Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations

Carlsson, Leif; Abrahamsson, Christina; Andersson, Birgit; Duker, Göran; Schiller-Linhardt, G

doi:10.1093/cvr/27.12.2186

Cited by 202 publications

(126 citation statements)

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“…5,6 "Proarrhythmic" compounds were selected from compounds with a TdP incidence Ͼ60%. "Less proarrhythmic compounds" were selected from compounds with a TdP incidence Յ25 (Table I).…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Ten minutes later, the compound under investigation was infused for 30 minutes; 5 minutes later, the dose was increased up to 10-fold. The first dose lengthened the guinea pig monophasic APD by 20% (Table I).…”

Section: Methodsmentioning

confidence: 99%

“…5,6 Briefly, 149 male New Zealand White rabbits (2.5 to 3.5 kg) were anesthetized with methohexital sodium (5 mg/kg IV) and ␣-chloralose (90 mg/kg IV) and were ventilated to maintain arterial blood gases and pH. Drugs were infused into an ear vein, and ECGs, arterial blood pressure, and heart rate were recorded on chart recorders and a computer (sampled at 500 Hz for 5 seconds each minute).…”

Section: In Vivo Experimentsmentioning

confidence: 99%

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Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

2001

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Background-Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class III), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). Methods and Results-The cardiac electrophysiological effects of 702 chemicals (class III or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by Ͼ50 ms, with induction of instability, triangulation, and reverse use-dependence (nϭ59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (nϭ19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (PϽ0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). Conclusions-Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.

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“…5,6 "Proarrhythmic" compounds were selected from compounds with a TdP incidence Ͼ60%. "Less proarrhythmic compounds" were selected from compounds with a TdP incidence Յ25 (Table I).…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: In Vivo Experimentsmentioning

confidence: 99%

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Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

2001

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“…azimilide (Jiang et al, 1999) and almokalant (Carmeliet, 1993). However, almokalant, which is a selective IK r -inhibiting compound, has the potential to induce TdP in the methoxamine-sensitised rabbit model and in man (Carlsson et al, 1993a;Darpö et al, 1996). Hence, the prepulse potentiation of hERG can not by itself explain the low proarrhythmic potential of AZD7009 but may contribute when combined with other protective properties.…”

Section: Mechanisms Underlying the Low Proarrhythmic Potential Of Azdmentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

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Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

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“…Verduyn et al, 1997;Hohnloser, 1997 . It was demonstrated that almokalant, a selective I blocker, signifiKr cantly reduced the incidence of coronary artery occlusionr reperfusion-induced arrhythmias but also showed marked Ž proarrhythmic activity Carlsson et al, 1993a;Farkas et . al., 1998 .…”

Section: Discussionmentioning

confidence: 99%

European Journal of Pharmacology

Engels

2004

European Journal of Pharmacology

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Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations

Abstract: The rate of infusion of repolarisation delaying agents may influence the dispersion of repolarisation and play a decisive role in the initiation of torsade de pointes.

Cited by 202 publications

References 0 publications

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

European Journal of Pharmacology

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