesello, Piero;Vacca, Giovanni
与其他器官一样，氧化应激诱导的损伤和细胞死亡可能是由自由氧自由基依赖性机制和导致细胞凋亡的信号转导途径改变引起的。在新建议的治疗氧化应激引起的损伤的方法中，据报道使用左西孟旦是相当有前途的。在本研究中，我们的目的是检查左西孟旦对麻醉大鼠肝脏氧化应激的保护作用，并分析线粒体三磷酸腺苷依赖性钾（mitoK（ATP））通道和一氧化氮（NO）的参与。在50只麻醉大鼠中，通过非创伤性门静脉阻断进行肝脏缺血/再灌注（I/R）。在一些动物中，在再灌注开始时将左西孟旦输注到门静脉中，而其他大鼠仅接受载体。此外，在一些大鼠中，左西孟旦是在门静脉内施用1-N ω-硝基-精氨酸甲酯（l-NAME）或5-羟基癸酸酯（5 HD）之后给予的。测定门静脉血流量，并取血测定转氨酶、硫代巴比妥酸反应物质（TBARS）、还原型谷胱甘肽（GSH）;肝活检标本采用免疫印迹法测定B细胞淋巴瘤2相关X蛋白、caspase-9、Akt、内皮型一氧化氮合酶（eNOS）活性。此外，还测定了caspase-3活性。在大鼠中，I/R引起凋亡标志物、转氨酶和TBARS增加，GSH和Akt活化减少。左西孟旦给药能够以剂量依赖性方式对抗氧化损伤和细胞凋亡，并增加GSH、Akt和eNOS活化。用l-NAME和5-HD预处理可阻断左西孟旦的上述作用。总之，本研究的结果表明，左西孟旦可以通过与NO产生和mitoK（ATP）通道功能相关的机制来发挥对缺血性肝损伤的保护作用。这些数据为左西孟旦在肝脏手术和移植中的应用提供了有趣的前景。肝移植20：361-375，2014。(c)2013年AASLD。
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-N omega-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. (c) 2013 AASLD.