卡维地洛对阿霉素心肌病兔室性心律失常的影响和作用机制探讨
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摘要
目的观察氧化应激对阿霉素心肌病兔电生理参数及电稳定性的影响,探讨二者之间的关系；观察卡维地洛对阿霉素心肌病氧化应激和心室结构的影响,检测肌浆网钙释放通道RyR2表达,探讨心律失常发生的机制。
方法日本长耳白兔随机分为空白对照组、阿霉素组、阿霉素+倍他乐克组(倍他乐克组)和阿霉素+卡维地洛组(卡维地洛组)。采用耳缘静脉注射阿霉素(lmg.kg-1IV每周两次,共16次)建立阿霉素心肌病模型,空白对照组耳缘静脉注射等量生理盐水。3周后,倍他乐克组和卡维地洛组分别给予倍他乐克(5mg.kg-1.d-1)和卡维地洛(5mg.kg-1.d-1)灌胃,空白对照组和阿霉素组每日以等体积生理盐水灌胃。1)两月后,采用超声心动图观察每组心脏结构的变化,检测兔血清中丙二醛(MDA)、超氧化物岐化酶(SOD)和NT-脑钠肽(NT-proBNP)水平。2)制备兔左室楔形心肌块的灌注模型,同步记录心内、外膜动作电位、容积心电图及跨室壁离散度(TDR),并记录快频率程序刺激条件下触发活动和室性心律失常的发生率。3)采用胶原酶消化法分离单个心肌细胞,应用膜片钳技术记录动作电位(AP),并记录延迟后除极(DADs)和触发活动(TA)的发生率。4)采用Western blotting测定RyR2蛋白表达水平。结果1)与空白对照组比较,阿霉素组左室舒张末径(LVEDd)增大、射血分数(LVEF)降低(P<0.05),血清SOD活性降低、NT-proBNP和MDA浓度升高(P<0.05)。阿霉素组与倍他乐克组LVEDd、LVEF、SOD、NT-proBNP和MDA无显著性变化；与阿霉素组比较,卡维地洛组LVEDd降低、LVEF升高(P<0.05),血清SOD活性增加、NT-proBNP和MDA浓度降低(P<0.05)。2)空白对照组、阿霉素组、倍他乐克组和卡维地洛组触发活动发生率分别为0/10、10/10、9/10和4/10,室性心律失常发生率分别为0/10、9/10、7/10和2/10。与阿霉素组比较,倍他乐克组触发活动和室性心律失常无显著性变化,卡维地洛组触发活动和室性心律失常显著性降低。3)与空白对照组比较,阿霉素组单细胞动作电位时程(APD)延长,RyR2和SERCA2a蛋白的表达水平下降,延迟后除极(DADs)和触发活动(TA)的发生率明显增加；阿霉素组和倍他乐克组APD、RyR2和SERCA2a蛋白的表达水平无明显变化,DADs和TA发生率也无显著性差异；卡维地洛组单细胞APD降低,RyR2蛋白的表达水平增加,DADs和TA的发生率明显降低(P<0.05)。
结论阿霉素组兔氧化应激增强,心脏结构和功能明显受损；倍他乐克不能降低阿霉素心肌病兔的氧化应激,而卡维地洛能降低其氧化应激,改善心功能；阿霉素心肌病心衰时,氧化应激增强,RyR2功能失调,心肌细胞钙泄漏增加,卡维地洛通过降低氧化应激,改善心肌RyR2功能抑制钙泄漏,从而降低TA和心律失常。
Objections:To investigate the effects of oxidative stress on cardiac structure and electrical stability in rabbits with adriamycin cardiomyopathy, and explore the relationship between oxidative stress and adriamycin cardiomyopathy. To investigate the effects of carvedilol on ventricular arrhythmias and the expression of ryanodine receptors2in rabbits with adriamycin cardiomyopathy and discuss mechanism of ventricular arrhythmias.
Methods:Japanese white rabbits were randomly divided into four groups:the control group, the adriamycin group, the metoprolol group and the carvedilol group. Rabbits in the adriamycin group, the metoprolol group and the carvedilol group were intravenously injected at auri-edge with adriamycin hydrochloride (1mg.kg-1) twice a week for8weeks, and the control group was injected with equal volumn of saline at the same timepoint.3weeks later, rabbits in the metoprolol group and the carvedilol group were intragastric administration with metoprolol and carvedilol (Smg.kg-1.d-1) respectively, and those in the control group and the adriamycin group were intragastric administration with equal volume of saline.1)2months later, left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiogram, and plasma levels of amino terminal-pro brain natriuretic peptide (NT-proBNP), superoxide dismutase(SOD) and malondialdehyde(MAD) were measured.2) The wedge preparations from the rabbit heart were perfused with Tyrode's solution, volume electrocardiogram, QT interval, transmural repolarization dispersion (TDR) and the incidences of triggered activity and ventricular arrhythmias were recorded.3) By enzymatic dissociation method single ventricular myocytes were isolated, then ction potentials (APs) were recorded by whole cell patch clamp technique. The incidences of delayed afterdepolarizations (DADs) and triggered activity (TA) were monitored under fast frequency electrical stimulation.4) The ryanodine receptor2and SERCA2a were measured by Western blotting.
Results1) Compared the control group, adriamycin significantly increased serum MDA, NT-proBNP and LVEDd, and decreased SOD and LVEF.(P<0.05). There was no significant difference in MDA, NT-proBNP, SOD, LVEF and LVEDd between the adriamycin group and the metoprolol group. Carvedilol markedly increased serum MDA and LVEF, decreased SOD, TNP and LVEDd compared with adriamycin group (P<0.05)2) No triggered activity and ventricular arrhythmias was induced in control group. The incidences of triggered activity and ventricular arrhythmias occurred in10/10and9/10rabbits in adriamycin group, in9/10and7/10rabbits in the metoprolol group, and in4/10and2/10rabbits in the carvedilol group respectively. The incidences of triggered activity and ventricular arrhythmias in the adriamycin group were significantly higher than those in the control group. However, the incidences were significantly lower in the carvedilol group when compared with those in the adriamycin group.3) Compared with the control group, single cell action potential duration (APD) was prolonged, RyR2and SERCA2a protein expression were reduced, the incidences of DADs and TA were obviously increased in the adriamycin group (P<0.05). There was no difference of APD, RyR2and SERCA2A protein expression level, and the incidences of DADs and TA between the adriamycin group and the metoprolol group. Compared with the adriamycin group, carvedilol can short APD, increase protein expression level of RyR2and SERCA2a and decrease the incidences of DADs and TA (P<0.05)
Conclusions:Oxidative stress was increased, and heart structure and function was significantly impaired in the adriamycin group. Carvedilol can improve abnormal cardiac structure and inhibit ventricular arrhythmias in rabbit with adriamycin cardiomyopathy. Carvedilol can inhibit ventricular tachycardia in rabbit with adriamycin cardiomyopathy and protect adriamycin-induced cardiotoxicity through decreasing oxygen free radial production, which is related to dysfunction of RyR2.
方法日本长耳白兔随机分为空白对照组、阿霉素组、阿霉素+倍他乐克组(倍他乐克组)和阿霉素+卡维地洛组(卡维地洛组)。采用耳缘静脉注射阿霉素(lmg.kg-1IV每周两次,共16次)建立阿霉素心肌病模型,空白对照组耳缘静脉注射等量生理盐水。3周后,倍他乐克组和卡维地洛组分别给予倍他乐克(5mg.kg-1.d-1)和卡维地洛(5mg.kg-1.d-1)灌胃,空白对照组和阿霉素组每日以等体积生理盐水灌胃。1)两月后,采用超声心动图观察每组心脏结构的变化,检测兔血清中丙二醛(MDA)、超氧化物岐化酶(SOD)和NT-脑钠肽(NT-proBNP)水平。2)制备兔左室楔形心肌块的灌注模型,同步记录心内、外膜动作电位、容积心电图及跨室壁离散度(TDR),并记录快频率程序刺激条件下触发活动和室性心律失常的发生率。3)采用胶原酶消化法分离单个心肌细胞,应用膜片钳技术记录动作电位(AP),并记录延迟后除极(DADs)和触发活动(TA)的发生率。4)采用Western blotting测定RyR2蛋白表达水平。结果1)与空白对照组比较,阿霉素组左室舒张末径(LVEDd)增大、射血分数(LVEF)降低(P<0.05),血清SOD活性降低、NT-proBNP和MDA浓度升高(P<0.05)。阿霉素组与倍他乐克组LVEDd、LVEF、SOD、NT-proBNP和MDA无显著性变化；与阿霉素组比较,卡维地洛组LVEDd降低、LVEF升高(P<0.05),血清SOD活性增加、NT-proBNP和MDA浓度降低(P<0.05)。2)空白对照组、阿霉素组、倍他乐克组和卡维地洛组触发活动发生率分别为0/10、10/10、9/10和4/10,室性心律失常发生率分别为0/10、9/10、7/10和2/10。与阿霉素组比较,倍他乐克组触发活动和室性心律失常无显著性变化,卡维地洛组触发活动和室性心律失常显著性降低。3)与空白对照组比较,阿霉素组单细胞动作电位时程(APD)延长,RyR2和SERCA2a蛋白的表达水平下降,延迟后除极(DADs)和触发活动(TA)的发生率明显增加；阿霉素组和倍他乐克组APD、RyR2和SERCA2a蛋白的表达水平无明显变化,DADs和TA发生率也无显著性差异；卡维地洛组单细胞APD降低,RyR2蛋白的表达水平增加,DADs和TA的发生率明显降低(P<0.05)。
结论阿霉素组兔氧化应激增强,心脏结构和功能明显受损；倍他乐克不能降低阿霉素心肌病兔的氧化应激,而卡维地洛能降低其氧化应激,改善心功能；阿霉素心肌病心衰时,氧化应激增强,RyR2功能失调,心肌细胞钙泄漏增加,卡维地洛通过降低氧化应激,改善心肌RyR2功能抑制钙泄漏,从而降低TA和心律失常。
Objections:To investigate the effects of oxidative stress on cardiac structure and electrical stability in rabbits with adriamycin cardiomyopathy, and explore the relationship between oxidative stress and adriamycin cardiomyopathy. To investigate the effects of carvedilol on ventricular arrhythmias and the expression of ryanodine receptors2in rabbits with adriamycin cardiomyopathy and discuss mechanism of ventricular arrhythmias.
Methods:Japanese white rabbits were randomly divided into four groups:the control group, the adriamycin group, the metoprolol group and the carvedilol group. Rabbits in the adriamycin group, the metoprolol group and the carvedilol group were intravenously injected at auri-edge with adriamycin hydrochloride (1mg.kg-1) twice a week for8weeks, and the control group was injected with equal volumn of saline at the same timepoint.3weeks later, rabbits in the metoprolol group and the carvedilol group were intragastric administration with metoprolol and carvedilol (Smg.kg-1.d-1) respectively, and those in the control group and the adriamycin group were intragastric administration with equal volume of saline.1)2months later, left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiogram, and plasma levels of amino terminal-pro brain natriuretic peptide (NT-proBNP), superoxide dismutase(SOD) and malondialdehyde(MAD) were measured.2) The wedge preparations from the rabbit heart were perfused with Tyrode's solution, volume electrocardiogram, QT interval, transmural repolarization dispersion (TDR) and the incidences of triggered activity and ventricular arrhythmias were recorded.3) By enzymatic dissociation method single ventricular myocytes were isolated, then ction potentials (APs) were recorded by whole cell patch clamp technique. The incidences of delayed afterdepolarizations (DADs) and triggered activity (TA) were monitored under fast frequency electrical stimulation.4) The ryanodine receptor2and SERCA2a were measured by Western blotting.
Results1) Compared the control group, adriamycin significantly increased serum MDA, NT-proBNP and LVEDd, and decreased SOD and LVEF.(P<0.05). There was no significant difference in MDA, NT-proBNP, SOD, LVEF and LVEDd between the adriamycin group and the metoprolol group. Carvedilol markedly increased serum MDA and LVEF, decreased SOD, TNP and LVEDd compared with adriamycin group (P<0.05)2) No triggered activity and ventricular arrhythmias was induced in control group. The incidences of triggered activity and ventricular arrhythmias occurred in10/10and9/10rabbits in adriamycin group, in9/10and7/10rabbits in the metoprolol group, and in4/10and2/10rabbits in the carvedilol group respectively. The incidences of triggered activity and ventricular arrhythmias in the adriamycin group were significantly higher than those in the control group. However, the incidences were significantly lower in the carvedilol group when compared with those in the adriamycin group.3) Compared with the control group, single cell action potential duration (APD) was prolonged, RyR2and SERCA2a protein expression were reduced, the incidences of DADs and TA were obviously increased in the adriamycin group (P<0.05). There was no difference of APD, RyR2and SERCA2A protein expression level, and the incidences of DADs and TA between the adriamycin group and the metoprolol group. Compared with the adriamycin group, carvedilol can short APD, increase protein expression level of RyR2and SERCA2a and decrease the incidences of DADs and TA (P<0.05)
Conclusions:Oxidative stress was increased, and heart structure and function was significantly impaired in the adriamycin group. Carvedilol can improve abnormal cardiac structure and inhibit ventricular arrhythmias in rabbit with adriamycin cardiomyopathy. Carvedilol can inhibit ventricular tachycardia in rabbit with adriamycin cardiomyopathy and protect adriamycin-induced cardiotoxicity through decreasing oxygen free radial production, which is related to dysfunction of RyR2.
引文
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