Vol. 290, Issue 1, 146-152, July 1999
Electrophysiological Effects of LU111995 on Canine Hearts: In
Vivo and In Vitro Studies1
Eugene A.
Sosunov,
Ravil Z.
Gainullin,
Peter
Danilo, Jr.,
Evgeny P.
Anyukhovsky,
Michael
Kirchengast2 and
Michael R.
Rosen
Departments of Pharmacology (E.A.S., R.Z.G., P.D., E.P.A., M.R.R.)
and Pediatrics (M.R.R.), College of Physicians and Surgeons of
Columbia University, New York, New York
 |
Abstract |
We studied the electrophysiological effects of LU111995 (1-15 mg/kg
p.o.) in conscious dogs with chronic atrioventricular block and
ventricular pacing at 50 to 130 beats/min. LU111995 had no effects on
idioventricular rhythm, QRS duration, and ventricular conduction time.
It significantly prolonged Q-T interval (by 5-8%) and
effective refractory period (ERP) (by 5-12%) with the maximal effect
at 4 h after a 10 mg/kg dose. At 10 and 15 mg/kg, it increased the
ERP/Q-T ratio. In vitro, the effects of LU111995 (1 × 10
7 to 1 × 105 M) on
action potentials of Purkinje fibers (PFs) and M cells were studied at
cycle lengths (CL) of 300 to 2000 ms. It had no effects on maximum
diastolic potential and action potential amplitude in either tissue.
High concentrations induced a moderate, rate-independent decrease of
max in M cells. In PFs and M cells,
it produced reverse use-dependent lengthening of action potential
duration (APD). In PFs at long CL, the drug exhibited a biphasic
concentration-dependent effect on APD: maximum prolongation (by 26% at
a CL of 2000 ms) was attained at 1 × 106
M, and a decrease of APD occurred at higher concentrations.
In M cells, the maximum effect on APD occurred at 3 × 106 M. Early afterdepolarizations were seen
in 50% of M cell preparations but only at CL of 2000 ms. Triggered
activity did not occur. In summary, LU111995 prolongs the Q-T interval
to a limited degree and is not arrhythmogenic over the physiological
range of CLs.
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Introduction |
In
some instances, drug-induced long Q-T intervals are associated with
torsade de pointes and sudden death (Tan et al., 1995
). The mechanism
generally assumed to be operative is reduction in the repolarizing
K+ currents, IKr and/or
IKs; prolongation of the cardiac action potential
duration (APD), and initiation of early afterdepolarizations (EADs)
that lead to the classic torsade de pointes arrhythmia (Roden and
Hoffman, 1985; Hondeghem and Snyders, 1990; Funck-Brentano, 1993).
These untoward events have led regulatory agencies to require the use
of established intact animal and isolated tissue models (or the
development of new models) to determine the likelihood of proarrhythmia
occurring on administration of new drugs that prolong repolarization.
LU111995
[(+)-(1S,5R,6S)-exo-3-[2-[6-(4-fluorophenyl)-3-aza-bicyclo[3.2.0]heptan-3-yl]ethyl]-1H,3H-quinazoline-2,4-dione
fumarate; Fig. 1) is a recently
identified antipsychotic agent with high 5-hydroxytryptamine2 and dopamine
D4 receptor affinities as well as
D4 versus D2 receptor
selectivity (Steiner et al., 1998). Because of concern over the effects
of some antipsychotic agents to excessively prolong repolarization and
induce proarrhythmia, the purpose of the present study was to determine
the effects of LU111995 on ventricular repolarization in vivo and in
vitro. Therefore, we investigated the actions of LU111995 on the ECG
and the ventricular effective refractory period (ERP) in conscious dogs
in which chronic atrioventricular block had been induced to permit
measurements over a range of heart rates that encompass the
physiological range. In vitro, the electrophysiological properties of
LU111995 were investigated in Purkinje fibers and mid myocardial cells
(M cells) (Sicouri and Antzelevitch, 1991). M cells were studied
because they constitute a significant fraction of ventricular
myocardium (Antzelevitch et al., 1994; Sicouri and Antzelevitch, 1995;
Anyukhovsky et al., 1996), they contribute importantly to T-wave
configuration and the Q-T interval, and, due to their exceptional
sensitivity to APD-prolonging agents, they develop EADs more readily
than epicardial or endocardial cells (Antzelevitch and Sicouri, 1994; Antzelevitch et al., 1996; Shimizu and Antzelevitch, 1997).
| |
Materials and Methods |
All experimental procedures conformed to the "Guiding
Principles of the Care and Use of Animals" of the American
Physiologic Society and were in accordance with the "Guide for the
Care and Use of Laboratory Animals" [DHEW (DHHS) publication (NIH)
85-23, revised 1985].
In Vivo Experiments.
Conditioned mongrel dogs of either sex
weighing 20 to 25 kg were fasted overnight and anesthetized with
propafol (6 mg/kg i.v.). After tracheal intubation, anesthesia was
maintained with isoflurane (2%) inhalation. Under sterile conditions,
a thoracotomy was performed in the right forth intercostal space, and
the heart was positioned in a pericardial cradle. To achieve a low
heart rate, complete heart block was produced by the injection of 0.1 to 0.3 ml of 40% formalin into the region of the AV node (Scherlag et
al., 1967; Anyukhovsky et al., 1996). An epicardial screw-type electrode (model 6917; Medtronic) was placed in the left ventricle near
the apex. The electrode lead was connected to a programmable Medtronic
pacemaker (MINIX 8340) that was placed in a s.c. pouch. For studying
ERP and for monitoring ventricular conduction time, three platinum
bipolar electrodes were sewn to the epicardium of the right ventricle
(electrodes were placed along a base-apex axis approximately 1-2 cm
apart). The wires from the electrodes were secured to the ribs,
tunneled s.c., and exteriorized through a small incision between the
scapulae. The pericardium was left open, the chest wall was closed in
layers, and the pneumothorax was evacuated by a chest tube. Each dog
was fitted with a jacket to prevent damage to the pacemaker and wires.
Animals were allowed to recover for 2 weeks. After recovery from
surgery and during 1 week before the drug protocols were begun, each
dog was trained to stand quietly in an animal sling during ECG
monitoring. At this time, the ECG had completely stabilized. During the
periods of recovery and training and between drug administration
protocols, ventricular pacing was maintained at 60 beats/min.
ECG parameters were measured at heart rates of 50 (when idioventricular
rhythm permitted), 60, 70, 80, 110, and 130 beats/min. The low heart
rates were considered of particular importance because drugs that are
reverse use dependent and induce torsade de pointes have a propensity
to do so at long cycle lengths (CLs) (e.g., Funck-Brentano, 1993).
Variability of the Q-T interval over the period of time of the study
was minimal (i.e., at CL = 1000 ms, <5 ms; Fig.
2). To ensure a steady state, each rate
was maintained for 3 min. To ensure a steady state, each rate was
maintained for 3 min before data were collected (Anyukhovsky et al.,
1996). ERP was determined at heart rates of 60, 80, and 130 beats/min. In these experiments, the heart was stimulated with 1-ms rectangular pulses of amplitude 2 × threshold (Pulsemaster A300, with
isolation unit A360; WPI, Sarasota, FL) through the right ventricular
epicardial electrode that was closest to the apex. After every 10 beats, an extrastimulus was delivered, the delay for which was
gradually decreased by 10- and then 1-ms decrements. The earliest
premature response that propagated to the most distant electrogram site was assumed to represent the end of the ERP. Conduction time was measured as the interval between the two bipolar right ventricular electrodes recorded when that located closest to the apex was stimulated. ECG and local electrogram signals were digitized with an
analog-to-digital converter (D-210; DATAQ Instruments Inc., Akron, OH) and stored in a personal computer for further analysis.
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Fig. 2.
Q-T intervals measured over a time period equal to
that of the total duration of the study. No significant changes
occurred in Q-T.
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Dogs were randomly assigned to receive 1, 3, 10, and 15 mg/kg LU111995
p.o. The highest dose used in early phase 2 studies was 200 mg/patient/day (Knoll, 1998), corresponding roughly to the 3 mg/kg dose
in dogs. Cardiovascular assessments, which required about 20 min in
toto, were performed at control (before drug administration) and 1, 2, 4, and 8 h after drug. Blood samples were drawn at appropriate intervals for measurements of serum levels of LU111995 and its major
metabolites, LU195730 and LU273973, which are generated by
glucuronydation (Steiner et al., 1998).
Serum drug concentrations were measured as follows: an HPLC method was
used for the simultaneous determination of LU111995, LU195730, and
LU273973 in dog plasma. LU81028 was the internal standard. After a
liquid-liquid plasma extraction procedure, chromatographic separation
was performed on a 4-µm Superspher 60, RPselect B analytical column
(250 × 4.0 mm) using a mixture of 0.05 M
KH2PO4 (pH 5)/acetonitrile (770:183, g/g) as the mobile phase with a flow rate of 0.9 ml/min at
35°C. The chromatographic peaks were measured by UV detection at 240 nm. The calibration curves were linear with correlation coefficients of
0.999 or better from 5 ng/0.5 ml to 80 ng/0.5 ml for all three
compounds in plasma. Other endogenous components did not interfere with
this method. Testing of the method with 0.5 ml of plasma at a working
range of 5 to 80 ng/ml yielded coefficients of variation of 3.8% to
17.8% for LU111995, 7.0% to 11.0% for LU195730, and 6.1% to 13.3%
for LU273973. Throughout the working range, the method yielded accurate
values from 93.4% to 107.0% for LU111995, 92.7% to 107.9% for
LU195730, and 95.4% to 107.5% for LU273973.
Dogs were restudied at weekly intervals, permitting a 7-day washout
period before the next dose was administered. Ten successful experiments were performed.
In Vitro Experiments.
Mongrel dogs of either sex weighing 20 to 22 kg were anesthetized with sodium pentobarbital (30 mg/kg i.v.).
Their hearts were removed through a left lateral thoracotomy and
immersed in cold Tyrode's solution equilibrated with 95%
O2/5% CO2 and containing 131 mM NaCl, 18 mM NaHCO3, 4 mM KCl, 2.7 mM
CaCl2, 0.5 mM MgCl2, 1.8 mM
NaH2PO4, and 5.5 mM
dextrose. Two types of preparations were used: free-running Purkinje
fibers (PFs) obtained from either ventricle and myocardial slices
(~10 × 5 × 1 mm) filleted from the posterobasal left
ventricular free wall parallel to the epicardial surface from the depth
of 3 to 5 mm beneath it. The preparations were placed in a tissue bath
and superfused with Tyrode's solution warmed to 37°C (pH 7.35 ± 0.05). Solution was pumped through the tissue bath at a flow rate of
12 ml/min, changing chamber content three times per minute. The bath
was connected to ground via a 3 M KCl/Ag/AgCl junction.
All preparations were impaled with 3 M KCl-filled glass capillary
microelectrodes that had tip resistances of 10 to 20 M
. The maximum
upstroke velocity of the action potential
(max) was obtained through
electronic differentiation with an operational amplifier. The
electrodes were coupled by an Ag/AgCl junction to an amplifier with
high input impedance and input capacity neutralization. Transmembrane
action potentials and max were
displayed on a digital storage oscilloscope (model 4074; Gould) and
stored in digitized form for subsequent analysis. For stimulation of
preparations, standard techniques were used to deliver square-wave
pulses 1.0 ms in duration and 1.5× threshold through bipolar
Teflon-coated silver electrodes. To investigate frequency dependence of
drug effects, the preparations were driven at CLs of 2000, 1000, 500, and 300 ms in sequence. Each frequency was maintained for 3 min before
the data were collected.
Experiments were started after preparations had fully recovered and
displayed stable electrophysiological characteristics. This required
1 h for PFs (Wyse et al., 1993) and 3 to 4 h for transmural
preparations (Anyukhovsky et al., 1996; Sosunov et al., 1997). After
control records were obtained, the preparations were superfused with
Tyrode's solution containing graded concentrations (1 × 107, 1 × 106,
3 × 106, and 1 × 105 M) of LU111995. Because
preliminary experiments had shown that steady-state effects on action
potential parameters were achieved in 25 to 30 min, the preparations
were equilibrated at each drug concentration for 30 min.
Statistical Analysis.
Data are expressed as mean ± S.E.M. The statistical techniques used were one- or two-way ANOVA for
repeated or nonrepeated measures, with Bonferroni's test when the
F value permitted (Winer et al., 1991). Microelectrode data
were analyzed from impalements maintained throughout the course of each
experiment. Significance was determined at P < .05.
| |
Results |
In Vivo Study.
The idioventricular rhythm, QRS duration,
conduction time, and Q-T duration all were stable and unchanging
throughout the duration of the 3-week study period (Table
1). LU111995 had a consistent effect on
the Q-T interval, as shown in Fig. 3.
Q-T prolongation ranged from 5% to 8% with the maximum at 4 h
after the 10 mg/kg dose (Fig. 3A). The magnitude of prolongation
diminished at 15 mg/kg. The maximum effects of 10 mg/kg at 4 h
after drug administration at all driving rates are presented in Fig.
3B. Prolongation reached significance at 60, 70, and 80 beats/min. The
magnitude of the Q-T interval prolongation is explored across all
doses in Fig. 1C.
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TABLE 1
Effects of LU111995 on idioventricular rhythm, QRS duration, and
ventricular CT
Control values were measured in 1-week intervals immediately before
LU111995 administration. LU111995 values are at 2 h postdrug
administration. QRS duration in control and after drug administration,
conduction time in control, and its changes after drug administration
 CT at heart pacing rate of 80 beats/min is presented. Values are
mean ± S.E.M. (n = 10).
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Fig. 3.
A, time course of LU111995 effects on the Q-T
interval at pacing rates of 60 and 130 beats/min. All doses of LU111995
are shown. Horizontal axis, time in hours after drug administration
(points at 0 h represent the Q-T interval before drug
administration). Values are mean ± S.E.M. (n = 10). * P < .05 for 10 mg/kg compared with
respective control (0 h). B, effects of LU111995 (10 mg/kg) on Q-T
interval at various pacing rates 4 h after drug administration.
Values are mean ± S.E.M. (n = 10). *
P < .05 compared with control at the same pacing
rate. C, dose-dependent effects of LU111995 on Q-T interval at pacing
rate of 60 beats/min and 4 h after drug administration. Values are
mean ± S.E.M. (n = 10). *
P < .05 compared with control (0 mg/kg).
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The effects of LU111995 on the ERP at heart rates of 60 and 130 beats/min are shown in Fig. 4A. All doses
prolonged the ERP significantly, with the maximal effect occurring at 2 to 4 h after drug administration. A similar picture was observed
at 80 beats/min (data not shown). The maximal percent increases were
5% at 1 mg/kg, 7% at 3 mg/kg, 12% at 10 mg/kg, and 9% at 15 mg/kg.
The changes in ERP at various pacing rates at 10 mg/kg and 4 h
after drug administration are shown in Fig. 4B. Note that significant
prolongation of ERP was seen across all rates tested. The magnitude of
ERP prolongation across all doses at a rate of 60 beats/min is
demonstrated in Fig. 4C. As in the case of the Q-T interval, a maximal
effect was observed at 10 mg/kg, and the effect decreased at 15 mg/kg.
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Fig. 4.
A, time course of LU111995 effects on the ERP at
pacing rates of 60 and 130 beats/min. All doses of LU111995 are shown.
Horizontal axis, time in hours after drug administration (points at
0 h represent the ERP before drug administration). Values are
mean ± S.E.M. (n = 10). *
P < .05 control (0 h) at the same dose. B, effects
of LU111995 (10 mg/kg) on the ERP at various pacing rates 4 h
after drug administration. Values are mean ± S.E.M.
(n = 10). * P < .05 compared
with control at the same pacing rate. C, dose-dependent effects of
LU111995 on the ERP at pacing rate of 60 beats/min and 4 h after
drug administration. Values are mean ± S.E.M.
(n = 10). * P < .05 compared
with control (0 mg/kg).
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Figure 5 illustrates the effects of
LU111995 on the ERP/Q-T ratio. ERP/Q-T increased at the 10 and 15 mg/kg doses, 2 and 4 h after drug administration (Fig. 5A). The
increase was 7%. With an acceleration of pacing rate, the effect
decreased; at 130 beats/min, no significant effect on ERP/Q-T ratio
was seen. The changes in ERP/Q-T at various pacing rates at 10 mg/kg
and 4 h after drug administration are shown in Fig. 5B.
Significant prolongation of ERP/Q-T was seen only at 60 beats/min. The
magnitude of effect across all doses at a stimulation rate of 60 beats/min is demonstrated in Fig. 5C. The drug induced a dose-dependent
increase of ERP/Q-T ratio that reached significance at 10 and 15 mg/kg.
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Fig. 5.
Time course of LU111995 effects on the ratio of ERP
to Q-T interval at a pacing rate of 60 beats/min. A, effects of all
doses. B, effect of the 10 mg/kg dose at 4 h. C, dose-dependent
effects at a pacing rate of 60 beats/min and at 4 h. Values are
mean ± S.E.M. (h = 10). * P < .05 compared with 0 h in A and C and control curve in B.
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Figure 6 demonstrates serum
concentrations of LU111995 and its metabolites achieved at each dosage
schedule. A maximal level of parent compound was achieved at 4 h
after administration and then slowly decreased. Maximal concentrations
of the metabolites LU195730 and LU273973 were 25- and 70-fold less,
respectively, than the parent compound. These levels were achieved at
2 h after LU111995 administration and then decayed faster than
that of the parent compound.
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Fig. 6.
Time courses of serum levels of LU111995 (A) and its
metabolites LU195730 (B) and LU273973 (C). All doses of LU111995 are
shown. Horizontal axis, time in hours after LU111995 administration.
Values are mean ± S.E.M. (n = 7 for 1 mg/kg,
n = 10 for 3, 10, and 15 mg/kg). *
P < .05 compared with 0 h (before LU111995
administration).
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In Vitro Study.
Figure 7
illustrates representative PF and M cell transmembrane potentials
recorded in control and in the presence of two LU111995 concentrations
(106 and 105
M), at the longest and shortest CLs. Control maximum
diastolic potential (MDP) at a CL of 1000 ms was 
92 ± 1 mV in
PFs and 91 ± 1 mV in M cells. There was no significant effect
of LU111995 on MDP at LU111995 concentrations up to 3 × 106 M at any cycle length (e.g., at
CL = 1000 ms, MDP = 91 ± 1 mV in PFs and 89 ± 1 mV in M cells at 3 × 106 M,
P > .05 compared with control). Only in PFs at the
fast rate of stimulation (300 ms) and at 1 × 105 M drug was a
significant decrease in MDP seen (to 89 ± 1 mV, P < .05). Similar results were seen for action
potential amplitude (A.P.D.) and
max in both tissues: in PFs,
amplitude and max were reduced
significantly only at CL of 300 ms and 105
M drug from 130 ± 1 to 126 ± 1 mV
amplitude and from 543 ± 28 to 455 ± 31 V/s
max (both P < .05).
In M cells, max, but not amplitude,
was reduced significantly at 3 × 106
M and 1 × 105
M drug at all cycle lengths. For example, at CL
of 1000 ms, control max was
351 ± 42 V/s, and this was reduced to 290 ± 20 V/s at 3 × 106 M and
293 ± 23 V/s at 1 × 105
M (both P < .05).
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Fig. 7.
Examples of the effects of LU111995 on PF and M cell
action potentials at CL of 2000 and 300 ms. Top, transmembrane action
potential. Bottom, max. Vertical
calibration is for the action potential and
max; horizontal calibration is for
the action potential. Numbers represent molar concentrations of the
compound. C, control.
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The most prominent effect of LU111995 was a lengthening of the APD in
both types of tissues. In PFs, at low stimulation rates, the compound
exhibited a concentration-dependent biphasic effect on APD to 90%
repolarization (APD90): the maximum prolongation was attained at 1 × 106 M,
and a decrease in APD90 was then seen at higher
concentrations (Fig. 8A). This decrease
was accompanied by significant shortening of APD to 50% repolarization
(APD50) (Fig. 8B). The
APD90 prolongation manifested reverse use
dependence: no prolongation took place at high stimulation rates.
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Fig. 8.
Concentration-dependent effects of LU111995 on PF APD
at 90% (A) and 50% (B) of full repolarization at all CLs. C, control.
* P < .05 compared with respective control
(n = 10).
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As in PFs, LU111995 induced reverse use-dependent prolongation of APD
in M cells (Fig. 9). At low stimulation
rates, about the same lengthening of APD90 and
APD50 was observed. The maximum effect was
attained at 3 × 106 M. In
contrast to PFs, no APD shortening was seen at high LU111995 concentrations. In three of six experiments with M cells, LU111995 of
3 × 106 M or more induced
EADs that developed at the end of the plateau (Fig. 7). These
depolarizations were observed only at the longest CL (2000 ms) and had
low amplitude. Triggered activity was never seen.
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Fig. 9.
Concentration-dependent effects of LU111995 on M cell
APD at 90% (A) and 50% (B) of full repolarization at all CLs. C,
control. * P < .05 compared with respective
control (n = 6).
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Discussion |
LU111995 had no effect on the variables measured in vivo except
for the Q-T interval and the ERP. The comparison of time courses of
Q-T interval changes (Fig. 3) and of LU111995 and its serum metabolite
levels (Fig. 9) suggests that the parent compound rather than its
metabolites was mainly responsible for Q-T prolongation. The extent of
Q-T increase was small, never reaching 10% even at its greatest
magnitude. Moreover, in clinical studies, at a maximum dosage of 200 mg/patient/day, the peak plasma level of parent compound attained was
approximately 500 ng/ml, with steady-state levels in the range of 50 to
100 ng/ml (Knoll, 1998). This suggests that the 3 mg/kg dose in dogs is
the likely clinical surrogate. This dose had minimal effects on the
Q-T interval.
The fact that the largest increase in Q-T interval occurred at the 10 mg/kg dose and that the Q-T interval decreased at the higher dose
suggests that in addition to inducing K+ channel
blockade, which would prolong the APD, the drug may reduce inward
plateau currents, thereby limiting the extent of prolongation of the
Q-T interval. In vitro results with PFs and M cells are consistent
with this suggestion. The drug significantly decreased APD50, a result consistent with inhibition of
Na+ and/or Ca2+ plateau
currents. Although no APD shortening was observed in M cells, a
decrease of the magnitude of APD lengthening occurred at the highest
drug concentration. Also consistent with an effect on inward
Na+ current was the decrease in
max of phase 0.
PFs are vulnerable to the effects of APD-prolonging agents. Their long
APD and steep APD-rate relationship make them a likely site for the
occurrence of EADs and triggered activity as seen especially at slow
stimulation rates (Brachman et al., 1983). In light of the above, the
action potential prolongation and reverse use dependence of LU111995
effects seen in PFs are a potential drawback. However, there was a
limit of LU111995-induced APD prolongation in PFs: maximal prolongation
was attained at 1 × 106 M,
and a shortening of APD occurred at higher concentrations. In this
setting of high LU111995 concentrations, EADs did not occur in PFs. In
contrast, EADs were seen in three of six M cell preparations but only
at the highest drug concentrations and at a cycle length (2000 ms)
outside the usual physiological range, although within the range of
long sinus pauses.
In vivo, the effect of LU111995 to prolong ERP was greater than its
effect on Q-T. The results of the experiments in vitro help explain
this action. In M cells, the drug induced a moderate, concentration-dependent decrease of
max that was independent of
simulation rate. Although not reaching a statistically significant level, a qualitatively similar effect was observed in PFs. This type of
local anesthetic action may prolong refractoriness and increase the
ERP/APD ratio (Bigger and Mandel, 1970; Gintant, 1990). Thus, even if
there were some arrhythmogenic potential of the Q-T prolongation, this
would tend to be counteracted by the greater prolongation of the ERP.
The inhibition of max implies a
decrease of conduction velocity that, however, was not seen in vivo.
This can be explained as follows: The LU111995-induced decrease of
max did not exceed 20%. The
speed of impulse propagation is directly related to the square root of
max (Buchman et al., 1985);
hence the max inhibition in our
study implies a less than 10% slowing of conduction velocity. This is
why no significant changes in CT and QRS duration was seen in the
experiments in vivo.
The results of the present study relate to an important additional
question: What type of isolated ventricular tissue adequately reflects
the effects of APD-prolonging agents on ventricular repolarization in
vivo? Free running PFs are widely used in vitro as a multicellular preparation. Because PFs have long APD and are sensitive to action potential prolonging effects of antiarrhythmic compounds (Varro et al.,
1986; Anyukhovsky et al., 1997), they are suitable for the estimation
of proarrhythmic propensity. However, to estimate in vitro the effects
of drugs on ventricular repolarization in vivo (on Q-T interval),
ventricular myocardial tissue is a more appropriate model. The
use of M cells here is reasonable because they constitute a significant
fraction of ventricular myocardium (Antzelevitch et al., 1994; Sicouri
and Antzelevitch, 1995; Anyukhovsky et al., 1996) and can contribute
importantly to T-wave configuration and the Q-T interval. In addition,
APD-prolonging agents produce a marked APD lengthening, EADs, and
triggered activity in M more than in endocardial or epicardial cells
(Antzelevitch and Sicouri, 1994; Antzelevitch et al., 1996; Shimizu and
Antzelevitch, 1997).
In summary, the results of the present study showed that in a model in
which heart rate was carefully controlled, LU111995 prolonged the Q-T
interval to an extent that is not considered of clinical importance.
Hence, in the absence of any contradictory information, there should be
minimal concern regarding the proarrhythmic potential of this
Q-T-prolonging drug when administered to an individual with a healthy heart.
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Acknowledgments |
We express our gratitude to Dietmar Schoebel for performing the
HPLC determinations, to Dr. Natalia Egorova for assistance with certain
of the experiments, and to Ms. Eileen Franey for her careful attention
to preparation of the manuscript.
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Footnotes |
Accepted for publication March 8, 1999.
Received for publication January 7, 1999.
1
This study was supported in part by U.S. Public Health
Service National Heart, Lung, and Blood Institute Grant HL53956 and by
Knoll AG.
2
Present address: Knoll AG, Ludwigshaten, Germany.
Send reprint requests to: Michael R. Rosen, M.D., Gustavus
A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College
of Physicians and Surgeons of Columbia University, Department of
Pharmacology, 630 West 168 St., PH7 West-321, New York, NY 10032. E-mail: emf3{at}Columbia.edu
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Abbreviations |
MDP, maximum diastolic potential;
APD, action
potential duration;
EAD, early afterdepolarization;
Vmax, maximum rate of rise of phase 0;
ERP, effective refractory period;
PF, Purkinje fiber;
CL, cycle length.
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References |
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Antzelevitch C and
Sicouri S
(1994)
Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: Role of M cells in generation of U waves, triggered activity and torsade de pointes.
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Antzelevitch C,
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Lukas A,
Nesterenko VV,
Liu DW and
Di Diego JM
(1994)
Regional differences in the electrophysiology of ventricular cells: Physiological and clinical implications, in
Cardiac Electrophysiology: From Cell to Bedside 2nd ed (Zipes DP andJalife J eds) pp 228-245,
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Abstract
Introduction
