European Journal of Pharmacology 564 (2007) 150 – 157

www.elsevier.com/locate/ejphar

Comparative antiarrhythmic efficacy of amiodarone and dronedarone

during acute myocardial infarction in rats
Maria G. Agelaki a , Constantinos Pantos b,⁎, Panagiotis Korantzopoulos a ,
Dimitrios G. Tsalikakis c , Giannis G. Baltogiannis a ,
Andreas Fotopoulos d , Theofilos M. Kolettis a
a
Department of Cardiology, University of Ioannina Medical School, 45110 Ioannina, Greece
b
Department of Pharmacology, University of Athens School of Medicine, 75 Mikras Asias Avenue, 11527 Goudi, Athens, Greece
c
School of Computer Sciences, University of Ioannina, 45110 Ioannina, Greece
d
Department of Nuclear Medicine, University of Ioannina Medical School, 45110 Ioannina, Greece

Received 10 November 2006; received in revised form 20 February 2007; accepted 26 February 2007
Available online 7 March 2007

Abstract

The effects of dronedarone, a non-iodinated derivative of amiodarone, on ventricular tachycardia and ventricular fibrillation post-myocardial
infarction are not well established. Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n = 18),
amiodarone (30 mg/kg, n = 20), or dronedarone (30 mg/kg, n = 17). After acute coronary artery ligation, a single-lead electrocardiogram was
continuously recorded for 24 h and episodes of ventricular tachycardia/fibrillation as well as mortality rates were analysed. Monophasic action
potential recordings were obtained from the left ventricular epicardium at baseline and 24 h post-myocardial infarction. Thyroid hormones and
catecholamines were measured using radioimmunoassay. Thyroid function was similar in the 3 groups. Compared to controls, amiodarone and
dronedarone equally decreased the number of ventricular tachycardia/fibrillation episodes by approximately 75%. Both agents prevented the
increase in monophasic action potential duration and in beat-to-beat variation. Norepinephrine levels were lower only after amiodarone treatment.
Despite the observed antiarrhythmic effect, total mortality did not differ between groups (38.8% in controls, 30.0% in the amiodarone group and
58.8% in the dronedarone group), because of excess bradyarrhythmic mortality in both drug groups that reached significance in the dronedarone
group. Dronedarone and amiodarone display similar antiarrhythmic efficacy post-myocardial infarction, partly by preventing repolarization
inhomogeneity. However, dronedarone increases bradyarrhythmic mortality possibly secondary to its negative inotropic effects.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Acute myocardial infarction; Ventricular arrhythmias; Amiodarone; Dronedarone; Mortality

1. Introduction concern. The development of thyrotoxicity has been attributed to

Amiodarone is one of the most effective antiarrhythmic
compounds currently available for the treatment of life-
threatening arrhythmias (Connolly, 1999). Amiodarone primarily
inhibits K+ channels, but it also exhibits all other known
antiarrhythmic mechanisms, including antiadrenergic activity
and inhibition of Na+ and L-type Ca++ channels (Connolly, 1999).
In clinical practice, the role of amiodarone is entrenched, but
its side-effect profile during chronic administration remains of
⁎ Corresponding author. Tel.: +30 210 7462560; fax: +30 210 779 0841.
E-mail address: cpantos@cc.uoa.gr (C. Pantos).
0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2007.02.052
the iodinated nature of the molecule (Singh, 2004). Dronedarone,
(SR 33589; N,N-dibutyl-3-[4-([2-butyl-5-methylsulphonamido]
benzofuran-3-yl-carbonyl) phenoxypropylamine) a structurally
related non-iodinated benzofuran-derivative of amiodarone, was
developed to overcome these toxic effects. However, the issue of
amiodarone-induced thyrotoxicity is not fully understood, as an
additional iodine-independent mechanism has been suggested (Di
Matola et al., 2000).
Amiodarone is effective in the treatment of ventricular
arrhythmias during acute myocardial infarction (Kodama et al.,
1997), but the efficacy of dronedarone in this setting is not well
established. Previous studies in anaesthetised animals indicated
 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157
that dronedarone and amiodarone have comparable antiarrhyth-
mic efficacy (Finance et al., 1995; Manning et al., 1995).
However, the variety in animal species and anaesthesia
protocols utilized introduce limitations in the interpretation of
antiarrhythmic effects. More importantly, in these studies, the
time window for the observation of ventricular arrhythmias was
confined to the immediate post-infarction period.
The aim of the present study was twofold: first, to examine
the effects of amiodarone and dronedarone on thyroid function;
and, second and foremost, to examine the antiarrhythmic
efficacy of amiodarone and dronedarone during acute myocar-
dial infarction in the rat model. The rat not only exhibits a high
frequency of ischaemic ventricular tachyarrhythmias, but also
their occurrence corresponds to the time course observed in
humans after acute myocardial infarction (Opitz et al., 1995).
We used the conscious rat model that permits the study of
ventricular tachyarrhythmias for extended periods of time,
without the confounding effects of anaesthesia. To shed light
into possible antiarrhythmic mechanisms of the two agents,
monophasic action potential was recorded from the lateral left
ventricular epicardium under general anaesthesia and plasma
catecholamine levels were measured 24 h post-infarction.
2. Materials and methods
The study was conducted in female Wistar rats, 20 ± 1 weeks
old. The animals received humane care, the investigation
complies with international guidelines and the protocol was
approved by the local national authority. All rats were housed in
individual cages, in a temperature controlled environment
(21 ± 1 °C), with a 12:12-h light–dark cycle and were given
water and standard rat chow ad libitum.
2.1. Drug administration
The rats were randomized to control, amiodarone, or
dronedarone groups. Both drugs were kindly provided by
Sanofi-Aventis, Montpellier, France and were administered by
gavage, once daily for 2 weeks, at a dose of 30 mg/kg. Before
each administration, a fresh solution was prepared in 0.6%
methylcellulose to obtain the necessary drug concentration in
3 ml. In the control group, 0.6% methylcellulose alone was
given for the same time period. The rats were weighed at the
beginning and at the end of the drug administration period.
2.2. Implantation of telemetry transmitter
On the fourteenth day of drug administration, a continuous
electrocardiogram telemetry transmitter (Dataquest, Data
Sciences International, Transoma Medical, Arden Hills, MN,
USA) was implanted in the abdominal cavity, using a previously
described method (Opitz et al., 1995). The animals were intubated
and mechanically ventilated (ventilator model 7025, Ugo Basile,
Comerio, VA, Italy) and anaesthetised with isoflurane. The
transmitter was secured in the abdominal cavity; the leads were
tunnelled under the skin and attached to the underlying tissue. The
positive electrode was sutured in a V4–V5 position and the
151
negative electrode under the right axilla. The rats were housed in
individual cages, placed on a receiver that continuously captured
the signal, independently of animal activity. The signal was
displayed in real-time with the use of a computer program (A.R.T.
2.2, Dataquest, Data Sciences International, Transoma Medical,
Arden Hills, MN, USA) and stored for analysis.
2.3. Monophasic action potential recordings
Twenty-four hours after telemetry transmitter implantation, the
rats were re-anaesthetised and a left thoracotomy was performed,
allowing dissection of the pectoral muscles. The heart was
exposed and the pericardium was carefully removed. The method
used in our laboratory for monophasic action potential recordings
has been described previously (Baltogiannis et al., 2005). A probe
(model 200, EP Technologies, Sunnyvale, CA, USA) was placed
on the lateral left ventricular wall. The signal was amplified with
the use of a preamplifier (model 300, EP Technologies,
Sunnyvale, CA, USA) and filtered at 50 Hz using a digital
notch filter (for elimination of power line interference). The signal
was further filtered using a band pass filter, allowing a signal
range between 0.05 Hz and 500 Hz. Two-minute recordings were
stored into a personal computer, equipped with an analog-to-
digital converter (BNC 2110, National Instruments Corporation,
Dallas, TX, USA). This recording duration is optimal, since it
provides sufficient number of analysable beats, whilst causing
minimal interference with the experimental procedure. The
software utilized in this study, developed and validated in our
Institution (Tsalikakis et al., 2003), permits recording and off-line
analysis. For purposes of this study, the action potential duration
at 90% of repolarization was measured at baseline and 24 h after
acute coronary artery ligation. During analysis, non-sinus beats
were excluded and 50 consecutive sinus beats per recording were
analysed. The standard deviation of action potential duration at
90% of repolarization was calculated for each recording, as a
measure of beat-to-beat variation, indicating electrical alternans
(Franz, 1999).
2.4. Generation of acute myocardial infarction and blood
sample collection
Coronary artery ligation was performed, as described
previously (Pfeffer et al., 1979), by an operator blinded to
treatment assignment. The left coronary artery was encircled and
ligated using a 6-0 suture, placed between the pulmonary artery
cone and the left atrial appendage; following these anatomical
landmarks ensures generation of similar infarct size in all
experiments. The incision was sutured in two layers and the
remaining air was aspirated from the thorax, allowing the
resumption of spontaneous respiration. A six-lead electrocardio-
gram was obtained and ST-segment elevation was considered a
proof of induced infarction. The animals were returned to their
cage and recording was continued for 24 h, or until spontaneous
death. Bradyarrhythmic death occurring during the first 5 min
post-ligation was attributed to the surgical procedure and these
animals were excluded from the study. No resuscitation attempts
were allowed at any time during the study.
152 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157
Twenty-four hours post-ligation, the survivors were re-
anaesthetised, blood was collected by internal jugular venous
puncture, centrifuged immediately and the serum was stored at
− 20 °C. The site of previous left thoracotomy was re-opened
and monophasic action potential recordings were repeated at the
same epicardial sites. The rats were subsequently sacrificed
using a lethal dose of potassium chloride and the heart was
harvested for measurement of infarct size.
2.5. Infarct size
The method used for measurement of infarct size has been
described previously (Ytrehus et al., 1994). The heart was excised,
frozen (in −20 °C for 1 h), hand-cut in five 2 mm slices, incubated
(in triphenyltetrazolium chloride for 15 min at 37 °C) and fixed (in
10% formalin for 20 min). The slices were scanned and the areas of
infarcted and non-infarcted myocardium were measured from both
slice sides and averaged. Planimetry was performed using a
previously validated software program (Image Tool, University of
Texas, USA). The measured areas were multiplied by slice
thickness to determine the volumes of infarcted and non-infarcted
myocardium for each slice. These values were summed and infarct
size (expressed as a percentage) was defined as the ratio between
infarcted and total left ventricular volume.
2.6. Measurement of thyroid hormone and catecholamine
serum levels
Serum levels of thyroxine, triiodothyronine, thyroid stimulating
hormone, epinephrine and norepinephrine were measured using
radioimmunoassay kits, obtained from BioSource Europe S.A.,
Nivelles, Belgium. Antibodies to thyroperoxidase and thyroglob-
ulin were measured using radioimmunoassay kits, obtained from
BRAHMS Aktiengesellschaft, Henningsdorf, Germany.
2.7. Sinus heart rate
We analysed continuous 5-min electrocardiogram record-
ings, from which non-sinus beats were excluded. Sinus heart
rate was calculated from the mean value of these RR intervals at
baseline, at the 5th, 30th and 60th minute post-ligation and
hourly thereafter.
2.8. Arrhythmia analysis
The acquired electrocardiogram tracings were displayed and
analysed off-line independently by two of the authors, blinded to
treatment assignment. We report the number of ventricular
tachycardia and ventricular fibrillation episodes, according to the
guidelines provided by the Lambeth Conventions for determina-
tion of experimental arrhythmias (Walker et al., 1988). The
duration of each ventricular tachycardia or fibrillation episode
was measured using the time-scale provided by the recording
software. Ventricular tachycardia was defined as 4 or more
consecutive ventricular ectopic beats, and ventricular fibrillation
as a signal in which individual QRS deflections could not easily
be distinguished from one another. Even with these guidelines,
separating ventricular tachycardia from fibrillation was often
difficult, and this has been the experience of others (Opitz et al.,
1995). Therefore, in this study, we report ventricular tachycardia
and fibrillation collectively, as ventricular tachyarrhythmias. For
each rat, ventricular tachyarrhythmias were divided by the actual
survival time (i.e. the time at risk for experiencing a tachyar-
rhythmia) and are reported as number of episodes per h alive.
Since different mechanisms have been suggested to account for
ventricular tachyarrhythmias occurring during the first and the
following hours after coronary occlusion, the number of
ventricular tachyarrhythmia episodes (per h alive) is also reported
separately for phase I (defined as the first hour post-ligation) and
for phase II (defined as the time interval from the 61st minute to
the end of the recording or to spontaneous death) (Clements-
Jewery et al., 2005). Tachyarrhythmic death was defined as
ventricular asystole, preceded by a sustained ventricular tachy-
arrhythmia episode and bradyarrhythmic death as ventricular
asystole, preceded by bradycardia (b 200 bpm) associated with
complete heart block.
2.9. Statistical analysis
All values are given as mean ± S.E.M. Student's t-test was
used for the comparison of thyroid hormones between animals
with different weight responses in the amiodarone group.
Differences in continuous variables between the 3 groups were
compared using one-way analysis of variance, followed by post-
hoc Tukey's multiple comparisons test. To assess changes of
continuous variables over time, we used analysis of variance for
repeated measures and we report F-values, degrees of freedom,
and P-values of main effects. The continuous variables describing
the arrhythmia frequencies were not normally distributed and
were compared using the Kruskal–Wallis analysis of variance.
This test was used also for assessment of variance in mortality
rates; if present, differences between groups were compared with
chi square (after Yates' correction). Statistical significance was
defined at an alpha level of 0.05.
3. Results
We studied 60 female Wistar rats, weighing 213± 2 g. Of these,
2 rats died during telemetry transmitter implantation and 3 during
ligation. Thus, the final study population consisted of 55 animals,
of which 18 (218 ± 3 g) were allocated vehicle, 20 (214± 6 g)
amiodarone and 17 (205 ± 4 g) dronedarone. After the 14-day
treatment period, the body weight increased by 10.0± 3.6 g in
controls, by 1.3 ± 2.8 g in the amiodarone group and by 11.4± 5.7 g
in the dronedarone group. Differences between groups failed to
reach statistical significance (F = 2.31, degrees of freedom = 2,
P = 0.11). The lower mean increase in the amiodarone group (albeit
statistically insignificant) was due to weight loss, observed in 3 rats
during treatment.
3.1. Sinus heart rate
There was a statistical variance (F = 11.6, degrees of
freedom = 2, P b 0.001) in baseline heart rate, being higher in
 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157
Fig. 1. Heart rate post-myocardial infarction in the three groups. Note the
differences between dronedarone and control after 15th hour and between
amiodarone and control after the 18th hour.
controls (345 ± 9 bpm), compared to either the amiodarone
group (300 ± 6 bpm, P b 0.001), or to the dronedarone group
(300 ± 5 bpm, P b 0.001). A statistical variance (F = 43.03,
degrees of freedom = 17, P b 0.0001) was found in heart rate
until the 15th hour post-ligation, without an effect between
groups (F = 0.17, degrees of freedom = 2, P = 0.84). Subsequent-
ly, and until the end of the observation period, heart rate in the
dronedarone group was higher (P b 0.030), compared to the
control group. Higher (P b 0.035) heart rate was found for the
amiodarone group compared to controls at the 18th hour post-
ligation until the end of the observation period. No differences
were found between amiodarone and dronedarone at any time
during the entire observational period (Fig. 1).
3.2. Infarct size
Mean infarct size was 38.3 ± 1.4% in the control group,
37.8 ± 1.1% in the amiodarone group and 39.9 ± 1.8% in the
dronedarone group, without significant differences between
groups (F = 0.48, degrees of freedom = 2, P = 0.62).
3.3. Ventricular tachyarrhythmias
A statistical variance was present between groups (H = 11.88,
degrees of freedom = 2, P = 0.0026), due to significantly fewer
ventricular tachyarrhythmia episodes in the amiodarone group
(4.0 ± 2.0 episodes/h, P = 0.022) and in the dronedarone group
(3.6 ± 2.4 episodes/h, P = 0.023), compared to controls (16.2 ± 4.5
episodes/h). However, no statistical variance was found in the
mean episode duration (6.9 ± 1.7 s in controls, 4.7 ± 1.1 s in the
amiodarone group and 12.4 ± 8.6 s in the dronedarone group,
H = 0.51, degrees of freedom = 2, P = 0.77).
The decrease in the number of episodes (per h alive) was
evident during both post-ligation phases (phases I and II, as
defined above). There was a significant variance in the number of
ventricular tachyarrhythmia episodes (per h alive) during phase I
(H = 9.81, degrees of freedom = 2, P = 0.0074). During this phase,
there were 4.7 ± 2.2 episodes in controls, 0.4 ± 0.4 in amiodarone-
and 0.1 ± 0.1 in dronedarone-treated rats. A variance was also
present during phase II (H = 6.52, degrees of freedom = 2,
P = 0.038), the number of episodes being 278.0 ± 117.6 in
153
Fig. 2. Ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes in
the three groups.
controls, 86.1 ± 45.4 in the amiodarone group and 62.1 ± 50.5 in
the dronedarone group. Fig. 2 depicts the hourly distribution of
ventricular tachyarrhythmia episodes during both phases.
3.4. Monophasic action potential duration
There was a statistical variance in left ventricular action
potential duration at 90% of repolarization (F = 25.62, degrees
of freedom = 2, P b 0.0001), that was due to an increase
(P b 0.001) in controls 24 h post-ligation, compared to baseline.
In contrast, no significant changes were observed over time in
any drug group (Table 1). Furthermore, a statistical variance was
found in beat-to-beat variability of left ventricular action potential
duration (F = 7.46, degrees of freedom = 2, P = 0.0035), due to an
increase (P = 0.0030) 24 h post-ligation (compared to baseline) in
controls. No significant changes were observed over time in any
drug group (Table 1).
3.5. Thyroid hormones and thyroid antibodies
No differences were found in triiodothyronine (F = 0.19,
degrees of freedom = 2, P = 0.82), thyroxine (F = 0.59, degrees
of freedom = 2, P = 0.55), or thyroid stimulating hormone
(F = 0.77, degrees of freedom = 2, P = 0.46) levels 24 h post-
ligation between groups. In addition, there was no indication of
thyroiditis, as evidenced by comparable levels of anti-thyroper-
oxidase (F = 0.93, degrees of freedom = 2, P = 0.40) and anti-
thyroglobulin (F = 0.88, degrees of freedom = 2, P = 0.42) between
groups (Table 2). However, there was a strong trend (P = 0.051)
towards a higher thyroxine/triiodothyronine ratio in the 3 rats that
Table 1
Action potential duration at 90% of repolarization (APD90) and beat-to-beat
variation in APD90 in the three groups
Control Amiodarone Dronedarone
APD90 baseline (ms) 93.1 ± 4.7 88.2 ± 2.4 87.5 ± 2.5
APD90 24 h (ms) 120.2 ± 5.2a 85.4 ± 2.1 88.5 ± 3.0
Beat-to-beat variation baseline (ms) 4.14 ± 0.45 3.30 ± 0.21 3.14 ± 0.26
Beat-to-beat variation 24 h (ms) 11.85 ± 2.92a 2.70 ± 0.21 3.28 ± 0.28
P b 0.01 compared to baseline.
a
154 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157

Table 2
Serum levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating
hormone (TSH), and thyroperoxidase (Anti-TPO), and thyroglobulin (Anti-Tgn)
antibodies in the 3 groups
Control Amiodarone Dronedarone
T3 (nmols/l) 3.11 ± 0.27 3.20 ± 0.31 3.41 ± 0.25
T4 (nmols/l) 99.50 ± 4.97 91.42 ± 5.56 94.64 ± 6.10
TSH (μIU/ml) 0.41 ± 0.03 0.47 ± 0.03 0.46 ± 0.04
Anti-TPO (μIU/ml) 62.33 ± 2.55 57.18 ± 3.18 57.84 ± 2.19
Anti-Tgn (μIU/ml) Not detectable 0.03 ± 0.02 Not detectable
No significant differences were found.
lost weight (33.48 ± 2.38) during amiodarone treatment, com-
pared to the remaining animals in the same group (26.99 ± 1.44).
3.6. Catecholamines
Epinephrine levels 24 h post-ligation were 5.81 ± 0.72
μg/l in controls, 7.38 ± 2.05 μg/l in the amiodarone group
and 11.16 ± 4.16 μg/l in the dronedarone group, without
significant differences between groups (F = 1.44, degrees of
freedom = 2, P = 0.25). In contrast, norepinephrine levels
24 h post-ligation displayed a significant variance (F = 7.83,
degrees of freedom = 2, P = 0.0022), that was due to lower
(P = 0.0017) levels in the amiodarone group (23.13 ± 8.80 μg/l),
compared to controls (74.60 ± 2.30 μg/l). Norepinephrine levels in
the dronedarone group (59.55 ± 19.43 μg/l) were comparable
(P = 0.54) to controls.
3.7. Mortality
3.7.1. Total mortality
During the 24-h observational period, total mortality was
38.8% (7/18 rats) in the control group, 30% (6/20 rats) in the
amiodarone group and 58.8% (10/17 rats) in the dronedarone
group. These differences did not reach statistical significance
(H = 3.17, degrees of freedom = 2, P = 0.20). However, there
were significant differences in the mode of death.
3.7.2. Tachyarrhythmic mortality
No rat (0%) in the amiodarone group died of ventricular
tachyarrhythmia and this percentage was lower (P = 0.017)
compared to controls (6 rats, 33.3%, 2 during phase I and 4
during phase II). In the dronedarone group, 2 (11.7%) rats (both
during phase II) died of ventricular tachyarrhythmia, this rate
being comparable (P = 0.26) to controls.
3.7.3. Bradyarrhythmic mortality
There was excess bradyarrhythmic mortality after treatment
with either amiodarone or dronedarone that reached statistical
significance only in the latter group. All bradyarrhythmic deaths
occurred during phase II and were observed in 1 (5.5%) control rat
(5.5 h post-ligation) and in 6 (30.0%) rats (17.9 ± 1.1 h post-
ligation) from the amiodarone group (P = 0.11). Compared to
controls, the incidence of bradyarrhythmic deaths was higher
(P = 0.015) in the dronedarone group (8 rats or 47.0%, 12.5 ± 1.2 h
post-ligation, earlier (P = 0.0079) compared to bradyarrhythmic
mortality in the amiodarone group).
4. Discussion
The strategies for the treatment of life-threatening ventricular
tachyarrhythmias have changed markedly during the past years.
The use of class I antiarrhythmic agents has declined, because of
increased proarrhythmia rates, and class III agents have become
the mainstay of pharmacologic therapy (Wellens, 2004). During
the past decade, there has been an active pharmacological
research towards the development of class III agents that will
combine the efficacy and low proarrhythmia rates of the prototype
drug amiodarone, but without its untoward effects (Khan, 2004).
In the present study, we investigated the effects of amiodarone and
dronedarone on thyroid function and on ventricular tachyar-
rhythmias during acute coronary ligation in rats.
4.1. Effects of dronedarone and amiodarone on thyroid
function
We confirm the previously reported (Pantos et al., 2002) lack
of a significant effect on thyroid hormone levels after chronic
dronedarone administration. Previous studies on chronic amio-
darone administration in rats found a modest decrease in plasma
levels of triiodothyronine, accompanied by an increase in serum
thyroxine (Aanderud et al., 1984; Kodama et al., 1997; Sogol
et al., 1983). In accordance with these studies, we report the
development of hyperthyroidism in 3 animals, evidenced by a
higher thyroxine/triiodothyronine ratio. However, the overall
changes in body weight and in thyroid function indices failed to
reach statistical significance between groups. The explanation for
the less pronounced effect of amiodarone on thyroid function in
our animal population may be twofold: First, a lower dose,
shorter treatment duration and/or shorter follow-up period was
present in our study. Second, we measured thyroid hormones 24 h
post-ligation; a considerable amount of evidence (Klein and
Ojamaa, 2001; Pantos et al., 2004) indicates that thyroid hormone
levels decline during acute infarction, as an adaptive response to
preserve energy homeostasis. Thus, any potential differences
induced by treatment with amiodarone might have been
eliminated in the post-ligation period.
4.2. Antiarrhythmic efficacy
In our study, a comparable antiarrhythmic effect was found for
amiodarone and dronedarone. Both drugs decreased the number
of ventricular tachyarrhythmia episodes, without affecting the
mean episode duration. Interestingly, their antiarrhythmic action
appears to be prominent during both post-infarction phases.
Although both agents are thought to act mainly by prolonging
repolarization, no increase in the action potential duration was
observed in our study, prior to infarct generation. Species
differences may account for this finding, since ventricular
repolarization in rats depends primarily on a large transient
outward K+ current (Cheng and Kodama, 2004). Thus, blockade
of the delayed rectifier K+ current by amiodarone may not prolong
repolarization (Rees and Curtis, 1993). Indeed, variable results
have been reported after amiodarone (Kadoya et al., 1985;
Kodama et al., 1992) or dronedarone administration (van Opstal
 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157
Fig. 3. Example of bradyarrhythmic death. Note the abrupt onset of bradycardia, following sinus tachycardia.
et al., 2001; Varro et al., 2001) and may be dose-dependent (Le
Bouter et al., 2004).
The most important novelty of our study is the extension of the
post-infarction observation period, to include the assessment of
phase II ventricular tachyarrhythmias. Their onset occurs after a
quiescent period and coincides with the gradual transition of
reversible into irreversible myocardial injury (Clements-Jewery
et al., 2005). Thus, the reduction in phase II tachyarrhythmias
after either amiodarone or dronedarone treatment, may be
secondary (a) to the ‘pure’ antiarrhythmic action and (b) to
cardioprotective effects of these agents, leading to a reduction of
border zone myocardial ischaemia. Most phase II tachyarrhyth-
mias originate from this zone (i.e., between infarcted and normal
myocardium), due to changes in the electrophysiological milieu,
favouring re-entry and abnormal automaticity (Clements-Jewery
et al., 2005). The possible anti-ischaemic properties of amiodar-
one include coronary vasodilation (Guiraudou et al., 2004) and
scavenging of oxygen free radicals (Ide et al., 1999). Dronedarone
is also a coronary vasodilator (Guiraudou et al., 2004), but this
agent may exert unique cardioprotective actions, by inhibiting
3,5,3′-triiodothyronine binding to thyroid receptor-alpha-1
(Pantos et al., 2005a,b). These actions may decrease intracellular
Ca2+ content (Pantos et al., 2005a,b), an important regulator of
ischaemia-induced ventricular tachyarrhythmias (Priori and
Napolitano, 2005).
Our study provides evidence in support of the cardioprotective
effects of both, amiodarone and dronedarone. In controls, we
found a prolongation of left ventricular repolarization and
electrical alternans 24 h post-ligation. Both these characteristics,
indicative of ischaemia and increased arrhythmogenesis (Franz,
1999; Horacek et al., 1984; Mohabir et al., 1991), were absent in
both drug groups. Similar anti-ischaemic action, evidenced by
action potential preservation, was reported for amiodarone and
dronedarone in the ischaemic isolated rat heart (Rochetaing et al.,
2001). Thus, the decrease in temporal dispersion of ventricular
repolarization after infarction, either as a direct electrophysiologic
action, or indirectly, as an anti-ischaemic effect, is an important
antiarrhythmic mechanism, common for both agents.
155
Another interesting finding of the present study was the
decreased norepinephrine plasma concentrations in amiodar-
one-, but not in dronedarone-treated rats. This finding is in
agreement with the previously reported partial norepinephrine
depletion in the heart after amiodarone administration (Du et al.,
1995). Amiodarone enhances intraneuronal norepinephrine
metabolism, leading to an impaired release during sympathetic
activation. (Du et al., 1995). This represents an additional
antiarrhythmic mechanism, unique for amiodarone, and deserves
further study.
4.3. Bradyarrhythmic mortality
We report a trend towards an increase in bradyarrhythmic
deaths after chronic amiodarone treatment. In the rat model,
bradyarrhythmic mortality is generally considered representative
of death due to heart failure (Opitz et al., 1995). Indeed, in our
experiments, all these deaths were preceded by sinus tachycardia,
followed by an abrupt onset of complete atrioventricular block
and ventricular asystole (Fig. 3). These observations may be
secondary to the negative inotropic effects of amiodarone (Drvota
et al., 1999) and are compatible with findings in clinical studies,
where increased mortality was reported after chronic amiodarone
treatment in patients with heart failure (Bardy et al., 2005).
A prominent finding of our study was the significant increase
in bradyarrhythmic mortality after chronic dronedarone admin-
istration, displaying identical electrocardiographic features to
those observed in the amiodarone group. Dronedarone, in
addition to its (common with amiodarone) antiadrenergic and
negative inotropic effects (Djandjighian et al., 2000), antag-
onises thyroid hormone binding to receptor-alpha-1 and down-
regulates the expression of alpha myocin heavy chain. These
effects may further deteriorate left ventricular function,
especially in the acute infarction setting, where thyroid hormone
signalling is altered (Pantos et al., 2005a,b). Our results are
consistent with findings in the clinical ANDROMEDA trial that
was prematurely terminated, due to a possible increased risk of
death due to heart failure.
156 M.G. Agelaki et al. / European Journal of Pharmacology 564 (2007) 150–157
4.4. Limitations
We feel that our study advances current thinking on the
pharmacologic management of ventricular tachyarrhythmias
during acute myocardial infarction. However, some potential
limitations should be acknowledged. First, plasma and/or tissue
levels of the drugs were not assessed. Second, no evaluation of
left ventricular function was performed. Lastly, a synergistic
effect of amiodarone and anaesthesia on left ventricular
dysfunction has been described (Rooney et al., 1995), that
might have interfered with monophasic action potential
measurements. However, these effects are very short-lived
and unlikely to have confounded our overall results.
4.5. Conclusions
Chronic oral amiodarone or dronedarone administration
decreases ventricular tachyarrhythmias in the rat model of acute
myocardial infarction. However, dronedarone increases bra-
dyarrhythmic mortality, most likely attributable to heart failure.
Future studies should evaluate whether lower pharmacological
dosages of these agents would maintain the antiarrhythmic
effect, but without the untoward bradyarrhythmic effects.
Acknowledgements
We wish to thank Sanofi-Aventis, Montpellier, France, for
providing amiodarone and dronedarone and Boston Scientific/
Iatriki Efzin, Athens, Greece, for offering the MAP probe and
preamplifier. The contribution of the Cardiovascular Research
Institute, Ioannina and Athens, Greece, is acknowledged.
Anastasia Alevizatou, RN, provided valuable help during the
experiments and Tzihad Albouharali, MD, performed all
radioimmunoassay measurements. Eleni Goga, MSc, was an
excellent research coordinator.
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