Abstract
BackgroundThe aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle.MethodsIon currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model.ResultsAction potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QTc interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QTc. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (IKr) and slow (IKs) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (ICa) was slightly diminished, but the transient outward (Ito) and inward rectifier (IK1) potassium currents were not influenced.ConclusionsDiclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.
Highlights
Drug induced prolongation of cardiac repolarization that manifests on the surface ECG as QT interval lengthening is considered to represent enhanced risk for proarrhythmia and sudden cardiac death
Effects of Diclofenac on Action Potential The effects of diclofenac on action potential configuration were studied in canine right ventricular muscle preparations and Purkinje fibers
The main results of the present study show that in the normal heart, diclofenac does not exert marked cardiac electrophysiological effects and does not enhance proarrhythmic risk, in hearts where repolarization reserve is attenuated, its moderate inhibition of IKs and IKs were measured using ms (IKr) may lead to prolongation of ventricular repolarization and may enhance proarrhythmic risk
Summary
Drug induced prolongation of cardiac repolarization that manifests on the surface ECG as QT interval lengthening is considered to represent enhanced risk for proarrhythmia and sudden cardiac death. There are certain situations when cardiac repolarization reserve [1,2,3] is attenuated due to ion channel protein encoding gene mutations, diseases or even lifestyle when otherwise minor subthreshold drug effects on cardiac repolarization may enhance repolarization instability with subsequently elevated proarrhythmic risk. As a possible example for such situations, a number of sudden deaths of young athletes were reported in the past several years. The majority of these events were sudden cardiac deaths (SCD) attributed to ventricular fibrillation. There are a number of factors that can play a significant role in the development of SCD in young athletes [5]. The aim of the present work was to characterize the electrophysiological effects of the non-steroidal antiinflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle
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