Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

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.

The Effects of Diclofenac and Ibuprofen on Heart Function and Oxidative Stress Markers in the Isolated Rat Heart

“…One of the possible mechanisms by which diclofenac exhibits depressive effects on the heart is through the reversible inhibition of the Na + currents and irreversible inhibition the L-type Ca 2+ channel currents in cardiac muscle cells (13,26). Moreover, ibuprofen also exhibits a similar influence (17) on ion channels, but in our results, there was no effect on cardiac contractility.…”

“…Diclofenac may also affect the duration of the action potential and heart rate (26). Kristof and co-authors concluded that chronic administration of diclofenac at therapeutic concentrations does not increase the risk of arrhythmia in intact hearts (26). In our experiments, we also used intact hearts, but considering our experimental protocol and acute administration of diclofenac, this mechanism may play a role in decreasing the heart rate.…”

Estudio farmacoepidemiológico acerca de uso de antiinflamatorios no esteroideos en pacientes de alto riesgo cardiovascular

“…Por otro lado, el diclofenaco, por su alta selectividad a la COX-2 y sus efectos dosis dependientes a nivel del corazón y vasos sanguíneos, se ha descrito como el AINES tradicional con mayor riesgo cardiovascular y cerebrovascular, e incluso algunos estudios señalan que incrementa el riesgo de muerte tan solo con 7 a 14 días de uso en pacientes con un infarto de miocardio previo (8,10,11) ; las dosis altas de diclofenaco, e incluso de ibuprofeno, se comparan con el riesgo que representan los inhibidores de la COX-2 (16) . Ello se debería a que el diclofenaco produciría la inhibición de los canales L de calcio y de los canales de sodio en los células cardiacas produciendo alteraciones en su relajación y contractilidad, pudiendo -en corazones no sanos-desencadenar falla cardiaca (17,18) . Pese a que la proporción de uso de AINES en pacientes con ARC fue baja, se sigue presentando tal situación que eleva la probabilidad de que los pacientes con alguna enfermedad cardíaca puedan presentar un nuevo evento tromboembólico o precipitar una falla cardíaca.…”

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

“…Impaired repolarization reserve importantly contributes to increased arrhythmia susceptibility in HF patients. In clinical practical terms it means that not only antiarrhythmic drugs with strong potassium channel blocking properties (Class IA, IB and Class III) can provoke TdP, VF and sudden cardiac death in HF patients, but the application of non-cardiovascular drugs that possess weaker K + current inhibitory effects, including some antibiotics [137], antimycotics [138], antihistamines [139], antipsychotics [140], NSAIDs [141], even dietary constituents [142], K + -losing diuretics etc., can further interfere with repolarization [143] and can lead to unexpected and serious ventricular arrhythmia development in this patient population. Importantly, the presence of repolarization prolonging genetic mutations responsible for different forms of long QT (LQT) syndromes can also exacerbate ventricular arrhythmias in HF.…”