Zhang Yiqiang, Xiao Jiening, Lin Huixian, Luo Xiaobin, Wang Huizhen, Bai Yunlong, Wang Jingxiong, Zhang Haiqing, Yang Baofeng, Wang Zhiguo
Research Center, Montreal Heart Institute.
Cell Physiol Biochem. 2007;19(5-6):225-38. doi: 10.1159/000100642.
Abnormal QT prolongation with the associated arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. We performed whole-cell patch-clamp studies in a rabbit model of alloxan-induced insulin-dependent diabetes mellitus. We demonstrated that heart rate-corrected QT interval and action potential duration (APD) were prolonged by approximately 20% with frequent occurrence of ventricular tachyarrhythmias. Several K(+) currents were found decreased in diabetic rabbits including transient outward K(+)current (I(to)) that was reduced by approximately 60%, rapid delayed rectifier K(+) current (I(Kr)) reduced by approximately 70% and slow delayed rectifier K(+) current (I(Ks)) reduced by approximately 40%. The time-dependent kinetics of these currents remained unaltered. The peak amplitude of L-type Ca% current (I(CaL)) was reduced by approximately 22% and the inactivation kinetics was slowed; the integration of these two effects yielded approximately 15% reduction of I(CaL). The inward rectifier K(+) current (I(K1)) and fast sodium current (I(Na)) were unaffected. Simulation with LabHEART, a computer model of rabbit ventricular action potentials, revealed that inhibition of I(to) or I(Ks) alone fails to alter APD whereas inhibition of I(Kr) alone results in 30% APD prolongation and inhibition of I(CaL) alone causes 10% APD shortening. Integration of changes of all these currents leads to approximately 20% APD lengthening. Protein levels of the pore-forming subunits for these ion channels were decreased to varying extents, as revealed by immunoblotting analysis. Our study represents the first documentation of I(Kr) channelopathy as the major ionic mechanism for diabetic QT prolongation.
异常QT间期延长及相关心律失常被认为是主要的心脏电紊乱，也是糖尿病患者死亡率的重要预测指标。糖尿病患者QT间期延长的确切离子机制尚不清楚。我们在四氧嘧啶诱导的胰岛素依赖型糖尿病兔模型中进行了全细胞膜片钳研究。我们发现，心率校正QT间期和动作电位时程（APD）延长了约20%，且频繁发生室性快速心律失常。在糖尿病兔中发现几种钾电流降低，包括瞬时外向钾电流（I(to)）降低约60%、快速延迟整流钾电流（I(Kr)）降低约70%以及缓慢延迟整流钾电流（I(Ks)）降低约40%。这些电流的时间依赖性动力学保持不变。L型钙电流（I(CaL)）的峰值幅度降低了约22%，失活动力学减慢；这两种效应综合导致I(CaL)降低约15%。内向整流钾电流（I(K1)）和快钠电流（I(Na)）未受影响。使用兔心室动作电位计算机模型LabHEART进行模拟显示，单独抑制I(to)或I(Ks)不会改变APD，而单独抑制I(Kr)会导致APD延长30%，单独抑制I(CaL)会导致APD缩短10%。所有这些电流变化的综合导致APD延长约20%。免疫印迹分析显示，这些离子通道的孔形成亚基的蛋白水平有不同程度的降低。我们的研究首次证明I(Kr)通道病是糖尿病QT间期延长的主要离子机制。
