Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits

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.

Automated summary

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.