• Mark L Dallas, Zhaokang Yang, John P Boyle, Hannah E Boycott, Jason L Scragg, Carol J Milligan, Jacobo Elies, Adrian Duke, Jérôme Thireau, Cyril Reboul, Sylvain Richard, Olivier Bernus, Derek S Steele, and Chris Peers.
• Division of Cardiovascular and Neuronal Remodelling, LIGHT, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, UK.
• Am. J. Respir. Crit. Care Med. 2012 Oct 1; 186 (7): 648656648-56.

RationaleClinical reports describe life-threatening cardiac arrhythmias after 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.ObjectivesTo understand the cellular basis of CO-induced arrhythmias and to identify an effective therapeutic approach.MethodsPatch-clamp electrophysiology and confocal Ca(2+) 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 levels, whereas telemetry was used to investigate effects of CO on electrocardiogram recordings in vivo.Measurements And Main ResultsCO increased the sustained (late) component of the inward Na(+) current, resulting in prolongation of the action potential and the associated intracellular Ca(2+) transient. In more than 50% of myocytes these changes progressed to early after-depolarization-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na(+) channel, Na(v)1.5. All proarrhythmic effects of CO were abolished by the NO 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.ConclusionsOur data indicate that the proarrhythmic effects of CO arise from activation of NO synthase, leading to NO-mediated nitrosylation of Na(V)1.5 and to induction of the late Na(+) current. We also show that the antianginal drug ranolazine can abolish CO-induced early after-depolarizations, highlighting a novel approach to the treatment of CO-induced arrhythmias.

39 keywords...

hide…