(Circulation. 1995;91:3010-3016.)
© 1995 American Heart Association, Inc.
Articles |
Erythromycin Blocks the Rapid Component of the Delayed Rectifier Potassium Current and Lengthens Repolarization of Guinea Pig Ventricular Myocytes
From Quebec Heart Institute, Laval Hospital and School of Pharmacy, Laval University, Ste-Foy, Quebec, Canada.
Correspondence to Jacques Turgeon, PhD, Quebec Heart Institute, Research Center, Laval Hospital, 2725, Chemin Ste-Foy, Ste-Foy, Quebec, Canada, G1V 4G5.
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Abstract |
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Background Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia. The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K+ currents involved in cardiac repolarization.
Methods and Results A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms. In this model, erythromycin 10-4 mol/L increased monophasic action potential duration measured at 90% repolarization (MAPD90) by 40±7 ms. Increase in MAPD90 was reproducibly observed in seven hearts studied. To study the mechanism of these effects on cardiac repolarization, a second set of experiments was performed in isolated guinea pig ventricular myocytes using the whole cell configuration of the patch-clamp technique. In these cells, erythromycin 10-4 mol/L decreased by about 40% (P<.05 versus baseline) the time-dependent outward K+ current elicited by short depolarizations (250 ms) to low depolarizing voltages (-20 to 0 mV). In contrast, the drug was without significant effects on the time-dependent K+ current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly IK1), and on the slow inward calcium current.
Conclusions The outward time-dependent K+ current blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for IKr. Selective block of this component of IK gives an explanation for the effects of erythromycin on cardiac repolarization. These effects were observed at clinically relevant concentrations reached after intravenous administration of the drug and warn for potential interactions with other action potential–lengthening drugs.
Key Words: action potentials • potassium • torsade de pointes • calcium channels
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Several cases of polymorphic ventricular tachycardia (torsade de pointes) due to excessive lengthening of cardiac repolarization have been described after intravenous or oral administration of erythromycin in humans.1 2 3 4 5 6 In some of those patients, predisposing factors to torsade de pointes3 or concomitant therapy with action potential–prolonging drugs3 7 was present. In contrast, in others, none of these predisposing factors could be identified.1 2 4 5 6
Changes in cardiac electrical activity caused by erythromycin were recently studied in muscle strips isolated from canine ventricle and in anesthetized dogs.8 9 Results obtained from these studies demonstrated that erythromycin can prolong action potential duration of Purkinje fibers, papillary muscles, and M-cells and may promote the development of early afterdepolarizations.8 9 Effects of erythromycin on cardiac repolarization were suggested to be due to either block of cardiac repolarizing currents (such as the delayed rectifier) or to stimulation of the sympathetic nervous system.2 8
In this study, effects of erythromycin on potassium and calcium currents involved in repolarization of guinea pig ventricular myocytes were studied using the whole cell configuration of the patch-clamp technique. Moreover, action potential–lengthening effects of erythromycin were studied in isolated guinea pig hearts perfused in the Langendorff mode using monophasic action potential signal measured at 90% repolarization (MAPD90) as an index of cardiac repolarization.10 11 Results obtained demonstrated selective block of the rapid component of the delayed rectifier potassium current (IKr) and lengthening of monophasic action potential. These results have been presented in abstract form.12
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Methods |
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Isolated Heart Experiments
Experiments were performed in accordance with our institutional guidelines on animal use in research. Animals were housed and maintained in compliance with the Guide to the Care and Use of Experimental Animals of the Canadian Council on Animal Care.
Heart Isolation and Perfusion Technique
Male Hartley
guinea pigs (weight, 300 to 350 g; Charles River
Laboratories) were anticoagulated by injection of heparin sodium (400
IU IP). Twenty minutes later, animals were anesthetized with sodium
pentobarbital (25 mg · kg-1 IP; Somnotol, MTC
Pharmaceuticals), and the hearts were rapidly extirpated and immersed
in cold (4°C) Krebs-Henseleit buffer. Each heart was cannulated and
retrogradely perfused via the aorta at a constant pressure equivalent
to 100 cm of H2O. To permit rapid exchange in perfusion
solutions, a double "baker" heart perfusion system (Ealing
Scientific Limited) and two parallel liquid columns were used.
Krebs-Henseleit bicarbonate buffer, which contained (in mmol/L) glucose
11.2, KCl 4.7, CaCl2 1.2, NaHCO3 25, NaCl
118.5, MgSO4 25, and KH2PO4 1.2,
was used as a perfusate. This solution was continually gassed with 95%
oxygen plus 5% carbon dioxide (pH 7.4, 37°C) and filtered through a
5.0-µm cellulose acetate membrane to remove any particulate
contaminants.
Electrophysiological Measurements
Hearts were electrically stimulated (programmable stimulator
model 5325, Medtronic) at a basic cycle length of 250 ms (4 Hz) at
three times threshold via two silver electrodes implanted in the
epicardium of the right ventricle. A monophasic action potential
catheter (Langendorff probe model 225, EP Technologies Inc) was
introduced in the left ventricle through the mitral valve and securely
positioned to obtain a visually adequate signal (amplitude >5 mV,
stable phase 4). During the protocol, monophasic action potential
signals were recorded on a computer for a duration of 6 seconds at
30-second intervals (digital sampling rate, 1 kHz) and stored on hard
disk for analysis. Monophasic action potential duration was
determined by analyzing all complete beats in the 6-second sample for
MAPD90. These values were averaged using a routine designed
specifically for this purpose and incorporated into the computer
program (CVRP92 Cardiovascular Research Partner, Datton System Enr). At
least 10 complexes were used for each measurement.
Protocols
A total of seven hearts were perfused
during a control period of
3.5 minutes to assess stability of the monophasic action potential
signal. Thereafter, perfusion solution was switched to one containing
erythromycin (Sigma Chemicals Inc) 10-4 mol/L for a period
of 5 minutes. Perfusion with Krebs-Henseleit buffer containing no drug
then was restarted.
Statistical Analysis
Data were
analyzed using a Student's paired t test.
The last three values of MAPD90 determined at baseline
(2.5, 3.0, and 3.5 minutes) and during the drug infusion period (7.5,
8.0, and 8.5 minutes) were averaged and compared. Statistical
significance was set at P<.05. All values are expressed as
mean±SD.
Patch-Clamp Experiments
Cell Preparation and Solutions
Experiments were performed on single ventricular myocytes
obtained from adult guinea pig hearts by use of an enzymatic
dissociation technique. All solutions used during the cell isolation
procedure were oxygenated and maintained at 37°C. The hearts were
mounted on a Langendorff apparatus and rinsed for 2 minutes with a
calcium-free solution (solution A) containing (in mmol/L) NaCl 132, KCl
4.8, MgCl2 1.2, HEPES 10, and glucose 5; pH was adjusted to
7.35 with NaOH. The hearts then were perfused with a
low-sodium–high-potassium HEPES-buffered solution (solution B, in
mmol/L: NaCl 17, HEPES 10, KCl 5.4, K-glutamate 128, and
MgCl2 1) for a period of 2 minutes. At the end of this
period, perfusion of solution B containing collagenase
(final concentration, 300 U/mL; Worthington Biochemical Corp) and
protease (0.7 U/mL; Sigma Chemicals Inc) was started and continued
until the system pressure dropped to 15 mm Hg (approximately 15
minutes). Hearts were reperfused with solution B for 3 minutes and then
with a solution made of a mixture of solution B and solution A (85:15)
containing 200 µmol/L CaCl2. Hearts were finally perfused
with a solution made of 60% solution B and 40% solution A
containing 500 µmol/L CaCl2. At this point, the
ventricles were cut down and minced slightly. After filtration through
200-µm nylon mesh, the dispersed cells were washed by centrifugation
(200 rpm, 2 minutes), resuspended in solution A containing 1.8 mmol/L
CaCl2, and maintained at 30°C before use.
The external solution used to superfuse cells during recordings of currents contained (in mmol/L) NaCl 145, KCl 4, MgCl2 1, HEPES 10, and glucose 5. Nisoldipine (Bayer Leverkusen) 2.10-7 mol/L was added to eliminate the slow calcium inward current (Isi), and Ca2+ was omitted in the extracellular solution to shift IKs activation to positive potentials.13 The pipette solution contained (in mmol/L) MgCl2 2, CaCl2 1, EGTA 11, MgATP 5, K2ATP 5, and HEPES 10; pH was adjusted to 7.2 with KOH, and final potassium concentration was fixed at 130 mmol/L with KCl.
The erythromycin 10-4 mol/L solution was prepared daily by dissolving 7.34 mg of the base in 100 mL of the physiological solution perfusing the cells.
Electrophysiological Measurements
A small aliquot of dissociated cells was placed in a 0.5-mL
chamber mounted on the stage of an inverted microscope (model CK2,
Olympus). Cells were allowed to adhere to the coverslip at the bottom
of the chamber and then were superfused continuously with the external
solution prewarmed (30°C) by a Peltier device (Medical System Corp).
In our experiments, complete replacement of external solution contained
in the chamber was achieved within 2 to 3 minutes when the superfusion
rate was 2 mL/min.
All currents were recorded in the whole cell,
voltage-clamp
configuration of the patch-clamp technique using an Axopatch-1D
amplifier (Axon Instruments Inc). Voltage-clamp command pulses were
generated by a 12-bit digital-to-analog convertor (model TL/1, Axon
Instruments Inc) controlled by the PCLAMP software
package (version 4.05b, Axon Instruments Inc). Heat-polished
patch-clamp pipette electrodes used (capillary glass from Radnoti Glass
Technology Inc; Starebore glass capillary tubing, 1.2 mm OD) had a tip
resistance of 3 to 5 M
(when filled with the pipette solution).
Series resistance was compensated 50% to 80% to improve fidelity of
whole cell voltage-clamp measurements.
Protocols
Rod-shaped cells with clear cross-striations, resting potential
of at least -78 mV, and stable delayed rectifier (IK) and
inward rectifier (IK1) currents (as assessed during a
baseline period of at least 4 minutes) were used. Effects of
erythromycin on the rapidly (IKr) and slowly
(IKs) activating components of IK were studied
in cells held at -40 mV (to inactivate INa) and
depolarized by pulses lasting either 250 ms (IK250) or 5000
ms (IK5000). Test potentials of depolarizing pulses varied
between -20 and +50 mV. IK was measured from the peak
magnitude of tail current obtained upon repolarization to -40 mV. A
voltage ramp was used to obtain the current-voltage (I-V) relation of
the inward rectifier potassium current (IK1). In this
protocol, cells were held at -40 mV before their membrane potential
was changed from -50 to -100 mV in 250 ms.
Slow inward calcium current (ICa-L) was elicited by depolarizing pulses (-20 to +50 mV) lasting 250 ms from a holding potential of -40 mV. Peak amplitude was measured at all test potentials. In these experiments, nisoldipine was omitted in the bath solution and calcium concentration was fixed at 1.8 mmol/L.
Data Storage and Analysis
Currents were low-pass
filtered at either 2 kHz
(IK250 and IK1 protocols) or 100 Hz
(IK5000 protocol) by a four-pole Bessel filter (-3
dB/octave). Currents were sampled at 4 kHz (IK1), 2 kHz
(IK250), and 400 Hz (IK5000) by use of a 12-bit
analog-to-digital convertor (TL-1 DMA, Axon Instruments Inc) and stored
on hard disk for subsequent analysis. Data are presented as
mean±SD; statistically significant block of IK250 and
IK5000 was tested by Hotelling's
T2
test, and the difference between block of IK250 and
IK5000 was assessed by a Student's t
test.14 Best fit of data was established by comparison of
2 analysis. The level of statistical
significance was set at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Experiments performed in isolated guinea pig hearts (n=7) demonstrated that erythromycin caused a significant increase in MAPD90 in all of the seven hearts tested (Fig 1
).
Overall mean increase in MAPD90 was
40±7 ms, and a typical example of monophasic action potential recorded
at baseline and during perfusion of erythromycin 10-4
mol/L is illustrated (Fig 1). Effects of erythromycin were time
related
and fully reversible upon removal of the drug (Fig 1).
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To understand the mechanism related to the effects of erythromycin on
cardiac repolarization, experiments were conducted in isolated cells
using the patch-clamp technique. Fig 2 shows activating
and tail currents of IK elicited by pulses (5000 ms)
varying from -20 to +50 mV followed by repolarization to -40
mV in a
cell perfused under control conditions. At test potentials of -20,
-10, and 0 mV, a time-dependent outward current activates rapidly,
reaching a steady-state level after few hundred milliseconds.
Respective activating and tail current amplitudes obtained between -20
and 0 mV were compared: While activating current amplitude measured at
0 mV is decreased compared with that measured at -10 mV, increasing
test potential increases IK tail current amplitude. These
behaviors are characteristics of IKr.15 For
test potentials 
+10 mV, an additional slowly activating
time-dependent current is elicited. In contrast to the rapid component
that reaches steady-state activation, elicited current by positive test
potentials continues to activate even after 5 seconds of
depolarization. Activating current amplitude measured after a test
potential of +50 mV is about 10 times that measured for depolarization
to 0 mV. Overall, these voltage- and time-dependent characteristics
described in these recordings are the footprints of IKr and
IKs, respectively.15
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) and deactivating (
) currents are illustrated in C.
Fig 3A illustrates recordings of currents elicited by
long pulses (IK5000) under control conditions and in the
presence of erythromycin 10-4 mol/L (Fig 3A).
Activating
currents were elicited by test potentials to -20 or +40 mV, while
deactivating tail currents were recorded after repolarization to -40
mV. In these records, erythromycin 10-4 mol/L reduced
time-dependent activating and tail currents at a test potential of -20
mV, while activating and tail currents were only slightly decreased at
a test potential of +40 mV. Difference current (erythromycin sensitive)
calculated for deactivating tails reached maximum amplitude at -10 mV,
which is characteristic of selective block of IKr.
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Records presented in Fig 4 show that during short
pulses (IK250) to low depolarizing potentials (-10 mV),
activating and tail currents recorded at baseline were almost
eliminated in a partially reversible manner by erythromycin
10-4 mol/L. Under these conditions, elicited
time-dependent outward current is largely IKr. Complete I-V
curve obtained in one cell for IK250 tail current is
illustrated in Fig 5. It can readily be appreciated that
erythromycin 10-4 mol/L blunted the hump observed under
control conditions for IK250 at potentials 
0 mV.
Moreover, decrease in tail current was observed at low depolarizing
potentials (<20 mV), where IKr is a major constituent of
total IK250.
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Voltage- and time-dependent characteristics of block of
IK250 and IK5000 by erythromycin
10-4 mol/L in seven cells tested are illustrated in Fig
6A. Cell-to-cell variability is illustrated in the lower
portion of the figure (Fig 6B). In these cells, inhibition of
IK250 appeared to be voltage dependent; inhibition
(P<.05 at all voltages tested) reached 38% at test
potentials of -20 or -10 mV but varied between 15% and 19% at
potentials +10 mV. Similarly, block of IK5000 was
significant at low depolarizing voltage (38% at -20 mV) but minimal
at positive potentials. At 0-mV test potential, inhibition of
IK250 and IK5000 by erythromycin was
significantly different (P<.02). These characteristics of
block of IK are the signature of selective block of
IKr, which is the only component present at low
depolarizing voltages in the absence of extracellular
Ca2+ and is of greater amplitude than
IKs during short (IK250) compared with long
(IK5000) pulses. Thus, variable proportions of
IKr and IKs in these recordings explain
apparent voltage dependency and time dependency of block.
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Kinetics of IK5000 tail current were determined at baseline
and during superfusion of cells with erythromycin 10-4
mol/L. Tail current was elicited by repolarization to -40 mV after a
test potential of 5000 ms varying from 0 to +50 mV. A biexponential
curve fitting well approximated the data at baseline and in the
presence of erythromycin (Fig 7). Fig 8
shows that the fast time constant, 
1, was significantly
increased by erythromycin at test potentials of 0 and +10 mV but not
for test potentials +20 mV.
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Finally, erythromycin did not alter the background current elicited by
a 250-ms voltage ramp from -50 to -100 mV, that is, in the range
of
potentials where the time-independent inward rectifier potassium
current (IK1) was present (Fig 9). As
well, slow inward calcium current appeared to be insensitive to
erythromycin 10-4 mol/L (Fig 10).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Results obtained in this study clearly indicate that erythromycin possesses direct cardiac electrophysiological effects. We believe these effects can be clinically relevant and may explain, at least in part, proarrhythmia described in humans,1 2 3 4 5 6 since (1) effects of erythromycin on cardiac IKr and on MAPD90 of isolated hearts were observed at a concentration (10-4 mol/L,
75 mg/L) reached during rapid intravenous injection of 1g of
the drug in humans16 ; (2) most of the erythromycin-induced
torsade de pointes cases have been observed after rapid intravenous
injection of the
drug1 3 4 5 6 or
during high oral
dosages2 ; and (3) other studies have indicated that
erythromycin can alter cardiac repolarization at concentrations >20
mg/L.3 8
In our experiments with isolated cells, composition of the
extracellular solution used to superfuse myocytes (nisoldipine
2.10-7 mol/L and omission of calcium) allowed us to better
separate the components of IK.13
IK obtained for low depolarizing potentials (from -20 to 0
mV) presented characteristics of IKr: rapid activation
that reaches a quasi–steady-state level after a few hundred
milliseconds and rectification properties clearly observed by comparing
activating and tail current amplitude at -10 and 0 mV (IK
activation amplitude decreases while tail current amplitude remains
almost constant). On the other hand, IK obtained at voltage
tests +10 mV presented characteristics of IKs: a
slowly activating time-dependent current with an early sigmoidal shape
that does not reach a steady-state level even after 5 seconds of
depolarization.15
Our results show that erythromycin 10-4 mol/L reduces
IK tail current mainly during short depolarizations to low
voltages. In fact, erythromycin 10-4 mol/L produces a
greater inhibition of IK tail current elicited after 250 ms
(IK250) for voltage steps tested between -20 and 0 mV
compared with that observed for voltage steps +20 mV. On the other
hand, when test depolarization was prolonged (5000 ms), erythromycin
10-4 mol/L reduced IK tail current only at
negative potentials (-20 and -10 mV). Thus, erythromycin inhibits
IK during activation characteristics typical of
IKr. Consequently, the hump observed in IK tail
current–voltage curve at -10 and 0 mV disappeared during exposure
of
the cell to erythromycin. Inhibition of IK by erythromycin
was time dependent: The longer was the pulse, the smaller was the
inhibition. Time-dependent block of IK can be explained by
relative proportions of IKs during short and long
depolarizing pulses, since IKs requires a longer time than
IKr to activate. Thus, voltage dependency and time
dependency of inhibition observed are consistent with a specific block
of IKr. Moreover, erythromycin-sensitive current had a
constant amplitude and kinetics (based on difference current of
IK5000 deactivating tails) after test potentials varying
from 0 to +50 mV. These results suggest voltage-independent block of
IKr.
Extent of block of IK250 and IK5000 exhibited relatively wide cell-to-cell variability. This was observed mostly at low depolarizing potentials (where amplitude of IKr and IKs are of the same magnitude) as for other selective blockers of either IKr or IKs.15 17 18 The phenomenon is believed to reflect cell-to-cell variability in the proportions of IKr and IKs. In fact, cell-to-cell variability could be explained by the study of cells from different tissue regions expressing various levels or densities of specific currents.19 20 21
Increase in the fast time constant (1) of IK
tail current observed at 0 and -10 mV during superfusion of
erythromycin was consistent with prominent block of IKr.
However, no obvious changes in 1 elicited after test
potentials to +20 to +50 mV were detected. Using E-4031 at a
concentration that fully blocked IKr (5 µmol/L),
Chinn22 has shown that block of IKr is
characterized by disappearance of the fast time constant of a
biexponential curve fitting of IK tail current. As
demonstrated, inhibition of IKr appeared to be voltage
independent. Thus, voltage-dependent increase in 1
observed with erythromycin in our experiments may reflect either slow
unblocking during deactivation or that erythromycin influences in a
voltage-dependent manner the closing properties of unblocked channels.
In contrast, Valenzuela et al18 have shown that the
IKr blocker imipramine did not change 1
after a 5-second depolarization to high voltage (+50 mV) even though
IKr appeared completely blocked
(IKtail/IKact ratio was constant).
It was suggested that QT-prolonging effects and proarrhythmia induced by erythromycin were related to modification of the sympathetic nervous system.2 In fact, proarrhythmic effects of erythromycin were abolished by the administration of propranolol and by left cervicothoracic sympathetic ganglionectomy. The exact mechanism of this effect is unknown but probably would involve elevation of cytosolic calcium levels by ß-adrenergic stimulation. Results obtained in this study confirm effects of erythromycin on cardiac repolarization. Moreover, they give an explanation to the interaction observed between erythromycin and dofetilide, a selective IKr blocker.8 In fact, a shift to the right in dofetilide dose-response curve was observed during combined administration of erythromycin. It can be suggested that competitive interaction at the same protein site is observed, since erythromycin and dofetilide block IKr. Furthermore, it adds a new mechanism for the explanation of the terfenadine-erythromycin interaction, which was previously explained only on the basis of a specific cytochrome P450 isozyme inhibition (CYP3A4) and accumulation of terfenadine as well as of its acid metabolite.7 It appears that both terfenadine and erythromycin are able to alter (and may even potentiate their effects on) cardiac repolarization, which may lead to proarrhythmic events in humans.7 24
Summary
The results obtained in this study demonstrated that
erythromycin blocks the delayed rectifier potassium current of isolated
cardiac myocytes. In isolated, buffer-perfused guinea pig heart,
prolongation of monophasic action potential was consistent with
demonstrated block of IKr. Effects were observed at a
clinically relevant concentration of the drug reached after rapid
intravenous administration of erythromycin at usual dosage (1 g).
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Acknowledgments |
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This work was supported by a grant from the Medical Research Council of Canada (MT 11876) and by operating grants from the Fonds de la Recherche en Santé du Québec (900114) and the Heart and Stroke Foundation of Canada. E.L. was the recipient of an FRSQ summer research studentship, and M.F.G. was the recipient of a summer research studentship from the MRC/Pharmaceutical Manufacturers Association of Canada. P.D. is the recipient of a Heart and Stroke Foundations of Canada fellowship and an Astra Pharma award. J.T. is the recipient of a scholarship from the Medical Research Council of Canada and of a scholarship from the Joseph C. Edwards Foundation. The authors also thank Michel Blouin for technical assistance and Serge Simard, MSc, for statistical analysis.
Received October 19, 1994; revision received December 13, 1994; accepted December 27, 1994.
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 C. Antzelevitch, L. Belardinelli, L. Wu, H. Fraser, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, R. J. Goodrow Jr, et al. Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S65 - S83. [Abstract] [PDF]
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 W.S. Redfern, L. Carlsson, A.S. Davis, W.G. Lynch, I. MacKenzie, S. Palethorpe, P.K.S. Siegl, I. Strang, A.T. Sullivan, R. Wallis, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development Cardiovasc Res, April 1, 2003; 58(1): 32 - 45. [Abstract] [Full Text] [PDF]
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C.-E. Chiang, H.-N. Luk, T.-M. Wang, and P. Y.-A. Ding Effects of sildenafil on cardiac repolarization Cardiovasc Res, August 1, 2002; 55(2): 290 - 299. [Abstract] [Full Text] [PDF]
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 S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]
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 B. Drolet, G. Rousseau, P. Daleau, R. Cardinal, and J. Turgeon Domperidone Should Not Be Considered a No-Risk Alternative to Cisapride in the Treatment of Gastrointestinal Motility Disorders Circulation, October 17, 2000; 102(16): 1883 - 1885. [Abstract] [Full Text] [PDF]
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 H. Ohtani, C. Taninaka, E. Hanada, H. Kotaki, H. Sato, Y. Sawada, and T. Iga Comparative Pharmacodynamic Analysis of Q-T Interval Prolongation Induced by the Macrolides Clarithromycin, Roxithromycin, and Azithromycin in Rats Antimicrob. Agents Chemother., October 1, 2000; 44(10): 2630 - 2637. [Abstract] [Full Text]
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P. Geelen, B. Drolet, J. Rail, J. Berube, P. Daleau, G. Rousseau, R. Cardinal, G. E. O'Hara, and J. Turgeon Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current Circulation, July 18, 2000; 102(3): 275 - 277. [Abstract] [Full Text] [PDF]
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B. Drolet, A. Emond, B. Pharm, V. Fortin, P. Daleau, G. Rousseau, R. Cardinal, and J. Turgeon Vitamin K Modulates Cardiac Action Potential by Blocking Sodium and Potassium Ion Channels Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 267 - 273. [Abstract] [PDF]
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 M. Khalifa, P. Daleau, and a. J. Turgeon Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 280 - 284. [Abstract] [Full Text]
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L. M. Shuba, Y. Kasamaki, S. E. Jones, T. Ogura, J. R. McCullough, and T. F. McDonald Action Potentials, Contraction, and Membrane Currents in Guinea Pig Ventricular Preparations Treated with the Antispasmodic Agent Terodiline J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1417 - 1426. [Abstract] [Full Text]
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 A. Mishra, H. S. Friedman, and A. K. Sinha The Effects of Erythromycin on the Electrocardiogram Chest, April 1, 1999; 115(4): 983 - 986. [Abstract] [Full Text] [PDF]
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M. Khalifa, B. Drolet, P. Daleau, C. Lefez, M. Gilbert, S. Plante, G. E. O'Hara, O. Gleeton, B. A. Hamelin, and J. Turgeon Block of Potassium Currents in Guinea Pig Ventricular Myocytes and Lengthening of Cardiac Repolarization in Man by the Histamine H1 Receptor Antagonist Diphenhydramine J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 858 - 865. [Abstract] [Full Text]
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 R. M. Ward, J. A. Lemons, and R. A. Molteni Cisapride: A Survey of the Frequency of Use and Adverse Events in Premature Newborns Pediatrics, February 1, 1999; 103(2): 469 - 472. [Abstract] [Full Text]
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P. Geelen, B. Drolet, E. Lessard, P. Gilbert, G. E. O'Hara, and J. Turgeon Concomitant Block of the Rapid (IKr) and Slow (IKs) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(3): 143 - 150. [Abstract] [PDF]
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B. Drolet, M. Khalifa, P. Daleau, B. A. Hamelin, and J. Turgeon Block of the Rapid Component of the Delayed Rectifier Potassium Current by the Prokinetic Agent Cisapride Underlies Drug-Related Lengthening of the QT Interval Circulation, January 20, 1998; 97(2): 204 - 210. [Abstract] [Full Text] [PDF]
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P. D. West, D. K. Martin, J. A. Bursill, K. R. Wyse, and T. J. Campbell Comparative Study of the Effects of Erythromycin and Roxithromycin on Action Potential Duration and Potassium Currents in Canine Purkinje Fibers and Rabbit Myocardium Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(1): 29 - 36. [Abstract] [PDF]
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