Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of I Kr blockade

Abstract

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 (I Na,L) could modulate the drug-induced reverse use-dependence in QT and T p-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 I Na,L enhancer), d,l-sotalol, clarithromycin and ranolazine (an I Na,L blocker) on rate-dependent changes in QT, T p-e and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T p-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 T p-e intervals, steeper QT-basic cycle length (BCL) and T p-e-BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 μM) to ATX-II or sotalol significantly attenuated QT-BCL, T p-e-BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 μM) moderately prolonged QT and T p-e without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T p-e-BCL slopes and further increased TdP score. CONCLUSION AND IMPLICATIONS Modulation of I Na,L altered drug-induced reverse use-dependence related to QT as well as T p-e, indicating that inhibition of I Na,L can markedly reduce the TdP liability of agents that prolong QT intervals. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.