(Circulation. 1997;96:4011-4018.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium
I. In Vitro Study
From the Department of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY.
Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 W 168 St, PH 7West-321, New York, NY 10032. E-mail franeye{at}cudept.cis.columbia.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background The antiarrhythmic action of quinidine is associated with a slowing of conduction and prolongation of repolarization. The latter effect has no consistent correlation with quinidine actions on action potential duration (APD) in isolated tissue experiments. To enhance our understanding of the mechanisms of quinidine action, we studied its effect on APD in canine epicardial, midmyocardial, and endocardial tissues.
Methods and Results Standard microelectrode techniques were used to study the effects of quinidine 2.5 to 20 µmol/L on APD in ventricular epicardial, endocardial, and transmural (M-cell) slabs at cycle lengths (CLs) from 300 to 4000 ms. Qualitatively different time courses of actions and concentration- and rate-dependent effects were seen in M cells compared with the others. In endocardium and epicardium, quinidine induced monotonic and concentration-dependent APD prolongation at all CLs. In contrast, the effects of quinidine in M cells varied from prolongation to shortening, depending on duration of superfusion, concentration, and CL. Experiments with E4031 and TTX suggested that in M cells, quinidine-induced APD lengthening was attributable to block of delayed rectifier potassium current and APD shortening was due to inhibition of TTX-sensitive steady-state sodium current.
Conclusions In vitro, there is a significant difference of quinidine effects in M cells versus epicardial and endocardial cells that appears to reflect differences in the contributions of specific ion channels to the APD at the three sites. The differences may influence the actions of quinidine on repolarization of the heart in situ and determine both the proarrhythmic and antiarrhythmic actions of the drug.
Key Words: quinidine • repolarization
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Quinidine and its congeners are the oldest antiarrhythmic drugs known to be effective in the treatment of diverse cardiac arrhythmias,1 and quinidine remains one of the most commonly prescribed drugs in the United States.2,3 Its antiarrhythmic activity usually is associated with a slowing of conduction and prolongation of repolarization4–8 seen on the ECG as QRS duration widening and QT interval prolongation, respectively. Experiments with isolated cardiac tissues have shown that quinidine-induced slowing of conduction is associated with reduced maximum upstroke velocity (
max) of the action
potential9–11 and is due to inhibition of the
fast inward sodium current.12,13 In contrast, the
effect of quinidine to prolong the QT interval has no
consistent correlation with its actions on APD in isolated
tissue experiments. For example, in Purkinje fibers, quinidine is
reported to prolong,11,14–18 have no effect
on,19,20 or even shorten the
APD.19,21–24 In ventricular
endocardial muscle, quinidine either
lengthens19,25 or
shortens26,27 the APD. Moreover, in an experiment
using two pieces of the same human papillary muscle, quinidine in the
same concentration repeatedly increased the APD in one piece and
decreased it in the other.28 Finally, in
ventricular epicardial muscle, quinidine caused a slight
but significant prolongation of transmembrane29
and monophasic30–32 action potentials
recorded in situ. A unique population of cells (M cells) has been described in the ventricular midmyocardium.33,34 The APD-rate relationship of M cells is considerably steeper than that of epicardium and endocardium, and the sensitivity of M cells to drugs that affect repolarization differs from those of epicardium and endocardium.35–37 Because M cells constitute a significant fraction of ventricular myocardium,34,38 they contribute importantly to T wave configuration and QT interval. Furthermore, we recently showed that the QT interval and repolarization of different myocardial layers in the left ventricle of the normal heart in situ correspond to repolarization of M cells in vitro rather than epicardial or endocardial cells.38 Consequently, the present study was designed to investigate the time course and concentration- and rate-dependent effects of quinidine on repolarization in ventricular epicardial and endocardial cells and in M cells. The experiments were performed in vitro and in vivo (see companion article39). The intent was to resolve the discrepancy between quinidine effects on repolarization in vivo and in vitro and in so doing to better understand the ECG expression of its actions.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mongrel dogs weighing 10 to 20 kg were anesthetized with sodium pentobarbital (30 mg/kg IV). Their hearts were removed through a left lateral thoracotomy and immersed in cold Tyrode's solution equilibrated with 95% O2/5% CO2 and containing (in mmol/L) NaCl 131, NaHCO3 18, KCl 4, CaCl2 2.7, MgCl2 0.5, NaH2PO4 1.8, and dextrose 5.5. Endocardial, epicardial, and transmural strips (
1.5x1.0x0.1
cm) were filleted with surgical blades either parallel or perpendicular
(transmural) to the surface of the anterobasal left
ventricular free wall.33,38 The
preparations were placed in a tissue bath, superfused with Tyrode's
solution warmed to 37°C (pH 7.35±0.05), and allowed to equilibrate
at a CL of 1000 ms. Solutions were pumped through the tissue bath at a
flow rate of 12 mL/min, with chamber content changed three times a
minute. The bath was connected to ground with a 3 mol/L
KCl–Ag/AgCl junction. Transmembrane potentials were
recorded by 3 mol/L KCl–filled glass capillary
microelectrodes (tip resistances of 10 to 20 M
) coupled by a
Ag/AgCl junction to an amplifier with a high-input impedance and
input capacity neutralization (model KS-700, World Precision
Instruments). max was obtained by
electronic differentiation with an operational amplifier; the system
was calibrated as previously described.40
Transmembrane action potentials and max
were displayed on a digital storage oscilloscope (model 4074, Gould)
and stored in digitized form in a personal computer for subsequent
analysis. For stimulation of preparations, standard techniques
were used to deliver 1- to 2-ms-long square-wave pulses 2.0 times
threshold through bipolar Teflon-coated silver
electrodes.40
Experiments were started after preparations had fully recovered and
displayed stable electrophysiological
characteristics. This required 3 hours for transmural, 4 hours
for endocardial, and 5 to 6 hours for epicardial
strips.38 Before pharmacological interventions,
control steady-state dependence of APD on CL of stimulation was
determined. The CLs used were 4000, 2000, 1000, 700, 500, and 300 ms.
Each frequency was maintained for 5 minutes before data were collected.
The CL was then returned to 1000 ms until the next frequency scan was
performed. Two cumulative concentrations (5 and 20
µmol/L) of quinidine were studied in each epicardial and
endocardial slab. Four concentrations (2.5, 5, 10, and 20
µmol/L) were studied in transmural slabs (two cumulative
concentrations per preparation). The preparations were allowed to
equilibrate for 90 minutes at each quinidine concentration before the
frequency scan was obtained. To study the actions of E4031 (1
µmol/L) and of TTX (2 µmol/L), the compounds
were added to Tyrode's solution, and after 30 minutes the frequency
scan was obtained. Then the preparations were superfused with Tyrode's
solution containing both quinidine and the test compound.
The question of stability of preparations was of great concern because
after complete equilibration, each experiment lasted >4 hours (90
minutes of superfusion with each quinidine concentration and 30 minutes
for each frequency scan; two cumulative concentrations were tested in
each experiment). Therefore, at the beginning of our study, sham
experiments (in the absence of quinidine) were performed with all types
of tissues. Fig 1
depicts the results
obtained and shows that APD remained stable in all preparations at all
stimulation rates during >4 hours of observation after
equilibration.
|
Statistical Analysis
Microelectrode data were analyzed from impalements
maintained throughout the course of each experimental protocol. Data
are expressed as mean±SEM. The statistical technique used was one- or
two-way ANOVA for multiple groups (or for repeated measures when
necessary), with Bonferroni's test when the F value permitted
this.41 Significance was determined at
P<.05.
Drugs
We purchased quinidine HCl and TTX from Sigma Chemical Co. E4031
was a gift from Helopharm, Berlin, Germany.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Representative transmembrane potentials of epicardial, midmyocardial, and endocardial cells are shown in Fig 2
. As has been described previously,
action potentials in M cells have a longer plateau and more rapid
upstroke velocity than those observed in epicardium or endocardium and
display a notch at the onset of the
plateau.33,34,38 Quinidine concentration- and
rate-dependently suppressed max in all
tissues and significantly attenuated the spike-and-dome morphology of
the epicardial and M-cell action potentials and had no significant
effect on maximum diastolic potential (Fig 2 and
Table). Note, however, that whereas
quinidine consistently prolongs APD in epicardium and
endocardium at the 20- and 90-minute time periods depicted in Fig 2, in
the M cells it initially prolongs and then shortens APD.
|
|
Fig 3 depicts the time course of APD
changes induced by different concentrations of quinidine in all tissues
studied. After onset of quinidine superfusion, the APD in epicardial
and endocardial cells monotonically increased and reached a steady
state in 70 to 90 minutes (Fig 3A). In both epicardial and endocardial
cells, this effect was concentration dependent, and it was more
prominent in endocardium.
|
In contrast, in M cells, the pattern of APD changes depended on
quinidine concentration (Fig 3B
). The lowest concentration (2.5
µmol/L) induced monotonic APD lengthening, which attained a
steady state in 60 to 70 minutes. At higher quinidine concentrations,
the M cell APD changes were biphasic: initially, the APD prolonged and
reached peak values in 15 to 20 minutes, then it slowly decayed to a
steady-state level. At 5 and 10 µmol/L, the APD at steady
state was at the control (predrug) value, whereas 20
µmol/L actually shortened APD. The curves presented in
Fig 3 were typical for all experiments. The average control value of
APD in M cells (eight experiments) was 285±13 ms; at quinidine 20
µmol/L, a peak value of 308±13 ms (P<.05 vs
control) was reached in 18.8±2 minutes; a steady state of 263±12 ms
(P<.05 vs control) was reached at 80±5 minutes.
Steady-state (ie, 90 minutes) quinidine effects on the APD in
epicardium and endocardium at different CLs are shown in Fig 4. In both tissues, quinidine
concentration-dependently prolonged the APD, and this effect manifested
modest reverse use dependence. A qualitative distinction was seen
between M cells and epicardial or endocardial cells in the CL
dependence of their response to quinidine (Fig 5). At the lowest concentration (2.5
µmol/L), quinidine induced prominent reverse use-dependent
effects such that maximal lengthening of APD was observed at long CLs
(Fig 5A). At 5 and 10 µmol/L, quinidine increased the APD
only at the shortest CL (300 ms) and had no effect at the other CL (Fig 5B and 5C). At the highest concentration (20 µmol/L),
there was significant APD prolongation at 300 ms and significant
shortening at 2000 and 4000 ms (Fig 5D). Fig 6 is a further demonstration of the
difference between the effects of quinidine on surface cells and M
cells. In endocardium (A) and epicardium (B), the pattern of
dose-dependent effects of quinidine on the APD was the same at CLs of
300 and 2000 ms, whereas in M cells (C), it depended on CL. At a CL of
300 ms, the APD in M cells increased dose-dependently and reached a
plateau at 5 µmol/L quinidine. At CL of 2000 ms, the APD
was significantly prolonged at 2.5 µmol/L, and this
effect subsided and reversed with increases of quinidine concentration
to 10 and 20 µmol/L.
|
|
|
To clarify the ionic mechanisms responsible for the complex
effects of quinidine on the APD in M cells, tissues were superfused
with E4031 or with TTX. The influence of pretreatment with a blocker of
the IKr, E4031,42 on
the time course of APD changes induced by 20 µmol/L
quinidine is shown in Fig 7A. E4031
significantly prolonged the APD, eliminated the quinidine-induced
transient APD prolongation, and accentuated the quinidine-induced
shortening of the APD (compare Figs 7A and 3B). Fig 7B summarizes the
influence of E4031 pretreatment on quinidine steady-state effects.
E4031 significantly increased the APD at all CLs in a reverse
use-dependent manner. The compound did not prevent (even accentuated)
quinidine-induced shortening of APD at long CLs. In contrast, at CL=300
ms, the prolongation of APD with quinidine+E4031 equaled that with
E4031 or quinidine alone (compare with Fig 5D).
|
Fig 8 depicts the influence of TTX,
a blocker of steady-state sodium current,43 on
the effects of quinidine 20 µmol/L on repolarization in M
cells. Qualitatively, TTX did not change the biphasic character of the
time course of quinidine-induced APD changes (Fig 8A). The amplitude of
transient APD prolongation remained unaltered in the presence of TTX.
However, the quinidine-induced APD shortening at 90 minutes of
superfusion was attenuated (compare Figs 8A and 3B). At steady state,
pretreatment with TTX eliminated quinidine-induced APD shortening at
long CLs and had no effect on APD lengthening at a CL of 300 ms (Fig 8B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We have found that the effects of quinidine on action potential repolarization differ importantly among endocardial, epicardial, and midmyocardial fibers and that these differences reflect, in part, drug concentration and duration of superfusion. The effects of quinidine on APD developed slowly:
90 minutes of
superfusion was required to reach steady-state effects in epicardial,
endocardial, and M cells. The same time to steady-state quinidine
effect on APD at a CL of 1000 ms was reported by Davidenko et
al18 for canine Purkinje fibers. In contrast,
most previously reported studies collected data at 10 to 60 minutes of
quinidine superfusion.9,11,14–17,19–28 Our
results suggest that these different durations of superfusion and
failure to attain a steady state may have contributed to the
inconsistency of reported quinidine effects on
repolarization. As to why so long a period is required for quinidine
effect to reach a steady state in studies in vitro, there are several
potential contributing factors; these include (1) the location of the
quinidine binding site on the interior of the channel, requiring that
it traverse the membrane before it binds44; (2)
low lipid solubility of quinidine45; (3) the
associated long-time constant for intracellular accumulation of
quinidine18; and (4) possible differences in drug
partition between blood and myocyte versus
physiological salt solution and myocyte. Different effects of quinidine were seen in M cells compared with epicardial and endocardial cells. Whereas in surface cells, all concentrations of quinidine prolonged APD at all CLs, in M cells, the pattern of rate dependence was clearly defined by quinidine concentration. At 2.5 µmol/L quinidine, there was reverse use-dependent prolongation of repolarization throughout the range of CLs studied and for the entire duration of the experiments. At 5 to 20 µmol/L, there was a biphasic effect of quinidine, initially prolonging APD and then, at steady state, shortening it except at very short CLs, at which the prolongation of APD persisted. Hence, at 5 to 20 µmol/L quinidine, APD prolongation was seen and persisted at CL=300 ms, whereas there was progressive loss of prolongation of APD and ultimately shortening of APD at the longer CLs.
We are aware of only one study in which the effects of a single low concentration (3 µmol/L) of quinidine on APD in M cells have been reported.36 The authors found that quinidine produced APD prolongation at short and long CLs; however, this effect was more prominent at slower stimulation rates. This is completely in agreement with our results with 2.5 µmol/L of quinidine. It is not clear whether this concentration is relevant to the therapeutic range attained clinically. The higher concentrations of quinidine have relevance for two reasons: (1) the tissue concentrations of quinidine in vivo can exceed those in plasma by a factor of up to 10,46,47 and (2) higher concentrations also have relevance to the understanding of toxicity.
The effects we have reported of higher quinidine concentrations on M cells have not, to the best of our knowledge, been published before and manifest very complex time courses, rate dependence, and concentration dependence. These complex effects can be explained by a competition of two quinidine actions, one of which prolongs the APD and another of which shortens it. The first (prolonging) action occurs at lower concentrations and develops more rapidly than the second, and the relative contributions of these two actions to APD depend on CL. This idea has previously been used to explain biphasic dose-dependent effects of quinidine on APD in Purkinje fibers at low stimulation rates.24
Quinidine has multiple actions on the inward and outward currents that determine the APD. Voltage-clamp studies in multicellular and single-cell cardiac preparations have demonstrated that quinidine inhibits Ito,13,48,49 IK,42,50–53 steady-state sodium current,27,51 and slow inward calcium current.13,26,27,51 However, these voltage-clamp studies do not permit prediction of time course, dose dependence, and rate dependence of quinidine effects on APD in myocardial tissue. For this reason, to investigate the ionic mechanisms responsible for quinidine-induced prolongation and shortening of the APD in M cells, we used specific blockers of two different transmembrane currents. The results with E4031 suggest that quinidine-induced APD prolongation is attributable mainly to a decrease in IKr, whereas the studies with TTX suggest that APD shortening is primarily a result of inhibition of the steady-state sodium current. These results, however, do not rule out the effects of quinidine on other currents, such as IKs. Also, these data suggest that IKr is more sensitive than steady-state sodium current and that its suppression develops more rapidly in response to quinidine. The complex dose- and rate-dependent quinidine effects in M cells can be explained as follows: the lowest quinidine concentration (2.5 µmol/L) has effects only on IKr and prolongs the APD at all CLs in a reverse use-dependent fashion. Higher concentrations inhibit both IKr and steady-state sodium current, with the net effect on the APD being determined by the relative contribution of each current to repolarization as well as by the extent of suppression of each current. Our results suggest that at a high quinidine concentration (20 µmol/L), the inhibition of TTX-sensitive steady-state sodium current is relatively more important at long CLs (with resultant APD shortening), whereas at the shortest CL (300 ms), blockade of IKr determines APD lengthening.
In light of the above, the distinction of quinidine effects on the APD in M cells and epicardial or endocardial cells may result from the fact that in surface ventricular cells, the steady-state sodium current is not as prominent as in Purkinje fibers54 and M cells.55 Thus, quinidine effects in the surface cells are attributed mainly to a decrease of IKr, resulting in APD lengthening at all CLs.
In conclusion, we have observed a significant difference in quinidine effects on the APD, with epicardial and endocardial cells showing one result and M cells another result, having complex time course, rate dependence, and concentration dependence. These results provoke the following important questions: (1) Does a similar difference in quinidine effects on repolarization between surface and intramural cells take place in the heart in situ? (2) Which pattern of rate- and dose-dependent quinidine effects on repolarization does the QT interval on surface ECG follow? The experiments on heart in situ in the companion article38 provide answers to these questions.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
These studies were supported in part by USPHS-NHLBI grant HL-28958 and by Helopharm. The authors express their gratitude to Dr Natalia Egorova for assisting with the performance of the experiments and to Eileen Franey for her careful attention to the preparation of the manuscript.
Received February 18, 1997; revision received August 15, 1997; accepted August 27, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Scherf D, Schott A. Extrasystoles and Allied Arrhythmias. Chicago, Ill: William Heinemann Medical Books; 1973.
2.
Morganroth J, Goin JE. Quinidine-related mortality in
the short-to-medium-term treatment of ventricular
arrhythmias: a meta-analysis. Circulation. 1991;84:1977–1983.
3. Salerno DM. Quinidine: is it a good drug or a bad drug? Postgrad Med. 1992;92:131–140.
4. Heissenbuttel RH, Bigger JT Jr. The effects of oral quinidine on intraventricular conduction in man: correlation of plasma quinidine with changes in QRS duration. Am Heart J. 1970;80:453–462.[Medline] [Order article via Infotrieve]
5. Malcolm AD, David GK. Quinidine in cardiology. Acta Leidensia. 1987;55:87–98.[Medline] [Order article via Infotrieve]
6. Jackman WH, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115–172.[Medline] [Order article via Infotrieve]
7. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implication for patient care. Am Heart J. 1986;111:1088–1093.[Medline] [Order article via Infotrieve]
8.
Nademanee K, Stevenson WG, Weiss JM, Frame VB,
Antimisiaris MG, Suithichaiyakul T, Pruitt CM. Frequency-dependent
effects of quinidine on the ventricular action potential
and QRS duration in humans. Circulation. 1990;81:790–796.
9. Campbell TJ. Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res. 1983;17:344–352.[Medline] [Order article via Infotrieve]
10.
Clarkson CW, Hondeghem LM. Evidence for specific
receptor site for lidocaine, quinidine, and bupivacaine associated with
cardiac sodium channels in guinea pig ventricular
myocardium. Circ Res. 1985;56:496–506.
11.
Roden DM, Hoffman BF. Action potential prolongation and
induction of abnormal automaticity by low quinidine concentration in
canine Purkinje fibers: relationship to potassium and cycle length.
Circ Res. 1985;56:857–867.
12. Lee KS, Hume JR, Giles W, Brown AM. Sodium current depression by lidocaine and quinidine in isolated ventricular cells. Nature. 1981;291:325–327.[Medline] [Order article via Infotrieve]
13. Wu MH, Su MJ, Lue HC. Age-related quinidine effects on ionic currents of rabbit cardiac myocytes. J Mol Cell Cardiol. 1994;26:1167–1177.[Medline] [Order article via Infotrieve]
14.
Mirro MJ, Watanabe AM, Bailey JC.
Electrophysiological effects of the optical isomers
of disopyramide and quinidine in the dog: dependence on
stereochemistry. Circ Res. 1981;48:867–874.
15.
Colatsky TJ. Mechanisms of action of lidocaine and
quinidine on action potential duration in rabbit cardiac Purkinje
fibers. Circ Res. 1982;50:17–27.
16.
Thompson KA, Blair IA, Woosley RL, Roden DM.
Comparative in vitro electrophysiology of quinidine, its major
metabolites and dihydroquinidine. J Pharmacol Exp Ther. 1987;241:84–90.
17. Roden DM, Iansmith DHS, Woosley RL. Frequency-dependent interactions of mexiletine and quinidine on depolarization and repolarization in canine Purkinje fibers. J Pharmacol Exp Ther. 1987;241:84–90.
18.
Davidenko JM, Cohen L, Goodrow R, Antzelevitch C.
Quinidine-induced action potential prolongation, early
afterdepolarizations, and triggered activity in canine Purkinje fibers:
effects of stimulation rate, potassium, and magnesium.
Circulation. 1989;79:674–686.
19. Varro A, Nakaya Y, Elharrar V, Surawicz B. Effect of antiarrhythmic drugs on the cycle length-dependent action potential duration in dog Purkinje and ventricular muscle fibers. J Cardiovasc Pharmacol. 1986;8:178–185.[Medline] [Order article via Infotrieve]
20. Monterro M, Beyer T, Schmitt C, Kubler W, Brachman J. Differential effects of quinidine on transmembrane action potentials of normal and infarcted canine Purkinje fibers. J Cardiovasc Pharmacol. 1992;20:304–310.[Medline] [Order article via Infotrieve]
21.
Carmeliet E, Saikawa T. Shortening of the action
potential and reduction of pacemaker activity by lidocaine, quinidine,
and procainamide in sheep Purkinje fibers: an effect on Na or K
currents? Circ Res. 1982;50:257–272.
22.
Burke GH, Loukides JE, Berman ND. Comparative
electropharmacology of mexiletine, lidocaine and quinidine in a cardiac
Purkinje fiber model. J Pharmacol Exp Ther. 1986;237:232–236.
23. Campbell TJ, Wyse KR, Pallandi R. Differential effects on action potential duration of class IA, B and C antiarrhythmic drugs: modulation by stimulation rate and extracellular K+ concentration. Clin Exp Pharmacol Physiol. 1991;18:533–541.[Medline] [Order article via Infotrieve]
24. Wyse KR, Ye V, Campbell TJ. Action potential prolongation exhibits simple dose-dependence for sotalol, but reverse dose-dependence for quinidine and disopyramide: implication for proarrhythmia due to the triggered activity. J Cardiovasc Pharmacol. 1993;21:316–322.[Medline] [Order article via Infotrieve]
25. Berman ND, Dorian P. Cellular mechanism underlying the efficacy of the sotalol-quinidine combination. J Cardiovasc Pharmacol. 1993;21:609–614.[Medline] [Order article via Infotrieve]
26.
Nawrath H. Action potential, membrane currents and
force of contraction in mammalian heart muscle fibers treated with
quinidine. J Pharmacol Exp Ther. 1981;216:176–182.
27.
Salata JJ, Wasserstrom JA. Effects of quinidine on
action potentials and ionic currents in isolated canine
ventricular myocytes. Circ Res. 1988;62:324–337.
28. Nawrath H, Eckel L. Electrophysiological study of human ventricular heart muscle treated with quinidine: interaction with isoprenaline. J Cardiovasc Pharmacol. 1979;1:415–425.[Medline] [Order article via Infotrieve]
29.
Prinzmetal M, Ishikawa K, Oishi H, Ozkan E, Wakayama J,
Baines JM. Effects of quinidine on electrical behavior in cardiac
muscle. J Pharmacol Exp Ther. 1967;157:659–664.
30. Brugada J, Sassine A, Escande D, Masse C, Puech P. Effects of quinidine on ventricular repolarization. Eur Heart J. 1987;8:1340–1345.
31.
Franz MR, Costard A. Frequency-dependent effects of
quinidine on the relationship between action potential duration and
refractoriness in the canine heart in situ. Circulation. 1988;77:1177–1184.
32. Duker G, Almgreen O, Carlsson L. Electrophysiological and hemodynamic effects of H234/09 (Almokalant), quinidine, and (+)-sotalol in the anesthetized dog. J Cardiovasc Pharmacol. 1992;20:458–465.[Medline] [Order article via Infotrieve]
33.
Sicouri S, Antzelevitch C. A subpopulation of cells
with unique electrophysiological properties
in the deep subepicardium of the canine ventricle. Circ Res. 1991;68:1729–1741.
34. Sicouri S, Antzelevitch C. Electrophysiologic characteristics of M cells in the canine left ventricular free wall. J Cardiovasc Electrophysiol. 1995;6:591–603.[Medline] [Order article via Infotrieve]
35. Sicouri S, Antzelevitch C. Afterdepolarization and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: the effects of acetylstrophantidin and Bay K8644. Pacing Clin Electrophysiol. 1991;14:1714–1720.[Medline] [Order article via Infotrieve]
36. Sicouri S, Antzelevitch C. Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol. 1993;4:48–58.[Medline] [Order article via Infotrieve]
37. Weissenburger T, Nesterenko VV, Antzelevitch C. Intramural monophasic action potentials (MAP) display steeper APD rate relations and higher sensitivity to class III agents than epicardial and endocardial MAPs: characteristics of the M cells in vivo. Circulation. 1995;92(suppl I):I-300. Abstract.
38.
Anyukhovsky EP, Sosunov EA, Rosen MR. Regional
differences in electrophysiologic properties of epicardium,
midmyocardium and endocardium: in vitro and in vivo
correlations. Circulation. 1996;94:1981–1988.
39.
Anyukhovsky EP, Sosunov EA, Rosen MR. Effects of
quinidine on repolarization in canine epicardium,
midmyocardium, and endocardium. II. In vivo study.
Circulation. 1997;96:4019-4026.
40.
Rosen MR, Merker C, Gelband H, Hoffman BF.
Effects of procainamide on the
electrophysiological properties of the
canine ventricular conducting system. J
Pharmacol Exp Ther. 1973;185:438–446.
41. Winer BJ, Brown DR, Michels KM. Statistical Principles in Experimental Design. New York, NY: McGraw-Hill Inc; 1991.
42.
Wettwer E, Grundke M, Ravens U. Differential effects of
the new class III antiarrhythmic agents almokalant, E-4031 and
D-sotalol, and quinidine, on delayed rectifier currents in guinea pig
ventricular myocytes. Cardiovasc Res. 1992;26:1145–1152.
43. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady-state TTX-sensitive ('window') current in cardiac Purkinje fibers. Pflugers Arch. 1979;379:137–142.[Medline] [Order article via Infotrieve]
44.
Yeola SW, Rich TC, Uebele VN, Tamkun MM, Snyders DJ.
Molecular analysis of a binding site for quinidine in a human
cardiac delayed rectifier K+ channel: role of S6
in antiarrhythmic drug binding. Circ Res. 1996;78:1105–1114.
45.
Nattel S, Bailey JC. Time course of the
electrophysiological effects of quinidine
on canine cardiac Purkinje fibers: concentration dependence and
comparison with lidocaine and disopyramide. J Pharmacol Exp
Ther. 1983;225:176–180.
46. Neff CA, Davis LE, Baggot JD. A comparative study of the pharmacokinetics of quinidine. Am J Vet Res. 1972;33:1521–1525.[Medline] [Order article via Infotrieve]
47. Cho YW. Quantitative correlation of plasma and myocardial quinidine concentrations with biochemical and electrocardiographic changes. Am Heart J. 1973;85:648–654.[Medline] [Order article via Infotrieve]
48.
Imaizumi Y, Giles WR. Quinidine-induced inhibition of
transient outward current in cardiac muscle. Am J
Physiol. 1987;253:H704–H708.
49.
Wang Z, Fermini B, Nattel S. Effects of flecainide,
quinidine, and 4-aminopyridine on transient outward and
ultrarapid delayed rectifier currents in human atrial myocytes.
J Pharmacol Exp Ther. 1995;272:184–196.
50. Colatsky TJ. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Circ Res. 1982;50:17–27.
51. Hiraoka M, Sawada K, Kawano S. Effects of quinidine on plateau currents of guinea-pig ventricular myocytes. J Mol Cell Cardiol. 1986;18:1097–1106.[Medline] [Order article via Infotrieve]
52.
Roden DM, Bennett PB, Snyders DJ, Balser JR, Hondeghem
LM. Quinidine delays IK activation in guinea pig
ventricular myocytes. Circ Res. 1988;62:1055–1058.
53.
Balser JR, Bennett PB, Hondeghem LM, Roden DM.
Suppression of time-dependent outward current in guinea pig
ventricular myocytes: actions of quinidine and
amiodarone. Circ Res. 1991;69:519–529.
54. Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Physiol. 1979;236:H561–H567.
55. Eddlestone GT, Zygmunt AC, Antzelevitch C. Larger late sodium current contributes to the longer action potential of the M cell in canine ventricular myocardium. Pacing Clin Electrophysiol. 1996;19:569. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  D. H. Lau, C. Clausen, E. A. Sosunov, I. N. Shlapakova, E. P. Anyukhovsky, P. Danilo Jr, T. S. Rosen, C. Kelly, H. S. Duffy, M. J. Szabolcs, et al. Epicardial Border Zone Overexpression of Skeletal Muscle Sodium Channel SkM1 Normalizes Activation, Preserves Conduction, and Suppresses Ventricular Arrhythmia: An In Silico, In Vivo, In Vitro Study Circulation, January 6, 2009; 119(1): 19 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Morita, D. P. Zipes, H. Morita, and J. Wu Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells Cardiovasc Res, April 1, 2007; 74(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 L. Carlsson Drug-induced torsade de pointes: the perspectives of industry Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K114 - K120. [Abstract] [PDF]
|
|
|
|
|
|
A. Bauer, R. Becker, K. D. Freigang, J. C. Senges, F. Voss, A. Hansen, M. Muller, H. J. Lang, U. Gerlach, A. Busch, et al. Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart Circulation, November 23, 1999; 100(21): 2184 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Merot, F. Charpentier, J.-M. Poirier, G. Coutris, and J. Weissenburger Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol Cardiovasc Res, November 1, 1999; 44(2): 303 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Sosunov, R. Z. Gainullin, P. Danilo Jr., E. P. Anyukhovsky, M. Kirchengast, and M. R. Rosen Electrophysiological Effects of LU111995 on Canine Hearts: In Vivo and In Vitro Studies J. Pharmacol. Exp. Ther., July 1, 1999; 290(1): 146 - 152. [Abstract] [Full Text]
|
|
|
|
|
|
E. P. Anyukhovsky, E. A. Sosunov, S. J. Feinmark, and M. R. Rosen Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium : II. In Vivo Study Circulation, December 2, 1997; 96(11): 4019 - 4026. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||