Al-Owais, MM, Hettiarachchi, NT, Kirton, HM et al. (5 more authors) (2017) A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K+ channels in carbon monoxide–induced proarrhythmic early afterdepolarizations. FASEB Journal, 31 (11). pp. 4845-4854. ISSN 0892-6638
Abstract
Exposure to carbon monoxide (CO) causes early afterdepolarization arrhythmias. Previous studies in rats indicated arrhythmias arose due to augmentation of the late Na+ current. The purpose of the present study was to examine the basis of CO-induced arrhythmias in guinea pig myocytes in which action potentials more closely resemble those of human myocytes. Whole-cell current- and voltage-clamp recordings were made from isolated guinea pig myocytes and also from HEK293 cells expressing wild-type or a C723S mutant form of Kv11.1 (ERG). We also monitored formation of peroxynitrite (ONOO-) in HEK293 cells fluorimetrically. CO, applied as the CO releasing molecule, CORM-2, prolonged action potentials and induced early after-depolarizations (EADs) in guinea pig myocytes. In HEK293 cells CO inhibited wild-type but not C723S mutant Kv11.1 K+ currents. Inhibition was prevented by an antioxidant, mitochondrial inhibitors or inhibition of nitric oxide formation. CO also raised ONOO- levels, an effect reversed by the ONOO- scavenger, FeTPPS which also prevented CO inhibition of Kv11.1 currents, and abolished the effects of CO on Kv11.1 tail currents and action potentials in guinea pig myocytes. Our data suggest that CO induces arrhythmias in guinea pig cardiac myocytes via ONOO--mediated inhibition of Kv11.1 K+ channels
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017, The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | carbon monoxide; nitric oxide; peroxynitrite, arrhythmia, potassium channel |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/13/61/30410 British Heart Foundation PG/09/013/26885 |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Jul 2017 12:53 |
Last Modified: | 23 Jun 2023 22:32 |
Status: | Published |
Publisher: | Federation of American Societies for Experimental Biology |
Identification Number: | 10.1096/fj.201700259R |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:118734 |