1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium-betaine and Andersen-Syndrome

Andersen-Tawil syndrome (ATS1)-associated ventricular tachycardias (VTs) are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug-induced ATS1 (DI-ATS1) evidenced increased arrhythmias from regions with high Na(+)/Ca(2+)-exchange expression.. Therefore, we hypothesize that reduced cytosolic Na(+) entry through either cardiac isoform of or tetrodotoxin (TTX)-sensitive Na(+) channels during DI-ATS1 can ameliorate arrhythmia burden.. DI-ATS1 was induced with 10 μM BaCl(2) and 2 mM extracellular K(+). Ca(2+) transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS, respectively, from Langendorff-perfused guinea pig ventricles.. Nonselective Na(+) channel blockade with 1 μM flecainide reduced amplitude (Ca(A)), slowed left ventricular CV, reduced tissue excitability, and abolished the incidence of VT while decreasing the incidence of PVA relative to DI-ATS1. Selective, TTX-sensitive Na(+) channel blockade with TTX (100 nM) during DI-ATS1 decreased Ca(A) and decreased the inducibility of VTs and PVA relative to DI-ATS1 without slowing CV. Ranolazine altered Ca(A), left ventricular CV, tissue excitability, and reduced inducibility of VT and PVA in a concentration-dependent manner. None of the aforementioned interventions altered diastolic Ca(2+) levels or Ca(2+) transient decay time constant.. These data suggest that cytosolic Na(+) entry and its modulation of Ca(2+) handling are necessary for arrhythmogenesis. During the loss of inward-rectifier K(+) current function, not only Na(+)/Ca(2+)-exchange dominance but Na(+) flux may determine arrhythmia burden. Therefore, selective inhibition of TTX-sensitive Na(+) channels may offer a potential therapeutic target to alleviate arrhythmias during states of Ca(2+) overload secondary to loss of inward-rectifier K(+) current function without compromising the excitability reserve.

Topics: Acetanilides; Action Potentials; Andersen Syndrome; Animals; Calcium Channels; Cytosol; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Guinea Pigs; Male; Piperazines; Pyridinium Compounds; Random Allocation; Ranolazine; Sensitivity and Specificity; Sodium Channels; Sodium-Calcium Exchanger; Tachycardia, Ventricular