© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties
Research Center, Department of Medicine, Department of Pharmacology and Therapeutics, Institut de Cardiologie de Montréal and McGill University, 5000 Bélanger Street East, Montreal, Quebec H1T 1C8, Canada
* Corresponding author. Tel. (+1-514) 376 3330; Fax (+1-514) 376 1355.
Received 29 May 1997; accepted 23 September 1997
 |
Abstract |
|---|
 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Objectives: This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide. Background: Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr blockade. Methods: Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length. Results: Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P<0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51±3% at a basic cycle length, BCL, of 400 ms and by 17±3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38±6%, BCL 400 ms; 35±10%, BCL 200 ms). Neither drug affected conduction. Conclusions: Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.
KEYWORDS Potassium channel blockers; Cardiac arrhythmias; Antiarrhythmic agents; ECG
|
1 Introduction |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Atrial fibrillation (AF) is the commonest arrhythmia requiring therapy in clinical practice, and its treatment remains problematic [1]. Over the past several years, there have been efforts to develop new antiarrhythmic drugs, particularly agents with novel patterns of ion channel blocking properties. One potentially interesting target is the K+ channel IKs, whose time-dependent deactivation upon repolarization may allow for channel activation to accumulate at rapid rates and to contribute to rate-dependent APD reduction [2]. In 1994, Busch et al. reported that a novel chlorophenylfuranyl compound, initially denoted by NE-10064 and later given the name azimilide, is a highly potent blocker of a cloned channel (minK) that in Xenopus oocytes produces a current that corresponds to IKs [3]. During initial development, azimilide was considered to be a potentially selective blocker of IKs; however, subsequent studies have shown that azimilide blocks IKr with greater potency than IKs [4–6]. This observation has led to questions about whether IKs blockade contributes to the in vivo actions of the drug, or whether the agent acts simply as an IKr blocker.
Azimilide has been reported to be effective against ischemia-related ventricular tachyarrhythmias in dogs [7, 8]and against ischemia/reperfusion arrhythmias in rats [9]. Preliminary findings suggests that azimilide can terminate atrial flutter in dogs with sterile pericarditis [10]and with a Y-shaped incision in the right atrium [11]. No information is available in the literature regarding the effects of azimilide in experimental AF, nor about the rate-dependence of the drug's effects on atrial electrophysiological properties. We therefore designed the present study to assess the actions of azimilide in a dog model of AF that we have used extensively to study antiarrhythmic drug actions [12–14]. We used the IKr blocker dofetilide [2]as a comparison agent, in order to evaluate whether the actions of azimilide resemble those of dofetilide, and can therefore be attributed to IKr blockade, or whether azimilide has distinct actions compatible with a significant contribution of IKs blockade to its antiarrhythmic properties.
|
2 Methods |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
2.1 General methods
Purpose-bred dogs (Marshall Farms, North Rose, NY) of either sex weighing 20 to 26 kg were anesthetized with morphine (2 mg/kg im initially, followed by 0.5 mg/kg iv every 2 h) and
-chloralose (120 mg/kg iv followed by an infusion of 29.25 mg/kg h–1) [15]. Dogs were ventilated mechanically with room air supplemented with oxygen via an endotracheal tube at 20 to 25 min with a tidal volume obtained from a nomogram. Arterial blood gases were measured every 2 h and kept in the physiological range (SaO2 >90%, pH 7.38 to 7.44). Catheters were inserted into the femoral artery for blood pressure recording and blood gas measurement, and into both femoral veins for drug administration and venous blood sampling. Catheters were kept patent with heparinized 0.9% saline solution. Body temperature was maintained at 37°C to 39°C with a circulating water temperature control system. The heart was exposed via a median thoracotomy and a pericardial cradle was created. Two bipolar stainless steel, Teflon-coated electrodes were inserted into the right atrial appendage for recording and stimulation, and one was inserted into the left atrial appendage for recording. A programmable stimulator (Digital Cardiovascular Instruments, Berkeley, CA) was used to stimulate the right atrium with 4 ms, twice diastolic threshold pulses. A ventricular demand pacemaker (GBM 5880, Medtronic, Minneapolis, MN) was used to stimulate the ventricles at 80/min when (particularly during vagal AF) the ventricular rate became excessively slow. A P23 1D transducer, electrophysiological amplifiers (Bloom Associates, Flying Hills, PA), and paper recorder (Astromed MT-95000, Toronto, ON, Canada) were used to record six standard ECG leads, atrial electrograms, and stimulation artifacts. The vagus nerves were isolated in the neck, doubly-ligated and divided, and bipolar electrodes inserted (see below) in each nerve. To block changes in ß-adrenergic effects on the heart, nadolol was administered as an initial dose of 0.5 mg/kg iv, followed by 0.25 mg/kg iv every 2 h.
2.2 Atrial fibrillation model
Drug effects on AF were studied in two ways. First, we analyzed the ability of each drug to terminate sustained AF maintained during continuous vagal nerve stimulation. Bipolar hook electrodes (stainless steel insulated with Teflon except for the distal 1 to 2 cm) were inserted via a 21-gauge needle within and parallel to the shaft of each nerve. Bilateral bipolar stimuli were applied with a stimulator (model DS-9F, Grass Instruments, Quincy, MA) set to deliver 0.1 ms square-wave pulses of 5 V applied intensity and a stimulation frequency equal to 60% of the frequency needed to produce asystole. Under control conditions, a short burst of rapid atrial pacing (10 Hz, four times threshold) was delivered to induce AF, that was ordinarily sustained over 30 min during vagal stimulation. In isolated cases, the vagal stimulation frequency had to be increased to produce sustained AF. In such cases, the bradycardic effect of the frequency selected was noted. The vagal stimulation frequency was adjusted under control conditions, and then readjusted after each dose of a drug to maintain the same bradycardic effect. AF was defined as a rapid (>500 min under control conditions), irregular atrial rhythm with varying electrogram morphology.
The second type of end point analyzed was the duration of non-vagal AF. AF was induced by burst atrial pacing as described above but in the absence of vagal stimulation and the duration of AF noted. This procedure was repeated 10 times under control conditions and in the presence of drug at each dose. The mean duration of AF was taken as an indicator of the ability to sustain AF under each condition.
2.3 Measurement of electrophysiological variables and vagal response
The atrial effective refractory period (ERP) was measured with the extrastimulus method, over a range of (S1S1) basic cycle lengths (BCL). A premature extrastimulus (S2) was introduced after every 15 basic stimuli, beginning with an S1S2 coupling interval at least 50 ms longer than the estimated ERP. The S1S2 interval was decreased in 10 ms decrements until failure to capture occurred, with the longest S1S2 interval consistently failing to produce a propagated response defining the ERP. Conduction velocity (CV) was determined by mapping atrial activation during 1:1 atrial pacing. Five multielectrode plaques containing a total of 112 electrodes were sewn to the epicardial surface of both atria as previously described [16, 17]. Previously described methods [18]were used to create activation maps during atrial pacing. A series of at least four right atrial electrodes in the line of rapid propagation from the stimulation site were identified, and conduction velocity determined by linear regression of distance from the stimulation site against local activation time. The same electrode sites were used for conduction velocity measurements under all conditions, after ascertaining that the activation pattern was constant. Both ERP and CV were measured after at least 1 min of stimulation at a given BCL to ensure steady-state effects. AF cycle length (AFCL) during vagal AF was determined as previously described [13]by determining the mean cycle length over a 1-s interval at each of the 112 recording sites, and then averaging to obtain an overall mean AFCL for each experimental condition.
The vagal nerve frequency-heart rate relation was determined under control conditions and in the presence of each dose of each drug. The vagal nerves were stimulated at a constant voltage and at frequencies ranging from 1 to 7 Hz. Stimulation at each vagal frequency was maintained for 30 s, with the heart rate assessed over the last 10 s of stimulation. A 30-s rest period was allowed after stimulation at each frequency, and we required that the sinus rate return to control values before stimulation at the next frequency.
2.4 Experimental protocols
The experimental groups studied are summarized in Table 1. Each dog received only one drug (azimilide or dofetilide) at doses indicated in Table 1. The first series of experiments were initial-dose ranging studies for AF termination. All drugs were administered intravenously via an infusion pump, with drug solutions prepared freshly on the day of the experiment and protected from light. Vagal stimulation parameters were defined under control conditions as described above, and maintenance of AF during 30 min of vagal stimulation under control conditions was verified. After a 10-min rest period, vagal stimulation was reinstituted and AF induced. Five minutes later, either azimilide (a series of doses of 4.5 followed by 9 mg/kg, four dogs) or dofetilide (sequential 0.06 mg/kg doses, two dogs) was administered (Group 1A). Azimilide was never effective without at least one dose of 9 mg/kg, and dofetilide doses of 0.06 mg/kg failed to terminate AF. Based on these initial experiments, a modified loading dose regimen was developed and tested in seven dogs (Group 1B). These dogs received an initial dose of 10 mg/kg of azimilide or 0.08 mg/kg of dofetilide, followed by a subsequent dose of 20 mg/kg of azimilide or 0.16 mg/kg of dofetilide if the first dose failed to terminate AF. The time course of effects on ERP and of blood levels (in the case of azimilide) was noted. Based on the latter observations, we concluded that dofetilide effects were well-maintained without a maintenance infusion, but that a maintenance infusion of half the loading dose per h would be needed to maintain stable azimilide concentrations and effects over time.
|
In the next series of experiments, six dogs (three for each drug) received the doses developed on the basis of preliminary studies in order to ensure stable effects over time (Group 2). The doses selected for dofetilide were loading doses of 0.08 and 0.16 mg/kg of dofetilide administered at 16 µg/kg min–1. The loading doses of azimilide were 10 mg/kg and 20 mg/kg, administered at 2 mg/kg min–1, and were followed by maintenance infusions of 5 mg/kg and 10 mg/kg h–1 respectively.
Groups 1A, 1B and 2 were used to define dose regimens with significant efficacy and stable actions over time. The final and definitive series of studies assessed the effects of these dose regimens on AF and atrial electrophysiology in seven dogs for each drug (Group 3). Under control conditions, ERP, CV, and AF duration were assessed in the absence and presence of vagal stimulation, and the maintenance of AF during 30 min of vagal stimulation was confirmed. An 8-s window of activation data was obtained during AF. AF was terminated by stopping vagal stimulation, and 10 min later AF was induced once again. After AF had been maintained for 5 min, the first dose of a drug was infused. If AF terminated within 15 min, the measurements obtained under control conditions were repeated. Since sustained AF could not be induced in the presence of drugs at doses that terminated AF, the experiment was then terminated. If AF was not stopped by the first drug dose, vagal stimulation was discontinued to allow a return to sinus rhythm. The electrophysiologic measurements were repeated, and sustained AF was once more induced in the presence of vagal stimulation. After 5 min of AF, the second dose of the same drug was infused. Electrophysiologic measurements were then repeated, following either drug-induced conversion to sinus rhythm or, if the latter did not occur within 15 min of the end of the loading dose, following the cessation of vagal stimulation to allow for restoration of sinus rhythm. An 8-s window of activation data during AF was obtained at the time of AF conversion (with a pre-trigger used to assure at least 4 s of data during AF prior to conversion). If AF was not converted to sinus rhythm, an 8-s window of data during AF was obtained immediately prior to stopping vagal stimulation.
Electrophysiologic measurements and vagal frequency-response curves were obtained in 7 Group 3 dogs for each drug. Drug efficacy in AF termination was analyzed for all dogs receiving the definitive loading doses. For azimilide, this included 7 Group 3 dogs, 3 Group 2 dogs and 4 Group 1B dogs. One azimilide dog in Group 1B died for unknown reasons several minutes after receiving the second loading dose and was not included in the efficacy analysis. For dofetilide, the efficacy analysis was based on 12 dogs: 7 from Group 3, 3 from Group 2 and 2 from Group 1B.
2.5 Statistical analysis
Group data are represented as the mean ±SE. Statistical analysis was by analysis of variance for repeated measures and a chi-square test for contingency comparisons. Two-tailed tests were used, and a P<0.05 was taken to indicate statistical significance.
|
3 Results |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Both azimilide and dofetilide slowed spontaneous rate, but neither drug significantly altered the bradycardic effect of vagal nerve stimulation as studied in Group 3 dogs (Fig. 1). In analyzing dogs for AF conversion, we used all dogs that received the definitive loading dose regimen for either drug (14 for azimilide, 12 for dofetilide as described in section 2.4 above). The lower doses of azimilide and dofetilide had comparable efficacy in converting vagal AF to sinus rhythm (Fig. 2, left). On the other hand, the higher dose of azimilide resulted in substantially greater effectiveness in converting AF (cumulative efficacy of 93%) compared to the higher dose of dofetilide (50%). When only Group 3 dogs (n=7 per group) are considered, the same pattern of efficacy is observed (43% each for low-dose azimilide and dofetilide; 100% for high-dose azimilide vs. 43% for high-dose dofetilide). Azimilide and dofetilide were very effective in reducing the duration of non-sustained AF occurring in the absence of vagal stimulation (Fig. 2, right).
|
|
Both azimilide and dofetilide increased ERP significantly (P<0.001 for each). The time course of drug effects was determined in Group 2 dogs. The effects of dofetilide were stable over time without a maintenance infusion (Fig. 3, left). The loading and maintenance infusion developed for azimilide was effective in maintaining drug effects on ERP (Fig. 3, right). The stability of azimilide effects was consistent with the ability of the maintenance infusions to sustain stable plasma concentrations (Table 2).
|
|
The electrophysiologic effects of azimilide and dofetilide at different cycle lengths are detailed in Table 3. As expected for class III agents, CV was not significantly altered. ERP was increased significantly by both drugs in both the absence and presence of vagal stimulation, with smaller effects noted (particularly for azimilide) in the presence of vagal stimulation. The relationship between cycle length and drug-induced ERP prolongation (expressed as a percentage over control values) are shown in Fig. 4. Dofetilide's effects showed significant reverse use dependence, in both the absence and presence of vagal stimulation. In contrast, azimilide's actions on ERP were frequency-independent. The second dose of dofetilide produced little additional effect, while the second dose of azimilide had a substantially larger action. Azimilide's effects were less in the presence of vagal nerve stimulation than in its absence.
|
|
In order to obtain insights into drug effects on activation during vagal AF, we calculated changes in the AFCL. As shown in Fig. 5, both drugs increased AFCL. The changes caused by azimilide in AFCL were larger than the changes the drug produced in ERP in the presence of vagal nerve stimulation. In order to analyze these results further, we compared AFCL changes in dogs with and without drug-induced termination (based on the seven dogs studied with each drug in the final protocol). Doses that terminated AF always produced very large increases in AFCL prior to termination, for example, low-dose azimilide increased AFCL by 69±20% in dogs in which it terminated AF, compared to 27±5% in dogs without termination; low-dose dofetilide increased AFCL by 82±22% in dogs with termination compared to 51±15% in dogs without termination. High-dose azimilide increased AFCL by 107±32% and terminated AF in all dogs who received it. The limited AFCL changes occurring with the higher dose of dofetilide are consistent with its inability to terminate AF in dogs that did not respond to the lower dose.
|
|
4 Discussion |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
We have found that the investigational antiarrhythmic agent azimilide is effective against AF in an experimental dog model. The drug increases atrial ERP in a frequency-independent fashion, and does not significantly alter CV, consistent with class III antiarrhythmic action. Dofetilide also demonstrated class III properties, with frequency-dependent actions on ERP different from those of azimilide.
The class III properties of azimilide and dofetilide are qualitatively similar to those of other agents of the same class, such as d-sotalol and ambasilide, that have been shown previously to be effective in the same model [14]. Increases in ERP without concomitant decreases in CV result in an increase in the wavelength for reentry, which determines the number of reentry circuits during AF and thus the stability of the arrhythmia [12–14, 19]. Preliminary reports have been presented which suggest efficacy of azimilide in canine atrial flutter [10, 11]. In the study of Restivo et al, efficacy was seen in the sterile pericarditis model of atrial flutter with an azimilide dose of 10 mg/kg, but 30 mg/kg was necessary to prevent completely arrhythmia reinduction [10]. In the study of Pinto et al. azimilide terminated atrial flutter in dogs with a Y-shaped atrial incision at doses ranging from 2 mg/kg to 11.7 mg/kg [11]. While direct comparisons between drug effects on atrial flutter and fibrillation must consider the differences in mechanisms between the arrhythmias [19, 20], our observations are consistent with those of the atrial flutter studies in terms of the approximate dose range for azimilide efficacy in canine models of atrial arrhythmia.
The potential ionic mechanisms of azimilide action have been somewhat controversial. Based on early studies [3], azimilide was initially thought to be a highly selective IKs blocker. Subsequent studies in other laboratories indicated that azimilide can block a variety of other currents, including IKr, ICa and INa [4–6, 21]. The IC50 for IKs block ranges from 0.7 µmol/l to 3 µmol/l [4–6, 22], while that for IKr block appears to be in the range of 0.2 µmol/l–0.4 µmol/l; IC50s for INa and ICa block are close to 20 µmol/l [6].
These observations raise the possibility that azimilide's in vivo actions might simply be due to its most potent effect, IKr inhibition. For this reason, we compared the in vivo actions of azimilide with those of the highly selective IKr blocker dofetilide [23, 24]. Dofetilide produced clear reverse use-dependent ERP prolongation, of the type previously observed in the same model [14]with the IKr blocker d-sotalol [25]. In contrast, azimilide produced frequency-independent ERP prolongation, suggesting the operation of mechanisms other than IKr blockade. The plasma concentrations achieved by the azimilide doses we used were in the order of 3 µmol/l for the lower dose and 10 µmol/l for the higher dose (Table 2). These concentrations are in the range reported to produce 50% and 80% block of IKs respectively [5, 6]. Ambasilide, another drug with IKs blocking capability [26], also produces much less frequency-dependent ERP prolongation compared to d-sotalol in the same model [14]. Our findings therefore point towards a significant role for azimilide's IKs blocking action in its electrophysiological effects in the dog atrium and its efficacy in the AF model we studied. It is noteworthy that significant densities of both IKr and IKs have been noted in canine atrial myocytes [27], consistent with a role for IKs in canine atrial repolarization. Furthermore, both IKr and IKs are present in human atrium [28], pointing to the potential clinical relevance of our findings.
While the available evidence points to a significant contribution of IKs blockade to the in vivo actions of azimilide, other possibilities must be considered. The higher dose of azimilide produced concentrations that can cause some inhibition of both INa and ICa, although the concentrations achieved were of the order of half the IC50 for these currents. The lack of azimilide effect on conduction velocity (Table 3) argues against important INa blockade. Calcium antagonists are ineffective in terminating clinical AF [1], arguing against a contribution of ICa inhibition to azimilide's efficacy in canine AF. Electrical remodelling due to AF can be prevented by calcium antagonists [29]. While it is unlikely that significant remodelling occurred during the relatively short periods of AF in the present study (
30 min), a contribution of reduced remodelling cannot be completely excluded.
Several of the observations in the present study are somewhat puzzling. First, while the second dose of dofetilide had larger effects than the first dose, the differences were rather small. If the first dose caused near-maximal IKr blockade, it would not be surprising if an additional dose produced a relatively small augmentation in drug effect. This possibility remains speculative without the ability to quantify IKr inhibition directly in vivo. The ERP-prolonging action of azimilide was substantially smaller in the presence of vagal stimulation compared to its absence (Fig. 3), in contrast to previous class I and III drugs we have studied, which tend to show larger effects in the presence of vagal nerve stimulation [12–14]. The mechanisms underlying this interesting discrepancy, and its potential clinical significance, remain to be determined. Since IKs activates slowly upon depolarization [25, 30], it is possible that the short action potentials resulting from vagal action leave little time for IKs activation, and thereby reduce both the contribution of IKs to repolarization and the effect of IKs blockade on the action potential. At very rapid rates, such as during AF, it is possible that even with short action potentials IKs can accumulate and contribute significantly to repolarization [2]. These considerations could explain (at least in part) the reduced effect of azimilide in the presence of vagal stimulation, as well as its ability to terminate AF despite relatively modest effects on ERP during 1:1 pacing in some cases. These concepts, while potentially interesting and appealing, remain speculative until they can be tested directly.
The present studies have several limitations which must be recognized. First, while the vagal AF model has distinct advantages for the study of mechanisms of drug action on AF [31], and has provided useful insights into the effects of a variety of class I and III drugs on the arrhythmia [12–14], its direct relevance to clinical AF is uncertain. Clear vagal involvement in clinical AF is unusual; on the other hand, background vagal tone may play an important permissive role, and antiarrhythmic drug responses in the canine vagal AF model resemble those of acute AF in man [31]. While the results presented herein are relevant to understanding the respective effects of dofetilide and azimilide on canine atrial electrophysiology and arrhythmias, they cannot be directly extrapolated to effects in patients. Second, there are important tissue and species differences in ion current expression and properties. Therefore, IKs block may have different effects in different systems. Indeed, Fermini et al. have shown reverse use-dependent effects of azimilide on ventricular ERP in the dog [5]. Whereas larger doses of azimilide were needed to increase ventricular ERP by 15% at faster rates in the ferret heart, indicating reverse use-dependence, the dose increase needed was much larger for dofetilide [32], consistent with the results of the present study. The blend of inward and outward currents during the action potential plateau, which is known to be species- and tissue-specific may be a crucial determinant of rate-dependent drug effects on APD. Finally, while our results indicate that azimilide alters canine atrial electrophysiology in a fashion different from that of dofetilide, they do not prove that the differences observed are due to IKs blockade. Previously demonstrated effects on other currents, such as those on ICa and INa, as well as effects on membrane currents and ion transport processes not yet studied, could also conceivably play a role.
Inter-animal variability resulted in some baseline differences between dogs receiving either drug. For example, baseline ERP was shorter in Group 3 dogs receiving azimilide compared to those receiving dofetilide (Table 3). The opposite was true of Group 2 dogs, among which baseline ERP was longer in those receiving azimilide compared to those receiving dofetilide (Fig. 3). We cannot exclude a role of baseline differences in contributing to differences in drug responses. On the other hand, relative efficacy rates in terminating AF were similar for Group 2 dogs (dofetilide 33%, azimilide 100%) compared to Group 3 dogs (dofetilide 43%, azimilide 100%), despite opposite differences in baseline ERP (Group 2: dofetilide<azimilide; Group 3: azimilide<dofetilide). These observations suggest that differences in baseline ERP are unlikely to account for the efficacy differences between azimilide and dofetilide that we observed.
It has been suggested that the development of IKs blockers may be an interesting pharmacologic approach to improve antiarrhythmic therapy by virtue of the more desirable rate-dependent profile of action they may possess compared to IKr blockers [2]. Since class III proarrhythmia preferentially occurs at low rates, while AF termination occurs during rapid atrial activation, the reverse use-dependence of IKs blockers limits efficacy and increases the risk of proarrhythmia, while drugs with preserved effects at rapid rates (like azimilide) would be expected to have greater ability to terminate AF with an acceptable risk of proarrhythmia. Azimilide was initially developed because of its potent IKs blocking actions. Our observations suggest that azimilide does have efficacy in experimental AF, and that its effects on ERP are better preserved at rapid rates than those of the IKr blocker dofetilide. The clinical significance of these observations, and the details of underlying ionic mechanisms, remain to be established in future studies.
Time for primary review 32 days.
|
Acknowledgements |
|---|
The authors thank Emma De Blasio for excellent technical assistance, Dr. Robert Brooks for helpful comments on the manuscript and Diane Campeau and Caroll Boyer for secretarial assistance with the manuscript.
|
References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Nattel S., Hadjis T., Talajic M. The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations. Drugs (1994) 48:345–371.[Web of Science][Medline]
- Jurkiewicz N.K., Sanguinetti M.C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III anti-arrhythmic agent. Circ Res (1993) 72:75–83.
[Abstract/Free Full Text] - Busch A.E., Malloy K., Groh W.J., Varnum M.D., Adelman J.P., Maylie J. The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit ISK channels expressed in xenopus oocytes and IKS in guinea pig cardiac myocytes. Biochem Biophys Res Comm (1994) 202:265–270.[CrossRef][Web of Science][Medline]
- Conder M.L., Smith M.A., Atwal K.S., McCullough J.R. Effects of NE-10064 on K+ currents in cardiac cells (abstract). Biophys J (1994) 66:A326.
- Fermini B., Jurkiewicz N.K., Jow B., et al. Use-dependent effects of the class III antiarrhythmic agent NE-10064 (azimilide) on cardiac repolarization: block of delayed rectifier potassium and L-type calcium currents. J Cardiovasc Pharmacol (1995) 26:259–271.[Web of Science][Medline]
- Yao J.A., Tseng G.N. Azimilide (NE-10064) can prolong or shorten the action potential duration in canine ventricular myocytes: dependence on blockage of K, Ca and Na channels. J Cardiovasc Electrophysiol (1997) 8:184–198.[Web of Science][Medline]
- Black S.C., Butterfield J.L., Lucchesi B.R. Protection against programmed electrical stimulation-induced ventricular tachycardia and sudden cardiac death by NE-10064, a class III antiarrhythmic drug. J Cardiovasc Pharmacol (1993) 22:810–818.[Web of Science][Medline]
- Drexler A.P., Micklas J.M., Brooks R.R. Suppression of inducible ventricular arrhythmias by intravenous azimilide in dogs with previous myocardial infarction. J Cardiovasc Pharmacol (1996) 28:848–855.[CrossRef][Web of Science][Medline]
- Brooks R.R., Carpenter J.F., Miller K.E., Maynard A.E. Efficacy of the class III antiarrhythmic agent azimilide in rodent models of entricular arrhythmia. Proc Soc Exp Biol Med (1996) 212:84–93.[CrossRef][Medline]
- Restivo M., Hegazy M., Caref E.B., et al. Effects of azimilide dihydrochloride on circus movement atrial flutter in the canine sterile pericarditis model. J Cardiovasc Electrophysiol (1996) 7:612–624.[Web of Science][Medline]
- Pinto J., Boyden P., Wit A., Brooks R. The effects of a class III antiarrhythmic agent NE-10064 which blocks the slowly activating delayed rectifier current (IKs) on canine atrial flutter (abstract). PACE (1994) 17:777.
- Wang Z., Pagé P., Nattel S. The mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. Circ Res (1992) 71:271–287.
[Abstract/Free Full Text] - Wang J., Bourne G.W., Wang Z., Villemaire C., Talajic M., Nattel S. Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness. Circulation (1993) 88:1030–1044.
[Abstract/Free Full Text] - Wang J., Feng J., Nattel S. Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide. Circulation (1994) 90:2032–2040.
[Abstract/Free Full Text] - St-Georges D, Matthews C, Nattel S. A continuous maintenance infusion technique for stable anesthesia with alpha-chloralose in the dog. Contemporary Topics in Laboratory Animal Science 1997;36:62–65.
- Wang Z., Feng J., Nattel S. Idiopathic atrial fibrillation in dogs: electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide. J Am Coll Cardiol (1995) 26:277–286.[Abstract]
- Liu L., Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol (1997) 273:H805–H816.[Web of Science][Medline]
- Nattel S., Jing W. Rate-dependent changes in intraventricular conduction produced by procainamide in anesthetized dogs: A quantitative analysis based on the relation between phase 0 inward current and conduction velocity. Circ Res (1989) 65:1485–1498.
[Abstract/Free Full Text] - Rensma P.L., Allessie M.A., Lammers W.J.E.P., Bonke F.I.M., Schalij M.J. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res (1988) 62:395–410.
[Abstract/Free Full Text] - Ortiz J., Niwano S., Abe H., Rudy Y., Johnson N.J., Waldo A.L. Mapping the conversion of atrial flutter to atrial fibrillation and atrial fibrillation to atrial flutter. Insights into mechanisms. Circ Res (1994) 74:882–894.
[Abstract/Free Full Text] - Zhang Z.H., Boutjdir M., Brooks R., Chen L., El-Sherif N. Characterization of azimilide effects on ion currents of the repolarization phase (abstract). Biophys J (1995) 68:A111.[CrossRef]
- Davies M.P., Freeman L.C., Kass R.S. Dual actions of the novel class III antiarrhythmic drug NE-10064 on delayed potassium channel currents in guinea pig ventricular and sinoatrial node cells. J Pharmacol Exp Ther (1996) 276:1149–1154.
[Abstract/Free Full Text] - Carmeliet E. Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther (1992) 262:809–817.
[Abstract/Free Full Text] - Kiehn J., Villena P., Beyer T., Brachmann J. Differential effects of the new class III agent dofetilide on potassium currents in guinea pig cardiomyocytes. J Cardiovasc Pharmacol (1994) 24:566–572.[Web of Science][Medline]
- Sanguinetti M.C., Jurkiewicz N.K. Two components of cardiac delayed rectifier K+ current. J Gen Physiol (1990) 96:195–215.
[Abstract/Free Full Text] - Zhang Z., Follmer C.H., Sarma J.S.M., Chen F., Singh B.N. Effect of ambasilide, a new class III agent, on plateau currents in isolated guinea pig ventricular myocytes: Block of delayed outward potassium current. J Pharmacol Exp Ther (1992) 263:40–48.
[Abstract/Free Full Text] - Yue L., Feng J., Li G.R., Nattel S. Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods. Am J Physiol (1996) 270:H2157–H2168. (Heart Circ Physiol 39).[Medline]
- Wang Z., Fermini B., Nattel S. Rapid and slow components of delayed rectifier current in human atrial myocytes. Cardiovasc Res (1994) 28:1540–1546.
[Abstract/Free Full Text] - Tieleman R.G., De Langen G.D.J., Van Gelder I.C., de Kam P.J., Grandjean J., Bel K.J., Wijffels M.C.E.F., Allessie M.A., Crijns H.J.G.M. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation (1997) 95:1945–1953.
[Abstract/Free Full Text] - Sanguinetti M.C., Jurkiewicz N.K. Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells. Am J Physiol (1991) 260:H393–H399. (Heart Circ Physiol 29).[Web of Science][Medline]
- Nattel S., Bourne G., Talajic M. Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation. J Cardiovasc Electrophysiol (1997) 8:469–480.[Web of Science][Medline]
- Wade-Whittaker F., Sansone D.L., Erickson B.K. Rate-dependent effects of azimilide (AZ) and dofetilide (DO) on cardiac refractoriness in the ferret. FASEB J (1996) 10:A64. (Abstract).
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Sticherling, S. Behrens, W. Kamke, A. Stahn, and M. Zabel Comparison of acute and long-term effects of single-dose amiodarone and verapamil for the treatment of immediate recurrences of atrial fibrillation after transthoracic cardioversion Europace, January 1, 2005; 7(6): 546 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. N. Singh and N. Wadhani Antiarrhythmic and Proarrhythmic Properties of QT-Prolonging Antianginal Drugs Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S85 - S97. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Nakashima, U. Gerlach, D. Schmidt, and S. Nattel In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions Cardiovasc Res, March 1, 2004; 61(4): 705 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Khairy and S. Nattel New insights into the mechanisms and management of atrial fibrillation Can. Med. Assoc. J., October 29, 2002; 167(9): 1012 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Derakhchan, C. Villemaire, M. Talajic, and S. Nattel The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF Cardiovasc Res, April 1, 2001; 50(1): 75 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Verduyn, J. M. v. Opstal, J. D. Leunissen, and M. A. Vos Assessment of the Pro-Arrhythmic Potential of Anti-Arrhythmic Drugs: An Experimental Approach Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 89 - 97. [PDF]
|
|
|
|
|
|
B. D Walker, C. B Singleton, H. Tie, J. A Bursill, K. R Wyse, S. M Valenzuela, S. N Breit, and T. J Campbell Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel Cardiovasc Res, October 1, 2000; 48(1): 44 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li, A. Benardeau, and S. Nattel Contrasting Efficacy of Dofetilide in Differing Experimental Models of Atrial Fibrillation Circulation, July 4, 2000; 102(1): 104 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J C Hancox, K C R Patel, and J V Jones Antiarrhythmics---from cell to clinic: past, present, and future Heart, July 1, 2000; 84(1): 14 - 24. [Full Text] [PDF]
|
|
|
|
|
|
P. Dorian and D. Newman Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview Europace, January 1, 2000; 2(4): 277 - 285. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Li, L. Zhang, J. Kneller, and S. Nattel Potential Ionic Mechanism for Repolarization Differences Between Canine Right and Left Atrium Circ. Res., June 8, 2001; 88(11): 1168 - 1175. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||