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Eur J Pharmacol. 2019 Aug 15;857:172444. doi: 10.1016/j.ejphar.2019.172444. Epub 2019 Jun 8.

Increase of late sodium current contributes to enhanced susceptibility to atrial fibrillation in diabetic mice.

Author information

1
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China.
2
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China. Electronic address: yangbf@ems.hrbmu.edu.cn.
3
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China. Electronic address: yjlu2008@163.com.
4
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China. Electronic address: wzg1@email.com.
5
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China. Electronic address: panzw@ems.hrbmu.edu.cn.

Abstract

Studies demonstrated that the incidence of atrial fibrillation is significantly increased in patients with diabetes mellitus. Increase of late sodium current (INaL) has been associated with atrial arrhythmias. However, the role of INaL in the setting of atrial fibrillation in diabetes mellitus remained unknown. In this study, we investigated the alteration of INaL in the atria of diabetic mice and the therapeutic effect of its inhibitor (GS967) on the susceptibility of atrial fibrillation. The whole-cell patch-clamp technique was used to detect single cell electrical activities. The results showed that the density of INaL in diabetic cardiomyocytes was larger than that of the control cells at the holding potential of -100 mV. The action potential duration at both 50% and 90% repolarization, APD50 and APD90, respectively, was markedly increased in diabetic mice than in controls. GS967 application inhibited INaL and shortened APD of diabetic mice. High-frequency electrical stimuli were used to induce atrial arrhythmias. We found that the occurrence rate of atrial fibrillation was significantly increased in diabetic mice, which was alleviated by the administration of GS967. In GS967-treated diabetic mice, the INaL current density was reduced and APD was shortened. In conclusion, the susceptibility to atrial fibrillation was increased in diabetic mice, which is associated with the increased late sodium current and the consequent prolongation of action potential. Inhibition of INaL by GS967 is beneficial against the occurrence of atrial fibrillation in diabetic mice.

KEYWORDS:

Action potential duration; Atrial fibrillation; Diabetic mice; Late sodium current

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