Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR.

No abstract

Under drug-free circumstances, a persistent high BVR in chronic-AVB dogs is remodelling dependent rather than a direct consequence of bradycardia acutely after AVB. Variability of this slower rate does not influence BVR. Dofetilide causes a transient increase in BVR only in proarrhythmic dogs. Thus, BVR may aid the identification of the TdP-susceptible patient.

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca 2+ channel antagonists, flunarizine and verapamil against TdP were investigated. EXPERIMENTAL APPROACHMongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca 2+ sparks in RyR2 R4496+/+ mouse myocytes; and (iii) peak and late INa in SCN5A-HEK 293 cells. KEY RESULTSDofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late INa. Ca 2+ sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONSRobust anti-arrhythmic efficacy was seen with both Ca 2+ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs. AbbreviationsAPD, action potential duration; BVR, beat-to-beat variability of repolarization duration; [Ca 2+ ]i, intracellular calcium concentration; CAVB, chronic AV-block; DADs, delayed afterdepolarizations; EADs, early after depolarizations; ICa,L, L-type calcium current; IKr, rapid component of the delayed rectifier current; IKs, slow component BJP British Journal of Pharmacology