Resting, and rate‐dependent depression of  of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

Pallandi, Regan T.; Campbell, Terry

doi:10.1111/j.1476-5381.1987.tb11300.x

Cited by 35 publications

(35 citation statements)

References 28 publications

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“…Previously, we hypothesized that this effect may reduce stimulation-induced conduction slowing and thereby prevent induction of ventricular tachyarrhythmias (El-Sherif, 1991;Koller et al, 1995;Kirchhof et al, 1998). In this study, however, the degree of stimulation-induced conduction slowing was similar at baseline and in amiodarone-treated hearts, potentially due to the inactivated sodium channelblocking effect of amiodarone (Pallandi and Campbell, 1987;Maruyama et al, 1995). Preventing stimulation-induced conduction slowing can therefore not fully explain the antiarrhythmic effect of PRR.…”

Section: Discussioncontrasting

confidence: 51%

“…PRR allows for full recovery of voltage-dependent sodium channels during the refractory period (Maruyama et al, 1995), as reflected by relatively rapid upstroke velocities of action potentials after an extra stimulus in isolated tissue preparations that are not different from upstroke velocities during fix frequent pacing (Pallandi and Campbell, 1987). Previously, we hypothesized that this effect may reduce stimulation-induced conduction slowing and thereby prevent induction of ventricular tachyarrhythmias (El-Sherif, 1991;Koller et al, 1995;Kirchhof et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Others have previously demonstrated that the acute effects of amiodarone include a prolongation of refractoriness beyond repolarization in isolated rabbit papillary muscle (Pallandi and Campbell, 1987;Maruyama et al, 1995). Maruyama et al (1995) already suggested that the sodium channel-blocking effect of amiodarone might be one of the reasons why this drug is an effective antiarrhythmic agent.…”

Section: Discussionmentioning

confidence: 99%

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Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Kirchhof¹,

Degen²,

Franz³

et al. 2003

J Pharmacol Exp Ther

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It is still incompletely understood why amiodarone is such a potent antiarrhythmic drug. We hypothesized that chronic amiodarone treatment produces postrepolarization refractoriness (PRR) without conduction slowing and that PRR modifies the induction of ventricular arrhythmias. In this study, the hearts of 15 amiodarone-pretreated (50 mg/kg p.o. for 6 weeks) rabbits and 13 controls were isolated and eight monophasic action potentials were simultaneously recorded from the epicardium and endocardium of both ventricles. Steady-state action potential duration (APD), conduction times, refractory periods, and dispersion of action potential durations were determined during programmed stimulation and during 50-Hz burst stimuli, and related to arrhythmia inducibility. Amiodarone prolonged APD by 12 to 15 ms at pacing cycle lengths of 300 to 600 ms (p Ͻ 0.05) but did not significantly increase conduction times or dispersion of APD. Amiodarone prolonged refractoriness more than action potential duration, resulting in PRR (refractory period Ϫ APD at 90% repolarization, 14 Ϯ 10 ms, p Ͻ 0.05 versus controls). PRR curtailed the initial sloped part of the APD restitution curve by 20%. During burst stimulation, pronounced amiodarone-induced PRR (40 Ϯ 15 ms, p Ͻ 0.05 versus controls) reduced the inducibility of ventricular arrhythmias (p Ͻ 0.05 versus controls). Furthermore, in 35% of bursts only monomorphic ventricular tachycardias and no longer ventricular fibrillation were inducible in amiodarone-treated hearts (p Ͻ 0.05 versus controls). Chronic amiodarone treatment prevents ventricular tachycardias by inducing PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. PRR without conduction slowing is a desirable feature of drugs designed to prevent ventricular arrhythmias.The need to prevent frequent appropriate discharges of implantable defibrillators, the side effects of long-term defibrillator therapy, and the increasing economic constraints in several health care systems have reemphasized the need for antiarrhythmic agents that prevent ventricular arrhythmias. Chronic amiodarone treatment reduces recurrent ventricular tachyarrhythmias (Connolly, 1999) and, in contrast to other antiarrhythmic agents, including potassium channel blockers, does not increase mortality or sudden death rates (Echt et al., 1991;Singh et al., 1995;Waldo et al., 1996;Wyse et al., 2001). Therefore, amiodarone is one of the few remaining treatment options to prevent recurrent ventricular arrhythmias (Connolly, 1999). Although amiodarone blocks multiple ion currents in the heart (Kamiya et al., 2001;Maltsev et al., 2001), the electrophysiological effects by which amiodarone exerts this unique antiarrhythmic action are not well understood.A series of premature stimuli applied at the shortest possible coupling interval allow earlier capture of each consecutive stimulus. This shortening of the effective refractory period (ERP) is not only caused by rate-dependent decrease in action potential duration (APD) bu...

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Kirchhof¹,

Degen²,

Franz³

et al. 2003

J Pharmacol Exp Ther

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“…However, the most severe adverse effect of the drug is pulmonary fibrosis, occurring in up to 13% of the patients receiving the amiodarone in doses higher than 400 mg day Ϫ1 (Martin and Rosenow, 1988). The etiology of the amiodarone-induced pulmonary toxicity is unknown.Desethylamiodarone, the major metabolite of amiodarone, also has antiarrhythmic activity, significantly increasing the action potential duration (class III antiarrhythmic effect) and decreasing the maximum rate of depolarization (class I antiarrhythmic effect) at clinically relevant concentrations (Pallandi and Campbell, 1987). This antiarrhythmic effect was shown to be in part dependent on gene expression rather than a direct effect on cell membrane channels or receptors…”

mentioning

confidence: 99%

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Varbiro¹,

Tóth²,

Tapodi³

et al. 2003

J Pharmacol Exp Ther

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Amiodarone is a widely used and potent antiarrhythmic agent that is metabolized to desethylamiodarone. Both amiodarone and its metabolite possess antiarrhythmic effect, and both compounds can contribute to toxic side effects. Here, we compare the effect of amiodarone and desethylamiodarone on mitochondrial energy metabolism, membrane potential, and permeability transition and on mitochondria-related apoptotic events. Amiodarone but not desethylamiodarone protects the mitochondrial energy metabolism of the perfused heart during ischemia in perfused hearts. At low concentrations, amiodarone stimulated state 4 respiration due to an uncoupling effect, inhibited the Ca 2ϩ -induced mitochondrial swelling, whereas it dissipated the mitochondrial membrane potential (⌬⌿), and prevented the ischemia-reperfusion-induced release of apoptosis-inducing factor (AIF). At higher concentrations, amiodarone inhibited the mitochondrial respiration and simulated a cyclosporin A (CsA)-independent mitochondrial swelling. In contrast to these, desethylamiodarone did not stimulate state 4 respiration, did not inhibit the Ca 2ϩ -induced mitochondrial permeability transition, did not induce the collapse of ⌬⌿ in low concentrations, and did not prevent the nuclear translocation of AIF in perfused rat hearts, but it induced a CsA-independent mitochondrial swelling at higher concentration, like amiodarone. That is, desethylamiodarone lacks the protective effect of amiodarone seen at low concentrations, such as the inhibition of calcium-induced mitochondrial permeability transition and inhibition of the nuclear translocation of the proapoptotic AIF. On the other hand, both amiodarone and desethylamiodarone at higher concentration induced a CsA-independent mitochondrial swelling, resulting in apoptotic death that explains their extracardiac toxic effect.Amiodarone (2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl-ketone hydrochloride) is one of the most effective antiarrhythmic drugs and is frequently used in the clinical practice for treating ventricular and supraventricular arrhythmias. It is a class III antiarrhythmic agent, prolonging action potential duration whose effect may involve blocking of ␤-adrenergic receptors, sodium channels, and L-type calcium channels (Singh and Vaughan Williams, 1970;Nokin et al., 1983;Nattel et al., 1987;Varro et al., 1996). It may also have a role in preventing mortality after myocardial infarction (Julian et al., 1997). Despite its effective antiarrhythmical properties, the use of amiodarone is often limited by its toxic side effects, including thyroid dysfunction, liver, and pancreas fibrosis (Amico et al., 1984;Martin and Howard, 1985). However, the most severe adverse effect of the drug is pulmonary fibrosis, occurring in up to 13% of the patients receiving the amiodarone in doses higher than 400 mg day Ϫ1 (Martin and Rosenow, 1988). The etiology of the amiodarone-induced pulmonary toxicity is unknown.Desethylamiodarone, the major metabolite of amiodarone, also has antiarrhyth...

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“…[1][2][3][4][5][6][7][8][9] Amiodarone is now considered one of the most promising drugs for the treatment of life-threatening ventricular tachyarrhythmias in patients with structural heart disease. [10][11][12][13][14] Nevertheless, as with other antiarrhythmic agents, torsade de pointes (TdP) following QT interval prolongation has been a concern during amiodarone therapy in the setting of bradyarrhythmias and hypokalemia, although the incidence of TdP associated with amiodarone therapy is reportedly low.…”

mentioning

confidence: 99%

Comparison of the In Vivo Electrophysiological and Proarrhythmic Effects of Amiodarone With Those of a Selective Class III Drug, Sematilide, Using a Canine Chronic Atrioventricular Block Model.

Yoshida

Sugiyama

Satoh

et al. 2002

Circ J

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miodarone is generally classified as a VaughanWilliams class III agent 1 and previous experimental studies have demonstrated that it effectively blocks the sodium and calcium channels and -adrenoceptors as well as the IKr, IKs, Ito, IK1, IKACh and IKNa potassium channels (IKr: rapidly activating component of delayed rectifier K + current; IKs: slowly activating component of delayed rectifier K + current; Ito: transient outward K + current; IK1: inward rectifier K + current; IKNa: Na + -activated K + current; IKACh: muscarinic acetylcholine receptor-operated K + current). [1][2][3][4][5][6][7][8][9] Amiodarone is now considered one of the most promising drugs for the treatment of life-threatening ventricular tachyarrhythmias in patients with structural heart disease. [10][11][12][13][14] Nevertheless, as with other antiarrhythmic agents, torsade de pointes (TdP) following QT interval prolongation has been a concern during amiodarone therapy in the setting of bradyarrhythmias and hypokalemia, although the incidence of TdP associated with amiodarone therapy is reportedly low. [15][16][17][18][19] However, the extent of the in vivo proarrhythmic potential of amiodarone remains incompletely understood because of the scarcity of adequate experimental model systems.The present study was designed to simultaneously assess the acute electrophysiological and proarrhythmic profiles of amiodarone using a canine chronic atrioventricular (AV) block model. 20,21 The model is a suitable large-animal model for the study of TdP because its hemodynamic status is stable despite an extreme bradycardia of 20-40 beats/min. [20][21][22][23][24][25][26] Previous studies have revealed the functional adaptations that predispose the canine AV block heart to acquired TdP; [21][22][23]26 namely, the repolarization period is prolonged not only by the bradycardia but also by the reduction of the delayed rectifier potassium currents (IKr and Iks). We administered amiodarone orally without anesthesia under continuous ECG monitoring to better mimic the clinical therapy, and compared the results with those of a selective IKr channel blocker, sematilide. 27-29 MethodsAll experiments were carried out according to the Guidelines for Animal Experiments of Yamanashi Medical University. Beagle dogs of either sex weighing approximately 10 kg were obtained through the animal Laboratory for Research of Yamanashi Medical University. Production of Complete AV BlockAV block was induced as previously described. 20 Briefly, the dogs were anesthetized with pentobarbital sodium (30 mg/kg, iv) and artificially ventilated with room air (Shinano, SN-480-3, Tokyo, Japan). Tidal volume and respiratory rate were set at 20 ml/kg and 15 strokes/min, respectively. Heparin calcium (200 IU/kg, iv) was administered to prevent blood clotting. The surface lead II ECG and systemic blood pressure at the right femoral artery were continuously monitored using a polygraph system (Nihon-Kohden, RM-6000, Tokyo, Japan) A quad-polar electrode catheter with a large tip of 4 mm (CordisCir...

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Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

Cited by 35 publications

References 28 publications

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Comparison of the In Vivo Electrophysiological and Proarrhythmic Effects of Amiodarone With Those of a Selective Class III Drug, Sematilide, Using a Canine Chronic Atrioventricular Block Model.

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