Effect of Lidocaine and Quinidine on Steady-State
Characteristics and Recovery Kinetics of (dV/dt) max in Guinea
Pig Ventricular Myocardium
By Chia-Maou Chen, Leonard S. Gettes, and Bertram G. Katzung
ABSTRACT
We studied the effects of quinidine and lidocaine on the steady-state relationship
between membrane potential and the maximum rate of rise of the action potential,
(dV/dt)max, and on the recovery kinetics of (dV/dt)max in guinea pig papillary muscles.
The steady-state relationships were determined in fibers stimulated at 0.2/sec and
depolarized with KC1. Recovery kinetics were determined at various resting membrane
potentials by assessing (dV/dt) max in progressively earlier premature action potentials.
Lidocaine caused a dose-dependent decrease in (dV/dt) max , shifted the curve defining the
steady-state relationship along the voltage axis in the direction of more negative
potentials, and slowed the recovery kinetics of (dV/dt)max . Quinidine caused a dosedependent decrease in (dV/dt)max but did not alter the shape of the curves defining either
the steady-state relationship or the recovery kinetics of (dV/dt)max. Both drugs depressed membrane responsiveness as determined in premature action potentials originating from incompletely repolarized fibers. Our study indicates that the mechanisms
whereby quinidine and lidocaine influence (dV/dt)max are different. It is possible that
this difference may underlie some of the differences in the clinical effects of these two
drugs.
• Most of the clinically effective antiarrhythmic
agents that exert a direct effect on the myocardial
cell either decrease the maximum rate of rise,
(dV/dt)max, of the action potential in nonpremature responses or alter the relationship between
membrane potential and (dV/dt) max in premature
responses arising from incompletely repolarized
fibers (1-3). In the steady state, (dV/dt) max depends on the membrane potential prior to depolarization and decreases as the membrane potential
becomes less negative (4). It has recently been
shown (5, 6) that the recovery of (dV/dt) max after a
preceding depolarization is considerably slower in
some types of cardiac fibers than earlier works
suggested and is also dependent on the membrane
potential at the onset of depolarization (6). Because of this factor, (dV/dt) max of premature action
potentials arising from incompletely repolarized
fibers is slower than predicted by the steadyFrom the Department of Medicine, University of Kentucky
Medical Center, Lexington, Kentucky 40506, and the Department of Pharmacology, University of California, San Francisco,
California 94143.
This study was supported by U. S. Public Health Service
Grant HL 13321-04 from the National Heart and Lung Institute.
This paper was presented in part at the meeting of the
American Heart Association, Atlantic City, New Jersey, November, 1973.
Please address reprint requests to Leonard S. Gettes, M.D.,
Cardiovascular Division, Department of Medicine, University of
Kentucky Medical Center, Lexington, Kentucky 40506.
Received June 3, 1974. Accepted for publication April 24,
1975.
20
state resting membrane potential-(dV/dt)max
relationship. Therefore, antiarrhythmic drugs
could induce changes in (dV/dt)max by altering either the steady-state relationship between
membrane potential and (dV/dt) max or the recovery characteristics of (dV/dt) max .
In 1957, Johnson and McKinnon (7) reported
that quinidine causes only a minimal decrease in
(dV/dt)max of guinea pig ventricular action potentials when the driving rate is 0.1/sec but leads to a
progressive decrease in (dV/dt) max as the driving
rate is increased. Heistracher (8) has shown that in
quinidine-treated fibers (dV/dt) max in the first
response following a quiescent period of several
minutes is not decreased. (dV/dt)max then decreases progressively with each subsequent response until a new steady-state value is achieved.
These two studies suggest that quinidine alters the
recovery of (dV/dt) max rather than the steady-state
relationship between membrane potential and
(dV/dt)max. Weidmann (9) has studied the relationship between (dV/dt) max and membrane potential in Purkinje fibers driven at the rate of 1/sec. He
has shown that this relationship is altered by
cocaine, procaine amide, and quinidine. However,
in view of the rate-dependent effect referred to
earlier, it is difficult to determine whether the
effect is due to a change in steady-state or kinetic
characteristics.
The present study was designed to assess the
effects of quinidine and lidocaine on the steadyCirculation Research, Vol. 37, July 1975
21
EFFECT OF DRUGS ON (dV/dt) n
state and recovery characteristics of (dV/dt)max
and thus to define more precisely the similarities
and differences in the mode of action of the two
drugs. These drugs were chosen because they exert
different effects on QRS duration and intraventricular conduction (3).
Methods
The experiments were conducted on guinea pig right
ventricular papillary muscles mounted in a three-compartment single sucrose-gap chamber (10). The proximal
and distal compartments of the muscle chamber were
perfused at a constant rate of 1.7 ml/min with normal
Tyrode's solution having the following millimolar composition: NaCl 137, KC1 5.4, CaCl2 1.8, MgCl2 1.05,
NaHCO3 11.9, NaH 2 PO 4 0.42, and glucose 5. The Tyrode's solution was equilibrated with 95% O2-5% CO2)
and the pH ranged between 7.2 and 7.4. The middle
compartment of the chamber was perfused with isotonic
sucrose solution equilibrated with 100% O 2 . The temperature was maintained at 37 ± 0.2°C.
Transmembrane potentials were recorded from the
proximal muscle end with two standard 3M KCl-filled
glass microelectrodes, one intracellular and the other
extracellular, placed closely together. These electrodes
were coupled by Ag-AgCl wire to a differential amplifier
having a high input impedance and variable capacity
neutralization.
The upstroke of the action potential was electronically
differentiated to yield a spike that precisely measured
the maximum rate of depolarization, (dV/dt) max . This
measurement was linear from 10 to 1000 v/sec. The
transmembrane action potentials and the differentiated
upstrokes were displayed on a dual-beam cathode ray
oscilloscope (Tektronix model 565) and photographed on
Polaroid or 35-mm film.
To determine the steady-state effects of the studied
drugs, the fibers were stimulated at a rate of 0.2/sec by
rectangular pulses 4 msec in duration and 1.2-1.8 times
diastolic threshold in strength (less than 20 jiamp). This
nonphysiological rate was chosen to ensure the complete
recovery of the action potential parameters between each
excitation. The membrane potential-(dV/dt)max relationship was determined by depolarizing the fiber from
its original resting potential of -80 to -90 mv to
approximately —60 mv by adding small quantities of 500
mM KC1 to the solution perfusing the test compartment.
This procedure raised the potassium concentration in the
test compartment to approximately 20 mM. The justification for this method has been previously described (6).
The method for determining the recovery kinetics of
(dV/dt)max has also been previously described (6). In
brief, a single test (or premature) stimulus 4 msec in
duration was introduced from a second stimulator in
series with and triggered by the first stimulus after every
eighth basic or conditioning response. The interval
between the conditioning and premature stimuli was
progressively decreased, and (dV/dt)max in the premature response was expressed as a function of the interval
between the end (within 1.0 mv) of the conditioning
action potential and the onset of the premature action
potential (see Fig. 6). This interval is referred to as the
test interval. Because threshold current intensity varies
Circulation Research, Vol. 37, July 1975
as a function of resting potential, stimulus interval, and
drugs, the premature stimulus strength was adjusted to
maintain a constant interval between the stimulus
artifact and the upstroke of the action potential and did
not exceed 2.5 times diastolic threshold. In both a prior
study (6) and in this study, varying the stimulus
duration between 1 and 5 msec was found to have no
effect on (dV/dt)max or on the recovery kinetics of
(dV/dt) max .
In each experiment, determinations were made before
and 30 minutes after the addition of 4-16 MS/rnl
(0.77-3.08 x 10"5M) of quinidine gluconate or 4-16 ugl
ml (1.72-6.87 x 10" 5 M) of lidocaine HC1. In all experiments reported, the microelectrode was maintained in
the same cell before and after the addition of the drug to
the perfusate. In some experiments, the effects of lidocaine and quinidine were tested during the continuous
impalement of the same fiber. This procedure is justified
because the effects of lidocaine are readily reversible (11,
12). In these experiments, the effects of lidocaine were
assessed first. The control observations were then repeated 30-60 minutes after perfusion with lidocaine-free
solution had been started. If the control observations
were identical to the prelidocaine results, the effects of
quinidine were assessed.
Results
EFFECTS OF LIDOCAINE ON THE STEADY-STATE CHARACTERISTICS
OF (dV/dt)mai
The effects of lidocaine were assessed in seven
experiments. Lidocaine caused a dose-dependent
decrease in steady-state (dV/dt) max that ranged
from 6% to 20% when the resting potential was
more negative than —85 mv. The decrease in
(dV/dt) max became more pronounced when the
resting potential was made less negative than -80
mv. These effects of lidocaine are illustrated by the
results shown in Figures 1 and 2. In Figure 1, the
effects of 6 ^g/ml of lidocaine on (dV/dt) max at
resting potentials of —87 mv and —66 mv are
shown. The decrease in (dV/dt) max was greater at
-66 mv, indicating a shift in the resting potential-(dV/dt) max curve. The results shown in Figure
2 illustrate the shift of the curve and the dose
dependent effect of lidocaine. On the left, the
absolute values of (dV/dt)max are plotted against
the resting potential. On the right, the curves have
been normalized. The membrane potential associated with a 50% reduction in (dV/dt) max was -68
mv before lidocaine, -71.5 mv after 4 Mg/nil of
lidocaine, and -74 mv after 16 /ug/ml of lidocaine
had been added to the perfusate. Thus, the curve
was shifted along the voltage axis in the hyperpolarizing direction, i.e., in the direction of more
negative membrane potentials, by 3.5 mv and 6 mv
after 4 and 16 /ig/ml of lidocaine, respectively, had
been added to the perfusate. The results of all of
the experiments are shown in Table 1. In six of the
22
CHEN. GETTES. KATZUNG
Lidocaine 6/jg/ml
Control
•riBB—•
0—
fSKS
• M l Mil
•vs
fill
MM
• SSii
••••r.lV
•87 mV
t 48%
0
111 •'»•
-66 mV
1 ISO
11
!•• •
A =47%
ioov/sec
40 mV
200msec
4msec
Effects of lidocaine, 6 ng/ml, on (dV/dt)ma, when the resting
membrane potential is -87 mv (top) and -66 mv (bottom). In
this and subsequent figures, the action potentials were recorded
at the slower sweep speed and the differentiated upstrokes,
shown to the right of the action potential, at the faster sweep
speed. The value of A to the right of each row is the percent
change in (dV/dt)max during the control or the lidocaine
perfusion. The value of A below each column is the percent
change in (dV/dt)max associated with the change in resting
potential. This decrease was greater during the lidocaine
perfusion than it was during the control perfusion.
»•;•. -i.r.i
OLidccaiitt
XLidocoirn I
seven experiments, lidocaine shifted the membrane
potential-(dV/dt)max relationship by more than 2
mv.
Weidmann (4) has shown in Purkinje fibers that
the changes in (dV/dt)max induced by increasing
the potassium (K + ) concentration of the perfusate
are due to the changes in membrane potential
alone. The experiments shown in Figure 3 were
performed to determine if the lidocaine-induced
shift in the membrane potential-(dV/dt) max relationship (inactivation curve) (Fig. 2) was due to
lidocaine alone or to the combined effects of K +
and lidocaine. The left and center sections of
Figure 3A show the decrease in resting potential
and (dV/dt)max associated with an increase in K +
from 5.4 to 9.4 DIM. The right section shows that
restoring the resting membrane potential by administering a constant hyperpolarizing current (I)
in the presence of the elevated K + concentration
restored (dV/dt)max to its original value. In Figure
3B, the experiment was performed in a fiber
perfused with 6 Mg/ml of lidocaine. As in Figure 3A,
restoration of the resting potential to its original
value in the presence of the elevated K+ concentration restored (dV/dt)max . In Figure 3C, the fiber
was also perfused with lidocaine-containing solution. In this experiment, the decrease in (dV/dt)max
was the same when the resting potential was
changed to the same level by increasing the K+
concentration from 5.4 to 9.4 mM (center) or by
administering a depolarizing current (right). These
experiments confirm Weidmann's observations (4)
and show that the shift in the membrane potential-(dV/dt) max relationship induced by lidocaine
is independent of the increase in K+ in the perfusate.
»
j
- IBO
X
-90
-80
EFFECTS OF QUINIDINE ON THE STEADY-STATE CHARACTERISTICS
OF (dV/dt)m,,
•
-70
-6
0
MEMBRANE POTENTIAL I V
-80
-70
-60
FIGURE 2
Effects of 4 and 16 ng/ml of lidocaine HCl on the steady-state
relationship between rest ing membrane potential and
(dV/dt)max in a fiber stimulated at 0.2/sec. Absolute values are
shown in the graph on the left and normalized values in the
graph on the right. Lidocaine caused a dose-dependent decrease
in (dV/dt)max at all resting potential levels and shifted the
normalized curves along the voltage axis in the direction of more
negative membrane potentials.
Quinidine, like lidocaine, caused a dose-dependent decrease in (dV/dt)max that ranged from 3% to
46% when the resting membrane potential was
more negative than -85 mv. However, Figures 4
and 5 show that, unlike lidocaine, the percent
decrease in (dV/dt)max was constant at all levels of
resting potential. The left section of Figure 5 shows
the absolute values of (dV/dt)max . In the right
section, the normalized curves show that the percent decrease in (dV/dt)max at any level of resting
potential was the same before and after the addition of quinidine. The results of 13 determinations
are shown in Table 2. In 9 determinations there was
no shift in the normalized (dV/dt) max -resting potential curve. In 4 determinations a 1-2-mv shift of
Circulation Research, Vol. 37. July 1975
23
EFFECT OF DRUGS ON (dV/dt) n
TABLE 1
Effect of Lidocaine HCl on Steady-State (dV/dt)max and on Membrane Potential Associated with a 50% Reduction in (dV/dt)max
Control
RMP
Lidocaine HCl
MP at 50%
(dV/dt) max
(mv)
Expt
(mv)
(dV/dt) max
(v/sec)
1
2
-90
-88
378
325
-66
-68
3
4
5
6
-86
-90
-85
-89
262
260
255
343
-66
-67.5
-65
-64
7
-88
223
-68.5
Dose
(Mg/ml)
8
4
16
6
6
4
5
10
6
(dV/dt) ma
(v/sec)
356
297
261
230
230
230
324
306
201
RMP = resting membrane potential, MP = membrane potential, and (dV/dt)n
the resting membrane potential shown in the second column.
the curve along the voltage axis in the direction of
more negative membrane potentials was observed.
EFFECTS OF LIDOCAINE ON THE RECOVERY OF (dV/dt) max
The results of a representative experiment from
this series of 13 experiments are shown in Figure 6.
In this experiment, the recovery of (dV/dt) max was
determined at resting potentials of -90 and -79
mv. Both control and lidocaine data could be fitted
by monoexponential curves. The arrows indicate
the time constants (r) of the recovery of
(dV/dt) max . Before lidocaine was added, the time
constant was 20 msec when the resting potential
was -90 mv and 40 msec when the resting membrane potential was -79 mv. This prolongation of
the recovery time constant associated with a decrease in resting potential is similar to that previously reported (6). After the addition of 8 Mg/rnl of
lidocaine, the time constant increased to 120 msec
when the resting potential was -90 mv and to 180
msec when the resting potential was -79 mv.
The lidocaine-induced prolongation of the time
constant of recovery of (dV/dt) max was also dose
dependent as is illustrated in Figure 7, which shows
the results of the 13 experiments. In 5 experiments,
the resting potential was held constant and the
recovery of (dV/dt)max was determined following
the addition of two concentrations of lidocaine to
the perfusate. The results of these experiments are
indicated in Figure 7 by the symbols joined by
vertical lines. In 2 experiments (including one of
the preceding 5) the time constant was determined
at two levels of resting potential without changing
the concentration of lidocaine. The results of these
experiments are also indicated on the figure by the
symbols joined by the diagonal solid lines.
Circulation Research, Vol. 37, July 1975
Change in
(dV/dt) max
(%)
6
9
20
12
11
10
6
11
10
MP at 50%
(dV/dt) max
(mv)
Shift
(mv)
-70.5
-71.5
-74.0
-71.0
-71.5
-67.0
-68.5
-71.0
-72.5
4.5
3.5
6.0
5.0
4.0
2.0
4.5
7.0
4.0
= maximum rate of depolarization associated with
EFFECTS OF QUINIDINE ON THE RECOVERY OF (dV/dt),,,,,
The results of a representative experiment from
this series of 15 experiments are shown in Figure 8.
The data shown in this figure were obtained during
the continuous impalement of the same fiber from
which the lidocaine data shown in Figure 6 were
obtained. Figure 8 shows that, although (dV/dt) max
at each test interval was decreased by quinidine,
the time constant of recovery of (dV/dt) max was not
altered. The results of all 15 experiments are shown
in Figure 9. These compiled results indicate that
quinidine exerted neither a dose- nor a voltagedependent effect on the recovery of (dV/dt) max .
EFFECTS OF LIDOCAINE AND QUINIDINE ON MEMBRANE
RESPONSIVENESS
The results of the experiments described earlier
suggest that the effects of the two drugs on membrane responsiveness, i.e., the membrane potential-(dV/dt) max relationship in premature responses initiated during the phase of incomplete
repolarization of the preceding action potential (11,
12), differ. We compared the steady-state membrane potential-(dV/dt) max relationship to membrane responsiveness curves in three fibers before
and after 6 /jg/ml of lidocaine had been added to
the perfusate and in three other fibers before and
after 8 Mg/ml of quinidine had been added. In all of
the experiments, the basic driving rate was 0.2/sec.
Figure 10 shows the effects of lidocaine on these
curves; the absolute values are shown on the left
and the normalized values on the right. Although
the (dV/dt) max associated with a membrane potential of -90 mv was depressed only slightly by
lidocaine, both the steady-state and the membrane
responsiveness curves were shifted along the volt-
24
CHEN, GETTES, KATZUNG
CONTROL
K=5.4
9.4
K = 5.4
9.4
9.4 + 1
LIDOCAINE
LIDOCAINE
5.4 + 1
FIGURE 3
Oscillographic records from experiments performed to determine whether the increase in K+
concentration shown between A and B and below C contributed to the lidocaine-induced changes in
(dV/dt)max . Hyperpolarizing (A and B, right) or depolarizing (C, right) current (I) was introduced in
the distal compartment of the sucrose-gap chamber. The current trace was set at the O-mu line prior
to the introduction of the constant current: the magnitude of the current injected is indicated in the
right sections of A-C by the deviation of the current trace from this line. The shortening of the action
potential duration in A and B {right) and the lengthening in C (right) were caused by the injected
current. The lidocaine concentration in B and C was 6 ng/ml.
age axis in the direction of more negative potentials. However, the lidocaine-induced shift in the
membrane responsiveness curve (7 mv, broken
lines) was of greater magnitude than the shift in
the steady-state curve (3 mv, solid lines). Similar
results were obtained in the two other lidocaine
experiments.
The effects of quinidine are shown in Figure 11.
Quinidine caused a 13% decrease in (dV/dt) max
which was present at all membrane potential levels
in both the steady-state and the membrane responsiveness curves. However, quinidine did not shift
either curve along its voltage axis. Similar results
were obtained in the two other quinidine experiments.
Discussion
Our study showed that lidocaine and quinidine
exert different effects on the steady-state and
recovery characteristics of guinea pig ventricular
fibers.
LIDOCAINE
Various investigators have shown that lidocaine
causes a dose-dependent decrease in (dV/dt)max in
atrial, ventricular, and Purkinje fibers (11-13)
Circulation Research, Vol. 37, July 1975
EFFECT OF DRUGS ON (dV/dt) n
Control
25
Quinidine Sftg ml
•88mV
0-
-65 mV
100V/sec
40mV
=56%
= 56%
200msec
4msec
Effects of quinidinegluconate, 6 ng/ml, on (dV/dt)max when the
resting potential is -88 mv (top) and -65 mv (bottom). The
figure is arranged as is Figure 1. The percent change in
(dV/dt)max associated with the change in resting potential was
the same during the control and the quinidine perfusions.
0 0
N
°O V
• ton I rot
OOuinidin*
XOuinidint I 2pg/ml
E
X
-7)
s
o
-6S
-)J
-8*
MEMBRANE POTENTIAL mV
FIGURE S
Effects of 8 and 12 nglml of quinidine gluconate on the
relationship between resting potential and (dV/dt)max in a fiber
stimulated at 0.2/sec. The figure is arranged as is Figure 2.
Quinidine caused a dose-dependent decrease in (dV/dt)maj at all
resting potential levels but did not shift the normalized curve.
Circulation Research, Vol. 37, July 1975
which is minimal at concentrations below 5 ftg/ml.
Ventricular conduction velocity is slowed slightly
in experimental animals (14) but not in man (15,
16). In addition, the QRS complex of the electrocardiogram is not widened by lidocaine (17).
Our results were consistent with these reports. We
found that lidocaine in concentrations below 10
Mg/ml caused less than a 12% decrease in (dV/
dt) max when the resting potential was in the range
of -80 to -90 mv. However, as shown in Figures 1
and 2 and as previously reported by Singh and
Vaughan Williams (13) for atrial and ventricular
fibers, the depression of (dV/dt)max became more
pronounced when the resting potential was decreased by increasing the extracellular K+ concentration. Vaughan Williams (18) has attributed this
result to a K +-induced shift in the lidocaine
dose-response curve. Our study showed that this
result was due to a lidocaine-induced change in the
steady-state relationship between resting membrane potential and (dV/dt)max which became
manifest at membrane potentials less negative
than -80 mv. We would therefore attribute the effect of the higher K + concentration to the associated decrease in resting membrane potential.
The effect of lidocaine on the relationship between (dV/dt)max and membrane potential in premature responses originating from incompletely
repolarized fibers, i.e., membrane responsiveness,
has been reported only for Purkinje fibers (11, 12).
In those experiments, less than 3 /ug/nil of lidocaine
did not alter or increased slightly the value of
(dV/dt)max when the membrane potential prior to
depolarization was less negative than the resting
potential. At concentrations greater than 3 ngjml,
(dV/dt)max was decreased. We showed a similar
decrease in membrane responsiveness when the
lidocaine concentration was 5 Mg/ml or greater. Our
results suggest that this decrease can be attributed
to the shift in the steady-state relationship between
(dV/dt)max and membrane potential, the prolongation of the recovery of (dV/dt)max observed in this
study, or both. Of these two factors, the prolongation of recovery appeared to be the more important,
since (1) the shift in membrane responsiveness was
more pronounced than the shift in the steady-state
curve (Fig. 10) and (2) the shift in the steady-state
curve did not occur until the resting potential was
less negative than -80 mv whereas the shift in
membrane responsiveness was apparent at membrane potentials more negative than -80 mv. The
prolongation of recovery is probably also responsible for the rate-dependent depression of conduction
26
CHEN. GETTES. KATZUNG
TABLE 2
Effect of Quinidine Gluconate on Steady-State (dV/dt)n „, and on Membrane Potential Associated with a 50% Reduction in (dV/dt)n
Control
Quinidine gluconate
MP at 50%
(dV/dt)max
(mv)
Expt
RMP
(mv)
(dV/dt)max
(v/sec)
1
2
3
4
-86
-90
-90
-85
216
380
316
255
-63
-67
5
-80
181
-64
6
7
8
9
10
-85
-85
-87
-88
-88
230
232
295
260
348
-61.5
-64.5
-68.5
Dose
(jig/ml)
(dV/dt)mal
(v/sec)
8
8
8
8
12
8
12
16
8
4
6
6
6
201
360
276
234
196
175
140
98
196
205
243
237
310
-66.5
-65
-66
-69
Change in
(dV/dt)may
(%)
7
5
13
8
23
3
23
46
15
12
17
9
11
MP at 50%
(dV/dt)max
(mv)
-63
-67
-66.5
-65
-65
-64
-65
-66
-62.5
-65.5
-68.5
-66
-69
Shift
(mv)
0
0
0
0
0
0
1.0
2.0
1.0
1.0
0
0
0
Abbreviations are the same as those in Table 1.
400
r
RMP-90
350
f
RMP -90
RMP -79
,—•
o
300 -
°
RMP-79
s
^
^
-
^
250 • Control
>
OLidocaine Sjig/ml
200 •
\
150 •
/
100
O
/
^
J
-on—
i
i
80
i
i
i
160
1
i
240
III
I Si i
200 fx»«c
i
i
320
•
400
i
i
480
TEST INTERVAL msec
FIGURE 6
Graphic representation of an experiment in which the effect of
lidocaine, 8 ng/ml on the recovery of (dV/dt)max was determined
when the resting membrane potential (RMP) was -90 and -79
mv. The arrows indicate the time constant (T) with which
(dV/dt)ma, in the premature action potential regained the
steady-state value. The method is illustrated in the insert. The
conditioning or basic action potentials (0.2/sec) are shown by
the solid lines and the premature action potentials by the
broken lines; the differentiated upstroke spikes are shown below
the action potentials. The test intervals were measured from the
end (within 1 mu) of the conditioning action potential to the
onset of the premature action potential.
velocity in Purkinje fibers reported by Bigger and
Mandel (19).
Our results suggest that, although lidocaine in
concentrations below 5 Mg/ml may not alter or may
depress only slightly the maximum rapid inward
current, it does alter the voltage-dependent
changes in sodium conductance (20). Such an
effect would explain the shift in the steady-state
curve even when the maximum (dV/dt) max was not
depressed. It is probable that in concentrations
greater than 5 ixg/m\ lidocaine does decrease the
maximum inward current. Such a decrease has
been demonstrated in the node of Ranvier (21) and
in squid axons (22) and is probably responsible for
the decrease in (dV/dt)max that occurred when the
lidocaine concentration exceeded 5-10 fig/m\.
The mechanism whereby lidocaine prolongs the
reactivation kinetics of the rapid sodium inward
current is not obvious from this study. Slowing of
the recovery of (dV/dt)max may be due to a direct
effect of lidocaine on the reactivation kinetics of
the rapid inward current (5) or to the kinetics with
which lidocaine itself reacts with its active site,
presumably on the inside of the membrane (23).
QUINIDINE
Other investigators have shown that quinidine in
concentrations of 10 Mg/ml or less decreases (dV/
dt) max in atrial, ventricular, and Purkinje fibers in
spontaneously beating preparations or in preparations stimulating at physiological rates (7, 9,
24-27). In addition, quinidine slows intraventricuCirculation Research, Vol. 37, July 1975
27
EFFECT OF DRUGS ON (dV/dtL
400 r
400
360
350
r
x xxx
320
300
• Control
O Lidocoina 4jjg/ml
• Lidocaina 8jjg/ml
280
X X
XLidocaina I2jjg/ml
8
C
250
A Lidocaina I6tig/ml
o°
240
200
200
150
• Control
-o
X Quinidine 8 ) j g / m l
8
b
OLidocaina 8 p g / m l
80
160 -
240
160
320
480
400
TEST INTERVAL msec
120
FIGURE 8
Graphic representation of the effect of quinidine on the recovery
of (dV/dt)mal . The lidocaine data are the same as those shown
in Figure 6 at the resting potential of -90 mv.
40
-90
-85
-80
-75
-70
MEMBRANE POTENTIAL mV
FIGURE 7
-65
-60
Effect of different concentrations of lidocaine on the time constant (T) of recovery of (dV/dt)max-resting membrane potential
relationship (13 experiments). Joined symbols indicate experiments in which the recovery of (dV/dt)max was determined for
more than one concentration of lidocaine or at more than one
level of resting potential.
lar conduction in closed-chested dogs (28) and in
man (29) and widens the QRS complex on the
electrocardiogram (17). The effects of quinidine on
(dV/dt)max have been shown to be rate dependent
(7, 8, 24, 28). At very slow driving rates (0.1/sec or
less), quinidine exerts little if any effect on (dV/
dt) max in guinea pig papillary muscles (7, 8). Our
results were consistent with this observation. At
rates of 0.2/sec, quinidine in concentrations of 8
Mg/ml or less caused an average decrease in (dV/
dt) max of less than 10% when the resting potential
was between —80 and —90 mv.
We were unable to demonstrate any effect of
quinidine on the recovery kinetics of (dV/dt)max at
any level of membrane potential. Driot and Carnier
(30) have reported that quinidine prolongs the
recovery of the rapid inward current in voltageclamped atrial fibers at 19°C. This result is not
easily reconciled with our findings. It is possible
that species and fiber differences and differences in
Circulation Research, Vol. 37, July 1975
experimental procedure are responsible for the
divergent results. On the basis of our experiments,
and contrary to our expectations, we could not
attribute the previously reported rate-dependent
effect of quinidine in mammalian fibers to a change
in reactivation kinetics. Rather, our results suggest that this effect must be due to other factors.
A rate-dependent depression of sodium-potassium-activated adenosinetriphosphatase, as reported by other investigators (31, 32), is a possible
mechanism.
Weidmann (9) has shown that quinidine, like
cocaine, decreases (dV/dt)max at all levels of resting
potential in Purkinje fibers driven at a rate of 1/sec.
We observed similar results in ventricular fibers
driven at a rate of 0.2/sec. However, unlike the
effect observed with lidocaine, the normalized
• Control
OQuinidine 8jig/ml
XQuinidine I2jig/fnl
0
(A
E 100
x
o 80
E
dv/dt,
80
AOuinidine I6pg/ml
60
Ul
O
u
UJ
^
e
20
0
8
O°
•#
40
~Q
i
-90
i
-85
i
-80
i
-75
MEMBRANE POTENTIAL
i
-70
i
-65
-60
mV
FIGURE 9
Results of 15 experiments in which the effects of quinidine on
the recovery of (dV/dt)max were assessed, T = time constant of
recovery.
28
CHEN, GETTES. KATZUNG
MEMBRANE POTENTIAL mV
FIGURE 10
Effects of lidocaine on the steady-state relationship between
membrane potential and (dV/dt)ma, (solid lines) and membrane
responsiveness (broken lines). The steady-state curves were
determined by depolarizing the fiber with KCl. The membrane
responsiveness curves were determined by inducing premature
responses before the completion of repolarization.
curve relating (dV/dt) max to resting potential was
not shifted in 9 of 13 observations; in the remaining
4 experiments, the shift did not exceed 2 mv.
The effect of quinidine on membrane responsiveness has not been reported previously for either
Purkinje or ventricular fibers. In our study, membrane responsiveness was depressed by quinidine.
However, like the steady-state effect, the depression was constant at all levels of membrane potential, and thus the normalized curves did not
change. This result is consistent with the observation that quinidine did not alter the steady-state or
recovery characteristics of (dV/dt)max and, coupled
with the steady-state results, suggests that quinidine did not alter the membrane potential-dependent conductance variables (20). Our results suggest
that the depression of both the steady-state and the
membrane responsiveness curves was a manifestation of the rate-dependent effect of quinidine
reported by others (7, 8).
Several different schemes for categorizing the
various antiarrhythmic drugs have been proposed
(1, 2, 33). The drugs have been separated into those
having a direct membrane effect (2), a ratedependent effect (33), or an effect on membrane
responsiveness (1). Our results suggest that drugs
having these effects can be subdivided into those
which alter the steady-state variables, those which
alter the kinetic variables, and those which act by
some other mechanism. Such subclassification
would place quinidine and lidocaine into different
categories.
Although our results were obtained at nonphysiological driving rates, it is possible that the differences which we observed may be pertinent to some
of the known differences in clinical effects of
quinidine and lidocaine. For instance, the ability of
quinidine but not of lidocaine to convert atrial
fibrillation to normal sinus rhythm and to widen
the QRS complex on the electrocardiogram may be
due to quinidine's rate-related effect on (dV/
dt) max . Our results predict that lidocaine will also
exert a rate-dependent effect on (dV/dt)max in
depolarized ventricular fibers when the diastolic
interval is short enough (approximately 300 msec)
to be influenced by the prolonged recovery of
(dV/dt)ma*. Furthermore, our results predict that
lidocaine will decrease (dV/dt) max in premature
responses without altering this parameter in the
nonpremature response, whereas quinidine's effect
on (dV/dt)max will occur in both the nonpremature
and the premature response. The results of studies
designed to test these predictions have been reported in abstract form (34).
Acknowledgment
The authors acknowledge with thanks the thoughtful critique
of the manuscript by Dr. Borys Surawicz.
References
1. BASSETT AL, HOFFMAN BF: Antiarrhythmic drugs: Electrophysiological actions. Annu Rev Pharmacol 11:143-170,
1971
2. VAUGHAN WILLIAMS EM: Classification of antiarrhythmic
-60
-90
MEMBRANE POTENTIAL mV
FIGURE 11
Effects of quinidine on the steady-state relationship between
membrane potential and (dV/dt)max (solid lines) and membrane responsiveness (broken lines).
drugs. In Symposium on Cardiac Arrhythmias, edited by
E Sandoe, E Flinsted-Jensen, and KH Olesen. Astra,
Sweden, Sbdertalje, 1970, pp 449-469
3. GETTES LS: Electrophysiologic effects of antiarrhythmic
drugs. Am J Cardiol 28:526-535, 1971
4. WEIDMANN S: Effect of the cardiac membrane potential on
the rapid availability of the sodium carrying system. J
Physiol (Lond) 127:213-227, 1955
Circulation Research, Vol. 37, July 1975
EFFECT OF DRUGS ON (dV/dt) n
5. HAAS HG, KERN R, EINWACHTER HM, TARR M: Kinetics of
6.
7.
8.
9.
10.
11.
12.
Na inactivation in frog atria. Pfluegers Arch 323:141-157,
1971
GETTES LS, REUTER H: Slow recovery from inactivation of
inward currents in mammalian myocardial fibers. J
Physiol (Lond) 240:703-724, 1974
JOHNSON EA, MCKINNON MG: Differential effect of quinidine and pyrilamine on the myocardial action potential at
various rates of stimulation. J Pharmacol Exp Ther
120:460-465, 1957
HEISTRACHER P: Mechanism of action of antifibrillation
drugs. Naunyn Schmiedebergs Arch Pharmacol
269:199-212, 1971
WEIDMANN S: Effects of calcium ions and local anesthetics
on electrical properties of Purkinje fibers. J Physiol
(Lond) 129:568-582, 1955
REUTER H, SCHOLZ H: Uber den Einfluss der extracellularen
Ca-Konzentration anf Membranpotential und Kontraktion isolierter Herzpreparate bei graduierter Depolarisation. Pfluegers Arch 300:87-107, 1968
DAVIS LD, TEMTE JV: Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers.
Circ Res 24:639-655, 1968
BIGGER JT, MANDEL WJ: Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers. J Clin Invest 49:63-77, 1970
13. SINGH BN, VAUGHAN WILLIAMS EM: Effect of altering
potassium concentration on the action of lidocaine and
diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 29:286-295, 1971
14. SUGIMOTO T, SCHAAL SF, DUNN NM, WALLACE AG: Electro-
physiologic effects of lidocaine in awake dogs. J Pharmacol Exp Ther 166:146-166, 1969
29
21. HILLE B: Common mode of action of three agents that
decrease the transient change in sodium permeability in
nerves. Nature (Lond) 210:1220-1222, 1966
22. NARAHASHI T, WANG CM: Effects of antiarrhythmic drugs on
ionic conductances of squid axon membranes (abstr).
Pharmacologist 15:178, 1973
23. NARAHASHI T, FRAZIER DT: Site of action and active form of
local anesthetics. Neurosci Res 4:65-99, 1971
24. VAUGHAN WILLIAMS EM: Mode of action of quinidine in
isolated rabbit atria interpreted from intracellular records. Br J Pharmacol 13:276-287, 1958
25. WEST TC, AMORY DN: Single fiber recording of the effect of
quinidine at atrial and pacemaker sites in the isolated
right atrium of the rabbit. J Pharmacol Exp Ther 130:
183-193, 1960
26. GETTES LS, SURAWICZ B, SHUIE JC: Effect of high K, low K
and quinidine on QRS duration and ventricular action
potential. Am J Physiol 203:1135-1140, 1962
27. 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 157:659-664, 1967
28. WALLACE AG, CLINE RE, SEALY WG JR, TROYER WJ JR:
Electrophysiological effects of quinidine. Circ Res
19:960-969, 1966
29. JOSEPHSON ME, SEIDES SF, BATSFORD WP, WEISFOGEL GM,
AKHTAR M, CARACTA AR, LAU SH, DAMATO AN: Electro-
physiological effects of intramuscular quinidine on the
atrio-ventricular conducting system in man. Am Heart J
87:55-64, 1974
30. DRIOT P, CARNIER D: Analyses en courant et voltage impose
des proprieties antiarrhythmiques de la quinidine appliquee au myocarde de la grenouille. CR Acad Sci [D]
(Paris) 274:3421-3424, 1972
15. ROSEN KM, LAU SH, WEISS MB, DAMATO AN: Effect of
31. KENNEDY KG, NAYLER WG: Effect of quinidine on the
lidocaine on atrioventricular and intraventricular conduction in man. Am J Cardiol 35:1-5, 1970
activity of a sodium-potassium activated, magnesiumdependent ATPase enzyme isolated from toad cardiac
muscle. Biochim Biophys Acta 110:174-180, 1965
32. SONG SY, SCHEUR J: Effects of pharmacologic agents on
myocardial sodium and potassium stimulated ATPase.
Pharmacology 1:209-217, 1968
16. BEKHETI S, MURTAGH JG, MORTON P, FLETCHER E: Effect of
lidocaine on conducting system of human heart. Br Heart
J 35:305-311, 1973
17. SURAWICZ B, LASSETER KC: Effect of drugs on the electrocardiogram. Prog Cardiovasc Dis 13:26-55, 1970
18. VAUGHAN WILLIAMS EM: Development of new antiarrhyth-
mic drugs. Schweiz Med Wochenschr 103:262-271, 1973
19. BIGGER JT, MANDEL WJ: Effect of lidocaine on conduction
in canine Purkinje fibers at the ventricular muscle-Purkinje junction. J Pharmacol Exp Ther 172:239-254,1970
20. HODGKIN AL, HUXLEY AF: Dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J
Physiol (Lond) 116:497-506, 1952
Circulation Research, Vol. 37, July 1975
33. TRITTHART H, FLECKENSTEIN B, FLECKENSTEIN A: Some
fundamental actions of antiarrhythmic drugs on the
excitability and contractility of single myocardial fibers.
Naunyn Schmiedebergs Arch Pharmacol 269:212-218,
1971
34. CHEN CM, GETTES LS: Combined effects of rate, membrane
potential and quinidine on (dV/dt)max in guinea pig
papillary muscle (abstr). Circulation 48(suppl IV):
IV-109, 1973