钙调蛋白激酶Ⅱ抑制剂对肥厚心肌细胞早期后除极的影响  

Effects of Calmodulin Kinase Ⅱ Inhibitor on Early Afterdepolarization in Hypertrophic Cardiac Myocytes

作　　者：柯俊[1] 张存泰[1] 马业新[1] 吕家高[1] 刘俊[1] 刘念[1] 阮燕菲[1] 白融[1] 林立[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院

出　　处：《内科急危重症杂志》2007年第6期292-294,311,共4页Journal of Critical Care In Internal Medicine

基　　金：国家自然科学基金资助项目(No:30470714)

摘　　要：目的:探讨钙调蛋白激酶Ⅱ特异性抑制剂KN-93对肥厚心肌细胞动作电位时程(APD)及早期后除极(EAD)发生率的影响。方法:选取雌性新西兰大白兔,通过缩窄腹主动脉制备兔心肌肥厚模型(LVH组),并设假手术组(sham组)作对照比较,仅游离腹主动脉,未进行缩窄。8周后,应用超声心动图观察左心室肥厚程度。采用胶原酶消化法分离单个心肌细胞,应用全细胞膜片钳技术记录动作电位(AP),分别给予低钾(2mmol/L)、低镁(0.25mmol/L)台氏液灌流(sham组、LVH组)、含KN-92(KN-92组)、KN-93(KN-93组)的低钾、低镁台氏液灌流,观察慢频率电刺激(0.25～0.5Hz)条件下各组心肌细胞EAD的发生率,同时观察KN-92、KN-93对肥厚心肌细胞APD的影响。结果:8周后,与Sham组相比,心肌肥厚组的心脏外形明显增大,左室壁明显增厚,模型建立成功。电流钳模式下记录动作电位,在低钾、低镁台氏液灌流及慢频率电刺激下,Sham组、LVH组、KN-92组(0.5μmol/L)及KN-93组(0.5μmol/L)EAD的发生率分别为0/12、11/12、10/12和5/12。当KN-92组及KN-93组中药物浓度增至1μmol/L时,肥厚心肌细胞EAD的发生率分别为10/12和2/12,同时其对APD无明显影响(P>0.05)。结论:钙调蛋白激酶Ⅱ特异性抑制剂KN-93能够有效抑制肥厚心肌EAD的发生,这可能是其抗肥厚心肌室性心律失常发生的主要作用机制。Objective：To investigate the effect of KN-93, a kind of calmodulin kinase Ⅱ inhibitor, on action potential duration （APD） and early afterdepolarization （EAD） in hypertrophic cardiac myocytes. Methods：Ventricular hypertrophy was induced by partial constriction of the abdominal aorta in New Zealand white rabbits. In sham group, the abdominal aorta was only exposed without constriction. Thickness of the walls of the left ventricle were measured by echocardiography 8 weeks later. Single ventricular myocytes were isolated by enzymatic dissociation method. Action potential （AP） was recorded by using whole cell patch clamp technique. Perfused with hypokalemic （2. 0 μmol/L） , hypomagnesaemic （0. 25 μmol/L） Tyrode＇s solution （sham group, LVH group） or the above solution containing additional KN-92（KN-92 group）, KN-93（KN-93 group）, the incidence of EAD under slow frequency electrical stimulation （0. 25-0. 5 Hz） were monitored, and the effect of KN-92 and KN-93 on APD in hypertrophic cardiac myocytes were observed. Results ：Thickness of the left ventricle wall in LVH group increased significantly compared to the sham group after 8 weeks. Model of cardiac hypertrophy was made successfully. In single ventricular cells under slow stimulation and perfused with hypokalemic, hypomagnesaemic Tyrode＇s solution, incidences of EAD in sham group, LVH group, KN-92 group （0. 5/μmol/L） and KN-93 group （0. 5/μmol/L） were 0/12, 11/12, 10/12, 5/12 respectively. When the concentrations of KN-92, KN-93 were added to 1 μmol/L, incidences of EAD in KN-92 group and KN-93 group were 10/12 and 2/12 respectively. However, APD of hypertrophic cardiac myocytes was not significantly altered by KN-93. Conclusions： Calmodulin kinase Ⅱ inhibitor KN-93 can suppress EAD in cardiac hypertrophy effectively. Arrhythmias suppression effect of KN-93 may be through prevention of EAD in hypertrophic myocardium.

关 键 词：钙调蛋白激酶Ⅱ KN-93 心肌肥厚 早期后除极 膜片钳技术 

分 类 号：R541.6[医药卫生—心血管疾病]