Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
dc.contributor.author | Malagueta Vieira, Layse | |
dc.contributor.author | Fernández Ruocco, Julieta | |
dc.contributor.author | Hortigon-Vinagre, Maria Pura | |
dc.contributor.author | Zamora, Víctor | |
dc.contributor.author | Zayas Arrabal, Julián | |
dc.contributor.author | Echeazarra Escudero, Leire | |
dc.contributor.author | Smith, Godfrey | |
dc.contributor.author | Vila Petroff, Martín | |
dc.contributor.author | Medei, Emiliano | |
dc.contributor.author | Casis Sáenz, Oscar | |
dc.contributor.author | Gallego Muñoz, Mónica | |
dc.date.accessioned | 2022-06-29T14:37:10Z | |
dc.date.available | 2022-06-29T14:37:10Z | |
dc.date.issued | 2022-05-27 | |
dc.identifier.citation | International Journal of Molecular Sciences 23(11) : (2022) // Article ID 6021 | es_ES |
dc.identifier.issn | 1422-0067 | |
dc.identifier.uri | http://hdl.handle.net/10810/56896 | |
dc.description.abstract | 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 (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG 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 Ito and IhERG. 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. | es_ES |
dc.description.sponsorship | This work was supported by The University of the Basque Country (Grant number PPG17/13), Gobierno Vasco (PIBA2018-58) and MICIIN (PID2020-118814RB-I00). V.Z.R. is recipient of a Fundación Alfonso Martín Escudero (SPAIN) postdoctoral fellowship. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICIIN/PID2020-118814RB-I00 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | cardiac electrophysiology | es_ES |
dc.subject | repolarization | es_ES |
dc.subject | cardiomyocyte | es_ES |
dc.subject | ion channels | es_ES |
dc.subject | ventricular arrhythmia | es_ES |
dc.subject | cardiac action potential | es_ES |
dc.subject | diabetes | es_ES |
dc.title | Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.date.updated | 2022-06-09T13:40:49Z | |
dc.rights.holder | © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | es_ES |
dc.relation.publisherversion | https://www.mdpi.com/1422-0067/23/11/6021 | es_ES |
dc.identifier.doi | 10.3390/ijms23116021 | |
dc.departamentoes | Fisiología | |
dc.departamentoeu | Fisiologia |
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Except where otherwise noted, this item's license is described as © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).