Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the ‘bad’ sodium current blockers

Authors

  • Hua Rong Lu,

    Corresponding author
    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica, Beerse, Belgium, and
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  • Jutta Rohrbacher,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica, Beerse, Belgium, and
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  • Eddy Vlaminckx,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica, Beerse, Belgium, and
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  • Karel Van Ammel,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica, Beerse, Belgium, and
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  • Gan-Xin Yan,

    1. Main Line Health Heart Center, Wynnewood, PA, USA
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  • David J Gallacher

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica, Beerse, Belgium, and
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  • Correction added after online publication 1 April 2010: the author Gao-Xin Yan was corrected to Gan-Xin Yan.

Dr Hua Rong Lu, Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., B-2340 Beerse, Belgium. E-mail: hlu@its.jnj.com

Abstract

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 Nav1.5 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 (INa) preferentially in the activated state (i.e. open channel) with slow binding and dissociation rates in a use-dependent manner, and lidocaine weakly blocked INa.

Conclusion and implications:  Slowing conduction by blocking INa could be potentially pro-arrhythmic. It is possible to differentiate between compounds with ‘good’ (lidocaine-like) and ‘bad’ (flecainide-like) INa blocking activities in these models.

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