Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
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...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/11/6021 |
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| author | Layse Malagueta-Vieira Julieta Fernández-Ruocco María P. Hortigón-Vinagre Víctor Zamora Julián Zayas-Arrabal Leyre Echeazarra Godfrey L. Smith Martín Vila Petroff Emiliano Medei Óscar Casis Mónica Gallego |
| author_facet | Layse Malagueta-Vieira Julieta Fernández-Ruocco María P. Hortigón-Vinagre Víctor Zamora Julián Zayas-Arrabal Leyre Echeazarra Godfrey L. Smith Martín Vila Petroff Emiliano Medei Óscar Casis Mónica Gallego |
| author_sort | Layse Malagueta-Vieira |
| collection | DOAJ |
| description | 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<sub>to</sub>). In vitro, incubation with metformin for 24 h also reduced I<sub>to</sub>, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced I<sub>hERG</sub> 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<sub>to</sub> and I<sub>hERG</sub>. 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. |
| first_indexed | 2024-03-10T01:16:21Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:16:21Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-af4ff86f5846446bb8695c202fa8cb432023-11-23T14:08:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012311602110.3390/ijms23116021Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic HeartLayse Malagueta-Vieira0Julieta Fernández-Ruocco1María P. Hortigón-Vinagre2Víctor Zamora3Julián Zayas-Arrabal4Leyre Echeazarra5Godfrey L. Smith6Martín Vila Petroff7Emiliano Medei8Óscar Casis9Mónica Gallego10Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, SpainInstitute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, BrazilInstitute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow, 126 University Place, Glasgow G12 8TA, UKInstitute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow, 126 University Place, Glasgow G12 8TA, UKDepartamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, SpainDepartamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, SpainInstitute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow, 126 University Place, Glasgow G12 8TA, UKCentro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, ArgentinaInstitute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, BrazilDepartamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, SpainDepartamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria-Gasteiz, SpainMetformin 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<sub>to</sub>). In vitro, incubation with metformin for 24 h also reduced I<sub>to</sub>, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced I<sub>hERG</sub> 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<sub>to</sub> and I<sub>hERG</sub>. 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.https://www.mdpi.com/1422-0067/23/11/6021cardiac electrophysiologyrepolarizationcardiomyocyteion channelsventricular arrhythmiacardiac action potential |
| spellingShingle | Layse Malagueta-Vieira Julieta Fernández-Ruocco María P. Hortigón-Vinagre Víctor Zamora Julián Zayas-Arrabal Leyre Echeazarra Godfrey L. Smith Martín Vila Petroff Emiliano Medei Óscar Casis Mónica Gallego Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart International Journal of Molecular Sciences cardiac electrophysiology repolarization cardiomyocyte ion channels ventricular arrhythmia cardiac action potential |
| title | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart |
| title_full | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart |
| title_fullStr | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart |
| title_full_unstemmed | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart |
| title_short | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart |
| title_sort | metformin reduces potassium currents and prolongs repolarization in non diabetic heart |
| topic | cardiac electrophysiology repolarization cardiomyocyte ion channels ventricular arrhythmia cardiac action potential |
| url | https://www.mdpi.com/1422-0067/23/11/6021 |
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