NaVβ1 enhanced the effect of lidocaine but abolished the effect of ranolazine on the DIII-VSD of NaV1.5 channels, resulting in differential use-dependent block and distinct ECG responses in mice.
Does the presence of accessory NaVβ subunits modulate the electrophysiological effects of lidocaine and ranolazine on cardiac NaV1.5 channels in preclinical models?
Accessory NaVβ subunits differentially modulate the effects of lidocaine and ranolazine on cardiac NaV1.5 channels, which may explain patient variability in response to class Ib antiarrhythmics.
Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, 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 NaVβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (NaVβ1) 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 NaVβ1 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.
Zhu et al. (Tue,) conducted a other in Arrhythmia (Basic Science). Lidocaine and Ranolazine vs. Baseline / Vehicle / WT controls was evaluated on NaV1.5 DIII-VSD conformational changes and INa use-dependent block. NaVβ1 enhanced the effect of lidocaine but abolished the effect of ranolazine on the DIII-VSD of NaV1.5 channels, resulting in differential use-dependent block and distinct ECG responses in mice.