Effects of ranolazine on torsades de pointes tachycardias in a healthy isolated rabbit heart model.

Abstract

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 INa but also IKr . 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 APD90 and increased dispersion of APD90 , simultaneously causing EADs and induction of TdP. The combination of d-sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD90 as compared to vehicle. Ranolazine at 5 μmol/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 μmol/L) in combination with d-sotalol caused further prolongation of APD90 , at the same time reduction in APD90 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.

• Authors: Samuel Sossalla, Nora Wallisch, Karl Toischer, Christian Sohns, Dirk Vollmann, Joachim Seegers, Lars Lüthje, Lars S Maier, Markus Zabel
• Journal: Cardiovascular therapeutics (Cardiovasc Ther) Vol. 32 Issue 4 Pg. 170-7 (Aug 2014) ISSN: 1755-5922 [Electronic] England
• PMID: 24785406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Chemical References

• Acetanilides
• Anti-Arrhythmia Agents
• Piperazines
• Sotalol
• Ranolazine
• Potassium

Topics

• Acetanilides (pharmacology)
• Action Potentials
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Cardiac Pacing, Artificial
• Dose-Response Relationship, Drug
• Heart Conduction System (drug effects, physiopathology)
• Heart Rate (drug effects)
• In Vitro Techniques
• Perfusion
• Piperazines (pharmacology)
• Potassium
• Rabbits
• Ranolazine
• Sotalol
• Time Factors
• Torsades de Pointes (etiology, physiopathology, prevention & control)