Zusammenfassung
Purpose: Torsades de pointes (TdP) tachycardias are triggered, polymorphic ventricular arrhythmias arising from early afterdepolarizations (EADs) and increased dispersion of repolarization. Ranolazine is a new agent which reduces pathologically elevated late I-Na but also I-Kr. Aim of this study was to evaluate the effects of ranolazine in a validated isolated Langendorff-perfused rabbit heart ...
Zusammenfassung
Purpose: Torsades de pointes (TdP) tachycardias are triggered, polymorphic ventricular arrhythmias arising from early afterdepolarizations (EADs) and increased dispersion of repolarization. Ranolazine is a new agent which reduces pathologically elevated late I-Na but also I-Kr. Aim of this study was to evaluate the effects of ranolazine in a validated isolated Langendorff-perfused rabbit heart model. Methods: TdP was reproducibly induced with d-sotalol (10(-4) mol/L) and low potassium (K) (1.0 mmol/L for 5 min, pacing at CL 1000 ms). In 10 hearts, ECG and 8 epi- and endocardial monophasic action potentials were recorded. Action potential duration (APD) was measured at 90% repolarization and dispersion defined as APD max-min. Results: D-sotalol prolonged APD(90) and increased dispersion of APD(90), simultaneously causing EADs and induction of TdP. The combination of d-sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD(90) as compared to vehicle. Ranolazine at 5 mu mol/L did not cause additional induction of EADs and/or TdP but also did not significantly suppress arrhythmogenic triggers. The higher concentration of ranolazine (10 mu mol/L) in combination with d-sotalol caused further prolongation of APD(90), at the same time reduction in APD(90) dispersion. In parallel, the incidence of EADs was reduced and an antitorsadogenic effect was seen. Conclusions: In the healthy isolated rabbit heart (where late INa is not elevated), ranolazine does not cause proarrhythmia but exerts antiarrhythmic effects in a dose-dependent manner against d-sotalol/low K-induced TdP. This finding-despite additional APD prolongation-supports the safety of a combined use of both drugs and merits clinical investigation.
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