@article{ref1,
title="Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ current",
journal="American journal of respiratory and critical care medicine",
year="2012",
author="Dallas, Mark L. and Yang, Zhaokang and Boyle, John P. and Boycott, Hannah E. and Scragg, Jason L. and Milligan, Carol J. and Elies, Jacobo and Duke, Adrian and Thireau, Jérôme and Reboul, Cyril and Richard, Sylvain and Bernus, Olivier and Steele, Derek S. and Peers, Chris",
volume="186",
number="7",
pages="648-656",
abstract="RATIONALE: Clinical reports describe life-threatening cardiac arrhythmias following environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown. OBJECTIVES: to understand the cellular basis of CO-induced arrhythmias and to indentify an effective therapeutic approach. METHODS: Patch-clamp electrophysiology and confocal Ca2+ and nitric oxide (NO) imaging in isolated ventricular myocytes was performed together with protein S-nitrosylation to investigate the effects of CO at the cellular and molecular level, whilst telemetry was employed to investigate effects of CO on electrocardiogram recordings in vivo. MEASUREMENTS AND MAIN RESULTS: CO increased the sustained (late) component of the inward Na+ current, resulting in prolongation of the action potential (AP) and the associated intracellular Ca2+ transient. In > 50% of myocytes these changes progressed to early after-depolarization (EAD)-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na+ channel, Nav1.5. All pro-arrhythmic effects of CO were abolished by the nitric oxide synthase inhibitor L-NAME, and reversed by ranolazine, an inhibitor of the late Na+ current. Ranolazine also corrected QT variability and arrhythmias induced by CO in vivo, as monitored by telemetry. CONCLUSIONS: Our data indicate that the pro-arrhythmic effects of CO arise from activation of NOS, leading to NO-mediated nitrosylation of NaV1.5 and so induction of the late Na+ current. We also show that the anti-anginal drug ranolazine can abolish CO-induced EADs, highlighting a novel approach to the treatment of CO-induced arrhythmias.<p /> <p>Language: en</p>",
language="en",
issn="1073-449X",
doi="10.1164/rccm.201204-0688OC",
url="http://dx.doi.org/10.1164/rccm.201204-0688OC"
}