尼可地尔后处理对大鼠心肌缺血损伤的保护作用及机制研究
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摘要
研究目的:经实验证明心肌缺血预处理和心肌缺血后处理是减轻心肌缺血损伤一个成功的方法。但缺血预处理需要在缺血前给予干预，这就要求预知心肌缺血发生的时间，并且需要复杂的有创性操作来实施局部缺血；与其相比缺血后处理虽然不需预知心肌缺血发生的时间，但仍需复杂的有创操作来完成，同样限制其开展。故此，有研究者提出用药物来代替缺血处理的假设，近几年药物预处理及后处理成为研究的新热点。
本研究以尼可地尔为研究手段探讨缺血后持续再灌注前的短暂时间窗内进行的药物后处理干预。研究尼可地尔药物后处理对心肌缺血损伤的保护作用并探讨其作用机制。尼可地尔是临床上唯一具有抗心绞痛作用的钾通道开放剂，从生化和组织学变化等方面研究这个药物作为后处理的干预手段对缺血心肌的保护作用的较少，尤其是国内更是少见。本研究用大低剂量ISO腹腔注射诱导急性心肌缺血性损伤模型，以保护线粒体为切入点，用药物后处理模拟缺血后处理，达到良好效果，为心肌缺血性疾病的对症治疗提供新思路，具有非常重要的现实意义。
研究方法:30只健康SD大鼠随机分为3组：盐酸异丙肾上腺素（ISO）组10只，腹腔注射盐酸异丙肾上腺素5mg·kg~(-1)，间隔24小时重复注射1次，共注射3次；对照组10只，大鼠腹腔注射等量生理盐水，方法同ISO组；尼可地尔后处理（NIC）组10只，注射ISO1h后于尾静脉注射尼可地尔(1mg·kg~(-1))，间隔24小时重复注射1次，共注射3次。ISO组和NIC组大鼠于第3次注射ISO后24h处死，同时处死对照组大鼠。各组大鼠处死前取血清进行心肌酶血清乳酸脱氢酶（LDH），磷酸激酸（CK）活性检测及心肌肌钙蛋白I（cTnI）活性检测；通过检测大鼠心肌MDA含量和SOD活性，观察尼可地尔对脂质过氧化的影响；常规HE染色观察各组大鼠心肌的组织形态学变化，评估心肌缺血损伤；TUNEL法检测各组大鼠心肌细胞的调亡情况，通过免疫组织化学染色法检测Caspase-3蛋白，双重免疫荧光染色及WesternBlot检测钾离子通道蛋白Kir6.2及线粒体电压依赖型阴离子通道（VDAC）在心肌组织的表达，进行Nitrotyrosine免疫组织化学染色；半定量PCR法检测IL-10在心肌组织的表达。
研究结果：对照组、尼可地尔后组大鼠LDH、CK没有统计学意义（P>0.05），两组均低于ISO组，差异具有统计学意义（P<0.05）；尼克地尔后处理组血清cTnI低于ISO组，具有统计学意义（P<0.01）。HE染色显示：ISO组大鼠伴有炎细胞浸润，局部心肌组织变性坏死；尼可地尔后处理组大鼠炎症反应轻微，坏死心肌细胞明显减少；对照组大鼠心肌无异常。免疫组织化学染色显示：ISO组大鼠心肌细胞胞浆可见大量表达Caspase-3；而对照组和尼可地尔组大鼠无表达。尼可地尔组细胞凋亡指数（AI）较ISO组明显降低（P<0.01）。双重免疫荧光染色显示ISO组局部心肌组织Kir6.2表达明显低于对照组。尼克地尔后处理组Kir6.2表达高于对照组；各组间VDAC表达基本一致。WesternBlot进一步证明尼克地尔后处理组Kir6.2表达增加。ISO组免疫组织化学染色可见大量心肌细胞胞浆表达Nitrotyrosine；对照组和尼克地尔后处理组无表达。尼克地尔后处理组Il-10的表达明显高于ISO组及对照组。
结论：
1.间隔24小时腹腔注射ISO5mg.Kg~(-1)3天可以有效复制急性心肌缺血模型。
2.尼可地尔药物后处理对心肌缺血损伤有明显保护作用。
3.尼可地尔药物后处理对心肌缺血损伤的保护作用，与开放线粒体KATP通道，减少心肌缺血时过量氧自由基的产生，提高心肌的抗氧化能力，抑制缺血后心肌细胞的凋亡和炎症反应有关。
Objective:The incidence of ischemic heart disease increased year by year, how to protect myocardial ischemia injury is the focus of current research. Proved by the experiment that myocardial ischemic preconditioning and ischemic postconditioning are successful methods, have been shown to reduce ischemia reperfusion arrhythmia, reduce necrosis. But due to ischemic preconditioning need to intervene before ischemia, which requires predict myocardial ischemia occurred at a time, and the need for complex invasive operations to implement local ischemia, so limits its development in clinic; Ischemic postconditioning may not need to predict ischemic time, but still depends on complex invasive operation to complete. so this approach is limited. The research on ischemic preconditioning and ischemic postconditioning are limited to basic research level.
Activation of mitochondrial KATP channel has been suggested in several studies as a principle mechanism of ischemic preconditioning. This has lead to the hypothesis that drugs that open mitochondrial KATP channel can mimic preconditioning and postconditioning (pharmacological preconditioning and pharmacological postconditioning).
Previous studies about the cardioprotective effects of nicorandil preconditioning have concentrated on the assessment of infarct size reduction. However, little attentions have been paid for investigating the cardioprotective effects of these drugs against ischemia/reperfusioninduced hemodynamic, biochemical and histological changes. The aim of the present study was directed to investigate the protective effects of nicorandil postconditioning on these changes associated with myocardial ischemia injury. Nicorandil has been reported to induce the cardioprotection by opening the mitochondrial KATP channels of the myocardiocytes. Up to now the mechanism of cardioprotection is not fully understood. The purpose of this study is to study the effect of nicorandil postconditioning on myocardial ischemic injury and its mechanism of action from the biochemical and histological changes. The rates were injected intraperitoneally with low dose isoproterenol to induce model of myocardial ischemic injury, laid the foundation for future research; This study in order to protect the mitochondria as the breakthrough point, use pharmacological postconditioning simulated ischemic postconditioning, achieved good results, provides a new idea for the symptomatic treatment of clinical myocardial ischemia and hypoxia, and has very important realistic significance.
Methods:30SD rats were divided into control group, isoproterenol group and nicorandil postconditioning group. Rats in ISO group were injected intraperitoneally with isoproterenol (5mg·kg-1) at an interval of24h for3days; Rats in control group only receied an injection of same amount of saline; Rats in nicorandil(lmg·kg-1) postconditioning group were injected intravenous1h after ISO injection for once perday lasting for3d. Cardiac injury enzyme creatine kinase (CK),lactate dehydrogenase (LDH) and cardiac troponine I (cTnI) for rats serum were evaluated before killing the rats. Histopathological changes were evaluated by routine HE staining and Caspase-3protein were determined by immunocytochemistry. Apoptosis was analyzed by TUNEL staining. Histopathological changes were evaluated by Kir6.2and VDAC immumofluorescence staining and Nitrotyrosine immunohistochemistry staining. Kir6.2expression was further detected by western blot.I1-10expression was analyzed by PCR.
Results:There are no significant difference in the levels of serum CK and LDH of rats in chontrol and nicorandil postconditioning group (P＞0.05), The levels
of CK and LDH were lower in control and nicorandil postconditioning group compared with ISO group (P＜0.05). Isoproterenol-induced rats showed significant increase in the levels of serum cTnI, which was decreased by Nicorandil (P＜0.01). HE staining showed local degeneratin,necrosis and inflammation in ISO group,but slightly necrosis and inflammation in nicorandil group. No pathological changes were detected in control group.
Immunohistochemistry staining showed that Caspase-3were positive in cardiocytes cytoplasm; however, all of the detrimental effects of large amount of ISO were attenuated by Nicorandil. The apoptosis indexes (AI) significantly decreased in nicorandil postconditioning group compared with ISO group (P＜0.01). Immunofluorescence staining showed that Kir6.2was increased in Nicorandil group, but decreased in ISO group. These results were further confirmed by Kir6.2Western Blot. However, in ISO treated rats, Nitrotyrosine was positive in cardiocytes cytoplasm, which were negative in Nicorandil and control groups. Furthermore, IL-10mRNA expression was increased in Nicorandil group compared with that in ISO group.
Conclusion:
1. The rates were injected intraperitoneally with low dose isoproterenol (5mg·kg-1) can induce model of myocardial ischemic injury.
2. Nicorandil pharmacological postconditioning has obvious protective effect on myocardial ischemia injury.
3. Nicorandil attenuates myocardial ischemia injury in the rats, and its meachanism maybe related with inhibiting oxidative stress generation and inflammatory response via opening opening of the mitochondrial KATP channel, inhibiting myocardial apoptosis and inflammatory reaction.
本研究以尼可地尔为研究手段探讨缺血后持续再灌注前的短暂时间窗内进行的药物后处理干预。研究尼可地尔药物后处理对心肌缺血损伤的保护作用并探讨其作用机制。尼可地尔是临床上唯一具有抗心绞痛作用的钾通道开放剂，从生化和组织学变化等方面研究这个药物作为后处理的干预手段对缺血心肌的保护作用的较少，尤其是国内更是少见。本研究用大低剂量ISO腹腔注射诱导急性心肌缺血性损伤模型，以保护线粒体为切入点，用药物后处理模拟缺血后处理，达到良好效果，为心肌缺血性疾病的对症治疗提供新思路，具有非常重要的现实意义。
研究方法:30只健康SD大鼠随机分为3组：盐酸异丙肾上腺素（ISO）组10只，腹腔注射盐酸异丙肾上腺素5mg·kg~(-1)，间隔24小时重复注射1次，共注射3次；对照组10只，大鼠腹腔注射等量生理盐水，方法同ISO组；尼可地尔后处理（NIC）组10只，注射ISO1h后于尾静脉注射尼可地尔(1mg·kg~(-1))，间隔24小时重复注射1次，共注射3次。ISO组和NIC组大鼠于第3次注射ISO后24h处死，同时处死对照组大鼠。各组大鼠处死前取血清进行心肌酶血清乳酸脱氢酶（LDH），磷酸激酸（CK）活性检测及心肌肌钙蛋白I（cTnI）活性检测；通过检测大鼠心肌MDA含量和SOD活性，观察尼可地尔对脂质过氧化的影响；常规HE染色观察各组大鼠心肌的组织形态学变化，评估心肌缺血损伤；TUNEL法检测各组大鼠心肌细胞的调亡情况，通过免疫组织化学染色法检测Caspase-3蛋白，双重免疫荧光染色及WesternBlot检测钾离子通道蛋白Kir6.2及线粒体电压依赖型阴离子通道（VDAC）在心肌组织的表达，进行Nitrotyrosine免疫组织化学染色；半定量PCR法检测IL-10在心肌组织的表达。
研究结果：对照组、尼可地尔后组大鼠LDH、CK没有统计学意义（P>0.05），两组均低于ISO组，差异具有统计学意义（P<0.05）；尼克地尔后处理组血清cTnI低于ISO组，具有统计学意义（P<0.01）。HE染色显示：ISO组大鼠伴有炎细胞浸润，局部心肌组织变性坏死；尼可地尔后处理组大鼠炎症反应轻微，坏死心肌细胞明显减少；对照组大鼠心肌无异常。免疫组织化学染色显示：ISO组大鼠心肌细胞胞浆可见大量表达Caspase-3；而对照组和尼可地尔组大鼠无表达。尼可地尔组细胞凋亡指数（AI）较ISO组明显降低（P<0.01）。双重免疫荧光染色显示ISO组局部心肌组织Kir6.2表达明显低于对照组。尼克地尔后处理组Kir6.2表达高于对照组；各组间VDAC表达基本一致。WesternBlot进一步证明尼克地尔后处理组Kir6.2表达增加。ISO组免疫组织化学染色可见大量心肌细胞胞浆表达Nitrotyrosine；对照组和尼克地尔后处理组无表达。尼克地尔后处理组Il-10的表达明显高于ISO组及对照组。
结论：
1.间隔24小时腹腔注射ISO5mg.Kg~(-1)3天可以有效复制急性心肌缺血模型。
2.尼可地尔药物后处理对心肌缺血损伤有明显保护作用。
3.尼可地尔药物后处理对心肌缺血损伤的保护作用，与开放线粒体KATP通道，减少心肌缺血时过量氧自由基的产生，提高心肌的抗氧化能力，抑制缺血后心肌细胞的凋亡和炎症反应有关。
Objective:The incidence of ischemic heart disease increased year by year, how to protect myocardial ischemia injury is the focus of current research. Proved by the experiment that myocardial ischemic preconditioning and ischemic postconditioning are successful methods, have been shown to reduce ischemia reperfusion arrhythmia, reduce necrosis. But due to ischemic preconditioning need to intervene before ischemia, which requires predict myocardial ischemia occurred at a time, and the need for complex invasive operations to implement local ischemia, so limits its development in clinic; Ischemic postconditioning may not need to predict ischemic time, but still depends on complex invasive operation to complete. so this approach is limited. The research on ischemic preconditioning and ischemic postconditioning are limited to basic research level.
Activation of mitochondrial KATP channel has been suggested in several studies as a principle mechanism of ischemic preconditioning. This has lead to the hypothesis that drugs that open mitochondrial KATP channel can mimic preconditioning and postconditioning (pharmacological preconditioning and pharmacological postconditioning).
Previous studies about the cardioprotective effects of nicorandil preconditioning have concentrated on the assessment of infarct size reduction. However, little attentions have been paid for investigating the cardioprotective effects of these drugs against ischemia/reperfusioninduced hemodynamic, biochemical and histological changes. The aim of the present study was directed to investigate the protective effects of nicorandil postconditioning on these changes associated with myocardial ischemia injury. Nicorandil has been reported to induce the cardioprotection by opening the mitochondrial KATP channels of the myocardiocytes. Up to now the mechanism of cardioprotection is not fully understood. The purpose of this study is to study the effect of nicorandil postconditioning on myocardial ischemic injury and its mechanism of action from the biochemical and histological changes. The rates were injected intraperitoneally with low dose isoproterenol to induce model of myocardial ischemic injury, laid the foundation for future research; This study in order to protect the mitochondria as the breakthrough point, use pharmacological postconditioning simulated ischemic postconditioning, achieved good results, provides a new idea for the symptomatic treatment of clinical myocardial ischemia and hypoxia, and has very important realistic significance.
Methods:30SD rats were divided into control group, isoproterenol group and nicorandil postconditioning group. Rats in ISO group were injected intraperitoneally with isoproterenol (5mg·kg-1) at an interval of24h for3days; Rats in control group only receied an injection of same amount of saline; Rats in nicorandil(lmg·kg-1) postconditioning group were injected intravenous1h after ISO injection for once perday lasting for3d. Cardiac injury enzyme creatine kinase (CK),lactate dehydrogenase (LDH) and cardiac troponine I (cTnI) for rats serum were evaluated before killing the rats. Histopathological changes were evaluated by routine HE staining and Caspase-3protein were determined by immunocytochemistry. Apoptosis was analyzed by TUNEL staining. Histopathological changes were evaluated by Kir6.2and VDAC immumofluorescence staining and Nitrotyrosine immunohistochemistry staining. Kir6.2expression was further detected by western blot.I1-10expression was analyzed by PCR.
Results:There are no significant difference in the levels of serum CK and LDH of rats in chontrol and nicorandil postconditioning group (P＞0.05), The levels
of CK and LDH were lower in control and nicorandil postconditioning group compared with ISO group (P＜0.05). Isoproterenol-induced rats showed significant increase in the levels of serum cTnI, which was decreased by Nicorandil (P＜0.01). HE staining showed local degeneratin,necrosis and inflammation in ISO group,but slightly necrosis and inflammation in nicorandil group. No pathological changes were detected in control group.
Immunohistochemistry staining showed that Caspase-3were positive in cardiocytes cytoplasm; however, all of the detrimental effects of large amount of ISO were attenuated by Nicorandil. The apoptosis indexes (AI) significantly decreased in nicorandil postconditioning group compared with ISO group (P＜0.01). Immunofluorescence staining showed that Kir6.2was increased in Nicorandil group, but decreased in ISO group. These results were further confirmed by Kir6.2Western Blot. However, in ISO treated rats, Nitrotyrosine was positive in cardiocytes cytoplasm, which were negative in Nicorandil and control groups. Furthermore, IL-10mRNA expression was increased in Nicorandil group compared with that in ISO group.
Conclusion:
1. The rates were injected intraperitoneally with low dose isoproterenol (5mg·kg-1) can induce model of myocardial ischemic injury.
2. Nicorandil pharmacological postconditioning has obvious protective effect on myocardial ischemia injury.
3. Nicorandil attenuates myocardial ischemia injury in the rats, and its meachanism maybe related with inhibiting oxidative stress generation and inflammatory response via opening opening of the mitochondrial KATP channel, inhibiting myocardial apoptosis and inflammatory reaction.
引文
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