LABORATORY INVESTIGATION
PHARMACOLOGY
Frequency-dependent effects of quinidine on the
relationship between action potential duration and
refractoriness in the canine heart in situ
MICHAEL R. FRANZ, M.D.,
AND
ANGELIKA COSTARD, M.D.
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ABSTRACT To determine the normal relationship in vivo between action potential duration (APD)
and effective refractory period (ERP) over a large range of steady-state cycle lengths (CLs) and to
determine how a sodium channel-blocking agent, quinidine, affects this relationship, we developed
a new contact electrode technique for simultaneous measurements of monophasic action potentials and
refractoriness at a single site in the beating heart in situ. Recordings were made from left ventricular
epicardium in open-chest dogs during steady-state pacing at CLs from 220 to 600 msec both before
and after therapeutic intravenous administration of quinidine. During baseline both APD at 90%
repolarization (APD90) and ERP were linearly correlated to CL with nearly identical slopes: y = 0.24x
CL+83.0 (r-'1.0; p<.0001) for APD90 and y=0.22x CL+82.3 (r=1.0; p<.0001) for ERP.
Expressed in percent repolarization, ERP coincided with a repolarization level of 79% to 83%, with
no appreciable influence of CL on this relationship. Quinidine increased APD90 by a small but
significant amount (8 to 12 msec), which was independent of CL. In contrast, the effect on ERP of
quinidine exhibited marked frequency dependence (p <.0002), producing progressively greater ERP
increase at shorter CLs, as compared with both baseline ERP and concomitant APD9J. The duration
by which ERP exceeded APD90 reached 44 + 14 msec at a CL of 220 msec. These data demonstrate
for the beating heart in vivo (1) a fixed baseline relationship between membrane repolarization and
refractoriness that is not altered by CL, and (2) a strongly frequency-dependent ability of quinidine
to increase ERP relative to APD90. Thus, simultaneous measurement of APD90 and ERP at the same
ventricular site detects frequency-dependent changes in membrane excitability and may be useful in
the characterization and quantification of antiarrhythmic drug effects in vivo.
Circulation 77, No. 5, 1177-1184, 1988.
STUDIES IN VITRO have demonstrated close correlation between action potential duration (APD) and
effective refractory period (ERP).1' 2 Therefore, when
the APD shortens, as during rapid pacing, the ERP also
shortens. This has clinical implications because ventricular arrhythmias are more likely to be induced at
shorter ERPs.3 4 Antiarrhythmic drugs, particularly
those in class IA,5 are known to delay recovery
of membrane excitability beyond membrane repolarization,6-8 and this may in part explain their
antiarrhythmic efficacy. More recently, it has been
shown that the effects of antiarrhythmic drugs may be
From the Division of Cardiology, Stanford University School of
Medicine, Stanford, CA.
Supported in part by a grant from the American Heart Association,
California Chapter. Dr. Costard was supported by a fellowship grant
from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg,
German Federal Republic.
Address for correspondence: Michael R. Franz, M.D., Cardiac
Arrhythmia Unit, Cardiology Division, CVRC 293, Stanford University
School of Medicine, 300 Pasteur Dr., Stanford, CA 94305.
Received Oct. 27, 1987; revision accepted Jan. 28, 1988.
Vol. 77, No. 5, May 1988
frequency dependent, and may be manifested progressively more with higher heart rates.7' 9-12
Experimental data on ventricular repolarization, refractoriness, and antiarrhythmic drug effects stem
almost exclusively from isolated, artificially superfused preparations in which intracellular potentials can
be measured simultaneously with stimulation threshold
in single cardiac cells. Such measurements have not yet
been duplicated in vivo because it has not been possible
to record both APD and ERP at the same time and the
same site in a beating heart. We therefore developed a
new, single-bipolar contact electrode technique that
permits simultaneous recording of monophasic action
potentials (MAPs) simultaneously with ERP determinations at the same ventricular site in the beating heart
in situ.
The first objective of this study was to determine the
normal relationship between ERP and APD in the
canine ventricle in situ over a large range of steady-state
cycle lengths (CLs). The second objective was to exam1177
FRANZ and COSTARD
ine the effect of a sodium channel-blocking drug,
quinidine, on the relationship between APD and ERP
and to determine whether this relationship is modified
by the frequency of stimulation.
Methods
Twenty-one mongrel dogs weighing 10 to 30 kg were anesthetized with a combination of intravenous urethane (625 mg/kg)
and ot-chloralose (80 mg/kg). The animals were intubated and
ventilated with humidified room air by a Harvard model 613
respirator with adjustment based on arterial blood gases
(Corning 165 pH/blood gas analyzer) measured every 30 min to
maintain oxygen tension greater than 85 mm Hg and pH between
7.35 and 7.45. A polyethylene catheter was placed in the femoral
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artery and connected to a Statham fluid-filled pressure transducer. Mean arterial blood pressure was displayed continuously
on a Beckman Instruments oscilloscope and remained stable
above 80 mm Hg throughout the experimental protocol. A
polyethylene catheter inserted into a femoral vein was used for
the intravenous infusion of quinidine. Hearts were exposed
through a left thoracotomy and suspended in a pericardial cradle.
MAP recordings. MAPs were recorded from the left ventricular epicardium with a contact electrode probe, as described
earlier.'3 This technique has been validated by quantitative
comparison with simultaneous intracellular recordings of action
potentials.'4 In brief, the MAP recording probe consists of an
L-shaped cantilever with two Ag-AgCl electrodes mounted on
its distal end (figure 1). The "exploring" electrode at the tip of
the probe is 1 mm in diameter and embedded in a thin collar of
epoxy cement. The reference electrode is located along the probe
shaft 5 mm proximal from the tip. A spring-loaded mechanism
built into the shaft of the cantilever provides continuous contact
of the tip electrode with the epicardial surface of the beating
heart. A soft piece of cylindrically shaped foam rubber soaked
with 0.9% saline solution is mounted over the distal end of the
probe, covering the proximal electrode and reaching to the tip,
where it forms a 1 mm thick anulus around the tip electrode. This
foam rubber serves as a small volume conductor that establishes
electrical continuity between the tip and reference electrode and
between the reference electrode and the epicardium. The probe
handle is mounted at the table and positioned so that the tip
electrode rests stably on either the anterior or lateral surface of
the left ventricle. Once the probe is positioned with the tip
exerting a contact pressure of approximately 30 g, MAPs of
stable amplitude and waveform can be recorded continuously
over long time periods (hours).
The MAP signals were recorded with high input impedance,
direct-current coupled, differential amplifiers (Grass Instru-
2mm
FIGURE 1. Schematic representation of contact electrode probe and
electrical circuit used for simultaneous MAP recordings and determination of refractoriness at a single epicardial site. See text for details.
1178
ments, Model P 16) along with 3 surface electrocardiographic
(ECG) tracings1-3 recorded with conventional ECG amplifiers
and written out by multichannel electrostatic recorder (Gould ES
1000) at a paper speed of 250 mm/sec. The frequency response
of the recording system was 0 to 5000 Hz and the accuracy of
measurements of the ADP at 90% repolarization (APD90) was
better than 2 msec, as assessed by two independent observers.
Refractory period determination at the recording site
(figure 2). Hearts were driven with basic stimuli through a pair
of needle electrodes placed in the right ventricular free wall.
Extrastimuli of 1 msec duration and twice diastolic threshold
strength were generated by a second stimulator and applied to
the left ventricle through the MAP recording electrodes (figure
1). Although this resulted in a large stimulus artifact in the MAP
recordings (mainly due to polarization of the Ag-AgC1 electrodes), it generally did not prevent the recognition of whether
the extrastimulus provoked a new propagated response (figure
2, compare response in A to that in B). If polarization was so
large as to drive the MAP tracing completely off-screen, propagated depolarization of the ventricle was verified by an appropriately timed premature and aberrantly conducted beat in the
surface electrocardiogram (figure 2, B). The extrastimulus current strength was measured as the voltage drop across a series
10 Q resistor; this low resistor value was appropriate because the
Ag-AgCl electrodes had a source impedance of only 10 to 80 Q.
Extrastimulus thresholds were tested during late diastole at each
steady-state CL, both before and after quinidine administration,
and if necessary, the stimulus strength was adjusted to twice
threshold.
Starting in late diastole, the extrastimulus coupling interval
was shortened in 5 msec decrements until refractoriness
occurred. Each ERP determination was made in the steady-state
and repeated to ensure reproducibility. Because the basic drive
stimuli were applied to the right ventricle and the extrastimulus
was applied to the left ventricle, the basic-to-extrastimulus interval included the interventricular conduction time, which may
vary with sudden interval changes. The local ERP was therefore
determined as the interval from the MAP upstroke of the last
steady-state response to the extrastimulus that just failed to elicit
a new response. Figure 2 gives an example of how the local left
ventricular epicardial ERP was determined simultaneously with
the MAP duration. As shown in figure 2,A, a stimulus delivered
190 msec after the MAP upstroke elicited a propagated response,
as appreciated by a subsequent MAP signal and a premature and
altered QRS complex. As shown in figure 2, B, a stimulus of
identical current strength delivered 5 msec earlier (at 185 msec)
failed to elicit a propagated response; this interval was the ERP
that was compared with the duration of the preceding steady state
MAP. APD90 was measured from the MAP upstroke to the time
of 90% repolarization according to the methods described
earlier.14 ERP was compared with APD90 recorded at the same
site; for the purpose of this study, postrepolarization refractoriness was defined as an ERP greater than APD90. To further
define the relationship between membrane repolarization and
refractoriness, the repolarization level (in percent of total MAP
amplitude) at which excitability recurred was also measured.
Effect of dilferent steady-state CLs. Pacingwas begun at the
longest basic drive CL able to overdrive the spontaneous heart
rate (usually 600 msec) and maintained constant for 2 min until
a steady state was reached. The basic CL was then decreased in
steps of 50 msec, each step being maintained for at least 2 min
to ensure steady state. ERP and APD90 measurements were made
with an extrastimulus introduced every 12 cycles without ensuing pause. The longest overdrive CL for statistical purposes was
600 msec in the 21 control dogs and 500 msec in the nine dogs
treated with quinidine (sinus nodes were not crushed). The
shortest steady-state CL studied was 220 msec.
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
APD9I
II
MAP
T1i 20 mV
_
B
CT
ERP
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Effect of quinidine on APD90 and ERP. After baseline
determination of APD90 and ERP, quinidine gluconate was
administered as a bolus of 3.85 mg/kg over 1 min, followed by
a constant infusion of 0.28 mg/kg/min.'5 Measurements were
resumed with the MAP electrode maintained at the same epicardial site after an equilibration period of 30 min. Blood samples for determination of quinidine serum concentration (American Bioscience Laboratories) were drawn 30 and 90 min after
the infusion was begun. Average quinidine plasma concentrations at 30 and 90 min were 3.3+0.5 and 3.2+0.7 ,ug/ml,
respectively. Two of 11 animals had drug levels below the
predefined therapeutic range (2.0 to 5.0 ,ug/ml) at either 30 or
90 min and their data were excluded from analysis.
Statistical evaluation of results. APD90 determinations
were averaged over the last five responses preceding each
extrastimulation at the end of a train of regular pacing and
compared with the average of two consecutive ERP determinations at steady state. The relationship of APD90 and ERP to
CL and the significance of this relationship were evaluated by
simple linear regression analysis, with confidence intervals set
at 95%. The significance of drug effect and frequency dependence of APD90 and ERP were evaluated by two-factorial analysis of variance for repeated measures with an F test for interaction. Group data are presented as the mean + SEM.
Results
MAPs could be recorded continuously from the
same epicardial site throughout the entire study protocol (up to 4 hr). Throughout this time period and
despite the continuous contact pressure exerted by the
tip electrode against the epicardium, the MAP recordings and pacing thresholds remained highly reproducible. After an initial stabilization period of 5 min,
the MAP amplitude did not change by more than 20%
for the subsequent investigational period of up to 4 hr.
The duration of the MAP at 90% repolarization
(APD9O) varied by no more than 5 msec (2%) and the
ERP was constant within the 5 msec limit of resolution
under baseline conditions (steady-state pacing in the
drug-free state) for test periods of 1 hr and more.
Vol. 77, No. 5, May 1988
and
FIGURE 2. Method of simultaneous
ERP determination at a single ventricular site. Each
panel shows surface ECG leads 1 and 2 and the MAP
recording from a left ventricular epicardial site. Si
denotes the artifact of the basic drive stimulus delivered to the right ventricle. CT is the interventricular
conduction time from the right ventricular stimulus
site to the left ventricular recording site. In A, an
extrastimulus (S2) of two times diastolic threshold
strength applied 190 msec after the onset of the previous depolarization through the MAP recording
electrodes produces a marked stimulus artifact and
elicits a new response; both a local MAP recording
and a propagated ECG ventricular response are seen.
In B, a stimulus of identical strength applied 5 msec
earlier produces only a stimulus artifact without local
or propagated ventricular response. This interval
(185 msec in this example) was the local ERP.
Threshold current strengths at end-diastole were 0.13
± 0.02 mA (n = 10) over the entire range of basic
CLs before quinidine and 0.25 + 0.06 mA (n = 6)
after quinidine at steady-state CLs longer than 500
msec. With CLs shorter than 400 msec, further
increases in diastolic threshold were sometimes
observed in the quinidine-treated dogs, and stimulus
strength was adjusted accordingly.
Relationship of
APD90
and ERP to steady-state CL
under control conditions. Figure 3 demonstrates the CL
dependence of both APD90 and ERP in 21 control
experiments. Both APD90 and ERP demonstrated a
close linear correlation to CLs ranging from 220 to
600 msec; over this range, the linear regression
equation was y = 0.24x CL + 83.0 (r = 1.0;
p <.0001) for APD90 and y = 0.22x CL + 82.3 (r =
1.0; p < .0001) for ERP. The nearly identical slopes
indicate that changes in ERP closely paralleled the
240 n=21
200
cD
a)
(n
E
-s--
200
300
400
Cycle length (msec)
FIGURE 3. Effect of different steady-state CLs on
under control conditions (n=21).
500
APD90
ERP
600
APD90 and ERP
1179
FRANZ and COSTARD
attendant change in APD90 at all CLs. On average, the
ERP was 11 + 3 msec shorter than APD90. At CLs
above 600 msec, both APD90 and ERP increased relatively less, thus deviating from the linear relationship
with CL.
As shown schematically in figure 4, inset, frequency-dependent changes in APD90 were due to a change
in plateau duration, while the slope of phase 3 remained
unaltered. A linear relationship between APD90 and
ERP might then indicate that excitability recurred
always at a similar repolarization level. This was
directly evaluated in nine experiments by expressing the
ERP as a function of percent repolarization. As shown
in figure 4, recovery from refractoriness occurred over
a narrow range of repolarization levels (79% to 83%),
and this range was independent of CL.
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Effect of quinidine on APD90 and ERP at different steadystate CLs. Quinidine increased APD90 uniformly over
the entire range of steady-state CLs studied (figure 5,
A). For instance, at steady-state CLs of 250, 350, 450,
and 550 msec APD90 after quinidine was an average of
11 + 3, 10 ± 2, 10 + 3, and 12 + 7 msec, respec-
tively, longer than control. Thus, the action potentialprolonging effect of quinidine was not significantly
influenced by the CL.
In contrast, the effect of quinidine on ERP was
strongly CL dependent (figure 5, B). At relatively long
CLs of 400 to 500 msec, quinidine prolonged the ERP
by only 19 to 22 msec (which is only slightly longer than
the concomitant increase in APD9O). However, at
shorter steady-state CLs, quinidine caused progressively greater increases in ERP of up to 61 + 21 msec
at a CL of 220 msec.
An increase in ERP that is not accounted for by an
identical increase in APD90 represents a shift in the
0
20 _
ERP
c
.0
._
40 _
_l
m
60
h
.0~
ERP
80
inn
uu z.
200
300
400
500
600
700
Cycle length (msec)
FIGURE 4. Relationship of ERP to level of relative nnembrane repolarization at different steady-state CLs under control c(onditions.
1180
A
240
220-
&3
200
0
180-
0
0.
<
160
CD)Ea)
0)
---
140
i7n 1
200
.
.
Control
Quinidine
v
250
300
350
400
450
500
Cycle length (msec)
240 -
B
220
200
-
C.)
0)
In
E
180 -
r
W
160 -
140
i
on i
200
.
250
Control
Quinidine
i
300
350
400
450
500
Cycle length (msec)
FIGURE 5. Effect of quinidine on APD90 (A) and ERP (B).
The effect of quinidine on APD90 was significant (p<.001), with no
interaction between different CLs and treatment. In contrast, ERP
after quinidine deviated progressively from the control ERP as the CL
was shortened. The effect of quinidine on ERP was significant (p < .01),
with a significant interaction between CL and treatment effect
(p< .0001).
normal relationship between repolarization and refractoriness, also known as postrepolarization refractoriness. Figure 6 depicts the amount of postrepolarization
refractoriness, obtained by subtracting APD90 from
ERP, as a function of steady-state CL. In the absence
of drug, the ERP-APD90 difference is negative (because the ERP is shorter than the APD9O) and insensitive to CL. In the presence of quinidine and at a CL
of 500 msec, ERP is only 9 + 3 msec longer than
APD90. With decreasing steady-state CL, ERP progressively increases relative to APD90 until at a CL of 220
msec ERP is 61 + 21 msec longer than control ERP,
and 44 + 14 msec longer than the concomitant APD90,
respectively. This frequency-dependent increase inpostrepolarization refractoriness is in striking contrast to
the baseline relationship between ERP and APD90,
which is essentially constant at all steady-state CLs
(figures 3 and 6).
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
70
0
0)
U)
E
APD and ERP vary substantially from site to site in
the
ventricle18'9 This may explain why previous deter-
60
50
40
30
\
30
a:
0~
C-
c:
l
20
10
0
T
-a-
\Control
_
uinidine
minations in vivo of APD and ERP, measured at different times and sites, correlated poorly.20 We found a
very close correlation between APD90 and ERP, which
is comparable to findings in vitro in
\
-10t
_________20________________________
200
250
300
350
400
450
500
Cycle length (msec)
cells.1'
single seems to
Therefore, our single-site recording method
eliminate errors caused by spatial nonuniformity of
electrophysiologic properties and as such provides the
basis for a more stringent evaluation of the relationship
between APD and ERP in vivo.
Cycle-length dependence of APD90 and ERP in the drugfree state. Both APD90 and ERP exhibited a close linear
with steady-state CLs ranging from 220 to
600 msec. A similar linear CL dependence
has been
demonstrated previously for intracellular action potendmntae rvosyfr nrclua
cinptn
tials recorded from isolated canine ventricular
muscle21' 22 and for MAPs recorded from human ven2
ms)
cyletw lengthP
APD9asafcorrelation
FIGU] RE 6. Diference between
ERP and APD90vas
functio
RE6Differe
u
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steady--stoindicate
sAll values grAte
CLoberepolandzafteionidefine. ERP
than ze ro indicate postrepolarization refractoriness. All ERP and APD90
determ inations in an individual experiment were made at the same left
ventric ular epicardial site. Quinidine increased ERP -APD90 significantly (p < .02), with a significant interaction (p <.0002) between CL and
treatm(ent
effect.
ship between APD and CL also has been observed,23
and this variance may be related to species differences
and/or a different range of CLs studied, as well as to
Disciussion
MCethodologic considerations. This study demonstrates
that rreliable stimulation of the ventricle in situ is possible with an electrode that rests on the myocardial
surfa Lce with slight pressure and that allows recording
of M APs from the same site. Stimulus thresholds at a
giver epicardial site were highly reproducible over
sever^al hours and were low in comparison with those
durin ig endocardial pacing with the use of conventional
electirode catheters.16 This, and the high stability of the
MAP amplitude and waveform, make it unlikely that
the p bersistent contact pressure exerted against the epicardiium results in significant myocardial damage.
As discussed in detail previously,13' 14, 17the contact
electirode pressure probably depolarizes and renders
inexc :itable the cells subjacent to the electrode tip; these
cells then provide a constant reference against which
the aLctive depolarizations and repolarizations of the
surro 'unding normal cells are measured. Previous studies siuggest that the MAPs recorded by this method
repre sents the electrical activity of a group of cells in
close proximity to the contact electrode tip. 13 14 The
relati ively low stimulus threshold in this study also
sugg ests that excitable cells exist within close reach of
the s timulating (and recording) electrode. Thus, it is
likelyy that the group of cells whose refractoriness was
explc )red overlapped closely with the group of cells
whos;e repolarization time course was examined.
Thte necessity to analyze the relationship between
APD and ERP at the same myocardial site has been
empi hasized by recent studies that showed that both
Vol. 7T, No. 5..
tricular endocardium. 17 However, a nonlinear relation-
May 1988
nonsteady-state
conditions.24
Refractory periods in isolated1' 2 or in vivo ventricular muscle25 also shorten with a decrease in CL, but
this relationship has in general not been explored over
a large range of steady-state CLs. Furthermore, these
earlier studies did not determine APD and ERP
together, and therefore allow no conclusion as to
whether the slope of the cycle-length relationship of
APD was identical to that of ERP and to what extent
the ERP-APD relationship was affected by antiarrhythmic drugs. The present study demonstrates for the heart
in vivo that the recovery of excitability occurs over a
narrow, fixed range of membrane repolarization that,
in the drug-free state, is not affected by heart rate.
Effect of quinidine on APD90 at different CLs. Previous
studies in vitro on the effect of quinidine on APD have
produced variable results. In some studies quinidine
prolonged the APD in Purkinje fibers and ventricular
muscle in a dose-dependent fashion,7' 26-28 and in others APD was not changed9 or was even shortened after
quinidine.29 30 Most preparations in vitro were driven
at CLs above the physiologic range of the respective
species, and in studies in which the effect of quinidine
on APD was measured over several CLs, the APDprolonging effect was attenuated at high rates. 7, 28, 31, 32
It is difficult to reconcile these differences in quinidineinduced effects on APD, because the widely varying
experimental conditions, species and fiber types investigated, electrolyte compositions, and pacing protocols
all may modulate quinidine's effect on APD. In this
1181
FRANZ and COSTARD
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study in vivo, therapeutic quinidine concentrations
produced a small but significant increase in APD90 of
epicardial muscle that was uniform over a physiologic
range of CLs.
Quinidine eifect on ERP at diiferent CLs. Previously
reported effects of quinidine on ERP are more consistent. Both in vitro and clinical studies generally have
demonstrated an increase in ERP after quinidine,7' 8, 27, 33 but the quantitative relationship to
attendant changes in APD has not been explored in
vivo. In those studies in vitro in which APD and ERP
were measured simultaneously, the effect of quinidine
was determined at a single, usually very long, CL. For
instance, Varro et al."1 found that at a drive CL of 500
msec quinidine-induced prolongation of ERP exceeded
that of APD by an average 5%. We also noticed only
a small increase in postrepolarization refractoriness
after quinidine when the hearts were paced at long CLs
(500 to 600 msec). However, when the CL was
decreased, ERP shortened less than APD90, resulting
in a progressive increase in the magnitude of quinidineinduced postrepolarization refractoriness. Chen et al.34
have shown previously in isolated preparations that
quinidine does not influence the normal relationship
between membrane voltage and membrane responsiveness at long cycle lengths. In contrast, significant
effects of quinidine on membrane excitability and refractoriness were observed at higher stimulation
frequencies.7 3 Our findings corroborate the frequency dependence of quinidine's effect for the canine
ventricle in situ.
Significance of postrepolarization refractoriness. Frequency dependence of antiarrhythmic drug effects
recently has received growing attention, primarily for
two reasons. First, as pointed out by Harrison,5 frequency dependency shows good correspondence with
current subclassifications of class I antiarrhythmic
agents and may provide a more scientific basis for such
classifications. Second, the phenomenon of frequency
dependence appears to be a useful tool for analyzing the
kinetics of drug-induced depression of the sodium
channel. Based on the frequency-dependence of antiarrhythmic drug effect, Hondeghem and Katzung36
advanced the modulated receptor hypothesis, which
helps explain and characterize the interference of antiarrhythmic drugs with the sodium channel. According
to this model, drug binding occurs much more avidly
during the depolarized state, and the time course with
which the block disappears is a function of the drug's
dissociation kinetics and membrane potential. In
essence, a drug with relatively slow dissociation from
the sodium channel exhibits greater cumulative effect
1182
at high heart rates than a drug with faster dissociation
kinetics, and a given drug produces greater suppression of excitability at high heart rates than at low
heart rates.
Sodium-channel block ordinarily is quantified by a
decrease in sodium current, INa, or the maximum
upstroke velocity, Vmax, of the transmembrane action
potential. These variables, however, cannot be measured in vivo. This limitation includes, at present, even
MAP recordings; although these have been shown to
reliably indicate transmembrane action potential duration, they have not yet been validated as an index of
transmembrane Vm.X. To identify frequency-dependent
effects of antiarrhythmic drugs in vivo, or even in the
clinical setting, several alternative electrophysiologic
variables have been used. Davis et al.37 measured
His-bundle conduction time (HV) in dogs and found
that lidocaine increased HV in a frequency-dependent
fashion that showed good agreement with data previously determined in vitro by use of Vmax. His-bundle
pacing, however, is difficult in patients. Morady et al.38
evaluated frequency-dependent effects of antiarrhythmic drugs in patients with the use of QRS duration, and
Duff et al.33 measured conduction times between two
distinct right ventricular sites as an indirect index of
sodium-channel excitability. However, intraventricular
conduction times and QRS duration are reliable estimates of conduction velocity only as long as the propagation pathway remains constant, and conduction
velocity is a reliable estimate of transmembrane Vmax
only as long as other variables determining conduction
velocity, such as changes in the degree of intercellular
coupling, can be controlled.39 It seems difficult to rule
out these influences in the beating heart in situ. In
addition, measurements of QRS duration lack precision and reliability, particularly at high heart rates.
The frequency dependence of quinidine-induced
postrepolarization refractoriness in this study had a
time course very similar to that previously described for
Vmax in isolated ventricular muscle.40 Although not
directly equatable, both indexes reflect the degree of
recovery from inactivation of the sodium channel and
share the property of frequency dependence. Further
studies are needed to determine the cellular mechanism
of drug-induced, frequency-dependent postrepolarization refractoriness and its quantitative relationship to
changes in sodium-channel conductance.
Clinical implications. With the use of the recently
introduced contact electrode catheter, stable continuous MAPs can be recorded from the human endocardium over long time periods.17 Preliminary studies41
have shown that simultaneous determinations of APD
CIRCULATION
LABORATORY INVESTIGATION-PHARMACOLOGY
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and ERP are possible, and it will be of interest to
determine the relationship between repolarization and
refractoriness, and the effect of rate and antiarrhythmic
drugs on this relationship, in clinical studies. This
could provide a new tool for the quantification and
characterization of the effects of sodium channelblocking agents in patients and, as recently suggested
by Hondeghem,42 may aid in tailoring a specific antiarrhythmic drug regimen to an individual patient.
Our results on the rate dependence of quinidine's
effect on refractoriness may also apply to certain clinical observations. Electropharmacologic studies usually assess the efficacy of an antiarrhythmic agent by
observing the inducibility of ventricular tachycardia by
extrastimuli that are delivered after a previous train of
relatively rapid pacing. A drug with relatively slow
dissociation kinetics (such as quinidine) would be
expected to increase refractoriness relative to APD and
thus exert a protective effect against extrastimulation.
Our method would allow the determination of whether,
and to what extent, drug efficacy during programmed
electrical stimulation is indeed related to the presence
of such a "window" of refractoriness that extends
beyond myocardial repolarization. Outside the electrophysiology laboratory, the patient's (slower) sinus
rhythm may allow initiation of ventricular tachycardia
by a single premature beat because the efficacy of the
prescribed agent may depend on a sufficiently high
heart rate. This may explain in part the divergence
between electropharmacologic test responses and clinical follow-up. The same rationale may apply to the
beneficial effect of overdrive pacing used in the management of drug-induced arrhythmias, such as torsade
de pointes.
We thank Robert Kernoff and Cecil Profitt for excellent technical assistance during the experiments, Irene Hill, Ph.D., for
valuable help in the statistical analysis, and Bertram Katzung,
M.D., Ph.D., for his very constructive criticisms during the
preparation of the manuscript.
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CIRCULATION
Frequency-dependent effects of quinidine on the relationship between action potential
duration and refractoriness in the canine heart in situ.
M R Franz and A Costard
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Circulation. 1988;77:1177-1184
doi: 10.1161/01.CIR.77.5.1177
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