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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics
JPET 295:779–785, 2000
Vol. 295, No. 2
2767/857028
Printed in U.S.A.
Potent and Reversible Effects of ATI-2001 on Atrial and
Atrioventricular Nodal Electrophysiological Properties in Guinea
Pig Isolated Perfused Heart1
M. J. PEKKA RAATIKAINEN, TIMOTHY E. MOREY, PASCAL DRUZGALA, PETER MILNER, MARIO D. GONZALEZ, and
DONN M. DENNIS
Departments of Anesthesiology (M.J.P.R., T.E.M., D.M.D.), Medicine, Division of Cardiology (M.D.G.), and Pharmacology and Experimental
Therapeutics (D.M.D.), University of Florida College of Medicine, Gainesville, Florida; Department of Internal Medicine, Division of Cardiology,
University of Oulu, Oulu, Finland (M.J.P.R.); and ARYx Therapeutics, Los Altos Hills, California (P.D., P.M.)
Accepted for publication July 5, 2000
This paper is available online at http://www.jpet.org
The major goal in the pharmacotherapy of supraventricular tachyarrhythmias is termination of ongoing arrhythmia
and prevention of its reoccurrence (Levy et al., 1998). In
patients with atrial fibrillation or flutter in whom normal
sinus rhythm cannot be restored, regulation of ventricular
rate by agents that delay atrioventricular (AV) nodal conduction and prolong refractoriness becomes the main therapeutic goal (Prystowsky et al., 1996; Blitzer et al., 1998; Levy et
al., 1998). Among currently available antiarrhythmic agents,
amiodarone seems to be the most effective drug to prevent
Received for publication March 31, 2000.
1
This study was supported in part by the National Institutes of Health
Grant HL56785-03 (to D.M.D.), the Council of Health of the Academy of
Finland and Finnish Foundation for Cardiovascular Research (to M.J.P.R.),
and Foundation for Anesthesia Education and Research (to T.E.M.). Dr. Morey
is a FAER/Zeneca Pharmaceuticals, Inc., New Investigator Award recipient.
The primary laboratory for this study was in the Department of Anesthesiology, University of Florida, Gainesville, FL.
and refractoriness. ATI-2001 prolonged the atrium-to-His bundle interval (22.1 ⫾ 2.6 versus 8.8 ⫾ 2.3 ms), His bundle-toventricle interval (2.8 ⫾ 0.4 versus 0.9 ⫾ 0.3 ms), AV nodal ERP
(72.5 ⫾ 7.3 versus 31.4 ⫾ 4.1 ms), and Wenckebach cycle
length (69.6 ⫾ 5.2 versus 35.8 ⫾ 4.1 ms) significantly more than
did amiodarone. Unlike amiodarone, the effects of ATI-2001
were markedly reversed upon discontinuation of drug infusion.
Given these data, ATI-2001 should not only be useful for terminating ongoing and preventing reoccurrence of atrial tachyarrhythmias but also to treat supraventricular tachycardias involving the AV node and to control ventricular rate during atrial
tachyarrhythmias. Whether the observed differences in the
pharmacokinetic properties render ATI-2001 superior to amiodarone in acute tachyarrhythmia management and less likely to
accumulate into tissues during chronic therapy remains to be
established.
atrial arrhythmias (Nattel, 1995; Kassotis et al., 1998). Although the role of amiodarone in the long-term management
of atrial and ventricular tachyarrhythmias is well entrenched in clinical practice, its side effect profile remains a
serious concern (Vrobel et al., 1989; Vorperian et al., 1997).
Furthermore, the usefulness of amiodarone for acute management of atrial arrhythmias is somewhat limited by its
complex pharmacokinetic properties and slow development
of class III effect (Roden, 1993; Podrid, 1995; Kodama et al.,
1997).
During recent years various analogs of the prototypical
compound have been developed to overcome the side effects of
amiodarone (Raatikainen et al., 1996; Kulier et al., 1999; Sun
et al., 1999). ATI-2001 is a novel ester analog of amiodarone.
The molecular structure of ATI-2001 is identical with that of
amiodarone, except for the presence of a methyl acetate side
chain in lieu of a butyl group at position 2 of the benzofurane
ABBREVIATIONS: AV, atrioventricular; HBE, His bundle electrogram; MAP, monophasic action potential; S-A, stimulus-to-atrium interval; A-H,
atrium-to-His bundle interval; H-V, His bundle-to-ventricle interval; BCT, basal conduction time; MAPD90, monophasic action potential duration
at 90% repolarization; ERP, effective refractory period; WCL, Wenckebach cycle length; ACL, atrial cycle length.
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ABSTRACT
We recently demonstrated that the short-acting analog of amiodarone, ATI-2001, caused favorable effects in guinea pig ventricular myocardium on electrophysiological substrates underlying tachyarrhythmia initiation, perpetuation, and termination.
Here, the acute effects of 1.0 ␮M ATI-2001 and 1.0 ␮M amiodarone (90-min infusion followed by 90-min washout period) on
atrial and atrioventricular (AV) nodal electrophysiological properties were studied in guinea pig isolated hearts. Neither ATI2001 nor amiodarone significantly prolonged atrial conduction
time. Compared with amiodarone, ATI-2001 caused significantly more rapid and greater prolongation of atrial monophasic action potential duration at 90% repolarization (maximal
change 21.4 ⫾ 3.7 versus 19.0 ⫾ 4.0 ms) and atrial effective
refractory period (ERP, 27.8 ⫾ 6.1 versus 9.2 ⫾ 2.3 ms). Shortening of the atrial cycle length from 250 to 200 ms did not
significantly alter drug-induced changes in atrial repolarization
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Materials and Methods
Chemicals
ATI-2001 {methyl 2-[3-(4-(2-diethylaminoethoxyl)-3,5-diiodo-)
benzoyl] benzofuraneacetate} was a gift from ARYx Therapeutics
(Los Altos Hills, CA). Amiodarone and all the chemicals used for the
Krebs-Henseleit perfusion medium were purchased from Sigma
Chemical Co. (St. Louis, MO). Stock solutions (10 mM) of ATI-2001
and amiodarone were prepared in pure ethanol and further dissolved
in perfusion medium immediately before experimentation.
Isolated Perfused Hearts
All experimental protocols were reviewed and approved by the
Animal Use Committee of the University of Florida Health Sciences
Center. The hearts were isolated from Hartley guinea pigs of either
sex, weighing 400 to 450 g, and perfused according to the Langendorff technique as previously described (Napolitano et al., 1996).
After completion of dissection and instrumentation, the hearts were
allowed to equilibrate for at least 20 to 30 min before the experimental protocols were begun. Unless otherwise indicated, the hearts
were paced (square-wave 3-ms pulses at twice threshold intensity) at
an atrial cycle length of 250 ms via a bipolar electrode placed on the
high atrioseptal area.
Electrophysiological Techniques and Measurements
During the experiments the His bundle electrogram (HBE) and
left atrial monophasic action potentials (MAP) were displayed in real
time and digitally stored at a sampling frequency of 2 kHz using a
Digidata 1200A analog-to-digital data acquisition board (Axon Instruments Inc., Foster City, CA) and Axotape data acquisition program (Axon Instruments Inc.) as detailed previously (Morey et al.,
1997).
HBE. The HBE was recorded using a unipolar Teflon-coated
stainless steel electrode placed in the His bundle position through a
small right atrial incision as previously described (Jenkins and Belardinelli, 1988). The stimulus-to-atrium (S-A), atrium-to-His bundle
(A-H), and His bundle-to-ventricle (H-V) intervals were used as
indices of intra-atrial, AV nodal (proximal AV), and His Purkinje
system (distal AV) conduction times, respectively. Intervals were
measured from digitally stored HBE using cursor measurements in
the Axotape program. In the event that an intervention caused a
second or third degree AV block, the longest stable A-H interval just
before the onset of AV block was considered the maximum dromotropic effect, and that value was used for data analysis.
MAPs. The MAP was recorded with a pressure contact silversilver chloride electrode (EP Technologies, Sunnyvale, CA) positioned in the immediate vicinity of the pacing electrode on the epicardial surface of the left atrium as previously described
(Raatikainen et al., 1998). Signals were considered adequate if their
amplitudes (from diastolic baseline to plateau) exceeded 8 mV. The
basal conduction time (BCT) and duration of the MAP at 90% repolarization (MAPD90) were measured using a custom-made computer
template written for Microsoft Excel 7.0 (Microsoft Corporation,
Redmond, WA).
Effective Refractory Periods (ERPs) and Wenckebach Cycle Length (WCL). Atrial ERP, AV nodal ERP, and WCL were
measured using previously described computer-assisted stimulation
protocols (Napolitano et al., 1996; Raatikainen et al., 1998). Briefly,
atrial and AV nodal ERPs were measured simultaneously using a
premature stimulation protocol in which the coupling interval between the last basic stimulus (S1) and the extra stimulus (S2) was
progressively shortened by 3 ms after every train of 15 basic stimuli
(S1S1). The longest S1S2 that failed to produce an atrial response (A2)
and His bundle (H2) was defined as the atrial and AV nodal ERP,
respectively. WCL was determined as the longest ACL that failed to
conduct through the AV node and produce a His bundle response
(second degree block) during a run in which the basic atrial cycle
length was decreased in 3-ms steps after every 10 basic stimuli. If a
drug caused second degree AV block during baseline stimulation, the
basic cycle length was considered the AV nodal ERP and WCL.
Pharmacological and Pacing Protocols
Drug Infusion. The concentration of drugs chosen was 1.0 ␮M,
based on our previous experiments (Raatikainen et al., 1996) and the
following clinical observations. The average steady-state plasma concentration of amiodarone has been 0.9 to 2 ␮M among the majority of
successfully treated patients, whereas the reported concentration for
those with side effects has usually been greater than 3 ␮M (Rotmensch et al., 1984). Because some of the electrophysiological effects of
amiodarone are slow to develop and slow to disappear (Roden, 1993;
Podrid, 1995; Kodama et al., 1997), we elected to compare the timedependent actions of equimolar drug concentrations over a relatively
long drug infusion (90 min) and washout period (90 min) instead of
trying to construct a true concentration-response curves for ATI2001 and amiodarone. After baseline electrograms were recorded,
the hearts were randomly treated for 90 min with either 1.0 ␮M
ATI-2001 or 1.0 ␮M amiodarone. Thereafter, the drugs were washed
out for another 90 min. In our previous study (Raatikainen et al.,
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moiety (Raatikainen et al., 1996). This structural modification renders ATI-2001 susceptible to metabolism by plasma
and tissue esterases and thus accelerates its elimination
from blood and body organs. In keeping with this premise, we
recently demonstrated in guinea pig isolated perfused heart
that, unlike amiodarone, the effects of ATI-2001 on ventricular conduction delay, repolarization, and refractoriness
were markedly reversed during washout of the drug. The
effects of ATI-2001 on ventricular electrophysiological properties were also more rapid to develop, and more potent than
those of an equimolar concentration of amiodarone (Raatikainen et al., 1996). Although the electrophysiological effects
of ATI-2001 in supraventricular tissues remained mostly uncharacterized, our preliminary findings suggested that ATI2001 might exert antiarrhythmic actions also in the atria and
AV node.
Once initiated, atrial fibrillation can rapidly modify atrial
electrical properties in a way that promotes perpetuation of
the arrhythmia, a process called atrial remodeling (Wijffels
et al., 1995). These changes include shortening of atrial refractoriness and loss of normal adaptation to rate. Because
atrial remodeling can develop after only a few hours of atrial
fibrillation, rapid termination is a highly desirable therapeutic goal. Development of an agent with amiodarone-like properties that has a more rapid onset of action would not only be
useful to terminate atrial fibrillation, but also to prevent the
long-term consequences of atrial remodeling.
Electrophysiological parameters critical to initiation, perpetuation, and termination of atrial tachyarrhythmias and to
regulation of ventricular rate during such arrhythmias include alteration of atrial conduction velocity, repolarization,
and refractoriness (Rensma et al., 1988; Janse, 1997), and
modulation of AV nodal conduction properties (Meijler et al.,
1996), respectively. In the present study, we determined the
effects of ATI-2001 on atrial conduction time, monophasic
action potential duration, and effective refractory period, and
on frequency-dependent AV nodal conduction delay in guinea
pig isolated perfused hearts. The changes caused by ATI2001 are compared with those of the prototypic compound
amiodarone.
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Supraventricular Effects of ATI-2001
1996) with a similar drug infusion and washout protocol, the vehicle
(ethanol) at the concentration used in this study caused no significant electrophysiological effects.
Electrophysiological Measurements. Time-dependent effects
of the drugs on atrial and AV nodal electrophysiological properties
were evaluated by measuring the BCT, MAPD50, and MAPD90 from
MAP recordings, and the S-A, A-H, and H-V intervals from digitally
stored HBE recordings at 30-min intervals. The effects of the drugs
on atrial refractoriness and on frequency-dependent AV nodal conduction were examined by measuring atrial ERP and by determining
AV nodal ERP and WCL every 30 min, respectively. All the abovementioned electrophysiological parameters were measured both during the baseline stimulation (ACL ⫽ 250 ms) and during a faster
atrial pacing rate (ACL ⫽ 200 ms). In a subset of hearts, a slower
rate of atrial pacing (ACL ⫽ 300 ms) was used to further evaluate the
frequency dependence of the AV nodal effects of the drugs. In these
experiments, atrial MAP recordings were precluded because the
atria had to be almost completely excised to facilitate pacing at the
slower rate.
All values are expressed as mean ⫾ S.E. of 6 to 10 experiments.
Statistical differences among mean values were analyzed using
ANOVA (one- or two-way when appropriate) followed by Tukey testing. P ⬍ .05 was considered statistically significant.
Results
Effects on Atrial Conduction Time, Repolarization,
and Refractoriness. The effects of ATI-2001 and amiodarone on atrial conduction time, measured as the S-A interval
from the continuously recorded HBE, are shown in Fig. 1.
Neither ATI-2001 nor amiodarone significantly prolonged
the S-A interval and the BCT (data not shown) in hearts
paced at a constant atrial cycle length of 250 ms. The maximum prolongation of the S-A interval caused by ATI-2001
and amiodarone was 18.3 ⫾ 6.2% (P ⫽ .33) and 7.40 ⫾ 5.3%
(P ⫽ .94), respectively. Upon discontinuation of the drug
infusion, the effects of ATI-2001 tended to return toward
baseline, whereas in the amiodarone-treated hearts the
atrial conduction time continued to increase. Shortening of
the basic ACL from 250 to 200 ms had no significant effect on
the effect of the drugs on atrial conduction time (data not
shown).
The effects of ATI-2001 and amiodarone on atrial MAP
duration at 90% repolarization (MAPD90), and on atrial ERP
in hearts paced at 250-ms basic atrial cycle length are de-
Fig. 1. Time-dependent effects of ATI-2001 and amiodarone on atrial
conduction time. Neither ATI-2001 (P ⫽ .33) nor amiodarone (P ⫽ .94)
caused a significant prolongation of the S-A interval. Each data point
represents the mean ⫾ S.E. of six hearts paced at a basic atrial cycle
length of 250 ms.
picted in Figs. 2 and 3, respectively. At a concentration of 1.0
␮M, ATI-2001 prolonged atrial MAPD and ERP more rapidly
and to a greater extent than did amiodarone. That is, the
drug-induced prolongation of the MAPD90 achieved statistical significance after 30- and 60-min infusion times in the
ATI-2001 and amiodarone groups, respectively. The maximum prolongation of atrial ERP was 34.0 ⫾ 8.3% in ATI2001-treated hearts, but only 10.9 ⫾ 2.9% (P ⬍ .01) in amiodarone-treated hearts. The threshold for a significant
change in atrial ERP was 30 min for the ATI-2001 group,
whereas in the amiodarone group no significant change occurred during the 90-min drug infusion period. Upon cessation of the drug infusion the effect of ATI-2001 on atrial
repolarization and refractoriness was partially reversed. In
contrast, the prolongation of atrial MAPD and ERP caused
by amiodarone continued to increase during the whole washout period.
A decrease of the basic ACL from 250 to 200 ms did not
significantly affect the atrial electrophysiological effects of
ATI-2001 or amiodarone. That is, a 90-min infusion of ATI2001 prolonged atrial MAPD90 and ERP by approximately
30% at both the slower (ACL ⫽ 250 ms) and faster (ACL ⫽
200 ms) atrial pacing rates (Fig. 4). Amiodarone also prolonged atrial repolarization and refractoriness in a relatively
frequency-independent manner, but to a lesser extent than
that of ATI-2001.
Effects on AV Nodal Conduction Time. Compared with
an equimolar concentration of amiodarone (1.0 ␮M), ATI2001 caused significantly more rapid and greater prolongation of the A-H interval (Fig. 5). In the ATI-2001 group,
prolongation of the A-H interval reached statistical significance after a 30-min infusion time. In contrast, amiodarone
did not significantly change the A-H interval during the
90-min drug infusion period (the A-H interval continued to
increase after stopping of the infusion). At the end of the
90-min drug infusion period, the A-H interval prolongation
was 69% (from 33.1 ⫾ 2.3 to 55.2 ⫾ 2.3 ms) and 26% (from
33.3 ⫾ 1.4 to 42.1 ⫾ 3.2 ms) above baseline values in the
ATI-2001- and amiodarone-treated hearts, respectively. Unlike amiodarone, the effects of ATI-2001 were readily reversible upon discontinuation of the drug infusion. In the ATI2001 group, the A-H interval shortened from the maximum
value of 55.2 ⫾ 2.3 to 43.6 ⫾ 3.3 ms during the washout
Fig. 2. Time-dependent effects of ATI-2001 and amiodarone on atrial
monophasic action potential duration at 90% repolarization (MAPD90).
Both ATI-2001 and amiodarone significantly prolonged atrial MAPD90.
The effect of ATI-2001 was more rapid to develop than that of amiodarone. Each data point represents the mean ⫾ S.E. of six hearts paced at
a basic atrial cycle length of 250 ms. P ⬍ .05: ⴱ, versus baseline.
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Data Analyses
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Fig. 4. Effect of basic ACL shortening on the effects of ATI-2001 and
amiodarone on atrial repolarization and refractoriness. Shortening of the
basic ACL from 250 to 200 ms did not significantly affect either ATI-2001or amiodarone-induced maximal prolongation of atrial the monophasic
action potential duration at 90% repolarization (MAPD90) and atrial
ERP. Each data point represents the mean ⫾ S.E. of six hearts after
90-min drug infusion. P ⬍ .05: ⴱ, ATI-2001 versus amiodarone at a given
ACL.
period. In contrast, the prolongation of the A-H interval
caused by amiodarone continued to increase after the drug
infusion was discontinued, reaching a maximal increase of
46% above baseline at the end of experimentation.
Although not statistically significant, there was a trend for
amiodarone and in particular for ATI-2001 to also increase
conduction time over the His-Purkinje system. ATI-2001 and
amiodarone prolonged the H-V interval from 11.1 ⫾ 0.7 ms
and 11.0 ⫾ 0.9 ms to 13.9 ⫾ 0.9 ms (25% increase above
baseline, P ⫽ .08) and 11.9 ⫾ 1.1 ms (8% increase above
baseline, P ⫽ .476), respectively. Similar to those results
observed on the A-H interval, the action of ATI-2001 but not
Fig. 5. Time-dependent effects of ATI-2001 or amiodarone on proximal
AV nodal conduction time. Both ATI-2001 and amiodarone significantly
prolonged the A-H interval. The effect of ATI-2001 was more rapid to
develop and greater than that of amiodarone. Unlike amiodarone, the
effect of ATI-2001 was significantly reversed upon discontinuation of the
drug. Each data point represents the mean ⫾ S.E. of 10 hearts paced at
a basic atrial cycle length of 250 ms. P ⬍ .05: ⴱ, versus baseline.
that of amiodarone appeared to reverse after discontinuation
of the drug infusion (Fig. 6).
Frequency-Dependent Negative Dromotropic Effect
on the AV Node. As predicted by the A-H interval changes,
ATI-2001 caused greater prolongation of AV nodal ERP
(maximal prolongation above baseline values 72.5 ⫾ 7.3 versus 31.4 ⫾ 4.1 ms, P ⬍ .001) and WCL (maximal prolongation
above baseline values 69.6 ⫾ 5.2 versus 35.8 ⫾ 4.1 ms, P ⬍
.001) than did an equimolar concentration of amiodarone.
Furthermore, these effects of ATI-2001 were rapidly reversed
upon discontinuation of the drug, whereas those of amiodarone continued to increase (Figs. 7 and 8). A third line of
evidence supporting the frequency-dependent negative
dromotropic action of ATI-2001 and amiodarone is shown in
Fig. 9. At a basic atrial cycle length of 200, 250, and 300 ms,
a 90-min infusion of 1 ␮M ATI-2001 caused high degree AV
nodal block in 83, 16, and 0% of the hearts, respectively.
These data also unequivocally show that the onset of ATI2001’s action on AV nodal conduction was faster than that of
amiodarone. For example, a 30-min infusion of ATI-2001 or
amiodarone caused high degree AV nodal block in 67 and 0%,
respectively, of the hearts paced at a 200-ms atrial cycle
length. Taken together, these data indicate that the negative
Fig. 6. Time-dependent effects of ATI-2001 and amiodarone on distal AV
nodal conduction time. Neither ATI-2001 (P ⫽ .08) nor amiodarone (P ⫽
.48) significantly prolonged the H-V interval. Each data point represents
the mean ⫾ S.E. of 10 hearts paced at a basic atrial cycle length of 250
ms.
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Fig. 3. Time-dependent effects of ATI-2001 and amiodarone on atrial
ERP. The effect of ATI-2001 was greater and more rapid to develop than
that of amiodarone. ATI-2001 significantly prolonged the atrial ERP,
whereas the effect of amiodarone, despite a clear tendency, did not reach
statistical significance during the 90-min drug infusion period (P ⫽ .06).
Each data point represents the mean ⫾ S.E. of six hearts paced at a basic
atrial cycle length of 250 ms. P ⬍ .05: ⴱ, versus baseline.
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Supraventricular Effects of ATI-2001
Fig. 9. Effect of basic ACL changes on the AV nodal effects ATI-2001 and
amiodarone (amio). The time of drug infusion for a given agent is shown
on the horizontal axis, and the amount (percentage of the total number of
the hearts in a given group) of the hearts in which the drug caused AV
block is shown on the vertical axis. AV block was defined to be of second
or third degree. Both ATI-2001 (n ⫽ 6) and amiodarone (n ⫽ 6) prolonged
AV nodal conduction time in a frequency-dependent manner. The effect of
ATI-2001 was more rapid to develop and more potent. P ⬍ .05: ⴱ, compared with the longest basic atrial cycle length (ACL ⫽ 300 ms).
greater than those caused by an equimolar concentration of
amiodarone.
Atrial Effects
Fig. 8. Time-dependent effects of ATI-2001 and amiodarone of the proximal WCL. Both ATI-2001 and amiodarone significantly prolonged the
WCL. The effect of ATI-2001 was greater and more rapid to develop than
that of amiodarone. Unlike amiodarone, the effect of ATI-2001 was significantly reversed upon discontinuation of the drug. Each data point
represents the mean ⫾ S.E. of 10 hearts paced at a basic atrial cycle
length of 250 ms. P ⬍ .05: ⴱ, versus baseline.
dromotropic effects of ATI-2001 and amiodarone were frequency dependent.
Discussion
In the present study, we characterized the acute effects of
a novel analog of amiodarone, ATI-2001, on atrial and AV
nodal electrophysiological properties in guinea pig isolated
perfused hearts. Although we observed significant differences in the effects of these two agents, the actions of ATI2001 were generally similar to those of the prototypical compound amiodarone. That is, during a relatively short infusion
time they both prolonged atrial repolarization and AV nodal
conduction time. Their effects on atrial repolarization and
refractoriness seemed to be frequency independent during
slow and faster atrial pacing rates, whereas their negative
dromotropic action in the AV node was highly frequency
dependent (significantly augmented upon shortening of the
ACL). The main differences between the drugs were as follows: 1) the onset of action and washout of the electrophysiological effects were faster in hearts treated with ATI-2001
than with those administered amiodarone; and 2) the maximal electrophysiological changes caused by ATI-2001 were
Most sustained atrial arrhythmias (e.g., atrial fibrillation)
are caused by reentrant excitation (Janse, 1997). Electrophysiological parameters critical to the development and perpetuation of reentrant tachycardias are changes in atrial
conduction velocity, repolarization, and refractoriness
(Rensma et al., 1988; Janse, 1997). Antiarrhythmic drugs
that effectively terminate and prevent the reoccurrence of
atrial arrhythmias either impair conduction (class I action)
or prolong repolarization (class III action) in atrial tissue.
Ideally, an antiarrhythmic agent should demonstrate frequency-dependent antiarrhythmic action (i.e., have the
greatest effect during tachycardia and minimal-to-no effect
during normal sinus rhythm). Subsequently, the effects of
ATI-2001 on these electrophysiological factors are discussed
and compared with those actions of the prototypical compound amiodarone.
Atrial Conduction. In the current study, neither ATI2001 nor amiodarone significantly prolonged atrial conduction times. Although not statistically significant, ATI-2001
tended to prolong the S-A interval more than did amiodarone
(25 versus 8% prolongation). Interestingly, there was a tendency of the S-A interval to continue to increase even after
the infusion of amiodarone was discontinued, whereas the
effects of ATI-2001 were almost totally reversed after cessation of the infusion. These findings are in accordance with
previous results from our laboratory (Raatikainen et al.,
1996), and indicate that ATI-2001 possesses some class I
activity. For amiodarone the class I antiarrhythmic action
has been associated with antiarrhythmic potential, especially in the acute setting, whereas effects on cardiac repolarization and refractoriness have been more evident during
long-term pharmacotherapy (Podrid, 1995). Given the results
of our previous experiments (Raatikainen et al., 1996) and
the data on other sodium channel blocking agents (Kus et al.,
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Fig. 7. The effects of ATI-2001 and amiodarone on AV nodal ERP. Both
ATI-2001 and amiodarone significantly prolonged the AV nodal ERP. The
effect of ATI-2001 was greater and more rapid to develop than that of
amiodarone. Unlike amiodarone, the effect of ATI-2001 was significantly
reversed upon discontinuation of the drug. Each data point represents
the mean ⫾ S.E. of 10 hearts paced at a basic atrial cycle length of 250
ms. P ⬍ .05: ⴱ, versus baseline.
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to 80% efficacy in acute atrial fibrillation (Costeas et al.,
1998).
Negative Dromotropic AV Nodal Effects
The initial pharmacotherapy of reentrant supraventricular
tachyarrhythmias involving the AV node should be directed
at interrupting the circuit at the level of the proximal AV
node (Ganz and Friedman, 1995). The potent negative
dromotropic effect of ATI-2001 is in concordance with our
previous finding that the analog reduces sinoatrial rate in
guinea pig spontaneously beating hearts (Raatikainen et al.,
1996). Specifically, ATI-2001 appears to depress excitability
and conduction in all tissues with slow (ICa-dependent) action
potentials. In addition, the effect of the “ideal” antiarrhythmic drug should be maximal during tachycardia and minimal
during slow heart rates (i.e., frequency dependent). Prolongations of the A-H interval at shorter atrial cycle lengths, the
AV nodal ERP, and WCL caused by ATI-2001 indicate that
the negative dromotropic effect of this drug became greater
as the atrial rate increased. Consequently, ATI-2001 would
be expected to terminate and/or prevent the onset of paroxysmal supraventricular tachyarrhythmias. Although the
pharmacokinetic properties of ATI-2001 (i.e., significantly
faster onset of action and rapid washout after cessation of the
drug infusion) seem superior to amiodarone, they are unlikely to provide any advantage over adenosine or i.v. verapamil in the acute treatment of reentrant supraventricular
tachyarrhythmias.
The AV node not only has an important role in the pathogenesis of paroxysmal supraventricular tachyarrhythmias
but also in controlling ventricular rate during atrial tachyarrhythmias. An important physiological characteristic of AV
nodal conduction is the phenomenon of frequency dependence, whereby conduction through the AV node becomes
progressively slower as the atrial rate is increased (Merideth
et al., 1968; Meijler et al., 1996). Drugs that exacerbate the
modulatory effects of atrial rate on AV nodal conduction
delay provide additional protection against excessive ventricular rate during rapid atrial fibrillation or flutter. Thus, it is
important to consider that ATI-2001 may possess some advantages over the older antiarrhythmic agents in the treatment of atrial tachyarrhythmias. For example, when used to
treat acute atrial flutter (and atrial fibrillation), sodium
channel blockers that effectively slow atrial conduction velocity, may paradoxically accelerate ventricular rate. That is,
as the atrial rate slows, the AV nodal conduction ratio may
change from 2:1 to 1:1, leading to an abrupt increase in
ventricular rate (Friedman and Stevenson, 1998). In contrast, the negative chronotropic (Raatikainen et al., 1996)
and dromotropic effects of ATI-2001 (and amiodarone) are
expected to lower ventricular rates before conversion.
Conclusions
In summary, acute ATI-2001 infusion results in multifaceted amiodarone-like effects on atrial and AV nodal electrophysiological properties. The drug suppresses excitability
and conductivity in both INa- and ICa-dependent cardiac
tissues, and prolongs the atrial action potential duration and
refractory period. Hence, ATI-2001 should not only be useful
for terminating and/or preventing atrial tachyarrhythmias,
but also for treating supraventricular tachyarrhythmias in-
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 16, 2017
1990; Nademanee et al., 1990), the effect of ATI-2001 on
atrial conduction velocity is likely to be frequency dependent.
Although the results of the cardiac arrhythmia suppression trials (CAST Investigators, 1989; CAST II Investigators,
1992) unequivocally demonstrated that sodium channel
blockers (i.e., flecainide, encainide) increase mortality in patients with recent myocardial infarction, subsequent analysis
has, however, shown that class IC agents can be safely used
to treat supraventricular arrhythmias in patients without
structural heart disease (Hohnloser and Zabel, 1992). With
regard to the class I action of ATI-2001, it should also be
noticed that rather than being a “pure” INa blocker, ATI-2001
possesses multiple electrophysiological properties that
closely mimic those of the parent molecule amiodarone. Compelling data from individual clinical trials and meta-analyses
of multiple smaller trials suggest that amiodarone is also
effective and safe for patients in whom class I agents have a
proclivity to increase mortality (e.g., patients with recent
myocardial infarction or severe heart failure) (Connolly,
1999). Whether these data can be extrapolated to ATI-2001
remains to be established.
Atrial Repolarization and Refractoriness. ATI-2001
significantly prolonged atrial repolarization and refractoriness. Similar to the effects on ventricular repolarization and
refractoriness (Raatikainen et al., 1996), the effects of ATI2001 on atrial MAPD90 and ERP more rapidly developed and
washed than those observed for an equimolar concentration
of amiodarone. Likewise, a 90-min infusion period of ATI2001 prolonged atrial MAPD90 and ERP almost equally at
both slower (ACL ⫽ 250 ms) and faster (ACL ⫽ 200 ms)
atrial-pacing rates. These findings are in agreement with
previous studies that demonstrated that, unlike some other
class III agents, the prototypical compound amiodarone also
exerts frequency-independent effects on cardiac repolarization (Anderson et al., 1989; Huikuri and Yli-Mayry, 1992;
Sager et al., 1993). Furthermore, the anticipated ability of
ATI-2001 to block sodium channels in a use-dependent manner (Raatikainen et al., 1996) should further delay recovery
of excitability, and thereby additionally lengthen refractoriness (i.e., postrepolarization refractoriness) as a function of
atrial rate. Such a property would not only enhance the
antiarrhythmic efficacy of the drug but also improve control
of heart rate during supraventricular tachyarrhythmias.
Reports on the effects of acute amiodarone on atrial action
potential duration have been conflicting. A moderate prolongation has been demonstrated by some investigators, but
others have shown no substantial change or even shortening
(Kodama et al., 1997). The observed differences can be explained at least in part by species-dependent differences in
the ionic currents mediating repolarization of the action potential. In the current study, amiodarone moderately prolonged the atrial monophasic action potential. Nevertheless,
the acute effects of ATI-2001 on atrial repolarization and
refractoriness were significantly faster and greater than
those of an equimolar concentration of amiodarone. As a
result of its rapid effect on atrial repolarization, ATI-2001
may be similar to the “pure” class III agents such as ibutilide
and dofetilide (Singh et al., 1999). These agents effectively
convert not only atrial fibrillation but also atrial flutter to
normal sinus rhythm. In contrast, class I agents (e.g., flecainide) have only a minor effect on atrial flutter despite their 70
Vol. 295
2000
volving the AV node and thereby controlling ventricular response. It is also tempting to speculate that because of its
more rapid washout kinetics, ATI-2001 would be less likely
than amiodarone to accumulate into extracardiac tissues.
Whether these properties will render ATI-2001 less hazardous than amiodarone for long-term treatment of atrial fibrillation and other supraventricular tachyarrhythmias remains
to be established.
References
785
Merideth J, Mendez C, Mueller WJ and Moe GK (1968) Electrical excitability of
atrioventricular nodal cells. Circ Res 23:69 – 85.
Morey TE, Martynyuk AE, Napolitano CA, Raatikainen MJ, Guyton TS and Dennis
DM (1997) Ionic basis of the differential effects of intravenous anesthetics on
erythromycin-induced prolongation of ventricular repolarization in the guinea pig
heart. Anesthesiology 87:1172–1181.
Nademanee K, Stevenson WG, Weiss JN, Frame VB, Antimisiaris MG, Suithichaiyakul T and Pruitt CM (1990) Frequency-dependent effects of quinidine on the
ventricular action potential and QRS duration in humans. Circulation 81:790 –
796.
Napolitano CA, Raatikainen MJ, Martens JR and Dennis DM (1996) Effects of
intravenous anesthetics on atrial wavelength and atrioventricular nodal conduction in guinea pig heart. Potential antidysrhythmic properties and clinical implications. Anesthesiology 85:393– 402.
Nattel S (1995) Newer developments in the management of atrial fibrillation. Am
Heart J 130:1094 –1106.
Podrid PJ (1995) Amiodarone: Reevaluation of an old drug. Ann Intern Med 122:
689 –700.
Prystowsky EN, Benson DWJ, Fuster V, Hart RG, Kay GN, Myerburg RJ, Naccarelli
GV and Wyse DG (1996) Management of patients with atrial fibrillation. A statement for healthcare professionals. From the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation 93:1262–
1277.
Raatikainen MJ, Napolitano CA, Druzgala P and Dennis DM (1996) Electrophysiological effects of a novel, short-acting and potent ester derivative of amiodarone,
ATI-2001, in guinea pig isolated heart. J Pharmacol Exp Ther 277:1454 –1463.
Raatikainen MJ, Trankina MF, Morey TE and Dennis DM (1998) Effects of volatile
anesthetics on atrial and AV nodal electrophysiological properties in guinea pig
isolated perfused heart. Anesthesiology 89:434 – 442.
Rensma PL, Allessie MA, Lammers WJ, Bonke FI and Schalij MJ (1988) Length of
excitation wave and susceptibility to reentrant atrial arrhythmias in normal
conscious dogs. Circ Res 62:395– 410.
Roden DM (1993) Pharmacokinetics of amiodarone: Implications for drug therapy.
Am J Cardiol 72:F45–F50.
Rotmensch HH, Belhassen B, Swanson BN, Shoshani D, Spielman SR, Greenspon
AJ, Greenspan AM, Vlasses PH and Horowitz LN (1984) Steady-state serum
amiodarone concentrations: Relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med 101:462– 469.
Sager PT, Uppal P, Follmer C, Antimisiaris M, Pruitt C and Singh BN (1993)
Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation 88:1063–1071.
Singh BN, Mody FV, Lopez B and Sarma JS (1999) Antiarrhythmic agents for atrial
fibrillation: Focus on prolonging atrial repolarization. Am J Cardiol 84:R161–
R173.
Sun W, Sarma JS and Singh BN (1999) Electrophysiological effects of dronedarone
(SR33589), a noniodinated benzofuran derivative, in the rabbit heart: Comparison
with amiodarone. Circulation 100:2276 –2281.
Vorperian VR, Havighurst TC, Miller S and January CT (1997) Adverse effects of low
dose amiodarone: A meta-analysis. J Am Coll Cardiol 30:791–798.
Vrobel TR, Miller PE, Mostow ND and Rakita L (1989) A general overview of
amiodarone toxicity: Its prevention, detection, and management. Prog Cardiovasc
Dis 31:393– 426.
Wijffels MC, Kirchhof CJ, Dorland R and Allessie MA (1995) Atrial fibrillation begets
atrial fibrillation. A study in awake chronically instrumented goats. Circulation
92:1954 –1968.
Send reprint requests to: Dr. Donn M. Dennis, Department of Anesthesiology, University of Florida College of Medicine, P.O. Box J-100254, Gainesville,
FL 32610-0254. E-mail: [email protected]
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 16, 2017
Anderson KP, Walker R, Dustman T, Lux RL, Ershler PR, Kates RE and Urie PM
(1989) Rate-related electrophysiologic effects of long-term administration of amiodarone on canine ventricular myocardium in vivo. Circulation 79:948 –958.
Blitzer M, Costeas C, Kassotis J and Reiffel JA (1998) Rhythm management in atrial
fibrillation–with a primary emphasis on pharmacological therapy: Part 1. Pacing
Clin Electrophysiol 21:590 – 602.
CAST Investigators (1989) Preliminary report: Effect of encainide and flecainide on
mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The cardiac arrhythmia suppression trial (CAST.) investigators. N Engl
J Med 321:406 – 412.
CAST II Investigators (1992) Effect of the antiarrhythmic agent moricizine on
survival after myocardial infarction. The cardiac arrhythmia suppression trial II
investigators. N Engl J Med 327:227–233.
Connolly SJ (1999) Evidence-based analysis of amiodarone efficacy and safety.
Circulation 100:2025–2034.
Costeas C, Kassotis J, Blitzer M and Reiffel JA (1998) Rhythm management in atrial
fibrillation–with a primary emphasis on pharmacological therapy: Part 2. Pacing
Clin Electrophysiol 21:742–752.
Friedman PL and Stevenson WG (1998) Proarrhythmia. Am J Cardiol 82:N50 –N58.
Ganz LI and Friedman PL (1995) Supraventricular tachycardia. N Engl J Med
332:162–173.
Hohnloser SH and Zabel M (1992) Short- and long-term efficacy and safety of
flecainide acetate for supraventricular arrhythmias. Am J Cardiol 70:A3–A9.
Huikuri HV and Yli-Mayry S (1992) Frequency dependent effects of d-sotalol and
amiodarone on the action potential duration of the human right ventricle. Pacing
Clin Electrophysiol 15:2103–2107.
Janse MJ (1997) Why does atrial fibrillation occur? Eur Heart J 18 (Suppl C):C12–
C18.
Jenkins JR and Belardinelli L (1988) Atrioventricular nodal accommodation in
isolated guinea pig hearts: Physiological significance and role of adenosine. Circ
Res 63:97–116.
Kassotis J, Costeas C, Blitzer M and Reiffel JA (1998) Rhythm management in atrial
fibrillation–with a primary emphasis on pharmacologic therapy: Part 3. Pacing
Clin Electrophysiol 21:1133–1145.
Kodama I, Kamiya K and Toyama J (1997) Cellular electropharmacology of amiodarone. Cardiovasc Res 35:13–29.
Kulier AH, Novalija E, Hogan Q, Vicenzi MN, Woehlck HJ, Bajic J, Atlee JL and
Bosnjak ZJ (1999) The effects of the new antiarrhythmic E 047/1 on postoperative
ischemia-induced arrhythmias in dogs. Anesth Analg 89:1393–1399.
Kus T, Dubuc M, Lambert C and Shenasa M (1990) Efficacy of propafenone in
preventing ventricular tachycardia: Inverse correlation with rate-related prolongation of conduction time. J Am Coll Cardiol 16:1229 –1237.
Levy S, Breithardt G, Campbell RW, Camm AJ, Daubert JC, Allessie M, Aliot E,
Capucci A, Cosio F, Crijns H, Jordaens L, Hauer RN, Lombardi F and Luderitz B
(1998) Atrial fibrillation: Current knowledge and recommendations for management. Working group on arrhythmias of the European Society of Cardiology. Eur
Heart J 19:1294 –1320.
Meijler FL, Jalife J, Beaumont J and Vaidya D (1996) AV nodal function during
atrial fibrillation: The role of electrotonic modulation of propagation. J Cardiovasc
Electrophysiol 7:843– 861.
Supraventricular Effects of ATI-2001