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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
JPET 285:687–694, 1998
Vol. 285, No. 2
Printed in U.S.A.
Electrophysiological Effects of MS-551, a New Class III Agent:
Comparison with dl-Sotalol in Dogs1
LUYI SEN, GUANGGEN CUI, YOSHIHIDE SAKAGUCHI and BRAMAH N. SINGH
Cardiovascular Research Laboratory and the Division of Cardiology, VAMC/LA and UCLA School of Medicine, Los Angeles, California
Accepted for publication January 5, 1998
This paper is available online at http://www.jpet.org
In recent years, numerous class III agents have been synthesized and are being characterized experimentally and
clinically (Colatsky el al., 1990). Interest in this series of
compounds has stemmed from the clinical success with amiodarone and dl-sotalol in the treatment of lethal ventricular
arrhythmias and sudden death (Mason and ESVEM Investigators, 1993). Although associated with a low to negligible
incidence of proarrhythmia, amiodarone’s propensity to induce organ toxicity (pulmonary toxicity, neurotoxicity, the
variegated and cumulative toxicity) that develops in a proportion of patients as a function of time limits the drug’s
long-term usefulness (Weinberg et al., 1993) in many patients. dl-Sotalol, exhibiting beta blocking properties and
producing a marked prolongation of the cardiac action potential duration in vitro and in vivo, has recently emerged as a
potent antiarrhythmic agent (The CASCADE Investigators,
1993). It too is not ideal compound as in certain subsets of
Received for publication August 21, 1997.
1
This work was supported by the Institute of Biological Sciences, Mitsui
Pharmaceuticals, Inc, Tokyo, Japan.
shifted significantly to the left compared with that induced by
sotalol. The EC50 was 0.5 6 0.1 mg/kg and 1.2 6 0.2 mg/kg for
MS-551 and sotalol, respectively (P , .05). When 0.5 mg/kg
MS-551 doses were used, no ventricular arrhythmia was induced by stimulation at 200-msec basic cycle length. When 1.5
mg/kg sotalol was administered, 5 of 15 developed torsade de
pointes, 2 of 15 developed ventricular fibrillation and 5 of 15
developed sustained ventricular tachycardia. The idioventricular rates and left ventricular pressures were reduced significantly by sotalol, not by MS-551. In conclusion, MS-551 is a
potent class III antiarrhythmic agent that selectively prolongs
repolarization in the ventricular myocardium and appears to be
devoid of autonomic effects. Dose for dose, it is more potent in
prolonging the APD90 and the right ventricular effective refractory period possibly with a lower tendency for the development
of proarrhythmia in a canine heart-block model.
patients it has been associated with life-threatening ventricular arrhythmia, particularly TdP (Cui et al., 1994). It may
also exacerbate heart failure, although the reported incidence of heart failure is lower than that for other beta blockers. Hence, the need to develop a potent and safer antiarrhythmic agent remains to be met. However, the quest for
less toxic alternative class III agents has thus far been met
with only a modest success (Kehoe et al., 1993). In recent
years, there has been an increasing interest in the possibility
of controlling cardiac arrhythmias, especially by homogeneously prolonging cardiac repolarization.
MS-551, a new investigational compound, is reported to be
a potent class III antiarrhythmic agent, which prolongs the
APD, QTc and VERP in rat (Chen et al., 1996), dog (Hashimoto, et al., 1995) and human (Isomoto et al., 1995). Distinct
from other class III agents, such as dofetilide and sematilide,
MS-551 and sotalol are nonselective potent K1 channel
blockers (Nakayas, 1993; Hashimoto et al., 1995; Sato et al.,
1995) and share many antiarrhythmic activities (Nakaya et
al., 1993; Singh, 1993; Hashimoto et al., 1995). Both drugs
ABBREVIATIONS: APD90, action potential duration at 90% repolarization time; LVP, left ventricular pressure; RVP, right ventricular pressure; TdP,
torsade de pointes; IVR, idioventricular rate; VT, ventricular tachycardia; NSVT, nonsustained ventricular tachycardia; SVT, sustained ventricular
tachycardia; VF, ventricular fibrillation; RVERP, right ventricular effective refractory period; MAP, monophasic action potential.
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ABSTRACT
MS-551 is a newly synthesized, nonspecific K1 channel
blocker. To elucidate its electrophysiological and potential
proarrhythmic effects relative to those of dl-sotalol in vivo, serial
changes in ECGs, endocardial and epicardial monophasic action potential durations, and left and right ventricular pressures
were measured simultaneously in pentobarbital-anesthetized
open-chest dogs. Complete heart block was produced by the
injection of 37% formaldehyde into the atrioventricular node.
Intravenous administration of MS-551 produced prolongation
of action potential duration at 90% repolarization time (APD90)
immediately after the beginning of infusion and reached plateau
at 10 min. MS-551 (1 mg/kg) caused 73 6 8% increase in
APD90 and 28 6 5% increase in QTc at basic cycle length of
700 msec. The maximal prolongation of APD90 induced by 1
mg/kg MS-551 was 39% greater than that by the same dose of
sotalol (P , .01). The dose-response curve of prolongation of
ventricular effective refractory period produced by MS-551 was
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Sen et al.
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Methods
Animal preperation. Thirty adult male mongrel dogs weighing
20 to 25 kg were studied after intravenous sodium pentobarbital
anesthesia (30 mg/kg). The animals were intubated and artificially
ventilated with room air using a positive-pressure Harvard respirator. The body temperature was kept within the physiological range.
With the dogs right side up, thoracotomy was performed via the fifth
right intercostal space, and the heart was suspended in a pericardial
sling. Care was taken to minimize blood loss. The right and left
femoral arteries and right jugular veins were exposed. A venous
cannula in the femoral vein was used to infuse normal saline to
replace spontaneous fluid losses and inject drugs. The Ag-AgCl bipolar dual purpose electrode catheter was inserted through the right
jugular vein and advanced into the right ventricle. Its electrode tip
was positioned in the right ventricular apex to record the endocardial
MAPs during sinus rhythm and during pacing at various frequencies.
The Swan-Ganz and pigtail catheters were introduced via the
femoral vein and artery and advanced into the right and left ventricular cavities to continuously monitor ventricular pressures. A
customized flexible Ag-AgCl electrode was used to record the epicardial MAPs by directly attaching to the epicardium of the right ventricular apex. The electrode catheter position was placed in a similar
position at the time for base-line electrophysiological study and
during subsequent electrophysiological testing of drugs (MS-551 and
dl-sotalol).
Electrodes were placed on the four limbs for monitoring the surface ECG. The surface ECG leads I, II and aVF and arterial blood
pressure were simultaneously displayed on a multichannel oscilloscope (M3VR12; Etar, Beverton, OR) screen and recorded on an
ink-jet recorder at a paper speed of 50 to 100 mm/sec.
The canine complete heart block model was used because it provides the choice of a wide range of stimulation frequencies, permit-
ting the precise evaluation of the effects of heart rate on hemodynamic and electrophysiological parameters. Formaldehyde (0.1 ml,
37%) was directly injected into atrioventricular node through the
groove between the right atrium and aorta before each experiment to
produce total heart block (Steiner and Kovalik, 1968). After complete
heart block was produced, the idioventricular rhythm that appeared
immediately after atrioventricular block was monitored for stability
for 30 min. If the rhythm tended to revert to normal sinus or if nodal
tachycardia with narrow QRS complexes developed, a second injection of formaldehyde was given.
Electrophysiological study. Electrophysiological study was
performed in the base-line drug-free state. A 7F catheter with two
platinum ring electrodes for pacing (located 2 mm from the catheter
tip) and a pair of Ag-AgCl electrodes (at the distal tip and 5 mm
proximal from the tip) (EP Technology, Palo Alto, CA) were used for
the recording of MAPs at the right ventricular apex. This catheter
permitted the determination of both the RVERP and the MAP duration at the same location (Franz et al., 1990). All pacing was
performed with a pulse duration of 2 msec, at a current intensity of
twice the late diastolic threshold, which was invariably #1 mA.
Recordings were obtained at paper speeds of 50 to 100 mm/sec (PPG
VR-16 or MIDAS, Lenexa, KA). MAP duration was determined after
steady state right ventricular pacing at cycle lengths of 700, 600,
500, 400, 300, 250 and 200 msec for 60 complexes at twice diastolic
threshold. Steady state recordings were obtained after 7 min of
pacing at each new rate. The amplitude of the MAP was determined
from the diastolic base line to the plateau and the APD90 from the
initial MAP upstroke to the point where repolarization was 90%
complete. Three APD complexes at each paced cycle length were
measured and mean values were calculated.
The RVERP was measured at the same catheter position as the
MAP recordings before and after the test drugs. After a basic drive
run of 10 S1 beats and an extrastimulus (S2) was applied during late
diastole with successive decrement of the coupling interval of the
extra stimulus by 5 msec. One-second pause was used between runs.
When S2 extrastimulus failed to elicit a propagated response on two
successive attempts, the S1-S2 interval was taken as the RVERP.
MAP recordings and RVERP determinations were obtained both
at base line and after an intravenous bolus with MS-551 or dl-sotalol.
The pacing protocol was identical for each dog for the investigation of
both MS-551 and dl-sotalol on different days. The end point of the
pacing protocol was the completion of the entire protocol.
The ECG standard was the same as that used in the initial study.
The QT interval was measured from the surface ECG obtained just
before the electrophysiology study. The lead with the most prominent T wave and the termination of which could be easily defined
was chosen at base line for the evaluation of changes due to drug
effects. The QT interval was measured in six successive complexes,
and each measurement was corrected by the Bazett’s formula for the
preceding RR interval (e.g., QTc 5 QT/=RR) (Bazett, 1920). The
mean of the six measurements was used for comparisons between
controls and drug-induced changes.
Drug protocol. Each dog was randomly assigned to sequential
drug testing with MS-551 and dl-sotalol using a cross-over protocol.
After control measurements had been obtained, MS-551 or dl-sotalol
was administrated as an intravenous bolus of 0.1, 0.5, 1.0, 2.0, 4.0
and 8.0 mg/kg body weight. Each intravenous bolus was completed in
5 min. The interval between two doses was 1.5 hr. The electrophysiological parameters were measured and recorded 1, 2, 3, 4, 5, 10, 15
and 60 min after the beginning of each dose of testing drug bolus.
The design of this study allowed a comparison of the individual
change induced by MS-551 and dl-sotalol with respect to their effects
on refractoriness, repolarization and the tendency to produce ventricular arrhythmias. To compare the relative degree of reversal of
the electrophysiological effects of MS-551 and dl-sotalol by catecholamine administration, all parameters were recorded before and after
$15 min of epinephrine (50 ng/kg/min) infusion. All drugs were
dissolved directly in distilled water immediately before use.
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have been found to have antiarrhythmic action against atrial
and ventricular arrhythmias in the conscious dog and isolated cardiac preparations (Hondeghem and Synders, 1990;
Kamiya et al., 1992). They both have been reported to be
effective on electrically induced VT in dogs with previous
myocardial infarction but are not effective on spontaneously
occurring VT produced by two-stage coronary ligation or digitalis intoxication (Hashimoto et al., 1995). Both drugs reduce
the incidence of sustained VF after reperfusion (Murakawa et
al., 1997). The potent defibrillatory effect of MS-551 and
sotalol has been thought to be related to the blockade of
channels other than IK. Recently, Hashimoto et al. (1995)
compared the reverse rate-dependent QT- prolonging effect
of MS-551 and d-sotalol in coronary ligation-reperfusion
model at slow and fast heart rates. Yamada et al. (1996)
compared the reverse frequency-dependent prolongation of
effective refractory period of sinoatrial node, papillary muscle and atrioventricular node induced by MS-551, sematilide
and E-4031. There is no report on comparison of simple
antiarrhythmic molecules, such as MS-551, with single action vs those with more complex compounds that act by
prolonging cardiac repolarization as their principal action,
such as dl-sotalol.
The purposes of this study were to systematically evaluate
the electrophysiological and proarrhythmic effects of MS-551
and dl-sotalol at comparable biological effective dose and to
quantitatively compare the reverse frequency-dependent
prolongation of cardiac refractoriness induced by these two
drugs at precise and wider frequency range by using the
complete AV block canine model.
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Comparison of MS-551 and dl-Sotalol
689
Results
Effects of MS-551 and dl-sotalol on QT and QTc. The
QT intervals were measured at base line and during right
ventricular pacing at a basic cycle length of 700 msec. Both
the uncorrected QT interval and QTc according to the Bazett’s formula demonstrated variable increases induced by
MS-551 as well as dl-sotalol. QT and QTc prolongation induced by MS-551 was evident at dose as low as 0.1 mg/kg.
These effects began to develop at the start of the bolus injection, followed by a slight gradual decrease in the rate of the
idioventricular rhythm, reaching a steady state at 10 min
from the commencement of the bolus injection. When the
heart was paced through the right ventricle at a basic cycle
length of 700 msec, MS-551 produced a dose-dependent prolongation of the QT interval that was 87% greater than that
on dl-sotalol at the peak effect of the drugs. Of note, the QTc
interval was prolonged more strikingly after MS-551 than
that after dl-sotalol (131.6 vs. 114%, at 2 mg/kg). The EC50
was 0.65 6 0.07 mg/kg on MS-551 (n 5 15) and 1.59 6 0.17
mg/kg for sotalol (n 5 15, P , .01). The overall changes as a
function of dose are shown on figure 1.
Effects of MS-551 and dl-sotalol on the right ventricular MAP. The mean data derived from studies with MS-551
and dl-sotalol with respect to the changes in APD90 relative
to the time course of effect are shown in figure 2, A and B.
MS-551, 1 mg/kg, prolonged the APD90 with an acute onset of
action (within 1 min) after the intravenous infusion. This
effect reached the steady state at '10 min (fig. 2A). The
APD90 was increased by 73 6 6% (n 5 15, P , .01). In
contrast, the increase in the APD90 induced by sotalol was
more gradual and reached plateau effect at '75 min. The
maximal change in APD90 induced by sotalol was 37% less
than that induced by MS-551 at 1 mg/kg. Figure 2B shows
the dose-response curves with respect to the changes in the
APD induced by MS-551 and sotalol. The maximal prolongation of APD induced by MS-551 was 67% greater than that
induced by dl-sotalol. The EC50 was 0.65 6 0.07 mg/kg for
MS-551 (n 5 15) and 1.59 6 0.17 mg/kg for sotalol (n 5 15,
Fig. 1. Dose-response relationship in the effects of MS-551 and dl-sotalol on QT and QTc intervals. Percent increases in these values are
plotted as a function of intravenous doses of the drugs. All measurements
were made when the steady state drug effects had reached. The maximal
changes induced by MS-551 were reached at '10 min after the start of
the drug infusion. The second dose was given 60 min after the previous
dose. The maximal effects caused by dl-sotalol were reached at '75 min
after the drug infusion was commenced. The second dose was given 120
min after the previous dose. The hearts were paced through the right
ventricle at a basic cycle length of 700 msec. Note the somewhat steeper
dose-response relationship in the case of MS-551.
P , .01), which were correspondingly similar to those observed for the prolongation of QTc in the case of the two
drugs.
Frequency-dependent effects of MS-551 and dl-sotalol on APD90 during steady state ventricular pacing.
As shown in Figure 3, both MS-551 and sotalol produced a
significant prolongation of the APD90 compared with the
base line during ventricular pacing at all cycle lengths tested.
The increment in APD90 over control was significantly
greater in the MS-551 group than that in the sotalol group at
cycle lengths from 200 to 700 msec (ANOVA, P , .01). However, the effects of both MS-551 and sotalol on APD90 were
reverse frequency dependent. The percent increases from the
base line in the APD90 in MS-551 group were 32% at 200
msec cycle length and 79% at 700 msec cycle length. Sotalol
produced an 8% increase in ADP90 at 200 msec cycle length
and 43% increase at 700 msec cycle length. The frequencydependent curve of sotalol was approximately parallel to that
on MS-551, indicating that the two drugs exerted quantitatively but not qualitatively differing effects on APD90. Thus,
they both exerted the phenomenon of reverse frequency-dependency of action with respect to ventricular repolarization.
Effect of MS-551 and dl-sotalol on the RVERP. The
changes in the RVERP induced by MS-551 and sotalol were
compared after complete AV block was established. As with
the APD90, intravenous administration of 0.1 to 8 mg/kg of
MS-551 or sotalol produced a dose-dependent prolongation of
RVERP at all paced cycle lengths compared with the base
line. The maximal effect of MS-551 on RVERP was 67%
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Definitions. VT was defined as five or more consecutive ventricular complex at a rate of .120 beats/min and was considered sustained when it persisted for .30 sec or required direct current
cardioversion for termination. VT was considered to be nonsustained
if it lasted $10 beats and reverted spontaneously to the original
rhythm within 30 sec. TdP was considered when ECG monitoring
revealed the spontaneous occurrence of a polymorphic VT containing
at least one change in the mean QRS axis during the course of the
arrhythmia and with seven consecutive beats with an excessive QT
interval prolongation immediately before the onset of the tachycardia. VF was defined as a ventricular tachyarrhythmia characterized
by disorganized electrical activity on the surface ECG.
Materials. MS-551 was a gift from Mitsui Pharmaceuticals (Mobara, Japan).
Statistical analysis. Results are expressed as mean 6 S.D. as an
index of dispersion of values around the mean. Student’s paired t test
was used for mean values of data, and Fisher’s exact test was used to
analyze categorical data. Mean values of electrophysiological and
hemodynamic data, changes in RVERP, APD90, QTc and RVERP/
APD 90 ratio during drug tests and consistency of these changes
compared with base line and drug tests as function of the paced cycle
length were evaluated using repeated measures ANOVA with the
Greenhouse-Geiser correction for within subject correlations. Differences were considered significant at P , .05.
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Sen et al.
Vol. 285
Fig. 2. Effects of MS-551 and dl-sotalol on MAP
duration. A, The effects of MS-551 (1 mg/kg) and
dl-sotalol (2 mg/kg) on APD90 are expressed as a
function of time. The mean data shown graphically
were derived from the studies with MS-551 and
dl-sotalol with respect to the changes in the
monophasic action potential recordings at 90% repolarization time. MS-551 produced a strikingly
steeper increases in the APD90 and reaching an
earlier peak. B, The dose-response relationship
with respect APD90 changes induced by MS-551
and dl-sotalol. The hearts were paced through the
right ventricle at the basic cycle length of 600
msec. The measurements were all made after the
steady state drug effects had been reached.
Fig. 4. A, Dose-dependent prolongation of
RVERP induced by MS-551 and dl-sotalol. Each
data point represents the percentage of increments in RVERP induced by MS-551 or dl-sotalol over that in control condition. B, Frequency-dependent effects of MS-551 and dl-sotalol on
RVERP. The mean 6 S.D. values represent the
percentage increments in RVERP induced by
MS-551 (1 mg/kg) or dl-sotalol (2 mg/kg) over
that in control condition. The hearts were paced
at cycle lengths from 250 to 600 msec.
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Fig. 3. Frequency-dependent effects of MS-551 and dl-sotalol on APD90.
The mean 6 S.D. values represent the percentage increments in APD90
induced by MS-551 (1 mg/kg) or dl-sotalol (2 mg/kg) over that in control
condition. The hearts were paced at cycle lengths from 250 to 600 msec.
higher than that after sotalol (n 5 15, P , .01). The EC50 was
0.57 6 0.06 mg/kg for MS-551 and 1.47 6 0.15 mg/kg for
sotalol. The mean data are summarized in figure 4A relative
to varying doses given by the method of cumulative addition.
Consistent with the finding with respect to the APD90, the
effect of dl-sotalol on the RVERP was also reverse-frequency
dependent (r 5 .04; P , .01) (fig. 4B). However, the percent
increments in the RVERP induced by MS-551 were smaller
for any given decrease in the pacing cycle length compared
with the effects induced by dl-sotalol (r 5 .09; P , .05).
Effects of MS-551 and dl-sotalol on the relation of
RVERP and APD90. Figure 5A shows the values for the
RVERP against APD90 at each cycle length (250 – 600 msec)
in 15 dogs before and after MS-551 or sotalol infusion. There
was a significant correlation for APD90 and RVERP before
and after MS-551 or sotalol infusion (r 5 .06, P , .01). Under
control conditions, the correlation between RVERP and
APD90 was linear. The RVERP-APD90 relation curve for MS551 (2 mg/kg) was significantly shifted to the left compared
with control (P , .05). The slope factor of the RVERP-APD90
relation curve was slightly increased in MS-551 group compared with that at control but did not reach the statistically
significant difference (P . .05). In contrast, the RVERPAPD90 relation curve was shifted to the right in the case of
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691
rhythmias that met the criteria for TdP was induced in 5 of
15 dogs, 2 developed ventricular fibrillation and 5 developed
sustained ventricular tachycardia. However, when 2 mg/kg
MS-551 was infused, TdP was induced by pacing at a 200
msec cycle length in 9 of 15 dogs. This pattern was similar to
that when 4 mg/kg sotalol was used (13 of 15 dogs developed
TdP, 1 of 15 developed sustained ventricular tachycardia).
An example of stable escape rhythm after successful AV
block is shown in figure 7A, and a representative recording of
TdP is shown in fig. 7B.
Relative effect of epinephrine on APD90 and RVERP
during MS-551 and dl-sotalol testing. After the maximal
effects of MS-551 or sotalol on APD90 and RVERP were
attained, epinephrine was infused at 50 ng/kg/min for 15
min. Epinephrine shortened the MS-551- induced prolongation of RVERP and APD90 determined at a cycle length of 600
msec by 69 6 12% and 58 6 13%, respectively. Similar
results were obtained when APD was obtained at a cycle
length of 400 msec. However, epinephrine did not attenuate
sotalol-induced lengthening of the RVERP and APD90. The
mean data are summarized in fig. 8, A and B.
Discussion
The principal findings of this study are (1) MS-551 produced a rapid onset and dose-dependent increase in the QT/
QTc, and in right ventricular APD90 and RVERP, with the
maximal effects being significantly greater than those on
sotalol. (2) MS-551 shifted the dose-response curves for
ADP90 and RVERP prolongation significantly to the left compared with sotalol. (3) The effects of both MS-551 and sotalol
on APD90 and RVERP were reverse frequency dependent. (4)
The RVERP/APD90 ratio in MS-551 group was significantly
higher than that in the sotalol group and at control. Unlike
those in the sotalol group, the RVERP/APD90 ratio was not
changed by the differing cycle lengths. (5) For a given degree
of APD prolongation, MS-551 appeared to exert less proarrhythmic effect than dl-sotalol. (6) The cycle length of ventricular escape rhythm was much (4 –7 times) longer in the
dogs that received sotalol than those given MS-551 group. (7)
MS-551 exerted no significant effect on the LVP that, however, was lowered by sotalol. The overall data, therefore,
Fig. 5. A, The correlation between the changes
in RVERP and APD90 induced by MS-551 or
dl-sotalol and at the control condition. Each
measurement was recorded when the heart was
paced at a basic cycle lengths at 300, 400, 500,
600 and 700 msec. B, Comparison of the frequency-dependent effects of MS-551 and dl-sotalol vs. respective control on the ratio of
RVERP/APD90.
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the sotalol group (P , .05), and the slope factor was the same
as that for control.
The RVERP/APD90 ratio, measured at twice diastolic
threshold, is presented in figure 5B. As the pacing rate was
increased under basal conditions, the APD90 and RVERP
shortened. Because the RVERP shortened to a lesser degree,
the ratio increased toward unity at the shortest paced cycle
lengths at control condition. In the presence of MS-551, the
ratio was not changed by increasing pacing cycle lengths.
However, sotalol had a similar profile as that in control
condition. Therefore, the change of RVERP/APD90 ratio induced by MS-551 from control condition at each cycle length
was less in shorter cycle lengths and greater in longer cycle
lengths (ANOVA, P , .05). Thus, at the longer cycle lengths
examined, the MS-551-induced prolongation of the RVERP
did not appear to be entirely secondary to increases in the
APD90.
Effects of MS-551 and dl-sotalol on IVR. After the
interruption of AV conduction, all animals developed a stable
escape rhythm with uniform QRS complexes. Sotalol prolonged the RR interval of the IVR by '22% within 2 min after
the initiation of the bolus injection and showed a very gradual decrease thereafter. The prolongation of the RR intervals
of the IVR complexes after dl-sotalol was significantly
greater than that after MS-551 (P , .01) (fig. 6A).
Effect of MS-551 and dl-sotalol on ventricular pressure. The animals receiving sotalol showed a significantly
greater depressant effect on ventricular pressures compared
with those treated with MS-551. As shown in figure 6B, the
left ventricular pressure was reduced 14% by sotalol (P ,
.01). There was no effect noted in MS-551-treated dogs over a
wide range of doses (0.1– 8 mg/kg). Sotalol also produced a
10% reduction in right ventricular pressure but not MS-551
(data not shown).
Comparative proarrhythmic effects of MS-551 and
dl-sotalol. The overall arrhythmogenic data for 0.5 mg/kg
MS-551 (ED50 for RVERP) in comparison to 1.5 mg/kg (ED50
for RVERP) sotalol and 2 mg/kg sotalol, which produced the
same degree of prolongation of the ERP, are summarized in
table 1. At a dose of 0.5 mg/kg MS-551, no ventricular arrhythmias were induced by stimulation at 200-msec basic
cycle length. At a dose of 1.5 mg/kg sotalol, ventricular ar-
Comparison of MS-551 and dl-Sotalol
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Sen et al.
Vol. 285
Fig. 6. A, Dose-dependent changes in heart rate
induced by dl-sotalol and MS-551. Each item of
datum was plotted as the percentage of changes
in the idioventricular rate induced by MS-551
and dl-sotalol over that under control conditions.
B, Time course of the changes in left ventricular
pressure induced by dl-sotalol (2 mg/kg) and MS551 (1 mg/kg).
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TABLE 1
Comparison of arrhythmogenic activity of MS-551 and dl-sotalol
(n/total)
MS-551 (0.5 mg/kg)
Sotalol (1.5 mg/kg)
Sotalol (2 mg/kg)
NSVT
SVT
TdP
VF
0/15
7/15
9/15
0/15
5/15
6/15
0/15
5/15
7/15
0/15
2/15
2/15
NSVT, nonsustained ventricular tachycardia; SVT, sustained ventricular tachycardia; TdP, torsades de pointes; VF, ventricular fibrillation.
indicate that despite the fact that both drugs prolonged the
time course of ventricular repolarization, there were significant differences between the effects of dl-sotalol and MS-551.
Such differences appeared to stem largely from the lack of
beta blocking activity in the case of MS-551, which, in our
studies, functioned essentially as a pure class III antiarrhythmic compound. The data provide the basis for a comparison of the properties of MS-551 with dl-sotalol (racemate) and d-sotalol, which is devoid of beta blocking activity.
Such a comparison is likely to be of much theoretical as well
as of practical therapeutic significance in light of the evolving
data that deal with differences between simple antiarrhythmic molecules with single actions vs those with more complex
compounds that act by prolonging cardiac repolarization as
their principal actions.
Significance of antiadrenergic properties in a class
III compound. The comparative data on the electrophysiological effects of MS-551 and dl-sotalol must be interpreted in
light of the emerging clinical experience, which has emphasized the preeminent role of sotalol and amiodarone in the
control of life-threatening ventricular arrhythmias (Singh,
1996). Amiodarone and sotalol share the common property of
lengthening repolarization and refractoriness. However, both
also have potent antiadrenergic actions, as do beta blockers;
amiodarone has additional electrophysiological effects together with an exceedingly complex pharmacokinetics and
membrane effects. The antiadrenergic actions of sotalol and
amiodarone are not readily nullified by exercise or by the
administration of concomitant catecholamines. Thus, their
class III actions are largely preserved despite catecholamine
stimulation. In contrast, the effects of other antiarrhythmic
agents that act by prolonging repolarization are offset or
even reversed as sympathetic activity is increased (Waldo et
Fig. 7. A, Typical recordings of the surface ECG, ventricular pressures,
and monophasic action potentials after the creation of complete AV block
in the dog by the direct injection of formaldehyde into the AV node. The
ECG, endocardial (End) and epicardial (Epi) MAPs and right (RV) and
left (LV) ventricular pressures were recorded simultaneously. B, A typical
example of TdP induced by MS-551. The arrhythmia was induced by
stimuli at 250 msec cycle length after 2 mg of MS-551 had been given.
al., 1996). The clinical profiles of sotalol and amiodarone do
not, however, allow conclusions regarding which components
of their electrophysiological properties are linked meaningfully to their clinical antifibrillatory and profibrillatory actions. Nevertheless, an understanding of the mechanisms of
action and of the clinical effects of the so-called pure class III
compounds (Singh, 1996) is likely to provide insights into the
significance of lengthening of APD in preventing VF. Their
development stemmed from the need to circumvent the perceived shortcomings of sotalol (beta blocker side effects and
1998
TdP) and amiodarone (complex side effect profile). For this
reason, there has been an intense focus on simpler molecules
that have the propensity to lengthen repolarization without
any other major associated pharmacological effects. Within
such a framework, MS-551 and the dextro-isomer of sotalol,
d-sotalol, function as pure class III agents, both being devoid
of significant beta blocking activities.
It is thus of major clinical significance that d-sotalol in a
recent double-blind, placebo-controlled study, Survival with
Oral D-Sotalol (SWORD), in postinfarction patients at risk
for high mortality (Morady et al., 1988) increased rather than
decreased total mortality presumably due to drug-induced
proarrhythmic reaction. One can therefore question what
might be the role of adrenergic antagonism in the case of
dl-sotalol, which has been found to decrease mortality in the
survivors of acute myocardial infarction (Julian et al., 1982).
It has also proved superior to class I agents in reducing
cardiovascular mortality in patients with SVT and in those
who survived cardiac arrest (Mason and ESVEM Investigators, 1993). It is known that in isolated myocytes, d- and
dl-sotalol in equimolar concentrations, produce an identical
percentage decreases in outward potassium currents. When
challenged with isoproterenol in an identical concentration,
693
increases in the outward potassium currents exceeded that in
the case of d-sotalol compared with dl-sotalol with corresponding shortening of APD and, by inference, of ERP (Groh
et al., 1995). It might be inferred that with pure class III
agents such as MS-551, d-sotalol and sematilide, among others, the expected beneficial increases in refractory period and
in the duration of MAPs might be nullified or even reversed
during catecholamine surges in the absence of accompanying
beta blockade. Our data in the current study showed that the
striking prolonging effects on the MAP duration as well as in
the refractory period induced by MS-551 was nullified by
epinephrine infusion. As might be expected, this reversal did
not occur in the case of dl-sotalol. Whether the clinical effects
of MS-551 on mortality in the setting of patients with coronary artery disease and depressed ventricular function are
likely to be similar to those of d-sotalol remains uncertain.
However, the parallelism between the known electrophysiological effects of MS-551 and those of d-sotalol suggests that
the therapeutic use of MS-551 should be modulated by beta
blockade.
Proarrhythmic actions of MS-551 and dl-sotalol. The
occurrence of the proarrhythmic reactions in the form of TdP
is now considered the Achilles’ heel of class III compounds
(Hohnloser and Singh, 1995). In our experimental model, the
frequency of the arrhythmia for a given dose was twice as
common with dl-sotalol than with MS-551. Furthermore, the
phenomenon of reverse frequency-dependence of APD90 or
RVERP, described for a number of newer class III agents
(Sager et al., 1993; Tande et al., 1990) was less striking and
the VERP/APD90 ratio (an unexplained finding because the
drug does not exhibit class I actions) was greater in the case
of MS-551 compared with the corresponding parameters on
sotalol. Similarly, often with a marked slowing of the heart
rate accompanied by excessive prolongation of repolarization
as might occur with sotalol (and not with pure class III
agents), given the appropriate clinical milieu, the proclivity
for the development of TdP will be augmented. On the other
hand, the theoretically lower incidence of TdP that might be
encountered with pure class III agents such as d-sotalol,
MS-551 and dofetilide, as a class, in concert with their potentially beneficial antifibrillatory actions may be negated by
catecholamine surges and fast heart rates, as was demonstrated in the case of MS-551 in our experimental model. Our
experimental findings in the current study with dl-sotalol are
consistent with the clinical data that the presence of sympathetic inhibitory effect in the setting of the lengthening of the
action potential duration may be essential for effecting a
favorable change in mortality in patients with ischemic heart
disease.
Effects on idioventricular escape rhythm and ventricular pressures. The observed effects of dl-sotalol and
MS-551 on these measured parameters appeared to stem
largely from their differing antisympathetic actions. Sotalol
increased sinus cycle length significantly, an effect that was
paralleled by an increase in the sinus node recovery time in
our anesthetized open-chest canine preparation. Depression
of sinus node automaticity as a result of b blocking activity
has been observed in numerous investigations (The CASCADE Investigators, 1993). Intravenous sotalol also had a
marked negative chronotropic action on the IVR. However,
the corresponding decrease induced by MS-551 was relatively small, consistent with the drug being devoid of anti-
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 2, 2017
Fig. 8. A, Reversal effect of epinephrine-induced changes in APD90 (A)
and RVERP (B) induced by dl-sotalol and MS-551. The hearts were paced
at 600 msec basic cycle length. MS-551 (4 mg/kg, M) increased both
APD90 and RVERP significantly compared with that in control (C). This
effect was reversed by epinephrine (50 ng/kg/min for 15 min) intravenous
infusion. However, the effects of the same dose of dl-sotalol (S) on both
APD90 and RVERP could not be reversed by epinephrine. C, control; E,
epinephrine.
Comparison of MS-551 and dl-Sotalol
694
Sen et al.
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sympathetic activity. The cycle length of ventricular escape
rhythm was much longer (4 –7 times) in the dogs that received sotalol compared with that in the MS-551 group. The
ventricular pressures (right and left) were significantly reduced by sotalol but not by MS-55, again reflecting the differing antisympathetic activities of the two compounds. The
action of MS-551 on cardiac hemodynamics was extremely
weak compared with those of dl-sotalol and resembled those
of d-sotalol reported previously (Holubarsch et al., 1995).
Summary and conclusions. In an open-chest anesthetized canine model in which AV block was produced by formaldehyde injection, the electrophysiological effects of MS-551
were compared with those of dl-sotalol. Dose for dose, MS551 was more potent than sotalol in prolonging the APD and
VERP; it exerted less reverse use and rate dependency on
repolarization with a lower proarrhythmic tendency and less
depressant effect on ventricular pressure and on escape ventricular rhythm after AV block compared with dl-sotalol. The
experimental findings in this study establish the electrophysiological profile of MS-551 as a pure class III agent, but its
clinical properties and utility remain to be defined by controlled studies.
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