美托洛尔对家兔肥厚心肌室性心律失常的影响
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摘要
目的观察口服美托洛尔对家兔肥厚心肌CaMKII的表达及内、外膜心肌细胞跨膜动作电位的影响,初步探讨其对肥厚心肌室性心律失常的影响及可能的作用机制。
方法将家兔随机分为假手术组、心肌肥厚组和美托洛尔组。假手术组开腹但不行腹主动脉缩窄术,心肌肥厚组和美托洛尔组采用腹主动脉缩窄术制备家兔心肌肥厚模型,喂养8周。8周后,提取三组家兔的左心室游离壁心肌组织蛋白,利用western-blot技术观察三组心肌CaMKII表达的变化。制备兔左心室楔形心肌块,利用浮置玻璃微电极法同步记录楔形心肌块内、外膜心肌细胞跨膜动作电位和跨壁心电图,观察各组QT间期和内、外膜心肌细胞跨膜动作电位以及跨室壁复极离散度(Transmural dispersion of repolarization,TDR),程序电刺激诱发室性心律失常,记录早期后除极(EAD)和尖端扭转型室速(Tdp)的诱发率。
结果心肌肥厚组较假手术组CaMKII蛋白的表达量明显增加(P<0.05),美托洛尔组较心肌肥厚组CaMKII蛋白的表达量明显降低(P<0.05);浮置玻璃微电极法显示:心肌肥厚组QT间期,内、外膜心肌细胞跨膜动作电位复极90%时程(APD90)和TDR均较假手术组明显增大(p<0.05)。美托洛尔与心肌肥厚组相比以上各项指标均明显缩短,二者差异有统计学意义(p<0.05);假手术组、心肌肥厚组,和美托洛尔组EAD的发生率分别为0/10、10/10和4/10,Tdp的发生率分别为0/10、7/10和1/10;心肌肥厚组与假手术组相比,EAD和Tdp的发生率差异有显著性(p<0.05),美托洛尔组与心肌肥厚组相比,EAD和Tdp的发生率明显降低,二者差异有统计学意义(p<0.05)。
结论1、心肌肥厚时CaMKII表达明显增高,心律失常发生率增加;
2、美托洛尔能抑制心肌肥厚时CaMKII的表达;
3、心肌肥厚时TDR升高,心律失常的发生率显著升高;
4、美托洛尔可降低肥厚心肌TDR,并且能明显降低EAD和Tdp的发生率。
Objective: To observe the effect of Metoprolol on ventricular arrhythmia in hypertrophic myocardium and transmembrane action potential of both wedge myocardium, and to explore the drug’s anti-arrhthmic mechanism.
Method: Rabbits are divided into sham operation group, hypertrophic-myocardium group and Metoprolol group. In sham operation group, laparotomy is performed but no abdominal aorta constriction. In both hypertrophic-myocardium group and Metoprolol group, hypertrophic-myocardium models are made through abdominal aorta constriction, which will be fed for 8 weeks. After 8 weeks, the protein would be extracted in myocardium of the left ventricular free wall from three groups, and then the change of CaMKII expression would be observed in myocardium by using the western-blot technique. Using floating glass micro-electrode method, transmembrane action potential of both wedge myocardium and myocardial cells in outer membrane and cross-wall ECG. Were recorded srmultaneously. The potential during QT intervals and transmembrane action in myocytes of inner and outer membranes and transmural dispersion of repolarization (TDR) would be observed. Induced rate of early afterdepolarization (EAD) and Torsade de Pointes (Tdp) would be recorded by using the programmed electrical stimulation.
Results: hypertrophic-myocardium models are successfully made. CaMKII protein expression in the hypertrophic-myocardium group significantly increases compared to sham operation group (P <0.05). CaMKII protein expression in the Metoprolol group significantly decreases compared to hypertrophic-myocardium group (P <0.05). 1. APD90 and TDR during QT intervals and transmembrane action in myocytes of inner and outer membranes of hypertrophic-myocardium group are significantly longer than that of the sham group (p <0.05); Above indices in Metoprolol group are significantly shorter than that in hypertrophic-myocardium group (p<0.05);2. The incidence of EAD in sham group, hypertrophic-myocardium group and Metoprolol group are 0/10, 10/10 and 4/10 respectively, and the incidence of Tdp are 0/10, 7/10 and 1/10 in these three groups respectively. There is significant difference between the incidence of EAD and Tdp in hypertrophic-myocardium group and sham group (p <0.05). Incidence of EAD and Tdp in Metoprolol group is significantly reduced compared witht that in hypertrophic-myocardium group (p <0.05).
Conclusion: 1.CaMKII expression significantly increases in the condition of myocardral hypertrophy.
2.Metoprolol can inhibit the CaMKII expression in hypertrophic myocardium.
3.TDR in hypertrophic myocardium increases the incidence of arrhythmia significantly.
4.Metoprolol can reduce TDR, and inhibit the incidence of EAD and Tdp.
方法将家兔随机分为假手术组、心肌肥厚组和美托洛尔组。假手术组开腹但不行腹主动脉缩窄术,心肌肥厚组和美托洛尔组采用腹主动脉缩窄术制备家兔心肌肥厚模型,喂养8周。8周后,提取三组家兔的左心室游离壁心肌组织蛋白,利用western-blot技术观察三组心肌CaMKII表达的变化。制备兔左心室楔形心肌块,利用浮置玻璃微电极法同步记录楔形心肌块内、外膜心肌细胞跨膜动作电位和跨壁心电图,观察各组QT间期和内、外膜心肌细胞跨膜动作电位以及跨室壁复极离散度(Transmural dispersion of repolarization,TDR),程序电刺激诱发室性心律失常,记录早期后除极(EAD)和尖端扭转型室速(Tdp)的诱发率。
结果心肌肥厚组较假手术组CaMKII蛋白的表达量明显增加(P<0.05),美托洛尔组较心肌肥厚组CaMKII蛋白的表达量明显降低(P<0.05);浮置玻璃微电极法显示:心肌肥厚组QT间期,内、外膜心肌细胞跨膜动作电位复极90%时程(APD90)和TDR均较假手术组明显增大(p<0.05)。美托洛尔与心肌肥厚组相比以上各项指标均明显缩短,二者差异有统计学意义(p<0.05);假手术组、心肌肥厚组,和美托洛尔组EAD的发生率分别为0/10、10/10和4/10,Tdp的发生率分别为0/10、7/10和1/10;心肌肥厚组与假手术组相比,EAD和Tdp的发生率差异有显著性(p<0.05),美托洛尔组与心肌肥厚组相比,EAD和Tdp的发生率明显降低,二者差异有统计学意义(p<0.05)。
结论1、心肌肥厚时CaMKII表达明显增高,心律失常发生率增加;
2、美托洛尔能抑制心肌肥厚时CaMKII的表达;
3、心肌肥厚时TDR升高,心律失常的发生率显著升高;
4、美托洛尔可降低肥厚心肌TDR,并且能明显降低EAD和Tdp的发生率。
Objective: To observe the effect of Metoprolol on ventricular arrhythmia in hypertrophic myocardium and transmembrane action potential of both wedge myocardium, and to explore the drug’s anti-arrhthmic mechanism.
Method: Rabbits are divided into sham operation group, hypertrophic-myocardium group and Metoprolol group. In sham operation group, laparotomy is performed but no abdominal aorta constriction. In both hypertrophic-myocardium group and Metoprolol group, hypertrophic-myocardium models are made through abdominal aorta constriction, which will be fed for 8 weeks. After 8 weeks, the protein would be extracted in myocardium of the left ventricular free wall from three groups, and then the change of CaMKII expression would be observed in myocardium by using the western-blot technique. Using floating glass micro-electrode method, transmembrane action potential of both wedge myocardium and myocardial cells in outer membrane and cross-wall ECG. Were recorded srmultaneously. The potential during QT intervals and transmembrane action in myocytes of inner and outer membranes and transmural dispersion of repolarization (TDR) would be observed. Induced rate of early afterdepolarization (EAD) and Torsade de Pointes (Tdp) would be recorded by using the programmed electrical stimulation.
Results: hypertrophic-myocardium models are successfully made. CaMKII protein expression in the hypertrophic-myocardium group significantly increases compared to sham operation group (P <0.05). CaMKII protein expression in the Metoprolol group significantly decreases compared to hypertrophic-myocardium group (P <0.05). 1. APD90 and TDR during QT intervals and transmembrane action in myocytes of inner and outer membranes of hypertrophic-myocardium group are significantly longer than that of the sham group (p <0.05); Above indices in Metoprolol group are significantly shorter than that in hypertrophic-myocardium group (p<0.05);2. The incidence of EAD in sham group, hypertrophic-myocardium group and Metoprolol group are 0/10, 10/10 and 4/10 respectively, and the incidence of Tdp are 0/10, 7/10 and 1/10 in these three groups respectively. There is significant difference between the incidence of EAD and Tdp in hypertrophic-myocardium group and sham group (p <0.05). Incidence of EAD and Tdp in Metoprolol group is significantly reduced compared witht that in hypertrophic-myocardium group (p <0.05).
Conclusion: 1.CaMKII expression significantly increases in the condition of myocardral hypertrophy.
2.Metoprolol can inhibit the CaMKII expression in hypertrophic myocardium.
3.TDR in hypertrophic myocardium increases the incidence of arrhythmia significantly.
4.Metoprolol can reduce TDR, and inhibit the incidence of EAD and Tdp.
引文
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[2].ZHANGT, MAIERLS, DALT ON ND,et al. The delt a Cisof orm of CAMK is act ivated in cardiac hypert rophy and induces dilated cardiomyopathy and heart failur e,Circ Res.2003;92(8):912 919[J].
[3].PASSIER R, ZENG R,FREY N,et al. CaM kinase sign alin ginduces cardiac hypert rophy and activates the MEF2 tran script ionfact or invivo J Clin Invest,.200;105(10):1395 1406[J].
[4].刘俊,张存泰,柯俊等.钙调蛋白激酶抑制剂对肥厚心肌心律失常的影响,中国心脏起搏与心电生理杂志.2007;21(2):158 161[J].
[5].张存泰,马业新等.立钙调蛋白激酶Ⅱ抑制剂抗肥厚心肌室性心律失常发生机制的研究.华中科技大学学报(医学版),2007;36(2):183[J].
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