(Circulation. 1999;100:2276.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart
Comparison With Amiodarone
From the Cardiovascular Research Laboratory, Section of Cardiology, VA Medical Center of West Los Angeles and UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Bramah N. Singh, MD, Section of Cardiology, 111E, VA Medical Center of West Los Angeles, 11301 Wilshire Blvd, Los Angeles, CA 90073.
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Abstract |
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Background—To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts.
Methods and Results—Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 µmol/L) in tissue bath. Action potential duration at 50% (APD50) and 90% (APD90) repolarization and upstroke dV/dt (Vmax) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (P<0.0001 for all). Ventricular APD50 and APD90 were lengthened by 20% to 49% as a function of dose (P<0.005 to <0.0001) and cycle length (P<0.001). SR100 effects were greater than those of AM100 (P<0.002). Vmax was decreased by both AM100 (P<0.0001) and SR100 (P<0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (P<0.0001 for all).
Conclusions—The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds.
Key Words: potentials • amiodarone • dronedarone • electrophysiology • drugs
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Amiodarone (AM) has now emerged as an unusually effective antiarrhythmic agent for controlling ventricular and supraventricular tachyarrhythmias.1 The fact that it might act by prolonging the myocardial action potential duration (APD) after long-term administration was initially suggested in 1970.2 Subsequently, it was found that beyond this class III action by inhibiting potassium channels,3 4 the drug exhibited all other known classes of antiarrhythmic mechanisms described by Singh et al.2 5 6 These include antiadrenergic activity and inhibition of fast sodium and slow calcium channels.6 Which of these effects might be responsible for the unique clinical antiarrhythmic and low proarrhythmic potentials of the drug remains unclear. Although the role of AM now is well entrenched in clinical practice, its side-effect profile remains of concern.7
AM is an iodinated compound. Its major toxicity profile
after drug ingestion as a function of time might be due to
iodine.1 The development of ocular and serious
pulmonary toxicity7 or thyroid
dysfunction8 9 has been attributed to the
iodinated nature of the molecule.8 However,
iodine as an integral component of the AM molecule might have other
consequences.10 Singh and Vaughan Williams2
found that the ventricular APD prolongation in rabbits
treated long-term with AM was abolished by administration of thyroxine.
There is evidence that the effect of AM might be due in part to
cardioselective inhibition of thyroid hormone action in
cardiac muscle.11 12 13 The question arose as to whether the
unique long-term electrophysiological
effects of AM might stem from its molecular interaction with thyroid
hormone receptors independently of iodine in the compound. The
development of the noniodinated benzofuran derivative
SR33589 (SR), or dronedarone (Sanofi-Recherche), structurally related
to AM (Figure 1
), provided the
opportunity to examine this possibility.
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The short-term effects of SR are similar to those of AM. In anesthetized animals,14 SR inhibited ischemia-induced arrhythmias, reduced heart rate, and exerted sympatholytic effects characteristic of AM.15 The present study compares the cellular electrophysiological and ECG actions of SR and AM after 3 weeks of oral administration. The short-term effects after superfusion with SR in papillary muscles of untreated animals were also examined.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Long-Term Studies
New Zealand White rabbits of either sex weighing 1.9 to 2.2 kg were used. Long-term studies were conducted in 5 separate groups, 7 animals per group. Each group was treated orally daily for 3 weeks with 1 of the following regimens: (1) vehicle only, consisting of 7 mL of 75% polyethylene glycol (MW 400) (control group); (2) SR at 50 mg/kg (SR50 group); (3) SR at 100 mg/kg (SR100 group); (4) AM at 50 mg/kg (AM50 group); and (5) AM at 100 mg/kg (AM100 group). The drugs were administered by gavage in a solution prepared fresh every day. Each dose of SR or AM was dissolved in 5.25 mL polyethylene glycol (MW 400) diluted to 7.0 mL with distilled water before administration. ECGs recorded from conscious restrained rabbits were stored in digitized form. The QTc was obtained by Bazett’s formula.
After completion of treatment, the rabbits were anesthetized
with sodium pentobarbital (30 mg/kg IV), and hearts were rapidly
removed and dissected in cold oxygenated Tyrode’s
solution. Tissue blocks (2x3 mm) from the middle part of the
sinoatrial (SA) node region and the papillary muscles (0.4 to 0.6
mm in diameter and 3 to 4 mm long) from right ventricle were
mounted in a tissue bath (10 mL volume) and superfused with Tyrode’s
solution (15 mL/min) at 37±0.5°C. Its composition (in mmol/L)
was as follows: NaCl 130, KCl 4.0, CaCl2 1.8,
MgSO4 0.5,
NaH2PO4 1.8,
NaHCO3 18.0, and dextrose 5.5. It was bubbled
with 95% O2 and 5% CO2,
with pH maintained at 7.40±0.02. SA node preparations were allowed to
beat spontaneously, whereas papillary muscles were electrically
stimulated through bipolar electrodes at 1 Hz. Standard microelectrode
techniques (glass capillaries filled with 3 mol/L KCl, tip resistance
10 to 20 M
) were used for recording of membrane action
potentials.16 The electrode was connected by Ag-AgCl wire
to a high-input impedance amplifier (Warner E-201). Signals were
amplified and displayed on an oscilloscope (Tektronics 2201). The
maximum slope of action potential upstroke (Vmax)
was obtained by electronic differentiation. The resting membrane
potential, action potential amplitude, Vmax, and
APD at 50% and 90% repolarization (APD50 and
APD90, respectively) were measured from the
papillary muscles. Maximal diastolic potential, spontaneous
cycle length, and Vmax were measured from the SA
node. Frequency-dependent effects of SR and AM in the papillary muscles
were evaluated at cycle lengths of 1200, 900, 600, and 300 ms. Action
potential recordings were obtained after 5 minutes of steady
stimulation at each cycle length. Data were digitized and stored on a
computer with pClamp software (Axon Instruments).
Short-Term Studies
Short-term studies were conducted in papillary muscle
preparations from 5 untreated animals in various concentrations (0, 1,
5, and 10 µmol/L) of SR in oxygenated Tyrode’s
solution. A 1 mmol/L stock solution of SR in polyethylene glycol
(PEG-400, Sigma-Aldrich) was initially prepared. The stock solution
was diluted as needed, with the final perfusate containing 1%
PEG-400; the control received only 1% PEG-400 without SR.
Data Analysis
The data are presented as mean±SD. The intergroup
comparisons of the cycle length–dependent effects on
APD50, APD90, and
Vmax in papillary muscles were made by ANOVA with
repeated measures, with cycle length as the within factor and the
treatment as the grouping factor. By use of this analysis, the
effects of treatment, the effects of cycle length, and the interaction
between treatment and cycle length were evaluated
simultaneously. All other parameters, including
the ECG and the SA nodal parameters, were evaluated by
1-way ANOVA. If ANOVA indicated significant differences among the
groups, pairwise comparisons of groups were made and the probability
values were adjusted for multiple comparisons. BMDP biomedical
statistical software was used (SPSS Inc).
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Results |
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Long-Term Studies
Whole-Animal Data
All animals remained active during treatment and gained weight, an average of 0.59±0.18 kg. There were no significant differences in ECG parameters or RR, PQ, QT, or QRS intervals among the groups before treatment. There was a significant prolongation of RR, QT, and QTc intervals in all drug-treated groups compared with control (Table 1
). However, the dose-related and
drug-specific changes in the RR, QT, or QTc intervals among the treated
groups did not attain statistical significance.
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Effects on Ventricular Action Potential
Characteristics
The mean values of the parameters measured from the
papillary muscles are summarized in Table 2. Representative traces
of action potentials at various cycle lengths for control, SR100, and
AM100 groups are presented in Figure 2. The mean data on
APD50 and APD90 for all
groups are plotted against cycle length in Figure 3. Both APD50 and
APD90 were prolonged significantly, by 31% to
56% and 28% to 47%, respectively, in the drug-treated groups
compared with control (P<0.0001). The patterns of cycle
length versus APD curves shown in Figure 3 were significantly
different (ie, significant interaction between treatment and cycle
length) between treatment groups and control (P<0.001). The
effects of drug treatment were significantly cycle-length–dependent in
all treated groups. The slopes of the APD50 and
APD90 plots against the cycle length of treated
groups were not significantly different. The
APD50 and APD90 of the
SR100 group were significantly more prolonged than those in the AM100
group (P<0.002). At the lower dose, there was a
significantly greater prolongation only in the
APD50 of the SR50 group compared with that of the
AM50 group (P<0.03). The prolongations in
APD50 and APD90 were
significantly dose-dependent for both drugs (P<0.005 to
<0.0001). The effective refractory period (ERP) measured at 900-ms
cycle length was highly correlated with the APD90
across the treatment groups (R=0.988; P<0.0001),
with ERP at 84% of APD90. Therefore, ERP data
were not analyzed separately.
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When APD data were compared at the shortest cycle length (300 ms), the
APD50 and APD90 of the AM50
group were not significantly prolonged compared with control, whereas
the APD of SR50, SR100, and AM100 were significantly prolonged over
control (Figure 3
). The relative prolongation of APD over mean
control values in the treated groups are presented in Figure 4. The percent prolongation of APD over
control at 300 ms in the SR100 group was significantly greater than
that in the AM100 group (APD50: 33.6% versus
13.2%, P<0.005; APD90: 27.0% versus
15.2%, P<0.05). Thus, APD prolongation caused by SR was
more prominent at shorter cycle lengths than that due to AM.
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The Vmax values of the papillary muscle
preparations were significantly lower with the shortening of the cycle
length in all groups (P<0.0001). However, the relative
differences among all groups, including the control group, were not
significantly cycle-length–dependent (Figure 5). Significant reduction of
Vmax compared with that in the control was
observed in SR100 (P<0.0001) as well as AM100 groups
(P<0.01). The dose-dependent reduction of
Vmax was significant in the case of SR
(P<0.01), but not AM (P=NS).
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Effects of SR and AM Treatments on the SA Nodal
Preparations
The mean data are summarized in Table 3. Representative traces
of relevant action potential recordings are presented
in Figure 6. There were no differences
among the groups with respect to maximum diastolic
potential, action potential amplitude, or Vmax of
the SA nodal preparations. However, the spontaneous cycle length was
significantly prolonged in the treated groups compared with those in
the control group (P<0.0001 for all). Spontaneous cycle
length was significantly more prolonged with SR than with the
corresponding dose of AM (P<0.0005) at both the lower (50
mg · kg-1 ·
d-1) and higher (100 mg ·
kg-1 · d-1)
doses.
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Short-Term Studies
The results are summarized in Figure 7. In contrast to long-term studies, both
APD50 (Figure 7A) and
APD90 (Figure 7B) were shortened in a
dose-dependent manner over the range of 1 to 10 µmol/L SR
concentration and 300- to 1200-ms stimulation cycle lengths. However,
consistent with the long-term study, Vmax
measured at a stimulation cycle length of 900 ms decreased in a
dose-dependent manner over the entire range of concentrations (Figure 7C).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Major Findings
The main findings of the study indicate that despite the deletion of iodine from the molecule compared with that in AM, the major electrophysiological properties of SR are very similar to those of AM. During short-term superfusion, SR shortened the APD, as reported for AM,17 but reduced the ventricular Vmax. In contrast, after 3 weeks of oral administration of both drugs, there was significant slowing of the sinus frequency in vivo and in vitro associated with a significant prolongation of ventricular APD. In the sinus node, the rate slowing after long-term treatment was due to the depression of phase 4 depolarization and lengthening of the APD. Both SR and AM produced comparable degrees of depression of Vmax as an index of inhibition of the ventricular myocardial sodium channel activity. Thus, the overall data show that SR is at least as potent as AM in its ability to alter the electrophysiological properties of ventricular muscle and those of the sinus node.
Frequency-Dependent Electrophysiological Effects
It is well known that the APD-lengthening effect of most class III
antiarrhythmic drugs is reduced by increases in rate and duration of
stimulation of cardiac muscle. Such an effect has been described as
reverse rate- and use-dependency,18 in contrast to the
increases in the effects of class I agents on blocking sodium channel
function. Hondeghem and Snyder18 suggested that reverse
use-dependency may be responsible for a high incidence of torsade de
pointes associated with most class III antiarrhythmic agents. This is
especially so in the case of those agents that exert their predominant
repolarization-blocking effects by inhibiting the rapid component of
the delayed rectifier K current,
IKr.19 In this regard,
the long-term effects of AM differ from those of most other class III
agents in inducing a negligible incidence of torsade de
pointes,20 an effect that has been attributed to marked
inhibition of the slow component of the delayed rectifier K current,
IKs.17 Whether SR might
also act by a similar or identical action on the
IKs is currently under study. However, our
present study showed that SR and AM both prolonged
APD50 and APD90 in a cycle
length–dependent manner while exhibiting a minimal degree of reverse
use-dependency. An unusual observation was that the percent
prolongation at the shortest cycle length (300 ms) studied in our
experiments was significantly greater with SR than that with AM at the
higher drug dose of 100 mg · kg-1
· d-1 tested. Thus, under the conditions of
our study, SR exhibited even less reverse use-dependency of
repolarization than that found with AM, which has been shown to display
minimal reverse use-dependency under in vivo
conditions.18 21 22
Significance of Blocking Myocardial Sodium Channels
In the present studies, the Vmax values
of papillary muscle transmembrane action potentials were significantly
reduced by both AM and SR, indicating inhibition of the fast Na
channel. Whether such an additional property might contribute to the
overall antiarrhythmic actions of these drugs remains uncertain. In AM,
the associated class I antiarrhythmic effect is of moderate
potency,21 23 24 but its rate-dependency has not been as
compellingly uniform.21 Our data indicating that SR, a
noniodinated benzofuran derivative, might have a similar
potency for blocking the fast channel in ventricular
myocardium are of particular interest relative to its
similarity to the overall properties of AM.
Potential Mechanisms of Heart Rate Slowing
Although the long-term in vivo effects of AM and SR in terms of
increases in RR, QT, and QTc intervals showed trends similar to those
of the in vitro data, the differences between the drugs did not attain
statistical significance. Also, there were no significant differences
between the 2 doses (50 and 100 mg ·
kg-1 · d-1)
tested, suggesting a saturation effect. However, our data did not
address the issue of whether a more prolonged drug exposure might lead
to further increases in the RR intervals. In the case of AM and SR, the
slowing of the sinus rate might be attributable to the lengthening of
APD with a delayed attainment of the maximal diastolic
potential in the sinus pacemaker, accompanied by drug-induced
depression of phase 4 depolarization by
antiadrenergic actions, as shown for AM in
vivo.25 The present results on the effect of AM on
spontaneous cycle length of the SA node are consistent with our
previous results.26 There is evidence that SR also
interacts with ß-adrenergic receptors of the rat heart at
intracellular sites.27
Benzofuran Derivatives and Thyroid Hormone Interactions
The overall similarities in the electropharmacological effects of
AM and its noniodinated derivative SR demonstrated here
have potentially important implications for new drug development. There
is a structural similarity between AM and thyroid hormones, including
the iodine in its aromatic ring (Figure 1). Iodine release in
the body after drug ingestion may cause an altered thyroid state, an
effect that is clearly related to iodine rather than to the molecular
structure of AM.28 It also has been suggested that several
of the most significant side effects of the drug—pulmonary
fibrosis, ocular deposits, and skin pigmentation—are related to iodine
contained in the AM molecule. Conversely, it is known that the cardiac
electrophysiological effects of long-term
AM29 closely resemble those of
hypothyroidism.10 In this regard, the effect of AM on
cardiac repolarization appears to have a measure of
specificity.11 12 13 A direct inhibition of the
T3 nuclear receptor binding by AM or its
metabolite desethylamiodarone has been postulated to result in
a hypothyroid state at a cellular level.11 AM and its
active metabolite have been shown to bind to different isoforms of
nuclear T3 receptors with variable
affinity.30 It is noteworthy that the brominated analogue
(without the iodine) of AM has been shown to have identical class III
antiarrhythmic actions comparable to those of AM.31 32
Thus, the data raise the possibility that neither the presence of a
halogen nor its type might be the basis for the unique
electrophysiological properties of
benzofuran derivatives as a class for the propensity to
homogeneously increase the duration of the cardiac action
potential. Our data in the present study demonstrating that the
long-term effects of SR, a nonhalogenated benzofuran derivative,
closely resemble not only those of long-term AM but also those reported
for hypothyroidism.10 Thus, in the clinical setting, SR
therapy may not have the same proclivity to induce altered thyroid
state or the iodine-related complications seen with AM. Conversely, the
similarity between the molecular structure of SR and thyroid hormone,
as in the case of AM, does not exclude the possibility that the
compound might exert its potentially beneficial electropharmacological
effect on cardiac muscle by cardioselective blockade of
T3 receptors in cardiac muscle.
Conclusions
The results of this study demonstrate that the major short-term
and long-term electrophysiological
properties of the noniodinated derivative (SR) of AM on
cardiac muscle are very similar to those of the parent compound. After
3 weeks of oral administration, AM and SR reduced sinus frequency in
vivo and in vitro with a significant prolongation in the APD in the
rabbit ventricular myocardium. This was
accompanied by a corresponding increase in the ERP. Both SR and AM
produced comparable degrees of depression of the
Vmax as an index of inhibition of the myocardial
sodium channels. Thus, the overall data show that SR is at least as
effective as AM in its ability to alter the
electrophysiological properties of
ventricular muscle and those of the sinus node. Its actions
are not mediated by the presence of iodine, but the similarity between
the molecular structure of SR and thyroid hormone, as in the case of
AM, suggests the possibility that its beneficial effect may stem from
other mechanisms, which may include cardioselective
blockade of T3 receptors in cardiac muscle.
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Acknowledgments |
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This study was supported by a grant-in-aid from Sanofi-Winthrop Recherche (Montpellier, France), which also provided amiodarone and dronedarone (SR33589). The encouragement of Dr Dino Nisato is greatly appreciated.
Received March 23, 1999; revision received June 29, 1999; accepted July 9, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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 B. N. Singh and E. Aliot Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G17 - G25. [Abstract] [Full Text] [PDF]
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 K. M Dale and C M. White Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter Ann. Pharmacother., April 1, 2007; 41(4): 599 - 605. [Abstract] [Full Text] [PDF]
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M. J. Tafreshi and J. Rowles A Review of the Investigational Antiarrhythmic Agent Dronedarone Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 15 - 26. [Abstract] [PDF]
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N. Wadhani, J. S. Sarma, B. N. Singh, D. Radzik, and C. Gaud Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions. Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2006; 11(3): 184 - 190. [Abstract] [PDF]
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 Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]
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 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]
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V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
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S. Le Bouter, A. El Harchi, C. Marionneau, C. Bellocq, A. Chambellan, T. van Veen, C. Boixel, B. Gavillet, H. Abriel, K. Le Quang, et al. Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart Circulation, November 9, 2004; 110(19): 3028 - 3035. [Abstract] [Full Text] [PDF]
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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]
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 P. Touboul, J. Brugada, A. Capucci, H. J.G.M. Crijns, N. Edvardsson, and S. H. Hohnloser Dronedarone for prevention of atrial fibrillation: A dose-ranging study Eur. Heart J., August 2, 2003; 24(16): 1481 - 1487. [Abstract] [Full Text] [PDF]
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B. N. Singh Atrial Fibrillation: Epidemiologic Considerations and Rationale for Conversion and Maintenance of Sinus Rhythm Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1_suppl): S13 - S26. [Abstract] [PDF]
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 H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker, and W. M. Wiersinga Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence Endocrinology, February 1, 2003; 144(2): 552 - 558. [Abstract] [Full Text] [PDF]
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 A. D Pitt, C. Fernandes, N. L Bewick, P. D Hemsworth, K. A Buhagiar, P. S Hansen, H. H Rasmussen, L. Delbridge, and D. W Whalley Chronic amiodarone-induced inhibition of the Na+-K+ pump in rabbit cardiac myocytes is thyroid-dependent: comparison with dronedarone Cardiovasc Res, January 1, 2003; 57(1): 101 - 108. [Abstract] [Full Text] [PDF]
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 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]
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C.-E. Chiang, H.-N. Luk, T.-M. Wang, and P. Y.-A. Ding Effects of sildenafil on cardiac repolarization Cardiovasc Res, August 1, 2002; 55(2): 290 - 299. [Abstract] [Full Text] [PDF]
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J. M. van Opstal, M. Schoenmakers, S. C. Verduyn, S.H. M. de Groot, J. D.M. Leunissen, F. F. van der Hulst, M. M.C. Molenschot, H. J.J. Wellens, and M. A. Vos Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome Circulation, November 27, 2001; 104(22): 2722 - 2727. [Abstract] [Full Text] [PDF]
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B. N. Singh and J. S. M. Sarma Mechanisms of Action of Antiarrhythmic Drugs Relative to the Origin and Perpetuation of Cardiac Arrhythmias Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 69 - 87. [PDF]
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 M. J. P. Raatikainen, T. E. Morey, P. Druzgala, P. Milner, M. D. Gonzalez, and D. M. Dennis Potent and Reversible Effects of ATI-2001 on Atrial and Atrioventricular Nodal Electrophysiological Properties in Guinea Pig Isolated Perfused Heart J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 779 - 785. [Abstract] [Full Text]
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S. K. Doshi and B. N. Singh Reviews: Pure Class III Antiarrhythmic Drugs: Focus on Dofetilide Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 237 - 247. [PDF]
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