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Circulation. 1997;96:4011-4018

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(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

Eugene A. Sosunov, PhD; Evgeny P. Anyukhovsky, PhD; ; Michael R. Rosen, MD

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
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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 ({approx}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{Omega}) 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 {approx}3 hours for transmural, {approx}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 1Down depicts the results obtained and shows that APD remained stable in all preparations at all stimulation rates during >4 hours of observation after equilibration.



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  		Figure 1. Stability of epicardial, endocardial, and transmural (M-cell) preparations. All preparations driven at a CL of 1000 ms were superfused with Tyrode's solution throughout protocol. First APD90-CL curves were obtained 3 hours after dissection for transmural, 4 hours for endocardial, and 5 to 6 hours for epicardial slabs. Second and third frequency scans were obtained 2 and 4 hours later, respectively.

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
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 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
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Representative transmembrane potentials of epicardial, midmyocardial, and endocardial cells are shown in Fig 2Down. 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 2Down and TableDown). Note, however, that whereas quinidine consistently prolongs APD in epicardium and endocardium at the 20- and 90-minute time periods depicted in Fig 2Down, in the M cells it initially prolongs and then shortens APD.



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  		Figure 2. Representative experiments illustrating transmembrane action potentials recorded from epicardial, endocardial, and M cells at CL of 1000 ms in control and after 20 and 90 minutes of exposure to 20 µmol/L quinidine. In each panel, top trace shows transmembrane action potential and bottom trace shows max. Vertical calibration is for action potential and max; horizontal for action potential.


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  		Table 1. Effects of Quinidine 20 µmol/L on Selected Action Potential Parameters of Epicardial, Endocardial, and M Cells at CLs of 300, 1000, and 4000 ms

Fig 3Down 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 3ADown). In both epicardial and endocardial cells, this effect was concentration dependent, and it was more prominent in endocardium.



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  		Figure 3. Time course of APD90 changes induced by different quinidine concentrations in epicardial (Epi) and endocardial (Endo, A) and transmural (B) slabs driven at CL of 1000 ms. Results from different preparations are superimposed. Arrows indicate start of quinidine superfusion. Records were made once every minute.

In contrast, in M cells, the pattern of APD changes depended on quinidine concentration (Fig 3BUp). 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 3Up 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 4Down. 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 5Down). 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 5ADown). 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 5BDown and 5CDown). At the highest concentration (20 µmol/L), there was significant APD prolongation at 300 ms and significant shortening at 2000 and 4000 ms (Fig 5DDown). Fig 6Down 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.



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  		Figure 4. Steady-state effects of quinidine (5 and 20 µmol/L) on APD90-CL relationship in surface epicardial (A) and endocardial (B) cells. Values are mean±SEM (n=8 for both tissues). *P<.05 vs control at same CL; **P<.05 for both 5 and 20 µmol/L at same CL.



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  		Figure 5. Steady-state effects of different quinidine concentrations on the APD90-CL relationship in M cells. Values are mean±SEM (n=9 for each quinidine concentration). *P<.05 vs control at same CL.



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  		Figure 6. Concentration-dependent effects of quinidine on APD90 on surface endocardial, surface epicardial, and M cells (A, B, and C, respectively) at CLs of 2000 and 300 ms. Values are mean±SEM (n=8, 8, and 9 for endocardial, epicardial, and M cell data, respectively). *P<.05 vs control (0 quinidine concentration).

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 7ADown. E4031 significantly prolonged the APD, eliminated the quinidine-induced transient APD prolongation, and accentuated the quinidine-induced shortening of the APD (compare Figs 7ADown and 3BUp). Fig 7BDown 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 5DUp).



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  		Figure 7. A, Representative experiment illustrating influence of E4031 (1 µmol/L) pretreatment on time course of changes in APD90 induced by quinidine in an M cell driven at CL of 1000 ms. Arrows indicate start of E4031 superfusion alone and in combination with quinidine 20 µmol/L. Records were made once every minute. B, Steady-state effects of quinidine (20 µmol/L) on APD90-CL relationship in M cells pretreated for 30 minutes with 1 µmol/L E4031. Values are mean±SEM (n=6). *P<.05 vs control; +P<.05 vs E4031 at same CL.

Fig 8Down 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 8ADown). 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 8ADown and 3BUp). 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 8BDown).



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  		Figure 8. A, Representative experiments illustrating influence of TTX (2 µmol/L) pretreatment on time course of APD90 changes induced by quinidine in M cell driven at CL of 1000 ms. Arrows indicate start of TTX superfusion alone and in combination with quinidine. Records were made once every minute. B, Steady-state effects of quinidine (20 µmol/L) on APD90-CL relationship in M cells pretreated for 30 minutes with 2 µmol/L TTX. Values are mean±SEM (n=6). *P<.05 vs control; +P<.05 vs nifedipine at same CL.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
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: {approx}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
 
APD = action potential duration
APD90 = action potential duration at 90% repolarization
CL = cycle length
ICa = slow inward calcium current
IK = delayed rectifier potassium current
IKr = rapid component of delayed rectifier potassium current
Ito = transient outward current
TTX = tetrodotoxin


*    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
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  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.



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