title: Inhibition of Na+ channels ameliorates arrhythmias in a drug-induced model of Andersen-Tawil syndrome.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112-5000, USA.
authors.forename: Przemysław B
authors.initials: PB
authors.lastname: Radwański
authors.forename: Amara
authors.initials: A
authors.lastname: Greer-Short
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials; D050030:Andersen Syndrome / Q000150:complications* / Q000503:physiopathology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000379:methods; D006168:Guinea Pigs; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011897:Random Allocation; D000069458:Ranolazine; D012680:Sensitivity and Specificity; D015222:Sodium Channels / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000175:diagnosis* / Q000209:etiology
chemical_list: D000083:Acetanilides; D015220:Calcium Channels; D010879:Piperazines; D011726:Pyridinium Compounds; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; C050019:1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium betaine; D000069458:Ranolazine