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Predicting drug‐induced slowing of conduction and pro‐arrhythmia: identifying the ‘bad’ sodium current blockers
Author(s) -
Lu Hua Rong,
Rohrbacher Jutta,
Vlaminckx Eddy,
Van Ammel Karel,
Yan GanXin,
Gallacher David J
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00646.x
Subject(s) - flecainide , lidocaine , sodium channel , purkinje fibers , sodium channel blocker , cardiology , medicine , ventricular tachycardia , anesthesia , chemistry , electrophysiology , sodium , atrial fibrillation , organic chemistry
Background and purpose: The regulatory guidelines (ICHS7B) for the identification of only drug‐induced long QT and pro‐arrhythmias have certain limitations. Experimental approach: Conduction time (CT) was measured in isolated Purkinje fibres, left ventricular perfused wedges and perfused hearts from rabbits, and sodium current was measured in Chinese hamster ovary cells, transfected with Na v 1.5 channels. Key results: A total of 355 compounds were screened for their effects on CT: 32% of these compounds slowed conduction, 65% had no effect and 3% accelerated conduction. Lidocaine and flecainide, which slow conduction, were tested in more detail as reference compounds. In isolated Purkinje fibres, flecainide largely slowed conduction and markedly increased triangulation, while lidocaine slightly slowed conduction and did not produce significant triangulation. Also in isolated left ventricular wedge preparations, flecainide largely slowed conduction in a rate‐dependent manner, and elicited ventricular tachycardia (VT). Lidocaine slightly slowed conduction, reduced Tp–Te and did not induce VT. Similarly in isolated hearts, flecainide markedly slowed conduction, increased Tp–Te and elicited VT or ventricular fibrillation (VF). The slowing of conduction and induction of VT/VF with flecainide was much more evident in a condition of ischaemia/reperfusion. Lidocaine abolished ischaemia/reperfusion‐induced VT/VF. Flecainide blocked sodium current ( I Na ) preferentially in the activated state (i.e. open channel) with slow binding and dissociation rates in a use‐dependent manner, and lidocaine weakly blocked I Na . Conclusion and implications: Slowing conduction by blocking I Na could be potentially pro‐arrhythmic. It is possible to differentiate between compounds with ‘good’ (lidocaine‐like) and ‘bad’ (flecainide‐like) I Na blocking activities in these models.