Effects of mexiletine on the canine cardiovascular system complicating cisapride overdose: potential utility of mexiletine for the treatment of drug-induced long QT syndrome

The purpose of this study was to test the potential utility of mexiletine for the treatment of drug-induced long QT syndrome in vivo. Beagle dogs were anesthetized with halothane inhalation (n =7). Monophasic action potential (MAP) of the right ventricle, ECG, systemic and left ventricular pressure, cardiac output and effective refractory period (ERP) of the right ventricle were measured. The electrically vulnerable period was estimated by the difference between MAP duration and ERP. An intentionally high dose of 1 mg/kg, i.v. of cisapride decreased the heart rate, mean blood pressure, left ventricular contraction and cardiac output and prolonged the ventricular repolarization phase and ERP, in which the increment was greater in the former than in the latter, indicating the increase of electrical vulnerability. The left ventricular end-diastolic pressure and atrioventricular as well as intraventricular conduction were hardly affected. Additional administration of an antiarrhythmic dose of 3 mg/kg, i.v. of mexiletine increased the heart rate, decreased the left ventricular contraction and cardiac output, suppressed the atrioventricular as well as intraventricular conduction, and prolonged the ERP, but shortened the ventricular repolarization phase. There was no change in the afterload and preload of the left ventricle. Thus, mexiletine decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced long QT syndrome.     

Effects of mexiletine on the canine model of sparfloxacin-induced long QT syndrome

Potential utility of mexiletine for the treatment of sparfloxacin-induced long QT syndrome was assessed using the in vivo halothane-anesthetized canine model. At 30 min after the administration of a supratherapeutic dose of sparfloxacin (30 mg/kg, i.v.), the mean blood pressure and heart rate decreased, whereas repolarization process and effective refractory period of the ventricular muscle were significantly prolonged. Additional administration of a clinically recommended dose of mexiletine (3 mg/kg, i.v.) at this time point increased the mean blood pressure, suppressed ventricular contraction, delayed atrioventricular as well as intraventricular conduction, and shortened repolarization process and effective refractory period. The extent of abbreviation of the repolarization was more prominent than that of the refractoriness, indicating that mexiletine could decrease the electrical vulnerability of the heart during sparfloxacin overdose. Thus, mexiletine may become a promising pharmacological strategy against the drug-induced long QT syndrome.     

Torsadegenic action of the antipsychotic drug sulpiride assessed using in vivo canine models

A patient had QT prolongation and syncope after starting sulpiride therapy. The present experiments were performed to clarify the causal link among the sulpiride administration, QT prolongation, and the onset of torsade de pointes. Two in vivo models were used: halothane-anesthetized dogs and chronic atrioventricular (AV) block dogs. In the halothane-anesthetized animals (n = 6), sulpiride (2 and 20 mg/kg intravenously) decreased total peripheral resistance and increased heart rate, cardiac output, and ventricular contractility concomitantly. A transient attenuation of these effects occurred soon after the high-dose administration. No significant change was detected in left ventricle preload and depolarization, but repolarization and effective refractory period were significantly prolonged after high-dose administration. The extent of changes was greater in repolarization than in refractoriness, indicating prolongation of the final repolarization phase (electrically vulnerable period). In the chronic AV block animals (n = 4), onset of torsades de pointes with marked QT prolongation was demonstrated after the administration of 60 and 120 mg/kg orally of sulpiride. These results suggest that the QT prolongation and the change in the final repolarization phase with increased sympathetic tone may be the mechanisms responsible for the arrhythmogenic effect of sulpiride. Thus, caution should be paid with the use of sulpiride in patients at risk for elevated plasma concentrations and having preexisting susceptibility to QT prolongation.     

Acute hypokalemia may not be an effective way to sensitize the in situ canine heart for sparfloxacin-induced long QT syndrome

Extents of the sparfloxacin (3 - 10 mg/kg, i.v.)-induced QT interval prolongation under normokalemic and hypokalemic conditions were assessed in halothane-anesthetized beagle dogs (n = 5). The hypokalemic condition was induced by an oral administration of furosemide (200 mg/kg per day) for 3 days, which decreased the serum potassium concentration from 3.65 +/- 0.13 to 2.35 +/- 0.13 mM (P < 0.05). However, the decrease of potassium concentration by itself did not affect the extent of the sparfloxacin-induced QT interval prolongation. These results indicate that acute hypokalemia may not severely sensitize the in situ heart for drug-induced long QT syndrome as previously thought.     

Role of autonomic nervous activity in the antiarrhythmic effects of magnesium sulfate in a canine model of polymorphic ventricular tachyarrhythmia associated with prolonged QT interval

This study was performed to examine the role played by the autonomic nervous system in the antiarrhythmic effects of magnesium sulfate (Mg) in a canine model of polymorphic ventricular tachyarrhythmia facilitated by anthopleurin-A and a slower heart rate induced QT interval prolongation. In 6 experiments, complete atrioventricular block was created to control the heart rate and bradycardia at 800- to 1500-ms cycle lengths was applied for 60 sec before and after drug-induced autonomic block. Transmural unipolar electrograms were recorded from multipolar needle electrodes, and activation-recovery intervals (ARI) were measured. Before drug-induced autonomic block, polymorphic ventricular tachyarrhythmia developed in all 6 experiments during bradycardia before but not after the administration of Mg (0.2 ml/kg intravenous bolus). During drug-induced autonomic block, triggered premature activity decreased without significant changes in underlying dispersion of repolarization and polymorphic ventricular tachyarrhythmia developed during bradycardia in 1 experiment. Administration of Mg during drug-induced autonomic block eliminated premature activity and polymorphic ventricular tachyarrhythmia during bradycardia. The distribution of left ventricular (LV) and right ventricular repolarization and dispersion of transmural repolarization were analyzed before and 60 sec after Mg administration during ventricular pacing at 80 bpm. Mg caused a modest shortening of ARI at all sites before and after drug-induced autonomic block. Since ARI shortening was greater at the mid-myocardial sites than at other LV sites, Mg decreased transmural ARI dispersion from 77 +/- 16 to 46 +/- 21 ms before drug-induced autonomic block and from 79 +/- 7 to 51 +/- 16 ms after drug-induced autonomic block. The antiarrhythmic effects of Mg in this model of long QT syndrome were attributable to its direct pharmacological properties and not to changes in ambient autonomic nervous activity. The blockade of sympathetic activity decreased the incidence of premature events and partially suppressed polymorphic ventricular tachyarrhythmia in this model.     

Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades

Drug-induced prolongation of the QT interval is often associated with the onset of Torsades de Pointes (TdP) resulting in a life-threatening ventricular arrhythmia. The potential of the proarrhythmic effects of the new fluoroquinolone antibacterial agents, levofloxacin and sparfloxacin, was examined in the chronic complete atrioventricular block dogs with stable idioventricular automaticity using Holter ECG monitoring in conscious state (Experiment 1). Next, to better analyze the mechanisms of the proarrhythmic property, the cardiovascular effects of these two drugs were compared in the halothane-anesthetized dogs under the monitoring of ECG, His bundle electrogram, systemic and left ventricular pressure, monophasic action potential, cardiac output, and effective refractory period (Experiment 2). In Experiment 1, oral administration of 6 mg/kg (n = 4) as well as 60 mg/kg (n = 4) of levofloxacin did not induce any ventricular premature depolarization. On the other hand, oral administration of 60 mg/kg of sparfloxacin (n = 4) induced TdP leading to ventricular fibrillation in all animals within 24 h, while 6 mg/kg of sparfloxacin (n = 4) did not induce any ventricular premature depolarization. In Experiment 2, intravenous administration of 0.3 mg/kg as well as 3.0 mg/kg of levofloxacin slightly increased cardiac output, but no significant changes were detected in the other parameters (n = 6). On the other hand, intravenous administration of 0.3 mg/kg of sparfloxacin prolonged the effective refractory period. Additional administration of 3.0 mg/kg of sparfloxacin decreased the heart rate and prolonged the effective refractory period and ventricular repolarization phase in a similar extent, but no significant changes were detected in the other parameters (n = 6). These results suggest that backward shift of the relative repolarization period in a cardiac cycle may be the mechanism responsible for the torsadegenic effect of sparfloxacin.     

A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs

INTRODUCTION: Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization. METHODS: Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05). CONCLUSION: Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification in cardiovascular safety assessment.     

Decreasing the infusion rate reduces the proarrhythmic risk of NS-7: confirming the relevance of short-term variability of repolarisation in predicting drug-induced torsades de pointes

1 The rate of infusion has been suggested to be important for drug-induced torsades de pointes (TdP) arrhythmias. We investigated the repolarisation-prolonging effects and proarrhythmic properties of NS-7, a neuroprotective drug in development, using two different infusion rates. 2 A fast (5 min intravenously (i.v.)) escalating dosing regimen (0.3 and 3.0 mg kg(-1), n=4) of NS-7 was investigated in anaesthetised control dogs in sinus rhythm (SR). This was compared to a slow infusion (60 min i.v.) of one dose (3.0 mg kg(-1), n=4) NS-7. The similar dosing regimens were investigated in anaesthetised dogs with chronic, complete AV block (CAVB), an animal model of TdP (n=6). 3 No electrophysiological effects were seen after 0.3 mg kg(-1) NS-7. Fast infusion of 3.0 mg kg(-1) caused prolongation of repolarisation, for example, heart rate corrected QT interval (QT(c)): in SR: 6+/-1%; in CAVB: 10+/-7%, which was accompanied by TdP in three of six CAVB dogs. No TdP were seen in SR dogs. 4 Slow infusion did not cause TdP in the same CAVB dogs, although NS-7 caused repolarisation to prolong with a similar magnitude (QT(c): 12+/-7%) as in the fast-infusion experiment. 5 Short-term variability (STV) is a novel parameter for the prediction of drug-induced TdP analysing the beat-to-beat variability of repolarisation. STV was only increased after the fast infusion in CAVB dogs (2.6+/-0.3 versus 6.0+/-1.4 ms, P<0.05), while there was no increase (2.1+/-0.2 versus 2.5+/-1.0 ms) after the slow infusion of NS-7. 6 Peak plasma concentrations attained were lower in slow (0.5+/-0.1 microg ml(-1) after 50 min) than in fast-infusion regimen (2.1+/-0.4 microg ml(-1) after 5 min; P<0.05). 7 The results support the conclusion that limiting peak plasma concentration by decreasing the rate of infusion of NS-7 reduces the proarrhythmic risk despite comparable prolongation in repolarisation parameters. The relevance of STV in predicting drug-induced TdP was confirmed.     

Understanding drug-induced torsades de pointes: a genetic stance

Drugs may produce a variety of arrhythmias, but drug-induced QT prolongation and the risk of the polymorphic ventricular tachycardia torsades de pointes (drug-induced long QT syndrome) has garnered the most attention. The wide array of drugs with potential for QT prolongation, the correspondingly large number of patients exposed to such drugs, the difficulty in predicting an individual's risk, and the potentially fatal outcome, make drug-induced long QT syndrome an important public health problem for clinicians, researchers, drug development programs, and regulatory agencies. This review focuses on the genetic risk factors and mechanisms underlying QT prolongation and proarrhythmia. The post-genomic era hints at an improved understanding (and prediction) of how the gene-environment interaction produces this particular adverse drug response.     

Cardiac electrophysiologic effects of orally administered DPI 201-106 in conscious canines: effects of pharmacologic autonomic blockade or cardiac transplantation

This study assessed the cardiac electrophysiologic effects of DPI 201-106 (DPI), a novel orally absorbable positive inotropic agent, the administration of which has been associated with electrocardiographic (ECG) QT and T-wave changes. In the intact conscious dog, oral administration of both 8 and 16 mg/kg DPI produced marked sinus cycle length prolongation (8 mg/kg, + 11%; 16 mg/kg, + 9%) within 60 min of DPI administration (p less than 0.05 vs. baseline). DPI also tended to prolong right atrial refractory periods, and increase sinus node recovery time. In addition, DPI exhibited a negative dromotropic effect on the atrioventricular (AV) node, prolonging both AV node effective and functional refractory periods and tending to increase the minimum atrial paced cycle length at which AV conduction of 1:1 was maintained. DPI also significantly increased right ventricular effective refractory period (ERP) at both doses studied and increased ventricular functional refractory period (FRP) at the 16-mg/kg dose. Finally, although DPI administration was associated with QT interval prolongation, this effect was slight when corrected for sinus cycle length (SCL) (QTc, +3%). When administered concomitantly with propranolol and atropine or after surgical cardiac denervation, DPI-induced electrophysiologic changes were largely attenuated or abolished. Thus, findings in this study indicate that the apparent cardiac electrophysiologic effects of DPI are predominantly of neurally mediated origin in this animal model.     

Evaluation of drug-induced QT prolongation in a halothane-anesthetized monkey model: Effects of sotalol

IntroductionCynomolgus monkeys are used in in vivo models of safety pharmacological studies to evaluate the effects of drug candidates on the cardiovascular system. Models using halothane-anesthetized animals have been used for the detection of drug-induced QT interval prolongation, but few studies with anesthetized monkeys have been reported.MethodsThe electrophysiological changes induced by dl-sotalol, a representative class III antiarrhythmic drug, were assessed in halothane-anesthetized monkeys (n = 4) or conscious and unrestrained monkeys (n = 4).ResultsIn terms of basal characteristics, the QT interval was longer and the heart rate (HR) was lower under anesthesia than those under conscious conditions. Intravenous administration of 0.1 to 3 mg/kg dl-sotalol to anesthetized monkeys decreased the HR and prolonged the QT interval, monophasic action potential (MAP) duration and ventricular effective refractory period in a dose-dependent manner. In addition, reverse use-dependent prolongation of MAP duration was detected by electrical pacing, whereas the terminal repolarization period was hardly affected at any dose. Oral administration of 3 to 30 mg/kg dl-sotalol to conscious monkeys also decreased the HR and prolonged the QT interval in a dose-dependent manner. When compared at similar plasma concentrations of sotalol, the extent of QT interval prolongation under halothane anesthesia was equal to or greater than that under conscious conditions.DiscussionThe sensitivity for detection of drug-induced QT prolongation under halothane anesthesia may be satisfactory compared with that under conscious conditions. The present examinations indicated the usefulness of a model using halothane-anesthetized monkeys for evaluation of drug-induced QT interval prolongation.     

Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiarrhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased susceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr channel blocker, dofetilide (Tikosyn, 0.025 mg/kg/5 min), and the less specific ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on anti-arrhythmic dosages reported in the literature. Monophasic action potential catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (dofetilide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was comparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmias.     

A new preclinical biomarker for risk of Torsades de Pointes: drug-induced reduction of the cardiac electromechanical window

Evaluation of new therapeutic agents for their potential to cause QT interval prolongation and drug-induced ventricular arrhythmia, like Torsades de Pointes (TdP), is a critical activity during drug development. The QT interval has been used as a surrogate biomarker to assess ventricular repolarization effects caused by drug-induced blockade of cardiac repolarizing currents, mainly I_Kr, but is imperfect in predicting proarrhythmia. Evidence suggests that left ventricular mechanical dysfunction may also contribute to ventricular arrhythmias; thus, electrical and mechanical alterations may have a role in drug-induced TdP. The electromechanical window (EMw) represents the time difference between the end of electrical systole (i.e. the QT interval) and the completion of ventricular relaxation (i.e. the QLVP_end interval), and appears to be a new potential biomarker for TdP risk. A reduction in the EMw (to negative values) has now been shown to be associated with the onset of TdP in an anaesthetized dog model of long QT1 syndrome. Therefore, the EMw represents a novel indicator of TdP risk that may add predictive value beyond assay of drug-induced QT interval prolongation.

LINKED ARTICLE

This article is a commentary on van der Linde et al., pp. 1444–1454 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00934.x     

QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement

INTRODUCTION: QT dispersion (QTd) can be measured from three leads of the ECG in patients with myocardial ischemia. However, whether QT and JT dispersion (QTd, JTd) can be calculated from a three-lead of the ECG in drug-induced long QT syndrome (LQTS) in animals remains elusive. Therefore, we determined to what extent a three-lead measurement of the surface ECG accurately detects dispersion of QT and JT in comparison with multi-lead assessments in anaesthetized rabbits, challenged with methoxamine and additionally infused intravenously with solvent or dofetilide. METHODS: Using several ECG leads in anaesthetized rabbits challenged intravenously with an alpha(1)-adrenoceptor agonist methoxamine, we assessed the QT and JT interval, as well as QT and JT dispersion, at baseline and in response to solvent or dofetilide (0.02 or 0.04 mg/kg/min iv for 60 min), an I(Kr) blocker. For that purpose, we recorded and analyzed the surface ECG and assessed QT and JT dispersion by four methods: (1) 12-lead ECG; (2) six precordial leads (V1-V6); (3) three leads most likely to contribute to the dispersion (aVF, V1, and V4); (4) three quasi-orthogonal leads (aVF, I, and V2). QT and JT dispersion were significantly lower in 6- and 3-lead measurements than in 12-lead measurement, both at baseline and during infusion of solvent or dofetilide. At 5 and 10 min of infusion, dofetilide at 0.02 or 0.04 mg/kg/min iv markedly increased QT and JT dispersion by 100% to 500% in all four ECG lead combinations. This dose regimen of dofetilide markedly prolonged QT and JT intervals in lead II, and was associated with high incidences of polymorphous ventricular tachycardia (PVT: 30% at 0.02 mg/kg/min; 100% at 0.04 mg/kg/min) and of ventricular fibrillation (VF: 17% with 0.02 mg/kg/min; 58% with 0.04 mg/kg/min). CONCLUSIONS: Our present study shows that the measurement of QT and JT dispersion in three surface ECG leads only (aVF, I, V2 or aVF, V1 V4), instead of 12 ECG leads, is an appropriate approach to assess drug-induced heterogeneity or dispersion of ventricular repolarization in anaesthetized rabbits, both at baseline and during arrhythmogenic sensitization with methoxamine and challenged with dofetilide.     

Electrophysiological, anatomical and histological remodeling of the heart to AV block enhances susceptibility to arrhythmogenic effects of QT-prolonging drugs

The present study was designed to investigate what kinds of adaptation occurred in the canine chronic AV block model, which has been used to study torsade de pointes (TdP). Dogs at 7-10 days (acute phase) and 28-56 days (chronic phase) after AV block were assessed. Ventricular effective refractory period and monophasic action potential duration were prolonged in chronic animals compared with acute animals; moreover the electrically vulnerable period was prolonged in chronic animals. Non-specific IKr channel blocker cisapride (1 and 10 mg/kg, p.o.) was administered without anesthesia to estimate the feasibility of QT prolongation. In chronic animals, QT prolongation followed by TdP was induced in one dog by the low dose and in all by the high dose, which was not observed in acute animals. MR images indicated increases of diameter and wall thickness of both ventricles in chronic animals. The degree of hypertrophy was prominent in the right ventricular wall and septal wall. Heart weight of the chronic animals was 1.7 times greater than that of normal control subjects. Photo- and electron-micrograph analyses showed myocardial cell hypertrophy with parallel increases of collagen fiber and extracellular space in chronic animals. These electrophysiological, anatomical and histological adaptations may predispose the chronic AV block heart to drug-induced QT prolongation with enhanced risk of re-entry and early after depolarization, leading to the onset of TdP.     

Choice of cardiac tissue plays an important role in the evaluation of drug-induced prolongation of the QT interval in vitro in rabbit

INTRODUCTION: Regulatory guidelines (CPMP/986/96, ICHS7B) recommend the use of isolated cardiac tissues, including Purkinje fibers, papillary muscles and ventricular trabeculae, for detecting potential drug-induced long QT. However, the differential sensitivity of these tissues in experimental drug-induced long QT is relatively unknown. We investigated the electrophysiological characteristics of these tissue types in vitro together with their different responses to drugs that are known to induce prolongation of the QT interval in man. METHODS: Electrophysiological parameters were measured in vitro using a micro-electrode technique. The isolated rabbit Purkinje fibers, papillary muscles or ventricular trabeculae were superperfused with Tyrode's solution and stimulated according to different stimulation protocols. The effects of dofetilide (1 x 10(-8) M), sertindole (1 x 10(-6) M), erythromycin (3 x 10(-4) M) and sparfloxacin (1 x 10(-4) M) were evaluated relative to solvent (n=8 to 12 for each group). RESULTS: In isolated Purkinje fibers, action potential duration at 90% repolarization (APD(90) at 1 Hz) was markedly prolonged by 55% (erythromycin), 103% (dofetilide), 118% (sertindole) and 88% (sparfloxacin) from baseline. The prolongation of APD(90) caused by these 4 compounds was associated with a 28% to 78% incidence of early afterdepolarizations (EADs) at 0.2 Hz only in the Purkinje fiber. In contrast, APD(90) was altered by erythromycin, dofetilide, sertindole and sparfloxacin only by +15%, +6%, -7% or +15%, respectively, in isolated papillary muscles, and by 33%, +28%, +4% or +16%, respectively, in ventricular trabeculae. EADs were not induced by these four compounds in papillary muscles or in trabeculae. Reducing the stimulation rate to 0.2 Hz resulted in a 33% prolongation of APD(90) in Purkinje fibers, while APD(90) was shortened by 10% in papillary muscles and by 20% in ventricular trabeculae. CONCLUSION: The present study demonstrates that the differential sensitivity of tissue types play an important role in the detection of drug-induced long APD and EADs. Indeed the Purkinje fiber was the only tissue type to display the well known phenomenon associated with I(kr) channel blockade (inverse-use dependence), when the stimulation rate was decreased below 1 Hz. Rabbit Purkinje fibers constitute the most sensitive tissue type for detecting drug-induced long action potential duration and EADs. As such the selection of tissue type needs to be taken into careful consideration in cardiac safety assessments when exploring drug induced long QT.     

Nonselective I(Kr)-blockers do not induce torsades de pointes in the anesthetized rabbit during alpha1-adrenoceptor stimulation

Selective I(Kr)- (the rapid component of the delayed rectifier potassium current) blockers are known to induce torsades de pointes (TdPs) in anesthetized rabbits during alpha1-adrenoreceptor stimulation. However, effects of nonselective I(Kr)-blockers, which produce TdPs in other animal models and in humans, are not known in this model. We examined two nonselective I(Kr)-blockers (quinidine, 1.25 mg/kg/min i.v [n = 7]; and terfenadine, 0.31 mg/kg/min i.v. [n = 7]) for their effects on electrocardiographic parameters and on incidence of cardiac arrhythmias in anesthetized rabbits during alpha1-adrenoceptor stimulation with methoxamine. We compared the drugs with two highly selective I(Kr)-blockers (dofetilide, 0.04 mg/kg/min i.v. [n = 7]; and clofilium, 0.08 mg/kg/min i.v. [n = 6]). Polymorphic ventricular tachycardia or TdPs were induced by dofetilide and clofilium at mean doses > or =0.33 mg/kg and 0.4 mg/kg i.v., in all animals tested (vs. none in solvent; p < 0.05). TdPs usually developed into ventricular fibrillation and developed after prolongation of QT/JT interval and of QT dispersion. Terfenadine and quinidine significantly increased PQ, QT, and QTc interval and largely increased QRS duration and QT dispersion. These compounds elicited intraventricular conduction defects and cardiac arrest, due to asystole, in all animals tested (vs. 0% in solvent; p < 0.05). Interestingly, these two nonselective I(Kr)-blockers did not produce TdPs or ventricular fibrillation in any animals tested. Our results thus indicate that selective I(Kr)-blockers elicit TdPs, whereas nonselective I(Kr)-blockers do not induce this type of arrhythmia in this rabbit model. Consequently, it should be noted that this rabbit model is not always useful to evaluate nonselective I(Kr)-blocker-induced TdPs and QT interval and QT dispersion, rather than TdPs, are also important indicators for drug-induced cardiac arrhythmias.     

Electropharmacologic characteristics of ventricular proarrhythmia induced by ibutilide.

The purpose of this study was to evaluate in vivo the proarrhythmic effects of ibutilide in dogs with or without ventricular hypertrophy. Fourteen dogs received repeated experiments both during the acute and chronic phases (8 weeks, with ventricular hypertrophy) of complete atrioventricular (AV) block. Twelve-lead ECG, monophasic action potentials in the left and right ventricle were recorded before and after each dose of ibutilide (0.01-0.08 mg/kg) during different ventricular rates. In these dogs, ibutilide increased QT interval, biventricular APD90, interventricular deltaAPD90 (difference between the left and right ventricular APD90), and QT dispersion, and induced early afterdepolarizations in a dose-dependent manner. The interventricular deltaAPD90, QT dispersion, and increases of QT interval were more pronounced during slower ventricular rates. There were greater QT interval, biventricular APD90 interventricular deltaAPD90, and QT dispersion values during chronic AV block than during acute AV block. Moreover, ibutilide can induce higher incidences of early afterdepolarizations and torsades de pointes [six (43%) of 14 versus 0 of 14; p < 0.05] during chronic AV block than during acute AV block. In conclusion, ibutilide can prolong ventricular repolarization and increase dispersion of ventricular repolarization in a dose-dependent and reverse rate-dependent manner. The high incidence of torsades de pointes in the dogs during chronic AV block suggests the importance of ventricular hypertrophy in the occurrence of ibutilide-induced proarrhythmia.     

Comparison of the cardiac electrophysiological effects of flecainide and hydroquinidine in anesthetized dog: concentration-response relationship.

The concentration-dependent effects of flecainide and hydroquinidine were studied in closed-chest anesthetized dogs. The electrophysiological effects of three doses (i.v. infusions followed by an appropriate perfusion to plateau the plasma levels) of flecainide (1, 2, and 3.9 mg/kg) and hydroquinidine (2, 4, 7.5 mg/kg) were tested. Sinus cycle length, QRS duration, His-Purkinje and AV nodal conduction times, Wenckebach period, atrial, nodal, and ventricular refractory periods, and corrected QT interval were measured before and 30 min after the beginning of each bolus infusion. Both hydroquinidine and flecainide increased the sinus cycle length, and slowed cardiac conduction to different degrees. Hydroquinidine and flecainide prolonged ventricular conduction; flecainide had a greater effect at the His-Purkinje level. Hydroquinidine exhibited only a weak and nonsignificant effect at the AV node, whereas flecainide dramatically prolonged conduction and refractoriness. The two drugs increased AERP equally. The QT interval and ventricular refractoriness were similarly prolonged to the same extent by both drugs (32 and 35% after the third doses of hydroquinidine and flecainide, respectively). The high plasma flecainide levels reached in our study (1.47 and 2.9 micrograms/ml after the second and third doses, respectively) may explain these effects, which are unexpected for a class Ic agent. These results suggest that flecainide could increase the QT interval, like a class Ia drug when its plasma level exceeds the therapeutic range.     

Characterization of the halothane-anesthetized guinea-pig heart as a model to detect the K+ channel blocker-induced QT-interval prolongation

Our previous study using the urethane-anesthetized guinea-pig model has shown that an I(Ks) blocker chromanol 293B hardly affects the QT interval itself nor potentiates the I(Kr) blocker-induced QT-interval prolongation. The former is in good accordance with the previous results in the human isolated intact ventricular tissue, but the latter is in sharp contrast with them. In this study, we characterized the ventricular repolarization ability of a newly developed halothane-anesthetized guinea-pig model by using I(Kr) and I(Ks) blockers. Intravenous administration of a selective I(Kr) blocker d-sotalol (3 mg/kg) prolonged the QT interval by +27 ms. On the other hand, intravenous administration of chromanol 293B (1 mg/kg) prolonged the QT interval by +35 ms, and additional administration of the same dose of d-sotalol further prolonged the QT interval by +48 ms. These results suggest that the abundance of the repolarization reserve among the current and previous models may be in the order of the urethane-anesthetized guinea-pig heart>human intact ventricular tissue>halothane-anesthetized guinea-pig heart. Thus, the halothane-anesthetized guinea-pig model may be considered to be more sensitive than the previous models in predicting the QT-interval prolonging effects of new drugs in patients with high risks for the acquired long QT syndrome.