Modulation of the late sodium current by ATX‐II and ranolazine affects the reverse use‐dependence and proarrhythmic liability of IKr blockade

• Published in: British journal of pharmacology Vol. 164; no. 2; pp. 308 - 316
• Main Authors: Jia, Shaobin, Lian, Jiangfan, Guo, Donglin, Xue, Xiaolin, Patel, Chinmay, Yang, Lin, Yuan, Zuyi, Ma, Aiqun, Yan, Gan‐Xin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Nature Publishing Group
• Subjects: Acetanilides; Animals; Anti-Arrhythmia Agents - pharmacology; Biological and medical sciences; Clarithromycin - pharmacology; Cnidarian Venoms - pharmacology; Heart Ventricles - drug effects; late sodium current; Medical sciences; Pharmacology. Drug treatments; Piperazines; Potassium Channel Blockers - pharmacology; Potassium Channels, Voltage-Gated - antagonists & inhibitors; Rabbits; Ranolazine; Research Papers; reverse use‐dependence; Sodium Channels; Sotalol - pharmacology; Torsades de Pointes - chemically induced; Torsades de Pointes - physiopathology; Tp‐e; Tp‐e/QT ratio and TdP; Antianginal agent; Late; QT; Coronary vasodilator agent; Ionic current; late sodium current; Ranolazine; reverse use-dependence; Sodium; T; Dependence; QT ratio and TdP; Piperazine derivatives
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01181.x

BACKGROUND AND PURPOSE Drug‐induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use‐dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (INa,L) could modulate the drug‐induced reverse use‐dependence in QT and Tp‐e (an index of dispersion of repolarization), and therefore the liability for TdP. EXPERIMENTAL APPROACH Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX‐II) (an INa,L enhancer), d,l‐sotalol, clarithromycin and ranolazine (an INa,L blocker) on rate‐dependent changes in QT, Tp‐e and proarrhythmic events were tested, either alone or in combination. Rate‐dependent QT and Tp‐e slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion. KEY RESULTS ATX‐II (30 nM) and sotalol (300 µM) caused a marked increase in QT and Tp‐e intervals, steeper QT‐basic cycle length (BCL) and Tp‐e‐BCL slopes (i.e. reverse use‐dependence), and TdP. Addition of ranolazine (15 µM) to ATX‐II or sotalol significantly attenuated QT‐BCL, Tp‐e‐BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and Tp‐e without causing R‐on‐T extrasystole or TdP, but addition of ATX‐II (1 nM) to clarithromycin markedly amplified the QT‐BCL and Tp‐e‐BCL slopes and further increased TdP score. CONCLUSION AND IMPLICATIONS Modulation of INa,L altered drug‐induced reverse use‐dependence related to QT as well as Tp‐e, indicating that inhibition of INa,L can markedly reduce the TdP liability of agents that prolong QT intervals.