(Circulation. 1997;96:4019-4026.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium
II. In Vivo Study
From the Departments 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
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Abstract |
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Background In the companion article, we report a significant difference in quinidine effects on the action potential duration between surface (epicardial and endocardial) cells and midmyocardial cells (M cells) of canine left ventricle in vitro. This article considers two questions raised by the previous study: (1) Are the complex quinidine effects in vitro reflected in its actions on the heart in situ? (2) What are the cellular determinants of quinidine effects on QT interval in ECG?
Methods and Results We used plunge and surface electrodes to measure activation-recovery intervals (ARIs) of bipolar electrograms obtained from epicardium, endocardium, and midmyocardium (3, 5, and 9 mm from epicardium) of canine left ventricle in conditions of AV block and right ventricular pacing. Quinidine was infused continuously; its plasma level increased from 1.6±0.1 µg/mL at 30 minutes to 7.6±0.7 µg/mL at 180 minutes. At cycle lengths (CLs) from 300 to 1500 ms, there was no ARI gradient across the ventricular wall before and during quinidine infusion. At a CL of 300 ms, therapeutic concentrations of quinidine prolonged ARIs and QT intervals. At a CL of 1500 ms, ARIs were significantly prolonged at low quinidine concentrations. With an increase of quinidine concentration, this effect subsided and disappeared.
Conclusions In situ, quinidine-induced prolongation of repolarization is uniform in all myocardial layers and follows the pattern observed in M cells in vitro. The ability of quinidine in therapeutic concentrations to prolong repolarization at rapid heart rates can contribute to its antiarrhythmic efficacy.
Key Words: quinidine • repolarization
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Introduction |
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Quinidine typically prolongs the QT interval in clinical settings.1,2 In contrast, experimental animal studies have demonstrated variable results: intravenous injection of quinidine to dogs induced little (10 to 20 ms)3–7 or transient8,9 QT prolongation or no QT changes at all.10,11 In the companion article,12 we show that in vitro, there are significant differences in quinidine effects on the surface (epicardial and endocardial) cells and deep myocardial cells (M cells) of the canine left ventricle. Whereas in epicardium and endocardium, monotonic and concentration-dependent prolongation of APD was observed at all CLs, the effects of quinidine on M cell action potentials varied from prolongation to shortening of APD, depending on duration of superfusion, drug concentration, and drive CL. In light of the above, the present study was designed to investigate the effects of quinidine on repolarization of the different myocardial layers of canine left ventricle in situ. Thus, our first objective was to apply new information obtained in vitro12 to the understanding of quinidine effects on repolarization in vivo.
Controversy exists over the extent to which heterogeneity in repolarization is expressed across the normal canine left ventricular wall in situ: we13 and others14–16 report little or no gradient, whereas still other laboratories report a significant gradient17,18 Regardless of the extent to which a gradient exists, there is the possibility that heterogeneity may increase in response to drug administration. The rationale is based on observations that cells from different myocardial sites may have different sensitivities to pharmacological agents.17,19,20 In the companion article, we report that in vitro, at high drug concentrations and low heart rates, quinidine produces opposing effects on repolarization in surface and deep myocardial cells: it significantly prolongs epicardial and endocardial APD and significantly shortens the APD in M cells.12 Hence, our second objective in this study was to understand the expression of these different cellular sensitivities to quinidine in determining the QT interval in vivo.
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Methods |
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Healthy mongrel dogs of either sex (18 to 22 kg) were premedicated with sodium thiopental 20 to 25 mg/kg IV and anesthetized with
-chloralose 100 mg/kg IV, which was
supplemented as needed during the experiment. Under controlled
ventilation, a thoracotomy was performed at the level of the fourth
right intercostal space, and the lateral surface of the right atrium
and basal portions of the right ventricle were exposed. The heart was
positioned in a pericardial cradle, and to achieve a slow heart rate,
complete heart block was produced by injection of 0.1 to 0.3 mL of 40%
formalin into the region of the AV node.13,21 For
stimulation of the heart, a bipolar electrode was sewn to the
epicardium over the right ventricular base. The incision
was closed by suture; another incision was made through the fourth left
intercostal space, and the heart was cradled in the open pericardium.
Intramural plunge electrodes and bipolar epicardial and endocardial
electrodes were implanted in the region of the left
ventricular outflow tract. Plunge recordings from
the endocardium were made with two Teflon-coated stainless steel wires
(diameter, 0.1 mm).22 The wires were passed
through 22-gauge needles and bent back at the bevel of the needle to
form small hooks. After the electrodes were plunged through the left
ventricular wall into the ventricular cavity,
the needle was removed, thus allowing the hooks to engage the
endocardium. Multiple transmural needle electrodes (0.5 mm in
diameter) for intramural electrogram recording, each with 10
thin insulated tungsten wires 50 µm in
diameter,23 were introduced as close to the
endocardial electrodes as possible. The needle was introduced
perpendicular to the epicardial surface and anchored with superficial
sutures through a small plastic disk, which was affixed to the shaft of
the needle. To decrease the injury induced by the movement of
myocardial layers during contraction, the shaft of the needle was
polished, and care was taken to avoid protrusion of the wire terminals.
The first pole was located 2.5 mm from the epicardial surface, and
all recording points were 1 mm apart. For bipolar
recordings, two neighboring poles were used. Three intramural
bipolar electrograms from an average of 3, 5, and 9 mm deep to the
epicardium were recorded in each experiment. Epicardial
electrograms were recorded from bipolar electrodes (1-mm spacing)
mounted on the inner surface of the plastic disk. In some experiments,
a second set of transmural electrodes was introduced into the
anterolateral left ventricular wall near the apex.
Electrical signals from five amplifiers (0.5- to 1000-Hz bandwidth),
together with the surface ECG (lead II), were digitized with an
analog-to-digital converter (D-210, DATAQ Instruments Inc) and stored
in a personal computer for further analysis. Then the signals
were differentiated, and the ARIs were measured from the steepest
deflection of the QRS complex to the steepest portion of the terminal
phase of the T wave. Substantiation of the method used for evaluation
of repolarization is given in the "Appendix."
Hearts were stimulated by 2-ms square-wave pulses delivered at
2.0 times the threshold through bipolar electrodes at the right
ventricular base. A femoral vein was cannulated for
administration of supplemental doses of -chloralose and for
quinidine infusion. The right femoral artery was cannulated for
monitoring blood pressure by standard techniques, and the left femoral
artery was cannulated for drawing of blood samples for measurement of
quinidine levels.
Protocol
After all electrodes had been placed, the open chest was covered
with a cloth to minimize temperature changes in the thoracic cavity,
and hearts were stimulated at a CL of 1000 ms. A control frequency scan
of ARIs was performed 30 minutes after placement of the electrodes.
Pacing was begun at a CL of 1500 ms (the longest CL that
consistently overdrove the idioventricular rhythm
in all dogs), and CL was then decreased to 1000, 700, 500, and 300 ms.
To ensure a steady state, each step was maintained for 3 minutes before
data were collected.13 Then the CL was returned
to 1000 ms, and quinidine hydrochloride was given as an
intravenous infusion at 0.06 mg ·
kg-1 · min-1 for
60 minutes followed by 0.30 mg ·
kg-1 · min-1 for
120 minutes. Frequency scans of ARI were obtained every 30 minutes
after the start of quinidine infusion. Arterial blood
samples for determination of serum quinidine concentrations were drawn
before and at 30-minute intervals during quinidine infusion. Serum was
separated and stored at -20°C for later analysis. Serum drug
concentrations were measured as follows: the serum samples were thawed
and mixed, and measured aliquots (1 mL) of each sample were taken.
Quinine was added to each sample as an internal standard (5
µg/mL), and the quinidine was extracted on a solid-phase
extraction column (Bond Elut, C18; Varian).
Solvents were allowed to pass through under gravity flow. Briefly, the
columns were prepared by application of methanol (2 mL) and then water
(2 mL). The serum samples were applied, and then the columns were
washed twice with water (1 mL). The columns were dried with a brief
application of vacuum. The quinidine was eluted in methanol (1
mL).
Aliquots of the eluate (25 µL) were reduced to dryness, redissolved in high-performance liquid chromatography mobile phase, and injected onto a C8 column (Supelcosil LC-8, 5 µm, 4.6x250 mm). The column was eluted with acetonitrile/water/triethylamine (15/85/0.3, vol/vol/vol; pH adjusted to 2.5 with phosphoric acid) at 1 mL/min, and the quinidine was detected by UV absorbance at 235 nm. The quinidine and quinine peaks were integrated with an HP 3390A integrator, and the concentration of quinidine in the serum samples was determined by comparison to a standard curve.
Statistical Analysis
Data are expressed as mean±SEM. The statistical technique used
was two-way ANOVA for repeated measures and Bonferroni's test when the
F value permitted this.24 Significance was
determined at P<.05.
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Results |
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The effects of quinidine on the QRS complex and on conduction are consistent with earlier reports, as shown in Figs 1
and 2.
Fig 1 shows the effects of quinidine on QRS duration at CLs of 1500 and
300 ms. During control, the change in drive CL had no effect on
duration. Quinidine infusion produced concentration-dependent QRS
prolongation, which was more marked at a short CL. As a result, at a
high quinidine concentration, the QRS duration at 300 ms was
significantly longer than at 1500 ms. Fig 2 depicts the effect of
quinidine on conduction times in different myocardial layers at CLs of
1500 and 300 ms. In control, conduction times increased gradually from
endocardium to epicardium. A low quinidine concentration had no effect
on conduction. A high concentration significantly and uniformly slowed
conduction in all myocardial layers, with the effect being more
prominent at fast heart rate.
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Fig 3 illustrates
representative electrograms recorded along the
epicardial-endocardial axis from the basolateral left
ventricular wall at a CL of 1500 ms in control and at 60
and 180 minutes of quinidine infusion. Data summarizing the effects of
quinidine on ARIs and arterial plasma concentrations of
quinidine in the course of all experiments are shown in Fig 4. At the longest CL (1500 ms), ARIs at
all depths as well as the QT interval increased during quinidine
infusion and reached a maximum value in 60 minutes, ie, at the end of
the initial quinidine infusion. Then, with continued infusion and
increase of the plasma quinidine level, ARIs shortened and returned to
control values at 150 to 180 minutes. With the shortening of CL to
1000, 700, and 500 ms, absolute values of quinidine-induced ARI
prolongations decreased; however, the time course of ARI changes was
the same as at a CL of 1500 ms. Qualitatively different time courses of
QT interval and ARI changes were observed at the shortest CL (300 ms).
ARI in all myocardial layers and QT interval were prolonged by
quinidine and remained significantly longer at the end of quinidine
infusion, ie, at the high quinidine concentration.
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The difference between quinidine effects at the longest and shortest CL
is clearly seen in Fig 5. At a CL of 300
ms, ARI in all myocardial layers and QT interval increased
concentration-dependently and reached a statistically significant
prolongation at 1.8 to 4.5 µg/mL of quinidine. In contrast, at
a CL of 1500 ms, all ARIs and QT intervals were significantly prolonged
at 1.8 µg/mL of quinidine, and this effect diminished with an
increase in quinidine concentration.
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Fig 6 demonstrates that quinidine effect
on ARI was qualitatively the same in all myocardial layers and depended
on both drug concentrations and CL. At a low plasma concentration (1.8
µg/mL at the end of the low-speed infusion), quinidine
manifested obvious reverse use dependence, and significant prolongation
of repolarization was seen at long CLs. In contrast, at a high
concentration (7.6 µg/mL at the end of the high-speed
infusion), there was significant ARI lengthening at 300 ms and no
effect at longer CLs.
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As in our earlier study,13 we found no
significant differences among ARIs measured at all depths and all CLs
in the absence of quinidine (Fig 7). Even
at the longest CL, the variation in ARIs did not exceed 25 ms.
Quinidine did not induce any differences among ARIs. It lengthened ARI
to about the same extent in all myocardial layers (parallel upward
shift of ARI-depth curves in Fig 7). The maximum prolongation was
observed at the longest CL and at a low quinidine concentration. The
high quinidine concentration had no effect at all CLs except 300 ms,
where significant ARI prolongation was found at all depths.
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In five experiments, a second set of transmural electrodes was
introduced at an additional left ventricular site. This was
located 
3 to 4 cm away from the primary site. Fig 8 shows the distribution of ARIs across
the ventricular wall at the additional site at the longest
and shortest CLs in control and at two (low and high) quinidine
concentrations. Quinidine concentrations were insignificantly different
from the values for the other group of animals. As at the primary
electrode site, there were no significant differences among ARIs at all
depths in control, and quinidine effects approximated those at the
primary site.
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Discussion |
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Before administering quinidine, we found no differences in duration of ARIs across the left ventricular wall at all stimulus CLs. These results coincide with the data of our earlier study, which was done under sodium pentobarbital anesthesia.13 The change in anesthesia had no effect on distribution of ARI across the ventricular wall. In vitro studies have demonstrated that distribution of M cells within the ventricular wall varies from site to site along the posteroanterior or apicobasal axes.25 Therefore, in the present study, we recorded ARIs from an additional site distant from the left ventricular outflow tract. No differences among ARIs were observed at the additional site. Thus, in the intact heart, we found little heterogeneity of repolarization across the free wall of the canine left ventricle. These results are in agreement with the data of Janse,14 Burgess et al,15 and Freigang et al,16 who were unable to detect longer refractory periods in midmyocardium in comparison to epicardium or endocardium of heart in situ. In contrast, a recent study by El-Sherif et al18 demonstrated the existence of moderate but statistically significant spatial dispersion of repolarization in the canine left ventricular wall,26–28 with longer ARI in the midmyocardium. We suggest three major reasons for the difference between our results and those of El-Sherif et al: First, to slow the heart rate, El-Sherif et al performed intense stimulation of the cervical vagosympathetic trunks. Because the sympathetic and parasympathetic nerves as well as the adrenergic and cholinergic receptors can be distributed nonuniformly within ventricular wall, such stimulation itself may produce heterogeneity of repolarization across the ventricular wall. Second, El-Sherif et al used multielectrode grids that consisted of a rigid acetyl plate with needle electrodes inserted through it. During systole, muscle layers move not only along the shafts of the needles but in the transverse direction as well. This transverse movement can produce additional injury due to the rigidness of the grid. We have shown previously13 that such injury can significantly affect ARI. Moreover, because the transverse displacement of myocardial layers may vary with depth, this may contribute to heterogeneity of injury, manifested as heterogeneity of repolarization across the ventricular wall. Finally, whereas we studied adult dogs, El-Sherif et al studied 10- to 12-week-old dogs. It is known that at
8 weeks of age, repolarizing currents still are maturing in canine
heart.29 Hence, age-related factors also may have
contributed to the differences in our results. Our companion study12 demonstrates prominent concentration dependence of quinidine effects on isolated myocardial tissues. Moreover, the concentration dependence was qualitatively different in surface and midmyocardial cells, making it important to examine quinidine effects on heart in situ over a wide range of drug concentrations. That is why in the present study, two constant speeds of quinidine infusion were used to attain two mean stationary concentrations: 1.8 and 7.6 µg/mL. These concentrations can be considered to be the lower and higher limits of the usual therapeutic range (2 to 7 µg/mL).30,31 In molar units, they equal 5.5 and 23.5 µmol/L, respectively, approximating the range of quinidine concentrations we used in vitro.12 The monotonic increase of quinidine plasma concentrations in the course of our experiments was reflected as monotonic, rate-dependent QRS widening and conduction delay.
In contrast to our in vitro results,12 the
effects of quinidine on repolarization were the same in all myocardial
layers of heart in situ. Thus, quinidine did not induce any spatial
heterogeneity of repolarization across the
ventricular wall of normal hearts. Fig 9A shows the dependence of QT interval on
CL in the absence of quinidine. Comparison with the in vitro data
(dotted lines) demonstrates a close fit of the QT interval with the APD
of M cells but not of epicardial or endocardial cells. The effects of
quinidine on repolarization in all myocardial layers in situ are very
similar to its effects on repolarization of M cells in vitro. This can
be seen in Fig 9B: concentration dependence of the effect of quinidine
on QT interval qualitatively coincides with concentration dependence of
its effect on the APD of M cells in vitro and significantly differs
from its effects on epicardial and endocardial cells in vitro.
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The results of the present study can explain the variability of quinidine effects on the QT interval reported in other experiments in vivo.3–11 The extent of QT and ARI prolongation depends importantly on heart rate and quinidine concentration. Different heart rates as well as different infusion procedures yielding different quinidine concentrations can account for the variability of quinidine-induced QT prolongation in these reported studies.3–11 We also have found no discrepancy between quinidine effects in vitro and in vivo: concentration- and rate-dependent quinidine effects on repolarization in situ are similar to those observed in vitro in M cells, which constitute the major part of the myocardium.13,32
Any explanation of the disparate effects of quinidine on APD in epicardium and endocardium versus M cells in vitro12 compared with its more uniform effects on myocardial repolarization in situ must take into account two factors: one is the very real differences in ionic contribution to the epicardial, endocardial, and M cell action potentials, as detailed previously by others.33–35 Specifically, IK tail-current density in M cells is considerably less than that in epicardium and endocardium. Given the lesser magnitude of IK in one cell type, the availability of comparable concentrations of an IK blocker like quinidine to all three cell types will result in different responses, as occurred in vitro.12 The second factor is the effects of electrotonic interaction on the ultimate expression of repolarization when cells are well coupled in vivo. It is reasonable to assume that in the types of tissue preparation used in our previous studies,12,13 in which epicardial, endocardial, and M cells are uncoupled by the experimental method, the action potential characteristics of the three cell types will be determined largely by the drug-channel interaction. In contrast, in the in vivo setting, the differences are tempered (or masked to some extent) by the coupling among cell layers. This implies as well that in settings in which cells are partially uncoupled, more heterogeneity of the effects of quinidine on the in situ heart will be seen, reflecting, in turn, the heterogeneity of repolarizing currents in the different cell populations.
In closing, in accordance with our previous observations,13 we have demonstrated that the behavior of myocardial ARIs in the intact heart corresponds to that of M cells in vitro rather than to epicardial or endocardial cells. In contrast to in vitro results,12 quinidine-induced prolongation of repolarization in situ is uniform in all myocardial layers. In addition, the present study shows that the response of the APD in M cells in vitro to quinidine is consistent with its effects on myocardial repolarization in situ. Thus, transmural slices incorporating M cells might be construed as the in vitro milieu most representative of the in vivo setting.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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These studies were supported in part by USPHS-NHLBI grant HL-28958 and the Wild Wings Foundation. 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.
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Appendix 1 |
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Correlation Between Transmural APD and ARI From Bipolar Electrograms Tested in Isolated Tissues
In the present study, we used bipolar electrodes for measurement of ARIs as an estimate of the APD. One of the benefits of the bipolar electrogram in comparison to the unipolar is that distant events influence both recording sites in the same fashion and are presumably canceled out. Only the potential difference between two poles is recorded. Moreover, theory predicts that ARI measured as the time elapsed between the maximum absolute signal recorded during the QRS complex and the peak of the T wave is an accurate measure of the APD.36 Whereas experimental substantiations for use of ARI as an estimate of the APD have been reported in detail for unipolar extracellular recordings,37,38 only preliminary data are reported for the adequacy of bipolar electrodes.39 This is why we performed experiments to examine the correlation between transmembrane APDs and ARIs from bipolar electrograms.
Endocardial and epicardial slabs were filleted from canine left ventricular wall, superfused with normal Tyrode's solution, and stimulated as previously described.12,13 Extracellular bipolar electrograms were recorded with Teflon-coated silver electrodes (interelectrode distance, 1 mm). Intracellular potentials were recorded through a glass microelectrode from a site as close as possible to the tip of the bipolar electrodes (usually located between the poles of the bipolar electrodes). The preparations were stimulated at CLs from 200 to 4000 ms as previously described.12,13
The results are shown in Fig 10
. As
indicated in the legend, two methods of ARI measurement were applied.
With both methods, significant correlation between ARIs and APDs was
observed. The slope of the correlation line in Fig 10B is closer to
unity than that in 10C. Therefore, the method of ARI measurement
presented in 10B was used in the present study.
Received June 10, 1997; revision received August 15, 1997; accepted September 1, 1997.
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