Metformin restores electrophysiology of small conductance calcium-activated potassium channels in the atrium of GK diabetic rats

Background: 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. Methods: 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. Results: 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. Conclusions: 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.