Fu Xi, Pan Yilong, Cao Qian, Li Bin, Wang Shuo, Du Hongjiao, Duan Na, Li Xiaodong
Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China.
Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, 110016, People's Republic of China.
BMC Cardiovasc Disord. 2018 Apr 10;18(1):63. doi: 10.1186/s12872-018-0805-5.
Small conductance calcium-activated potassium channels (SK channels) play a critical role in action potential repolarization in cardiomyocytes. Recently, the potential anti-arrhythmic effect of metformin in diabetic patients has been recognized, yet the underlying mechanism remains elusive.
Diabetic Goto-Kakizaki (GK) rats were untreated or treated with metformin (300 mg/kg/day) for 12 weeks, and age-matched Wistar rats were used as control (n = 6 per group). Electrocardiography, Hematoxylin-eosin staining and Masson's trichome staining were performed to assess cardiac function, histology and fibrosis. The expression levels of the SK channels in the myocardium were determined by real-time PCR and Western blotting. The electrophysiology of the SK channels in the cardiomyocytes isolated from the three groups of rats was examined by patch clamp assay, with specific blockade of the SK channels with apamin.
Metformin treatment significantly reduced cardiac fibrosis and alleviated arrhythmia in the diabetic rats. In the atrial myocytes from control, GK and metformin-treated GK rats, the expression of KCa2.2 (SK2 channel) was down-regulated and the expression of KCa2.3 (SK3 channel) was up-regulated in the atrium of GK rats as compared with that of control rats, and metformin reversed diabetes-induced alterations in atrial SK channel expression. Moreover, patch clamp assay revealed that the SK current was markedly reduced and the action potential duration was prolonged in GK atrial myocytes, and the SK channel function was partially restored in the atrial myocytes from metformin-treated GK rats.
Our data suggests an involvement of the SK channels in the development of arrhythmia under diabetic conditions, and supports a potential beneficial effect of metformin on atrial electrophysiology.
小电导钙激活钾通道（SK通道）在心肌细胞动作电位复极化过程中起关键作用。近来，二甲双胍对糖尿病患者潜在的抗心律失常作用已得到认可，但其潜在机制仍不清楚。
对糖尿病Goto-Kakizaki（GK）大鼠不进行治疗或用二甲双胍（300mg/kg/天）治疗12周，将年龄匹配的Wistar大鼠作为对照（每组n = 6）。进行心电图检查、苏木精-伊红染色和Masson三色染色以评估心脏功能、组织学和纤维化情况。通过实时PCR和蛋白质印迹法测定心肌中SK通道的表达水平。采用膜片钳测定法检测从三组大鼠分离的心肌细胞中SK通道的电生理特性，并用蜂毒明肽特异性阻断SK通道。
二甲双胍治疗显著降低了糖尿病大鼠的心脏纤维化并减轻了心律失常。在对照大鼠、GK大鼠和经二甲双胍治疗的GK大鼠的心房肌细胞中，与对照大鼠相比，GK大鼠心房中KCa2.2（SK2通道）的表达下调，KCa2.3（SK3通道） 的表达上调，而二甲双胍逆转了糖尿病引起的心房SK通道表达改变。此外，膜片钳测定显示，GK大鼠心房肌细胞中的SK电流显著降低，动作电位时程延长，而在经二甲双胍治疗的GK大鼠的心房肌细胞中SK通道功能部分恢复。
我们的数据表明SK通道参与糖尿病状态下心律失常的发生，并支持二甲双胍对心房电生理具有潜在有益作用。
