QTU-Prolongation and Torsades de Pointes Induced by Putative Class III Antiarrhythmic Agents in the Rabbit

Carlsson, Leif; Almgren, Olle; Duker, Göran

doi:10.1097/00005344-199008000-00014

Cited by 234 publications

(172 citation statements)

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“…AZD7009 was selected as a candidate drug for clinical development based upon its low proarrhythmic potential as assessed in a sensitive preclinical proarrhythmia model (the methoxamine-sensitised rabbit model of TdP) (Carlsson et al, 1990) and was later shown also to possess low proarrhythmic potential in the isolated arterially perfused dog and rabbit left ventricular wedge preparations (Wu et al, 2005). In the ventricular wedge preparation, action potentials were simultaneously recorded from endocardial, midmyocardial and epicardial cells and, in addition, a transmural pseudo ECG were recorded.…”

Section: Low Proarrhythmic Potentialmentioning

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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Section: Low Proarrhythmic Potentialmentioning

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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“…The rabbit ventricular cell may be a suitable preparation for the evaluation of class III effect because a variety of voltagegated K+ channels including It. channels (Hiraoka & Kawano, 1989; Giles & Imaizumi, 1988) are known to exist in the cells as in human cardiac cells (Escande et al, 1987).In addition, it has recently been reported that many class III drugs easily induce torsades de pointes in rabbits (Carlsson et al, 1990). Therefore, in order to minimize the life-threatening proarrhythmias it is of importance to evaluate class III effects in rabbit ventricular cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of MS‐551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes

Nakaya

Tohse

Takeda

et al. 1993

British J Pharmacology

131

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1 Electrophysiological effects of MS-551, a new class III antiarrhythmic drug, were examined and compared with those of (+)-sotalol in rabbit ventricular cells. 2 In rabbit ventricular muscles stimulated at 1.0 Hz, MS-551 (0.1-10 LM) and (+)-sotalol (3-100I1M) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization (V.,a). The class III effect of MS-551 was approximately 30 times more potent than that of (+)-sotalol. 3 Class III effects of MS-551 and (+)-sotalol showed reverse use-dependence, i.e., a greater prolongation of APD at a longer cycle length. 4 In rabbit isolated ventricular cells, 3 gM MS-551 and 100 JLM sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than -50 mV and saturated around + 20 mV. 5 MS-551 at a higher concentration of 10 JAM decreased the transient outward current (Ito) and the inward rectifier potassium current (IKI) although 100 tLM sotalol failed to inhibit these currents.6 MS-551 is a non-specific class III drug which can inhibit three voltage-gated K+ channels in rabbit ventricular cells.

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“…2,3 Therefore, these I Kr blockers may act in a proarrhythmic manner during bradycardia, with minimal therapeutic potency against tachyarrhythmias. 4,5 Chromanol 293B has recently been reported to selectively block I Ks . Moreover, it prolonged APD in a frequency-independent manner in guinea pig and human ventricular myocytes.…”

mentioning

confidence: 99%

“…9 Such fundamental differences in channel kinetics may be expected to have a bearing on APD prolongation and on the efficacy of different class III antiarrhythmic agents. 4,13 We compared the densities and the kinetics of I Kr and I Ks in guinea pig and rabbit ventricular myocytes and assessed the effects of E-4031 (I Kr blocker) and chromanol 293B (I Ks blocker) on APD. Specific action potential prolongation at short cycle length is feasible by I Ks blockade in the guinea pig, but not in the rabbit.…”

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Density and Kinetics of I _Kr and I _Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I _Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

et al. 2001

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Background-Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K ϩ current (I K ) may help to develop agents effective at high heart rate. Methods and Results-We assessed the density and kinetics of the 2 components of the delayed rectifier K ϩ current, I Kr and I Ks , in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I Ks and E-4031 for I Kr ) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques.In guinea pig ventricular myocytes only, blockade of I Ks causes APD prolongation in a frequency-independent manner, whereas blockade of I Ks in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I Kr in both species. This result can be explained primarily by the higher density of I Ks in guinea pig ventricle and by its slow deactivation kinetics, which allows I Ks to accumulate at high heart rate because little time is available for complete deactivation of it during diastole. Conclusions-Density and kinetics of components of I K explain why blockade of I Ks is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

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QTU-Prolongation and Torsades de Pointes Induced by Putative Class III Antiarrhythmic Agents in the Rabbit

Cited by 234 publications

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

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

Effects of MS‐551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes

Density and Kinetics of I _Kr and I _Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I _Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

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QTU-Prolongation and Torsades de Pointes Induced by Putative Class III Antiarrhythmic Agents in the Rabbit

Cited by 234 publications

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

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

Effects of MS‐551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes

Density and Kinetics of I Kr and I Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

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Density and Kinetics of I _Kr and I _Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I _Ks Blockade at High Heart Rate in Guinea Pig and Rabbit