Journal
JCI INSIGHT
Volume 6, Issue 15, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.143092
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Funding
- Washington University Institute for Clinical and Translational Sciences
- NIH National Center for Research Resources [UL1 RR024992]
- American Heart Association [15PRE25080073]
- NIH National Heart, Lung, and Blood Institute [R01 HL136553, R01 HL-034161, R01 HL-142520]
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The study found that the accessory Na-V beta 1 and Na-V beta 3 subunits have different effects on the antiarrhythmic drugs lidocaine and ranolazine on Na(V)1.5 channel; recordings from mouse ventricular myocytes showed that loss of Scn1b affects the potencies of lidocaine and ranolazine differently; in vivo experiments suggested that Na-V beta 1 modulated drug responses at the whole-heart level.
Native myocardial voltage-gated sodium (Na-V) channels function in macromolecular complexes comprising a pore-forming (alpha) subunit and multiple accessory proteins. Here, we investigated the impact of accessory Na-V beta 1 and Na-V beta 3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant Na-V channel alpha subunit, Na(V)1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in Na(V)1.5. In the presence of Na-V beta 1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by Na-V beta 1/beta 3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (Na-V beta 1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that Na-V beta 1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.
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