Dofetilide, N-[4-[2-(methyl[2-[4-[(methylsulfonyl) amino]phenoxy]ethyl]amino]ethyl]phenyl] methane sufonamide (UK-68, 798) (Fig. 1), is a new synthetic class III antiarrhythmic agent (Vaughan Williams' classification). Electrophysiological studies (1,2) have shown that dofetilide inhibits the inward rectifier channels but has no effect on the cardiac Ca and Na channels. As a result of this effect, dofetilide prolongs action potential duration (APD) as well as effective refractory period (ERP). Dofetilide was reported to be effective in treating or preventing some animal arrhythmias, such as ventricular tachycardia and fibrillation (VT, VF) induced in acutely or chronically ischemic hearts (3-6).
We previously reported effects of various antiarrhythmic drugs on canine ventricular arrhythmias occurring as a result of two-stage coronary ligation or digitalis or epinephrine administration (7-9) and classified antiarrhythmic drugs based on their pharmacological effectiveness (10). Using the same models and adding the coronary ligation and reperfusion-induced ventricular arrhythmia model, which is considered to be induced mainly by reentry mechanism, we recently examined new class III antiarrhythmic agents, E-4031, D-sotalol, MS-551 (11,12), sematilide (13), and intravenous amiodarone (14). Among the class III antiarrhythmic drugs, D-sotalol, E-4031, and MS-551 were effective in suppressing the occurrence of VF immediately after coronary reperfusion, but sematilide and amiodarone were not. In the present study, we included another reentry arrhythmia model, that of programmed electrical stimulation (PES)-induced arrhythmia in dogs with old myocardial infarction (MI) to characterize dofetilide as compared with other class III drugs.
Production of two-stage coronary ligation-induced arrhythmia
Six Beagle dogs of either sex weighing 8.0-10.0 kg were anesthetized initially with intravenous (i.v.) thiopental sodium 30 mg/kg and intubated. As reported previously (7), the chest was opened and a two-stage coronary ligation of the left anterior descending artery (LAD) was performed in dogs under halothane anesthesia.
Experiments were performed without anesthesia 24 and 48 h after the dogs recovered from coronary ligation. The arrhythmias lasted >48 h after coronary ligation, and the hemodynamic parameters were stable for the <2-h observation period if drugs were not administered, as previously reported (14). The lead II ECG, atrial electrogram from implanted electrodes sutured on the left atrial appendage, and the instantaneous and the electronically derived mean blood pressure (MAP) were recorded continuously with a telemetry system (Nihon Kohden WEB-5000, Tokyo, Japan). A maximal effective dose of dofetilide 100 μg/kg (15) was infused for 10 min with a syringe pump (Terumo, Tokyo, Japan), and arterial blood samples were drawn from one lumen of a double-lumen cannula in the femoral artery just before (0 min) and at 10, 30, and 60 min after the start of the infusion.
Production of digitalis-induced arrhythmia
Eleven mongrel or Beagle dogs of either sex weighing 7.5-13.0 kg were anesthetized with pentobarbital sodium 30 mg/kg i.v. and intubated. As reported previously (8), 40 μg/kg ouabain was injected intravenously, followed by an additional 10 μg/kg every 20 min until stable VT was produced. The arrhythmias and the hemodynamic parameters except MAP were stable for the >1-h observation period if drugs were not administered, as previously reported (14). The blood pressure (BP) gradually decreased even in the control dogs, probably due to the decrease in the ouabain concentration without an additional injection and the loss of its vasoconstrictive effect. Dofetilide 100 μg/kg/10 min was administered with a syringe pump. Arterial blood samples were drawn from one lumen of a double-lumen cannula inserted in the femoral artery just before (0 min) and at 5, 10, 30, and 60 min after the start of infusion. The lead II ECG, atrial electrogram from catheter tip electrodes in the right atrium, instantaneous BP, and MAP were continuously recorded.
Production of epinephrine-induced arrhythmia
Six female Beagle dogs weighing 7.5-11.5 kg were anesthetized initially with intravenous thiopental sodium. As reported previously (9), after intubation, 1.0% halothane vaporized with 100% oxygen was administered with a volume-limited ventilator (20 ml/kg, 15 strokes/min). Epinephrine was infused through the left femoral vein at a rate of 1.5 μg/kg/min with a syringe pump. If multifocal VT lasting throughout the infusion period was not induced, a higher infusion rate was used. The arrhythmias lasted >20 min, and the hemodynamic parameters were almost stable for this short period if drugs were not administered, as previously reported (14). Three minutes after the start of epinephrine infusion, dofetilide 100 μg/kg/10 min was infused and arterial blood samples were drawn from one lumen of a double-lumen cannula inserted into the femoral artery just before (0 min) and at 5, 10, and 15 min after the start of infusion. The lead II ECG, atrial electrogram from catheter tip electrodes in the right atrium, instantaneous BP, and MAP were continuously recorded.
Production of coronary ligation and reperfusion arrhythmia
Thirty Beagle dogs of either sex weighing 8.0-11.5 kg were divided into two experimental groups as reported previously (13). Group 1 dogs (n = 16) were anesthetized initially with thiopenal sodium 30 mg/kg i.v. and intubated. Anesthesia was maintained by 1.0% halothane, vaporized with 100% oxygen with a volume-limited ventilator (20 ml/kg, 15 strokes/min). We used halothane to induce low heart rate (HR) state, at which the reverse use-dependent QT prolongation, if present, becomes prominent. Group 2 dogs (n = 14) received intravenous bolus injection of 30 mg/kg pentobarbital sodium, followed by an infusion of 5 mg/kg/h. We used pentobarbital to induce high HR state, at which the reverse use-dependent QT prolongation is blunted.
In both groups, the chest was opened, and the LAD was isolated just proximal to the first diagonal branch. Because the incidence of occurrence of coronary ligation and reperfusion arrhythmia has been shown to be quite variable, randomized experiments using a pair of Beagles (by coin-flip); 1 received drug infusion and the other received 0.9% NaCl infusion. At 30 min after the start of infusion of either dofetilide 100 μg/kg/h or saline, when the value of QTc became stable, the LAD was ligated with a nylon thread, which was released 20 min later to allow examination of reperfusion responses. The drug solution was infused until the end of the experiment.
A pair of epicardial electrodes was sutured on the border zone of the ischemic area of the left ventricle for continuous recording of the ventricular surface electrograms. QT interval was assessed from the lead II ECG and the ventricular surface electrogram. The QTc interval was calculated by a Bazett's formula: QTc = QT/√RR. The HR was measured from lead II ECG, and the BP was continuously monitored through a double-lumen arterial cannula in the femoral artery. Arterial blood samples were obtained from one lumen of a cannula inserted in the femoral artery just before (0 min) and 10 and 29 min after the start of dofetilide infusion and just before LAD reperfusion (49 min).
Production of programmed electrical stimulation (PES)-induced arrhythmia
Nine Beagle dogs of either sex weighing 8.0-11.0 kg were anesthetized initially with intravenous thiopental sodium 30 mg/kg and intubated. As reported previously (13), the chest was opened and a two-stage coronary ligation of the LAD was performed under halothane anesthesia; then the chest was closed. Seven to 12 days after operation, when MI was established, the dogs were anesthetized with intravenous pentobarbital sodium 30 mg/kg plus 5 mg/kg/h and intubated. The chest was opened again, and the electrical stimulation was performed through the silver bipolar epicardial electrodes sutured to the noninfarcted left ventricular wall. The electrodes were connected to a programmable stimulator (Nihon Kohden SS-201J) through an isolator (Nihon Kohden SEN-7203). The lead II ECG, instantaneous BP, and MAP pressure were continuously recorded through a cannula in the femoral artery.
The basic pacing interval (S1-S1) was set at 300 ms, which was shorter than the cycle length of the spontaneous HR. The excitation threshold measurement was preceded by each series of PES. After a train of 15 pacing stimuli, a single extrastimulus (S2) was delivered by shortening the S1-S2 interval in a 5-ms step until arrhythmia or refractoriness occurred. If S2 failed to induce arrhythmia, double extrastimuli (S2 and S3) were delivered with the S1-S2 interval just exceeding the ERP. S3 was introduced initially at the same interval as S2, which was then decreased again in 5-ms steps. The stimulation protocol was fixed once arrhythmia such as VF, sustained VT (SVT), nonsustained VT (NSVT), or premature ventricular contractions (PVCs) were induced or the ERP was reached. VT was defined as more than three consecutive PVCs. NSVT was defined as VT lasting <30 s, and SVT was defined as VT lasting >30 s.
Dogs in which ventricular arrhythmia was induced by PES at least twice during the control period were used further for pharmacological analysis. SVT or VF was terminated with a direct-current defibrillator. After 30-min dofetilide infusion at a rate of 100 μg/kg/h, the same stimulation protocol was repeated. The experiment was approved by the Animal Care and Use Committee of Yamanashi Medical University.
Evaluation of antiarrhythmic effects
The severity of two-stage coronary ligation and digitalis- and epinephrine-induced ventricular arrhythmias was expressed by the arrhythmic ratio- The number of PVCs divided by the number of all QRS complexes recorded for the same time period, and the ventricular beats were judged by the shape of the ventricular complex as it differed from the normal QRS complex. The arrhythmic ratio before drug injection was almost 1, as shown in the control values of the figures and, as reported previously (14), there were no spontaneous improvements in these ratios. If the values after drug administration decreased significantly from the time 0 value, as determined by the analysis of variance (ANOVA) followed by paired t test (p < 0.05), the drug was judged to have significant effects.
Dofetilide (supplied by Pfizer Pharmaceuticals, Inc.) was first dissolved in HCl (0.01 N) and then diluted by saline to meet the concentrations needed.
Determination of dofetilide plasma levels
The arterial blood samples were collected in heparinized syringes at predetermined times and centrifuged at 3,000 g for 5 min. The plasma was stored at about -80°C until the assay was performed. Concentrations of the drug were determined by a radioimmunoassay method (16) at Pfizer Pharmaceuticals, Inc.
For the coronary ligation and reperfusion arrhythmia model, ANOVA was used to compare the values of QTc, HR, and MAP between the drug-treated and the saline-treated experiments. Incidence of arrhythmias was compared by chi-square test; p < 0.05 was considered significant.
For the electrical stimulation-induced arrhythmia model, ANOVA was used to compare the QTc, HR, and MAP values before and after the drug treatment. Incidence of arrhythmias was compared by Wilcoxon signed-ranks test and, in the case of p < 0.05, the drug was judged to have significant effects. Values are mean ± SEM.
Two-stage coronary ligation-induced arrhythmia
After 1-2 days of coronary ligation, multifocal VT occurred continuously in all dogs. The arrhythmic ratios of the unanesthetized dog 24 and 48 h after coronary occlusion were 0.99 ± 0.01 (n = 6) and 0.92 ± 0.08 (n = 6), respectively (Figs. 2 and 3), showing no statistically significant difference between them. Because anti-arrhythmic effects are not predicted for class III drugs, a supramaximal dose of dofetilide 100 μg/kg/10 min was infused.
For 24-h arrhythmia, dofetilide decreased the total HR from 8 min of drug infusion and the decrease persisted until the end of the observation period and decreased the atrial rate at 6 min of drug infusion, but had no effect on the number of conducted beats, arrhythmic ratio, or MAP, as shown in Fig. 2. For 48-h arrhythmia, dofetilide at the same infusion rate decreased only the atrial rate and had no effect on the total HR, MAP, conducted beats, or arrhythmic ratio (Fig. 3). The mean plasma concentrations of the drug reached the maximal value of 173 ng/ml at 10 min after the infusion for the 24-h experiment and of 168 ng/ml for the 48-h experiment.
After a total intravenous injection of 40-80 μg/kg ouabain, almost all beats were of ventricular origin. The same supramaximal infusion rate of dofetilide 100 μg/kg/10 min induced VF in 2 of 11 dogs, immediately in 1 and 14 min after the start of drug infusion in the other. As shown in Fig. 4, dofetilide had no consistent antiarrhythmic effect. After dofetilide infusion, the arrhythmias continued in 4 of 9 dogs, but were suppressed in 5. In 3 of these 5, arrhythmia recurred during the 60-min observation period. The summarized data of 9 dogs showed the total HR atrial rate, and MAP to be significantly decreased and the number of conducted beats increased at the 30-min timepoint (Fig. 5). Figures 4 and 5 show that the decreasing effect of dofetilide on the arrhythmic ratio did not correlate with the drug plasma concentration.
The mean plasma concentrations of the drug reached the maximal value of 348 ng/ml at 10 min after the infusion, which was about twice as high as the concentrations attained by the same infusion rate in the coronary ligation- and epinephrine-induced arrhythmia experiments.
As reported previously (9), epinephrine infusion for 3 min at a rate of 1.5 μg/kg/min induced VT with almost all the beats consisting of PVCs. Dofetilide, at the same rate of 100 μg/kg/10 min used in the coronary ligation and digitalis arrhythmia experiments, significantly decreased the atrial rate and MAP, but did not change the total HR, number of conducted beats, or arrhythmic ratio (Fig. 6). The mean plasma concentrations of dofetilide reached a peak value of 164 ng/ml (n = 6) at 10 min after the drug infusion.
Coronary ligation and reperfusion arrhythmia
Group 1: Halothane-anesthetized Beagles. HR and MAP of all Beagles anesthetized with halothane was 114 ± 4 beats/min and 102 ± 4 mm Hg (n = 16). As shown in Table 1 and Fig. 7, dofetilide prolonged the QTc interval 43% (from 0.40 to 0.56 √s just before LAD ligation), as compared with -1% change (from 0.40 √s) in the control group. Dofetilide decreased the HR 18% (from 117 to 96 beats/min just before ligation). There was no change in the HR in the control group (from 111 beats/min just before occlusion). The number of mean total PVCs of the drug- and saline-treated groups during the ligation period was not significant (378 and 15 beats/20 min, respectively). In addition, during the 30-min dofetilide infusion before coronary occlusion, 3 of 8 dogs evidenced induced PVC and/or VT, indicating that the drug has proarrhythmic effect. Immediately after coronary reperfusion, 1 of 8 dogs that received dofetilide and 3 of 8 dogs that received saline infusion fibrillated (NS). These fatal VFs occured soon after reperfusion. The mean dofetilide plasma concentrations at 0, 10, 29, and 49 min were 0, 42, 62, and 83 ng/ml, respectively.
Group 2. Pentobarbital-anesthetized Beagles. By changing the anesthesia to intravenous pentobarbital, which increases the HR, we repeated the dofetilide experiment using the same infusion protocol used in group 1. HR and MAP under pentobarbital anesthesia was 178 ± 5 beats/min and 109 ± 4 mm Hg (n = 14). As shown in Table 1, the QTc of the drug-treated group increased significantly from 0.34 to 0.40 √s before ligation (with 19%); in the saline-treated group, there was almost no change (from 0.35 √s). Dofetilide decreased the HR 14%. Also in this pentobarbital anesthesia condition, there was no difference between the number of mean total PVCs in drug- and saline-treated groups (208 and 212 beats/20 min of coronary occlusion, respectively). Immediately after coronary reperfusion, 4 of 7 dogs fibrillated in the drug-treated groups, and 6 of 7 dogs in the saline-treated group fibrillated (NS). Therefore, in this model, dofetilide had neither antiarrhythmic nor proarrhythmic effects. The dofetilide mean plasma concentrations of 0, 10, 29, and 49 min were 0, 32, 44, and 60 ng/ml.
In dogs with old MI, PES induced a variety of ventricular arrhythmias: 4 VF, 1 SVT, and 4 NSVT in 9 dogs. As shown in Fig. 8, dofetilide (100 μg/kg/h) significantly reduced the severity of these arrhythmias. After drug infusion, 2 of 4 VF dogs became noninducible (NI), but the other 2 fibrillated again. One SVT and four NSVT became NI. In this experiment, QTc increased by 15%.
Dofetilide is a highly selective blocker of the rapidly activating component of the rectifier K channel (IKr) with no effects on Na or Ca channels (1,17,18). We previously examined other class III agents, such as E-4031 (11), D-sotalol (11) and MS-551 (12), sematilide (13), and intravenous amiodarone (14) on several canine models of arrhythmias and detected some differences among the class III drugs. Consequently we evaluated dofetilide using the same models to characterize its antiarrhythmic efficacy in comparison with other class III drugs.
Our present results indicate that dofetilide had significant antiarrhythmic effect on the arrhythmias induced by PES electrical stimulation and appeared to have some additional effects on the arrhythmias induced by digitalis. Among the five models that we used, three models (i.e., arrhythmias produced by two-stage coronary ligation, digitalis, and epinephrine) are spontaneously occurring arrhythmias and are believed to be automaticity arrhythmias. Because IKr is not responsible for generating automaticity, these arrhythmias are not expected to be suppressed by class III (K channel blockers) agents (11-13). In this experiment, however, dofetilide was shown to have some antiarrhythmic effects on the digitalis-induced arrhythmia model.
In 24- and 48-h two-stage coronary ligation arrhythmias, dofetilide had neither antiarrhythmic effect nor aggravating effect as do other class III drugs, even though the plasma concentration of almost 200 ng/ml is high enough to increase QT interval, as judged by our QT-prolonging concentration of <100 ng/ml determined in our coronary ligation and reperfusion experiments. As for other cardiohemodynamic effects, dofetilide significantly decreased the atrial rate. Yang and colleagues (20) already reported that UK-68, 798 (dofetilide) decreased spontaneous atrial rate by 6-21% and suggested that this negative chronotropic effect is linked with K channel blockade. Results of other studies also support this finding (15,21). In the 24-h experiment, there was a long-lasting decrease in the total HR; this effect was not observed in the 48-h experiment. The present experiment does not explain this finding.
In ouabain-induced arrhythmia, dofetilide in a dose that increased the plasma concentration to a level sufficient to prolong QT interval showed antiarrhythmic effects in some dogs. In 5 of 9 dogs, dofetilide decreased the arrhythmic ratio, and in 3 of the 5 dogs ventricular arrhythmia recurred as the plasma concentration decreased during the observation period (Fig. 4), but 2 dogs remained in sinus rhythm until the end of the experiment. The summarized data shown in Fig. 5 indicate significant decrease in the total HR, atrial rate, and MAP and increase in the number of conducted beats. The gradual decrease in MAP may have been due to the decrease in ouabain effect, but other effects on the cardiac rhythm may be due to dofetilide, because the toxic effect of ouabain induced VT usually lasted >1 h in our previous experiments (8,14). It is difficult for us to explain this antiarrhythmic effect, because our ouabain-induced arrhythmia has so far been suppressed only by Na channel blockers, and dofetilide has not been reported to have Na channel-blocking effect even at the high concentrations attained in such experiments (1). Vos and associates reported that R56865, a new cardioprotective agent with class III effects, suppressed ouabain-induced VT in conscious chronically atrioventricular-dissociated dogs (22). Because the ouabain-induced arrhythmia in their study was suppressed by not only class I but also class IV antiarrhythmic drugs, the arrhythmia induced in our study may be different from theirs. Indeed, the antiarrhythmic effect of dofetilide on digitalis-induced arrhythmia in our study was not observed in experiments in which we used other class III drugs except amiodarone (14). Although this effect of dofetilide is thus unique, the weak nature of the antiarrhythmic effect and the use of the supramaximal dose, as well as the two cases of induction of VF, indicate that this antiarrhythmic effect may not be of importance in predicting clinical usefulness of dofetilide. The high plasma concentration of dofetilide attained in the digitalized dogs, even when the same dose was used, may indicate the existence of some interaction of dofetilide and ouabain or of hemodynamic changes occurring in the renal and hepatic circulation; our present experiments could not clarify this.
In epinephrine-induced arrhythmia, dofetilide had no antiarrhythmic or proarrhythmic effect, quite different from findings with other class III drugs we have tested, such as E-4031 and sematilide, because they aggravated such arrhythmia (11,12). Either these two drugs often changed the epinephrine-induced VT to VF, or only one-tenth of doses used for the two-stage coronary ligation and digitalis arrhythmias could be administered without aggravating epinephrine-induced arrhythmias. However, the negative chronotropic effect of dofetilide was also observed in the dogs infused with epinephrine. The decrease in the atrial rate is in agreement with another report (20) which showed that dofetilide dose-dependently reduced the maximal positive chronotropic effect induced by isoprenaline in a noncompetitive manner, which implies that the negative chronotropic effect of dofetilide is not produced by the interaction with β-adrenoceptors.
Class III agents, such as D-sotalol, E-4031, MS-551, sematilide, and dofetilide, with which we have examined prolongation of QTc interval and ERP, are believed to prevent the occurrence of arrhythmias selectively or to suppress the existing arrhythmias induced by reentry mechanism. Therefore, for evaluation of antiarrhythmic efficacy of class III drugs, reentry arrhythmia models must be used. We used two canine reentry arrhythmia models. The coronary ligation and reperfusion arrhythmia is believed to be produced in part by reentry of excitation occurring at and around the acutely infarcted myocardium, but the intiating ectopic beats may be induced by great humoral and electrophysiological changes enhancing automaticity occurring in the reperfused myocardium (23,24). We previously used this model of arrhythmia to demonstrate antiarrhythmic effects of E-4031 (11), D-sotalol (12), and MS-551 (12). The other model is PES-induced arrhythmia in dogs with old MI, which is believed to be produced solely by reentry mechanism.
In coronary ligation and reperfusion arrhythmia, either in halothane or pentobarbital-anesthetized Beagles, dofetilide was not effective in decreasing the number of PVCs during the 20-min LAD complete ligation or the occurrence of coronary reperfusion VF. This result is different from our previous findings with E-4031, MS-551, and D-sotalol. E-4031 and MS-551 were effective in suppressing the occurrence of coronary reperfusion VF in the slow HR halothane-anesthetized Beagles, but D-sotalol, even with prominent QT prolongation, was not effective (11,12,20). However, when pentobarbital was used as an anesthetic, both D-sotalol and MS-551 were effective in suppressing the VF. Neither dofetilide nor sematilide (13) was effective in either halothane or pentobarbital anesthesia conditions. Several reports have shown that dofetilide prolonged APD and QTc interval with a reverse use dependency (1,2,25,26). In the present study, dofetilide exhibited this property of reverse use dependency. In halothane-anesthetized dogs (average HR of 114 beats/min), dofetilide prolonged QTc by 43%; in the pentobarbital-anesthetized dogs (average HR of 178 beats/min), however, dofetilide increased QTc only by 19%, even though the plasma concentrations attained were almost the same in these two groups. MS-551 also showed such reverse use dependency, but D-sotalol did not show this property (12) in our previous experiments. Therefore, it is difficult to correlate this reverse use dependent effect on the QT interval with the effectiveness on VF suppression.
In PES-induced arrhythmias, dofetilide showed anti-arrhythmic effect. The severity of arrhythmias induced in the control period was reduced, and in many dogs arrhythmia became noninducible. This result is consistent with two other reports on dofetilide using similar models. Black and co-workers (4) reported that UK-68, 798 (dofetilide) significantly reduced the incidence of PES-induced VT, and Zuanetti and Corr (6) also reported that UK-68, 798 prevented the induction of VT. These studies showed that the QTc prolongation induced by dofetilide must have contributed to the suppression of arrhythmia induced by reentry mechanism.
With regard to the arrhythmogenic effect of dofetilide in the control period of the coronary ligation and reperfusion experiments, PVC and/or VT occurred before the coronary ligation was performed in halothane-associated Beagles (3 of 8 Beagles), but in none in the pentobarbital-anesthetized Beagles. This may have been due to the use of halothane, because more severe arrhythmogenic effects were also observed only in our halothane-anesthetized dogs that received E-4031 and MS-551 (11,12). Halothane is known not only to decrease the sinoatrial rate and intensify QT prolongation, but also to induce arrhythmias, especially with catecholamines (27). Therefore, with the concomitant use of halothane, dofetilide, like other new class III drugs, showed arrhythmogenic effects in some dogs, and such side effects may occur in clinical situations when the QT interval is dramatically increased during use of class III drugs.
Some matters were not elucidated by the present study, including the reason for the lack of antiarrhythmic effect of dofetilide on the VF induced by coronary reperfusion, as well as the mechanisms underlying the antiarrhythmic effect on ouabain-induced arrhythmia.
Although further studies are needed to understand the effects of dofetilide, the present study and others indicate its effectiveness in suppressing reentry arrhythmias; other studies also showed positive inotropic effects of dofetilide in cat papillary muscle (28) and in anesthetized dogs (29). Therefore, dofetilide is likely to become an efficacious drug in preventing selected arrhythmias occurring due to a reentrant mechanism, especially in patients with a previous MI, and may be more advantageous than conventional class I antiarrhythmic agents, which have cardiodepressant actions.
Acknowledgment: This work was supported by Grant No.04454541 from the Japanese Ministry of Education, Science and Culture and a grant from Pfizer Pharmaceuticals Inc. We thank Pfizer Pharmaceuticals Inc. for providing dofetilide and A. Ozawa for excellent technical assistance.
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