Inhibition of the cardiac Na⁺ channel Nav1.5 by carbon monoxide.
Sublethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias, and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na(+) channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na(+) current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognized CO-sensitive intracellular signaling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of NO formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to DTT immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, l-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na(+) current (which can lead to Brugada syndrome-like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation, and is dependent on channel redox state.
From the Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health and.
Jacobo
J
Elies
From the Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health and.
Mark L
ML
Dallas
From the Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health and.
John P
JP
Boyle
From the Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health and.
Jason L
JL
Scragg
Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Adrian
A
Duke
Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Derek S
DS
Steele
From the Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health and c.s.peers@leeds.ac.uk.
Chris
C
Peers
D002248:Carbon Monoxide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects*; D010084:Oxidation-Reduction
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D002248:Carbon Monoxide
Arrhythmia; Carbon Monoxide; Heart; Nitric Oxide; Patch Clamp Electrophysiology; Sodium Channels