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

Xi Fu,Qian Cao,Shuo Wang,Xiaodong Li,Yilong Pan,Bin Li,Na Duan,Hongjiao Du

doi:10.1186/s12872-018-0805-5

Xi Fu, Qian Cao + Show 6 more

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https://doi.org/10.1186/s12872-018-0805-5

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Abstract

BackgroundSmall 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.MethodsDiabetic 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.ResultsMetformin 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.ConclusionsOur 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.

Highlights

Small conductance calcium-activated potassium channels (SK channels) play a critical role in action potential repolarization in cardiomyocytes
ECG of metformin-treated GK rats showed sinus rhythm and relatively regular P waves (Fig. 2). These results demonstrated a protective effect of metformin on the structure and electrophysiology of the atrium under diabetic conditions
Metformin treatment significantly increased KCNN2 expression and decreased KCNN3 expression in the atrium of GK rats (P < 0.05). These results indicated that the expression pattern of the SK channels in rat atrial myocytes was altered under diabetic conditions and metformin abolished diabetes-induced changes in the expression of atrial SK channels

Summary

Introduction

Small conductance calcium-activated potassium channels (SK channels) play a critical role in action potential repolarization in cardiomyocytes. Type 2 diabetes mellitus (T2DM) accounts for 90-95% of all diagnosed cases of diabetes, and it confers an approximately twofold-increased risk of cardiovascular diseases [2, 3]. Small conductance calcium-activated potassium channels (SK channels) are important players in cardiac action potential repolarization [7]. The SK channels consists of three isoforms, namely, KCa2.1, KCa2.2 and KCa2.3, which are encoded by KCNN1, KCNN2 and KCNN3, respectively. All the three SK isoforms are detected in rat atrial and ventricular myocytes with higher abundance of SK1 and SK2 in the atria than that in the ventricles [8].

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