Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart

International Journal of Molecular Sciences

Martín Vila Petroff¹  Layse Malagueta-Vieira²  Leyre Echeazarra²  Óscar Casis²  Mónica Gallego²  Julián Zayas-Arrabal²  Emiliano Medei³  Julieta Fernández-Ruocco³  Víctor Zamora⁴  Godfrey L. Smith⁴  María P. Hortigón-Vinagre⁴ 

[1] Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina;Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, Spain;Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK;

关键词: cardiac electrophysiology;    repolarization;    cardiomyocyte;    ion channels;    ventricular arrhythmia;    cardiac action potential;   

DOI  :  10.3390/ijms23116021

来源: DOAJ

【 摘 要 】

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (I_to). In vitro, incubation with metformin for 24 h also reduced I_to, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced I_hERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of I_to and I_hERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.

【 授权许可】

Unknown