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Vol. 290, Issue 3, 1417-1426, September 1999
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada (L.M.S., S.E.J., T.O., T.F.M.); Nihon University School of Medicine, 2nd Department of Internal Medicine, Itabashi-ku, Tokyo, Japan (Y.K.); and Sepracor Inc., Marlborough, Massachusetts (J.R.M.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Terodiline was widely prescribed for urinary incontinence before reports of adverse cardiac effects that included bradycardia, QT lengthening, and ventricular tachyarrhythmia. The present study on guinea pig papillary muscles and ventricular myocytes was undertaken to gain insight into the cardioactive properties of the drug. Clinically relevant concentrations (<10 µM) of terodiline lengthened the action potential duration by up to 12%; higher concentrations shortened the duration in a concentration-dependent manner. The drug depressed maximal upstroke velocity in a use-dependent manner; the IC50 value was near 150 µM in muscles driven at 1 Hz, 60 µM at 3 Hz, 38 µM at 5 Hz, and 3 µM at 1 Hz in muscles depolarized with 14 mM K+. Submicromolar terodiline frequently had a small positive inotropic effect, whereas micromolar concentrations depressed force in a frequency-dependent manner. Voltage-clamp results on myocytes indicate that terodiline inhibits three membrane currents that govern repolarization: 1) E4031-sensitive, rapidly activating K+ current with an IC50 value near 0.7 µM as previously reported; 2) slowly activating, delayed-rectifier K+ current with an IC50 value of 26 µM; and 3) L-type Ca2+ current with an IC50 value of 12 µM. These findings are correlated with the changes in action potential configuration and developed tension and discussed in relation to the cardiotoxic effects of the drug.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Terodiline,
a drug with structural similarities to prenylamine and fendiline, was
originally marketed in Sweden in the mid-1960s as a prophylactic agent
in angina pectoris. The results of studies on isolated bronchial muscle
(Iravani and Melville, 1975
) and patients with obstructive pulmonary
disease (Castenfors et al., 1975) suggested that terodiline had
anticholinergic properties. Anticholinergic activity, as well as
Ca2+ antagonism, was documented in subsequent
investigations on isolated bladder (Husted et al., 1980). Based on this
spectrum of activity, terodiline was investigated for the treatment of
urinary incontinence in adults and of nocturnal enuresis in children
(Elmér, 1984; Peters, 1984). The outcome of these trials was
withdrawal of the drug as an antianginal agent in 1985 and
reintroduction in more than 20 countries in 1986 as an effective
treatment for urinary incontinence. It quickly became the drug of
choice for this condition in Europe (Langtry and McTavish, 1990) but
was withdrawn in 1991 after reports of serious cardiac side effects,
including bradycardia, atrioventricular block, prolongation of the Q-T
interval of the electrocardiogram, and ventricular tachyarrhythmia
(torsades de pointes) (Connolly et al., 1991; Stewart et al., 1992).
The drug is currently available for clinical investigation and is a
prototype structure for the development of newer drugs for the
treatment of unstable bladder (Take et al., 1996).
Although the specific electrophysiological mechanism or mechanisms that
trigger drug-induced torsades are uncertain (Roden et al., 1996;
Woosley, 1996), knowledge of the mechanisms of cardiac action of
various torsades-inducing drugs contributes to improved understanding
of the arrhythmia. In this regard, there have been investigations into
the alterations of electrophysiological parameters, contraction, and
membrane ionic currents caused by class Ia antiarrhythmic quinidine
(Nawrath, 1981; Imaizumi and Giles, 1987), class III antiarrhythmic
sotalol (Campbell, 1987), the antidepressent imipramine (Valenzuela et
al., 1994), antihistamines terfenadine and astemizole (Berul and Morad,
1995; Salata et al., 1995), and the antibiotic erythromycin (Nattel et
al., 1990; Daleau et al., 1995).
To our knowledge, there have been two previous studies on the direct
effects of terodiline on cardiac cell function. Pressler et al. (1995)
found that exposure of canine Purkinje fibers to clinically relevant
concentrations (1-10 µM) of terodiline shortened the action
potential duration (APD; 50% repolarization) by ~40%. More
recently, we determined that the rapidly activating component of
delayed-rectifier K+ current
(IKr) in guinea pig ventricular myocytes is
inhibited by terodiline with IC50 values near 0.7 µM and that slowly activating IKs is inhibited
by high concentrations of the drug (Jones et al., 1998). Although the
latter actions would have lengthening influences on venticular action
potentials and may therefore be important factors in QT lengthening, it
is unclear whether other actions of the drug on ventricular cells might
not outweigh the lengthening influences and shorten the action
potential as reported for Purkinje fibers. To obtain further
information on these and other aspects of terodiline action on
ventricular muscle, we recorded action potentials and developed tension
in guinea pig papillary muscles treated with 0.1 to 100 µM
concentrations of the drug, and we measured Ca2+
and K+ membrane currents in guinea pig
ventricular myocytes.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Papillary Muscles. Papillary muscles were obtained from the right ventricles of adult guinea pig hearts. The guinea pigs (250-350 g) were sacrificed by cervical dislocation, and the hearts were quickly removed and placed in oxygenated (95% O2/5% CO2) Krebs' solution that contained 113.1 mM NaCl, 4.6 mM KCl, 2.45 mM CaCl2, 1.15 mM MgCl2, 21.9 mM NaHCO3, 3.48 mM NaH2PO4, and 10.0 mM glucose (pH 7.4). Muscles were excised and mounted in a Perspex bath (0.25 ml volume) perfused with solution (36 ± 0.2°C) at 4 to 6 ml/min. The mural end of the muscle was fixed by a clamp, and the tendinous end was fixed by a pin or attached to an isometric force transducer (model UC2; Gould Statham, Oxnard, CA). Muscles were adjusted to a length that produced ~75% peak developed tension (resting tension of 50-90 mg).
Muscles were stimulated at 1 Hz with 3-ms-long pulses of 1.2-times threshold strength via a bipolar Ag/AgCl electrode and equilibrated for 60 to 90 min before data collection. When normal Krebs' solution was replaced by Krebs' solution with higher (8-14 mM) than standard (4.6 mM) K+ concentration, there was no compensation for the change in osmolality. Action potentials were recorded with a high-input impedance amplifier (model 750; WP Instruments, New Haven, CT) using conventional microelectrodes filled with 3 M KCl (resistance 8-15 M
), and the upstroke was electronically differentiated to
record upstroke velocity (
). The action potentials were
displayed on a storage oscilloscope (model 5103N; Tektronix, Beaverton,
OR) and recorded on film, with a chart recorder (model RS 3400; Gould,
Cleveland, OH) and/or by computer via Axoscope (Axon Instruments,
Foster City, CA).
Ventricular Myocytes.
Single ventricular myocytes were
enzymatically isolated as described previously (Ogura et al., 1995).
The excised hearts were mounted on a Langendorff column and
retrogradely perfused (37°C) through the aorta with
Ca2+-free Tyrode's solution containing
collagenase (0.08-0.12 mg/ml; Yakult Pharmaceutical Co., Tokyo, Japan)
for 10 to 15 min. The cells were dispersed and stored at 22°C in a
high-K+, low-Na+ solution
supplemented with 50 mM glutamic acid and 20 mM taurine. A few drops of
the cell suspension were placed in a 0.3-ml perfusion chamber mounted
on an inverted microscope stage. After the cells had settled to the
bottom, the chamber was perfused (~2 ml/min) with Tyrode's solution
at 36°C. The Tyrode's solution contained 140 mM NaCl, 5.4 mM KCl,
1.8 mM CaCl2, 1 mM MgCl2,
10 mM glucose, and 5 mM HEPES, pH 7.4 with NaOH. In some experiments,
this solution was replaced by K+-free Tyrode's
or K+-, Ca2+-free Tyrode's
that included 0.2 mM Cd2+.
when filled with pipette solution, and liquid junction
potentials between external and pipette-filling solution were nulled
before patch formation. Series resistance ranged between 3 and 7 M
and was compensated by 60 to 80%. Membrane current signals were
filtered at 3 kHz and digitized with an A/D converter (Digidata 1200A;
Axon Instruments) and pCLAMP software (Axon Instruments) at a sampling
rate of 8 kHz before analysis.
Drugs.
Terodiline was supplied by Sepracor Inc.
(Marlborough, MA) and freshly dissolved in dimethyl sulfoxide (DMSO)
(Sigma Chemical Co., St. Louis, MO) immediately before use. The highest
final concentration of DMSO in the superfusate was 0.1% (for 100 µM terodiline), a DMSO concentration that has no significant effects on
electrical and contractile activity in guinea pig papillary muscles or
on Ca2+ and K+ currents in
guinea pig ventricular myocytes (Ogura et al., 1995). E4031 was
obtained from Eisai (Tokyo, Japan) and handled in the same manner as terodiline.
Statistics. Results are expressed as mean ± S.E., and single comparisons were made using Student's t test. Differences were considered to be significant when p < .05.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Concentration-Dependent Effects of Terodiline on Action Potential Parameters
Duration and Amplitude.
The records in Fig.
1, A-C, illustrate the effects of 0.3, 3, and 15 µM terodiline on the configuration of action potentials in
guinea pig papillary muscles. The lower concentrations lengthened the
action potential, whereas 15 µM lowered the plateau voltage and
slowed phase 3 repolarization.
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10 µM
terodiline and slightly depressed by higher concentrations.
Control and drug-treated muscles were subsequently stimulated at 3 Hz
for 5 min and at 5 Hz for an additional 3 min. In the control muscles,
APD20 declined to 74 ± 2% (3 Hz) and
57 ± 2% (5 Hz) of the 0-min 1-Hz duration,
APD90 declined to 79 ± 1% (3 Hz) and
62 ± 2% (5 Hz), and APA declined by 2 to 4 mV (Fig.
2). APD20 and
APD90 also declined when terodiline-treated
muscles were driven at 3 and 5 Hz, with the overall outcome that the
increases in rate had little effect on the percentage changes induced
by the drug (Fig. 2A). APA in drug-treated tissues was also affected by
rate; reductions at high concentrations were up to 35 mV larger at 5 Hz
than at 1 Hz, due primarily to reductions in overshoot (Fig. 2C).
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Maximal Upstroke Velocity.
Terodiline reduced maximal upstroke
velocity (max) to 97 ± 1% (3 µM),
78 ± 4% (30 µM), and 57 ± 6% (100 µM) in muscles
driven at 1 Hz (Fig. 3A). Depolarization
of the resting membrane was not a factor in the reductions caused by
<30 µM drug but may have been at 100 µM (depolarization of 2-8
mV, n = 6). For reference, Pressler et al. (1995) found
that 
25 µM terodiline caused marked depolarization and
inexcitability of canine Purkinje fibers.
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max in terodiline-treated muscles, with
estimated IC50 values declining from 150 µM (1 Hz) to 60 and 38 µM at 3 and 5 Hz, respectively (Fig. 3A). Lowering
the resting potential by elevating external K+
concentration from the standard 4.6 mM also affected the inhibition of
max. For example, depolarization from
~
89 to 62 mV with 14 mM K+ resulted in
marked inhibition of (reduced) max by
normally ineffective 0.3 µM terodiline (Fig. 3C) and abnormal
beat-to-beat variation in plateau generation with 3 µM drug (Fig.
3D). max data obtained in experiments with
4.6, 8, 11.6, and 14 mM solutions indicate that the
IC50 values declined from 
150 µM in normally polarized muscles to 3 µM in muscles depolarized with 14 mM
K+ (Fig. 3E).
Effects on Force of Contraction
Terodiline had concentration-dependent effects on developed
tension in muscles stimulated at 1 Hz for 30 min. At the lowest concentration tested (0.1 µM), the drug induced a 5 to 15% increase in 6 of 11 muscles. Higher concentrations were purely inhibitory (IC50 near 15 µM), in part due to an
abbreviation of the time to peak tension (Fig.
4, A-C). Increasing the stimulation
rate to 3 and 5 Hz increased developed tension in muscles
treated with 1 µM terodiline to the same degree as in control
muscles (Fig. 4C). However, the frequency-dependent inotropy was
blunted in muscles treated with 3 to 5 µM terodiline and
"reversed" in some muscles treated with 10 to 100 µM drug (Fig.
4C).
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Effects on Membrane Currents
Overview.
The records and analysis shown in Fig.
5 provide an overview of the
concentration-dependent inhibitory effects of terodiline on membrane
currents in guinea pig ventricular myocytes superfused with Tyrode's
solution and dialyzed with K+ solution. The
myocytes were depolarized for 500 ms from prepulse 40 mV to elicit
inward L-type Ca2+ current (ICa,
L) and outward delayed-rectifier K+
current (IK) and repolarized to 40 mV to elicit
outward tail IK. Exposure to 0.3 µM terodiline
for 8 min had little effect on either peak ICa,
L or time-dependent IK at positive
potentials, but it reduced tail IK at 40 mV
(Fig. 5A). However, exposures to higher concentrations of the drug (10 and 100 µM) caused reductions in ICa, L and
time-dependent IK, as well as further reductions in tail IK (Fig. 5, B-D).
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Effects on IK.
Guinea pig ventricular
IK is composed of IKr (a
component that is rapidly activated at potentials up to ~10 mV and
specifically inhibited by E4031) and IKs (a
component that is slowly activated at positive potentials) (Sanguinetti
and Jurkiewicz, 1990). Figure 6A, a-c,
illustrates that tail IK measured after 500-ms
depolarizations can be resolved into tail IKr and
tail IKs by the application of 3 µM E4031, that
low concentrations of terodiline suppress the E4031-sensitive tail, and
that 30 µM terodiline reduces the amplitude of the E4031-insensitive
tail by ~50%. A more detailed analysis of terodiline action on tail
IKr indicates that the IC50 value is near 0.7 µM (Jones et al., 1998).
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) and depolarized for 2 s to positive potentials for
measurement of time-dependent outward currents. Records from
representative myocytes exposed to 5 and 100 µM terodiline indicate
that the drug had concentration-dependent inhibitory effects on
IKs elicited by depolarizations up to 80 mV (Fig.
6B, a and b). The effects on current amplitude at 40 mV were used to
determine the concentration-response relationship, and the data are
well described by a Hill equation with an IC50 value of 26 µM and a coefficient of 0.85 (Fig. 6B, c).
Effects on Peak ICa, L.
To evaluate the effects of
terodiline on peak ICa,L, myocytes that were
superfused and dialyzed with K+-free solutions
(to minimize K+ currents) were pulsed at 0.1 Hz
with 200-ms steps from 40 to 0 mV, treated with terodiline, and then
exposed to 0.4 mM Cd2+ to establish the
zero-ICa,L background current level. The drug reduced the amplitude of ICa,L in a
concentration-dependent manner (Fig. 7, A
and B), and this action was sensitive to pulsing rate: in three
myocytes, trains of 25 pulses at 3 Hz depressed
ICa,L (0.1 Hz) to a much larger extent in the
presence of the drug than in its absence (Fig. 6C).
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Relation to Action Potential and Contraction. The relevance of the voltage-clamp findings to muscle activity was examined by measuring the effects of 3 µM terodiline on papillary muscles that were pretreated with 5 µM E4031. E4031 slowed repolarization at potentials below ~15 mV (Fig. 7E), and the stable APD90 after 15 min was 127 ± 2% of control duration (n = 5). Subsequent exposure to 3 µM terodiline for 30 min lowered the plateau voltage and reduced the lengthened APD90 by 9 ± 2% (n = 5). It seems likely that the plateau reduction and APD90 shortening were due to inhibition of ICa, L and that this inhibition was primarily responsible for the accompanying negative inotropy [after 15-min E4031, developed tension was 126 ± 3% of 0-min control (n = 5); after an additional 30-min terodiline, developed tension was 71 ± 6%].
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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APD, Contraction, and Membrane Currents.
The findings on APD,
contraction, and membrane currents are best correlated by considering
them under three terodiline concentration ranges: submicromolar (<1
µM), micromolar (1-5 µM), and high micromolar (10 µM).
Submicromolar concentrations induced small but significant lengthenings
of the action potential that were almost certainly due to partial
inhibition of IKr (IC50 ~ 0.7 µM), and micromolar concentrations induced additional lengthening
as expected from more complete inhibition of IKr.
However, the degree of lengthening (e.g., 12% with 3 µM) was smaller
than the 27% lengthening in muscles treated with
IKr-inhibiting E4031. The most likely explanation for this shortfall is that the lengthening influence related to IKr inhibition was partially offset by the
shortening influence related to reduced peak
ICa,L (IC50 = 12 µM). In
accord with this interpretation, 3 µM terodiline shortened the APD in
muscles pretreated with E4031. High micromolar terodiline depressed
max and the plateau, and this was most
likely due to inhibition of Na+ current and
additional inhibition of ICa,L. The
plateau-abbreviating influence related to these actions is likely to
have been at least partially counteracted by a lengthening influence
related to inhibition of IKs
(IC50 = 26 µM). Finally, there were indications
(lower resting potential; lower outward holding current at 40 mV)
that inhibition of inward-rectifying K+ current
may have slowed phase 3 repolarization in muscles treated with high
concentrations of the drug.
), and we found that 5 µM E4031 augmented force
by 26% in accord with findings on rabbit papillary muscles (Cingolani
et al., 1991). The link between inhibition of IKr
and positive inotropy is a lengthening of the action potential that
allows a larger influx of Ca2+ (compare with
Clark et al., 1996). Although action potential lengthening was more
pronounced with micromolar than with submicromolar terodiline, this did
not result in a larger positive inotropy. On the contrary, 1 µM
terodiline depressed contraction, and this was almost certainly related
to the concentration-dependent reduction in ICa,L
(see Shuba and McDonald, 1994; Grantham and Cannell, 1996). In
addition, there may well be a correlation between terodiline-induced abbreviation in time to peak tension (Fig. 4A) and terodiline-induced acceleration of the inactivation of ICa,L (Fig.
7A). A further link between ICa,L and contraction
in drug-treated preparations was that both processes were inhibited by
increases in pulsing rate. Kura et al. (1992) suggested that terodiline
block of smooth muscle ICa,L is rate-dependent.
Frequency- and Voltage-Dependent Inhibition of
max
Significant inhibition of max occurred
with 3 µM terodiline (reduction to 97 ± 1%) when muscles were
driven at 1 Hz, and with 1 µM when they were driven at 5 Hz.
Drug-induced inhibition of max was also
accentuated when muscles driven at 1 Hz were partially depolarized with
elevated K+; in the 14 mM
K+ trials (resting potential lowered from ~89
to 62 mV), the IC50 value for inhibition by
terodiline was near 3 µM (or roughly five times lower than the
IC50 value for tetrodotoxin in normally polarized guinea pig ventricular preparations; Baer et al., 1976).
max findings on papillary
muscles correlate with those reported by Pressler et al. (1995) in
their study on canine cardiac Purkinje fibers. For example, they found
that significant (~11%) inhibition required 5 µM terodiline when
the mean resting potential was 90 mV (2.7 mM
K+) but only 2 µM when it was 82 mV (5.4 mM
K+) and that inhibition by 10 µM drug was 25%
larger at 2 Hz than at 0.67 Hz. These investigators also recorded a
10% lengthening of the His-ventricle interval in anesthesized dogs
when plasma terodiline was ~4 µM and attributed it to slowed
conduction related to Na+ channel block by the drug.
Adverse Reactions to Terodiline.
The adverse cardiac effects
of terodiline include slowing of heart rate, atrioventricular
conduction disturbances, QT prolongation, and malignant ventricular
tachycardia (torsades de pointes) (Connolly et al., 1991; Stewart et
al., 1992). Because both Na+ and Ca2+ currents
are essential for pacemaking and nodal conduction (Munk et al., 1996;
Kodama et al., 1997), it seems likely that inhibition of these currents
contributes to the bradycardia and atrioventricular block observed in
patients receiving terodiline. In addition, action potential
lengthening and more positive diastolic potential related to inhibition
of delayed-rectifier K+ current may make important
contributions to these disturbances (see Ono and Ito, 1995).
). The
therapeutic concentration is ~1.5 µM, and a concentration of 9.3 µM was measured in one elderly patient (Connolly et al., 1991).
Action potentials in guinea pig papillary muscles were lengthened in
the presence of 0.1 to 10 µM terodiline, and although this
lengthening was moderate (peak 12% at 3 µM), it is in good agreement
with the degree of lengthening of the monophasic action potential in
dogs (Pressler et al., 1995) and rate-corrected Q-T interval in dogs
(Natsukawa et al., 1998) and humans (Stewart et al., 1992; Thomas et
al., 1995).
Torsades de pointes is a malignant ventricular arrhythmia associated
with a wide variety of drugs administered for their antiarrhythmic properties (e.g., quinidine, sotalol, amiodarone) or for entirely different purposes (e.g., terfenadine, erythromycin, terodiline), with
the common outcome that they lengthen the Q-T interval (Roden et al.,
1996; Woosley, 1996). The electrophysiological alterations responsible
for this arrhythmia are not fully characterized, but it has been
postulated that bradycardia, action potential prolongation, and early
afterdepolarizations are crucial factors (Jackman et al., 1988; Thomas
et al., 1995; Roden et al., 1996). We found no indications of either
early or delayed afterdepolarizations in terodiline-treated muscles,
most likely because development of these arrhythmogenic events is
inhibited when excitatory inward currents are suppressed (compare with
Hayashi et al., 1987; January and Shorofsky, 1990; Woosley, 1996).
These predicted antiarrhythmic influences of terodiline
notwithstanding, concomitant blockade of Na+ and
K+ channels has proarrhythmic potential related to slowed
conduction and increased heterogeneity in repolarization time courses
(see Follmer and Colatsky, 1990; Sicouri and Antzelevitch, 1993),
especially when the block of the Na+ channels is
use-dependent (Starmer et al., 1991). Unlike guinea pig myocardium,
transient outward current contributes to early repolarization in the
human myocardium (Beuckelmann et al., 1993), and it is possible that
terodiline affects this current in a proarrhythmic manner. Finally,
other factors that predispose to acquired ventricular tachyarrhythmia
(e.g., hypokalemia, myocardial ischemia, antiarrhythmic drugs) may be
important in the cardiotoxicity of terodiline (Thomas et al., 1995).
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Acknowledgments |
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We thank Dr. An-Chi Guo and Gina Dickie for excellent technical assistance.
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Footnotes |
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Accepted for publication April 21, 1999.
Received for publication February 24, 1998.
1 This work was supported by the Medical Research Council of Canada, the Heart and Stroke Foundation of New Brunswick, and Sepracor Inc. L.M.S. was supported by an award from the Dalhousie Medical Research Foundation.
Send reprint requests to: Dr. T. F. McDonald, Department of Physiology and Biophysics, Dalhousie University, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. E-mail: terence.mcdonald{at}dal.ca
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Abbreviations |
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, upstroke velocity;
APA, action
potential amplitude;
APD, action potential duration;
APD20, action potential duration at 20% repolarization level;
APD90, action potential duration at 90% repolarization
level;
DMSO, dimethyl sulfoxide;
ICa, L, L-type
Ca2+ current;
IK, delayed-rectifier
K+ current;
IK1, inward-rectifying
K+ current;
IKr, rapidly activating component
of IK;
IKs, slowly activating component of
IK;
max, maximal upstroke velocity.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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, n = 14)
and from muscles treated with 0.3 µM terodiline (TER; 
,
n = 8). The data are expressed as percentages of
values measured at the start (0 min) of the 30-min trials. E, summary
of concentration-dependent effects of terodiline on APD20,
APD90, and APA. Test muscles were exposed to a single
concentration of the drug for 30 min, and measurements at this time
were expressed as percentages of 0-min values. Number of muscles in
parentheses. 
p < .05, *p < .001 versus control.
