钙调蛋白激酶抑制剂对肥厚心肌心律失常的影响

Effect of calmodulin-dependent protein kinase inhibitor on the arrhythmias in rabbit with ventricular hypertrophy

目的研究钙调蛋白激酶Ⅱ(CaMKⅡ)抑制剂KN-93对肥厚心肌细胞心律失常发生率和钙调蛋白激酶活性的影响,探讨肥厚心肌易于发生心律失常的机制。方法雌性大耳白兔随机分成假手术组、心肌肥厚组(LVH组)、KN-93组和KN-92组。应用彩色多普勒超声观察左室肥厚程度;同步记录楔形心肌块心电图和内、外膜心肌细胞跨膜动作电位,低钾、低镁、慢频率刺激下,观察各组尖端扭转型室性心动过速(Tdp)的诱发率;同时测定CaMK活性的变化。结果LVH组Tdp发生率高于假手术组(P<0.05),KN-93能降低肥厚心肌室性心律失常的发生率;LVH组CaMK的活性高于假手术组(P<0.05),KN-93能有效降低肥厚心肌细胞内CaMK活性,而KN-92没有该作用。结论肥厚心肌恶性心律失常的发生与钙调蛋白激酶活性增高密切相关。CaMKⅡ可能成为抗心律失常新的靶点。

Objective To investigate the effect of Ca^2＋/calmodulin-dependent protein kinase （CAMK） Ⅱ inhibitor KN-93 on the arrhythmias in rabbit with ventricular hypertrophy. Methods Female rabbits were divided into 4 groups： sham operation group, LVH group （ left ventricular hypertrophy）, KN-93 （ LVH and treatment with KN-93 ） and KN-92 group（ LVH and treatment with KN-92）. The LVH models were created by a partially constriction of the abdominal aorta in rabbits. Echocardiography was employed to measure the thickness of the walls of the ventricle before and after the operation. Transmembrane action potentials from epicardium and endocardium were simuhaneously recorded together with a transmural ECG by using arterially perfused rabbit ventricular wedge preparations. CaMK activity was determined by γ-32^p incorporation. Assay of CaMK activity of all groups was performed. Results The induce rate of Tdp in LVH group was higher than that of sham group （ P 〈 0.05 ）. Increased activity of CAMK and the induce rate of Tdp in LVH were suppressed by KN-93. The inactive analog KN-92 had no effect on the activity of CAMK. Conclusions The resuh that KN- 93 suppresses activity of CAMK may be associated with its therapeutic mechanism for antiarrhythmias. CaMK Ⅱ may be an antiarrhythmic drug target.