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目的观察钙调蛋白激酶Ⅱ抑制剂 KN-93对心肌肥厚兔室性心律失常的影响。方法雌性新西兰大白兔随机分为4组:假手术组(Sham 组)、心肌肥厚组(LVH 组)、心肌肥厚+KN-93组(KN-93组)、心肌肥厚+KN-92组(KN-92组),每组10只。LVH、KN-93及 KN-92组通过缩窄腹主动脉制备兔心肌肥厚模型,Sham 组仅游离腹主动脉未进行缩窄。8周后制备兔左室楔形心肌块的灌注模型,同步记录心内、外膜动作电位及跨壁心电图,观察低钾(2 mmol/L)、低镁(0.25 mmol/L)台氏液灌流及慢频率刺激条件下各组早期后除极(EAD)和尖端扭转型室性心动过速(Tdp)的发生率,并记录在不同起搏周期下 QT 间期、动作电位时程(APD)及跨室壁复极离散度(TDR)的变化。结果在低钾、低镁台氏液灌流及2000～4000 ms 慢频率刺激下,Sham、LVH、KN-92组(0.5 μmol/L)及 KN-93组(0.5 μmol/L)EAD 的发生率分别为0/10、10/10、9/10和5/10,Tdp 的发生率分别为0/10、5/10、4/10和1/10;当 KN-92组及 KN-93组中药物浓度增至1 μzmol/L 时,EAD 的发生率分别为9/10和3/10,Tdp 的发生率分别为 4/10和1/10。而且KN-93组、KN-92组对 QT 间期、APD及 TDR 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能够有效抑制心肌肥厚兔室性心律失常的发生,其主要作用机制是通过减少 EAD 的发生来实现。
Objective To observe the effect of calcineurin Ⅱ inhibitor KN-93 on ventricular arrhythmia in hypertrophic rabbit. Methods Female New Zealand white rabbits were randomly divided into 4 groups: Sham group, LVH group, KN-93 group (KN-93 group), myocardial hypertrophy + KN-92 group -92 group), 10 in each group. LVH, KN-93 and KN-92 groups were prepared by narrowing the abdominal aorta in rabbit models of cardiac hypertrophy, Sham group only free abdominal aorta did not narrow. After 8 weeks, perfusion models of left ventricular wedge-shaped myocardial blocks were prepared and the intracardiac and epicardial potentials and transmyocardial electrocardiogram were recorded synchronously. The effects of low potassium (2 mmol / L) and low magnesium (0.25 mmol / L) (EAD) and torsades de pointes (Tdp) in each group under the conditions of low frequency stimulation were recorded, and the changes of QT interval, action potential duration (APD) And transmural repolarization dispersion (TDR) changes. Results The incidence of EAD in sham, LVH, KN-92 group (0.5 μmol / L) and KN-93 group (0.5 μmol / L) Respectively. The incidence of Tdp was 0/10, 10/10, 4/10 and 1/10 respectively when the rates of Tdp were 0/10, 10/10, 9/10 and 5/10 respectively. When KN-92 and KN-93 When the drug concentration was increased to 1 μ mol / L, the incidence of EAD was 9/10 and 3/10 respectively, and the incidence of Tdp was 4/10 and 1/10, respectively. And KN-93 group, KN-92 group had no significant effect on QT interval, APD and TDR (P> 0.05). Conclusion KN-93, a specific inhibitor of calmodulin kinase Ⅱ, can effectively inhibit the occurrence of ventricular arrhythmia in rabbit with hypertrophic myocardium. Its main mechanism is to reduce the incidence of EAD.