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dc.contributor.authorAl-Owais, M.M.
dc.contributor.authorHettiarachchi, N.T.
dc.contributor.authorKirton, H.M.
dc.contributor.authorHardy, Matthew E.
dc.contributor.authorBoyle, J.P.
dc.contributor.authorScragg, J.L.
dc.contributor.authorSteele, D.S.
dc.contributor.authorPeers, C.
dc.date.accessioned2018-07-16T09:19:03Z
dc.date.available2018-07-16T09:19:03Z
dc.date.issued2017-11-01
dc.identifier.citationAl-Owais MM, Hettiarachchi NT, Kirton HM, Hardy ME, Boyle JP, Scragg JL, Steele DS and Peers C (2017) A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K+ channels in carbon monoxide–induced proarrhythmic early afterdepolarizations. FASEB. 31(11): 4845-4854.en_US
dc.identifier.urihttp://hdl.handle.net/10454/16500
dc.descriptionyesen_US
dc.description.abstractExposure to CO causes early afterdepolarization arrhythmias. Previous studies in rats have indicated that arrhythmias arose as a result of augmentation of the late Na+ current. The purpose of the present study was to examine the basis for CO-induced arrhythmias in guinea pig myocytes in which action potentials (APs) more closely resemble those of human myocytes. Whole-cell current- and voltage-clamp recordings were made from isolated guinea pig myocytes as well as from human embryonic kidney 293 (HEK293) cells that express wild-type or a C723S mutant form of ether-a-go-go–related gene (ERG; Kv11.1). We also monitored the formation of peroxynitrite (ONOO−) in HEK293 cells fluorimetrically. CO—applied as the CO-releasing molecule, CORM-2—prolonged the APs and induced early afterdepolarizations 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 NO formation. CO also raised ONOO− levels, an effect that was reversed by the ONOO− scavenger, FeTPPS [5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrinato-iron(III)], which also prevented the CO inhibition of Kv11.1 currents and abolished the effects of CO on Kv11.1 tail currents and APs in guinea pig myocytes. Our data suggest that CO induces arrhythmias in guinea pig cardiac myocytes via the ONOO−-mediated inhibition of Kv11.1 K+ channels.en_US
dc.description.sponsorshipBritish Heart Foundationen_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1096/fj.201700259Ren_US
dc.rights© 2017. The Authors. Published by FASEB. 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.en_US
dc.subjectNitric oxideen_US
dc.subjectPotassium channelen_US
dc.subjectCardiac ERG (Kv11.1) K+ channel inhibitionen_US
dc.subjectMyocytesen_US
dc.titleA key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K+ channels in carbon monoxide–induced proarrhythmic early afterdepolarizationsen_US
dc.status.refereedyesen_US
dc.date.Accepted2017-07-05
dc.date.application2017-07-25
dc.typeArticleen_US
dc.type.versionPublished versionen_US
refterms.dateFOA2018-07-29T02:38:58Z


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