EXCITABILITY AND CONDUCTION/Peon et al.
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Holman RL, McGill HC Jr, Strong JP, Geer JC: Techniques for
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Puchtler H, Meloan SN, Terry M: On the history and mechanism of
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Wolinsky H, Daly MM: A method for the isolation of intima-media
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Downing DT: Photodensitometry in the thin-layer chromatographic
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The Relationship of Excitability to Conduction
Velocity in Canine Purkinje Tissue
JORGE PEON, GREGORY R. FERRIER, AND GORDON K. MOE
SUMMARY The relationship between interelectrode conduction time and "take-off" potential (TOP)
was studied with microelectrode techniques in isolated canine false tendons. Conduction of regular or
test beats initiated during phase 4 depolarization or late phase 3 repolarization speeded as TOP
decreased. Similarly, beats initiated during digitalis-induced oscillatory afterpotentials demonstrated
more rapid conduction at lower TOP. Because of the frequency-coupled nature of the oscillations,
conduction times became rate dependent. Phenytoin antagonized digitalis oscillations and reversed
speeding of conduction attributable to the oscillations. No uniform relationship between speed of
conduction and maximum upstroke velocity of the action potential could be demonstrated in the above
experiments or when speed of conduction was varied by changes in concentration of K+ or Ca2+.
However, speed of conduction could be demonstrated to vary directly with changes in excitability as
measured by intracellular current injection.
CONDUCTION velocity in excitable tissues is determined by a variety of factors, both passive and active.' In
mammalian cardiac tissues, action potential amplitude
and the maximum rate of change of the action potential
upstroke are regarded as the most important factors
underlying variations in conduction velocity.23 This relationship has been accepted widely; published studies
frequently offer only measurements of upstroke velocity
as evidence for changes in conduction velocity. This practice is especially surprising in light of a number of wellknown exceptions.
Exceptions to the proposed relationship were noted
From the Masonic Medical Research Laboratory Utica, New York.
This study was supported in part by Grant HL-15759 from the National
Institutes of Health.
Dr. Peon's present address is: Instituto Nacional de Cardiologia, Mexico, D.F., Mexico.
Address for reprints: Gregory R- Ferrier, Ph.D., Masonic Medical
Research Laboratory 2150 Bleecker Street, Utica, New York 13503.
Received July 13, 1977; accepted for publication February 22, 1978.
almost with its formulation. Weidmann4 demonstrated
that the upstroke velocity of the action potential of Purkinje tissue declined as the membrane potential at the
time of excitation (take-off potential or TOP) was reduced
below normal resting values. Singer et al.3 confirmed this
observation and demonstrated that, over a certain range
of TOP, changes in conduction velocity could be correlated with changes in upstroke velocity of the action
potential. However, they noted that this relationship was
not demonstrable at TOP more negative than —70 mV.
Reduction of TOP from normal resting values was accompanied by considerable reduction of action potential amplitude and upstroke velocity, but conduction velocity
remained unchanged unless the tissue was depolarized to
less than —70 mV. In fact, as reported by Arbel et al.,5
speeding of conduction may be observed in response to
moderate depolarization during phase 4 or during the
final period of repolarization of the action potential (late
phase 3). Speeding of conduction during late phase 3
correlates well with the period of supernormal excitability
CIRCULATION RESEARCH
126
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as demonstrated by Spear and Moore.6 The authors of
each of these studies suggested that increased excitability
could account for the observed speeding of conduction in
response to moderate depolarization.
The effect on conduction of moderate variations of
potassium concentration provides another exception. Elevation of potassium concentration from 2 to approximately 6 mM results in speeding of conduction.7 This
occurs despite a considerable reduction of take-off potential (TOP). Dominguez and Fozzard8 found no alteration
in cable properties sufficient to explain speeding of conduction in sheep Purkinje fibers subjected to a rise in
potassium concentration from 2.7 to 4.0 mM, nor was the
observed reduction of membrane potential accompanied
by a shift in threshold potential. They suggested that the
probable cause of increased conduction velocity was the
increased excitability that developed as TOP approached
the threshold potential.
The concept that conduction velocity would vary as a
function of excitability did not originate with those studies. Blair and Erlanger9 demonstrated that conduction
velocity in amphibian nerve fibers varied inversely as a
hyperbolic function of the minimum strength of extracellular stimuli required to recruit the fibers in question.
Furthermore, the relationship with excitability was well
maintained when relative excitability was appraised in
terms of complete strength-duration curves. In cardiac
tissues, the relative proximity of membrane potential to
threshold during terminal repolarization, slow diastolic
depolarization, and manipulation of the ionic environment is reflected in the excitability of the tissue as measured by intracellular current injection.10 In the present
study, excitability and maximum upstroke velocity are
evaluated as possible determinants of conduction velocity
in canine ventricular specialized conducting tissue.
The previously noted exceptions to the proposed dependency of conduction on upstroke velocity occur within
a physiological range of conditions. Similarly, the present
study of conduction velocity is restricted to membrane
potentials greater than —70 mV and to variations in ionic
concentration within limits compatible with life. We studied the effects on conduction velocity of variations in
TOP resulting from "normal" pacemaker activity and
pacemaker activity related to digitalis-induced oscillatory
afterpotentials." Variations in concentration of potassium
and calcium also were studied. Variation of calcium concentration results in changes in threshold potential10 with
little or no change in maximum diastolic potential.10'12
The results first presented constitute a reexamination of
upstroke velocity as a determinant of conduction velocity.
The final section is concerned primarily with excitability.
The results indicate that, within the range of conditions
studied, measurements of upstroke velocity are of little
or no predictive value with respect to conduction velocity.
Variations in conduction velocity appeared to be a function of excitability rather than of upstroke velocity or
TOP.
Methods
Experiments were performed on cardiac Purkinje tissue
from adult mongrel dogs of either sex. Hearts were re-
VOL. 43, No. 1, JULY 1978
moved from animals anesthetized with sodium pentobarbital (30-35 mg/kg, iv). The hearts were fibrillated electrically and false tendons from either ventricle were excised and placed in a reservoir of oxygenated modified
Tyrode's solution. A preparation, selected for minimum
branching and maximum length, was transferred to a
tissue bath through which the perfusate flowed continuously. The perfusate, bubbled with a 95% O2-5% CO2 gas
mixture, was maintained at 37°C and had the following
millimolar composition: NaCl, 137.0; KC1, 4.0; NaH2PO4,
0.9; NaHC03, 12.0; CaCl2) 2.5; MgSO4, 0.5; and dextrose
5.5.
Preparations werefixedwith stainless steel pins at both
ends to the wax bottom of a tissue bath. Stimulation was
accomplished through chlorided silver electrodes. The
anode was placed at a remote site within the tissue bath.
Two cathodes, one applied to each side close to the same
end of the preparation, achieved uniform wavefronts for
even the earliest propagated test responses. Extracellular
stimuli were rectangular pulses, 1-3 msec in duration, and
were 1.5 times the threshold voltage. The exact duration
used in any given experiment was the maximum, up to 3
msec, that would not overlap the upstroke of the action
potential recorded from the site nearest the stimulating
electrodes. Pulses were obtained from an optically isolated stimulator (Pulsar 61, Frederick Haer and Company) which was triggered by an additional digital interval generator. Unless otherwise specified, preparations
were driven by trains of 10-20 members separated by 3sec pauses.
Transmembrane activity was recorded at two sites,
using glass microelectrodes filled with 2.7 M KC1 (resistance 10-20 Mfi). One microelectrode was located approximately half way along the false tendon to ensure separation of the upstroke of the recorded action potential
from the stimulus artifact, and the second electrode was
used to record activity near the end farthest from the site
of stimulation. This procedure necessarily reduced the
absolute conduction time to only a very few milliseconds
in most experiments. However, electronic noise and biological variability remained well below the 5-25% changes
in conduction time studied (see Fig. 6). Furthermore,
impalements maintained for data collection were selected
to provide as nearly as possible the maximal diastolic
potentials obtainable from the preparation. Therefore,
the upstrokes recorded from the two sites were rapid and
almost always parallel, thereby facilitating measurement
of interelectrode conduction time. No measurements of
data were made in those instances in which one or both
impalements showed evidence of significant deterioration. Also, data collected under different sequentially
applied conditions were compared only if the same two
impalements were maintained throughout the sequence.
Recordings from one of the sites were electronically differentiated to provide a measure of maximum action
potential upstroke velocity. Prior to impalement, known
voltage ramps (100-1000 V/sec) applied across a test
resistance between tissue bath and ground were used to
test and calibrate the entire recording and differentiating
circuitry, including the microelectrode and appropriately
adjusted negative capacitance circuits.
127
EXCITABILITY AND CONDUCTION/Peon et al.
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Excitability was assessed by intracellular application of
current pulses of 5-msec duration. Current injection was
accomplished through one of the recording microelectrodes using a technique described previously.13 Frequently, conduction time, maximum upstroke velocity,
TOP, and threshold current requirements were all assessed for a given test beat occupying a specific point in
a sequence of stimulation. To accomplish this, threshold
current was first determined with current pulses of gradually increasing or decreasing magnitudes on sequential
passages of the pattern. Once threshold was determined,
the next test stimulus was delivered via the extracellular
electrodes, thus allowing conduction time, TOP, and maximum upstroke velocity to be measured as soon as possible after the determination of threshold current.
The microelectrode records, differentiated signal, current strength, and stimulus pattern were displayed on an
oscilloscope (Tektronix 5103N) and photographed with a
Grass camera.
Drugs used in this study were prepared as concentrated
stock solutions. Appropriate amounts were added directly
to the reservoir of Tyrode's solution to achieve the final
concentrations. Acetylstrophanthidin* was prepared as a
stock containing 1 X 10~4 g/ml of a 6% aqueous solution
of ethanol. Phenytoin (diphenylhydantoin: Dilantin,
Steri-vial; Parke-Davis) was dissolved in the diluent provided (5 x 1CT2 g/ml). For experiments in which different
concentrations of potassium or calcium were used, separate reservoirs of Tyrode's solution were prepared with
the appropriate concentrations. Since the variations were
small, no attempt was made to compensate for osmotic
differences.
Results
Conduction Velocity in Response to Phasic
Changes in Transmembrane Potential
Conduction velocity was measured in seven experiments in which slow diastolic depolarization was enhanced by superfusion of the preparations with Tyrode's
solution containing a reduced concentration of potassium
(2 IDM). During pauses in the regular driven rhythm,
extrasystoles were initiated at various intervals during
slow diastolic depolarization. An example is shown in
Figure 1 (inset; bottom right). In this example, two extrasystoles were interpolated in the pause. The interrelationships between conduction time, maximum upstroke velocity, and TOP are plotted in Figure 1 for the extrasystoles and for the preceding and following regular responses. Thus the effects of four different TOP were
assessed. Maximum upstroke velocity fell as TOP decreased with diastolic depolarization, but in confirmation
of Arbel et al., 5 and in direct contrast to observations of
Singer et al.3 made at lower TOP, conduction times were
shortened.
Variation of TOP in response to phase 4 depolarization
is not limited to situations incorporating extrasystoles.
Different TOP also can be achieved by changes in heart
rate. In the presence of phase 4 depolarization, conduction
* Generously supplied by Eli Lilly Co., Indianapolis, Indiana.
velocity can become rate dependent, as shown in Figure
2. Low potassium (2 rain) was used to promote slow
diastolic depolarization. The preparation was driven with
trains of beats at diffferent basic cycle lengths (BCL),
four of which are illustrated in Figure 2. At the shortest
dV/dt
CT
2.60
360
2.55
350
2.50
2.45
340
2.40
- 330
2.35
L
92 5
95
100
105
"TAKE OFF" POTENTIAL |mv)
FIG U HE 1 Relationships of interelectrode conduction time and
maximum upstroke velocity (dV/dt) to the transmembrane potential at the time of excitation [take-off potential (TOP)].
Stimuli were applied extracellularly at a remote site. The
sequence of stimulation is indicated in the inset. Upstroke
velocity increased at high membrane potentials. However, corresponding conduction times indicate slowing of propagation.
2.45
2.40
2.35
100
2.30
1000
2.25 •
92.5
95
"T»KE OFF" P O T E N T I A L
97.5
(m»)
FIGURE 2 Rate dependency of conduction time in response to
change in TOP due to phase 4 depolarization. Insets at right
illustrate the lower (more polarized) portions of driven responses at four different basic cycle lengths (BCL). As diastolic
intervals lengthened, TOP decreased and conduction times
shortened.
CIRCULATION RESEARCH
128
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BCL, each beat was initiated at the maximum diastolic
potential. At longer BCL, as diastolic depolarization progressed, the basic beats occurred at lower TOP. The
resultant relationship between conduction time and TOP
is graphically illustrated. Reduction of membrane potential with slow diastolic depolarization was associated with
speeding of conduction. Conduction was rate dependent;
slower conduction was associated with high rates and
faster conduction with low rates.
The above relationships were observed with changes in
TOP during diastole. A more complex situation occurs
when variation of TOP is assessed at various times during
repolarization of a preceding action potential. The relationships of conduction time and maximum upstroke
velocity to variations in TOP achieved by this method at
two different concentrations of potassium are shown in
Figure 3. In Figure 3A, the potassium concentration was
2 mM and the maximum diastolic potential was 95 mV.
As beats were initiated progressively earlier than full
repolarization, conduction times first decreased to a minimum and then progressively lengthened. The short conduction times centering around 85 mV correspond to the
supernormal period of conduction described by Spear and
Moore6 and are probably related to the supernormal
period of excitability. Although the slope of the relationship between conduction time and TOP reversed, this
was not reflected in the curve of membrane responsiveness (i.e., dv/dt vs. TOP3).
The data illustrated in Figure 3B were recorded at a
potassium concentration of 4 mM. The relationships are
essentially the same as those in Figure 3A, except for a
moderate reduction in maximum diastolic potential.
VOL. 43, No. 1, JULY
1978
Again, as beats were initiated progressively earlier than
full repolarization, TOP decreased and there was an initial
reduction in conduction time followed by a prolongation.
The magnitude of the period of supernormal conduction
appears to be reduced. However, the absolute values of
the minimum conduction time were essentially the same.
The apparent diminution of the magnitude of supernormality was caused by the shorter conduction time of beats
initiated at the reduced maximum diastolic potential
characteristically achieved at the higher concentration of
potassium. In experiments in which 6 mM K was studied,
this effect was accentuated, and frequently repolarization
proceeded no further than the TOP corresponding to
"supernormal conduction." Changes in concentration of
potassium appeared not to alter the relationship between
conduction time and TOP. Instead, the observations suggest that the well known speeding of conduction seen
with moderate elevations of potassium concentration can
be explained by failure of repolarization to proceed beyond membrane potentials corresponding to supernormal
conduction.
Digitalis: Effects of Oscillatory Afterpotentials on
Conduction
Digitalis has been shown to induce oscillatory afterpotentials (OAP) coupled to preceding action potentials."
Examples of OAP, induced by acetylstrophanthidin and
coupled to trains of action potentials, are illustrated in
Figure 4. When trains of responses at a cycle length of
600 msec are separated by pauses of several seconds, OAP
increased in amplitude with the first 8-10 members of
each train, and each driven beat in the series is initiated
B
3.5
3.5
r
450
450
400
400 —
3.0
3.0
350*
350 %
300
300
2i
2.5
65
75
15
"TAKE OFF" POTENTIAL ( • »
95
75
" T H E OFF"
•5
95
POTENTIAL (•»)
FIGURE 3 Interelectrode conduction times and maximum upstroke velocity (dV/dt) of driven responses occurring during the
repolarizing phase of a preceding action potential. The relationships in A were determined when the potassium concentration was
2 mM; those in B from the same preparation were determined when the potassium concentration was 4mM. In both, TOP decreased
with increased prematurity of the test beat. Conduction times shortened to a minimum (supernormal conduction) and then gradually
lengthened. In contrast, dV/dt showed only a progressive decrease. The absolute values of conduction times for any given TOP were
almost unchanged by alterations in potassium concentrations. The maximum diastolic potential was less in 4 mM than in 6 mM
potassium, and this limited the final prolongation of conduction times associated with repolarization.
129
EXCITABILITY AND CONDUCTION/Peon et al.
at a progressively lower TOP.14 At higher driven rates
(cycle length <400), each action potential is initiated at
the maximum diastolic potential before significant loss in
TOP occurs. Thus, as also illustrated in Figure 4, trains
of beats at short BCL (300 msec) may demonstrate a high
and almost constant TOP.
Data from an experiment in which TOP was modified
by OAP are shown in Figure 5. The BCL was 600 msec
and each train contained 10 members. The data illustrated are from a single train. Figure 5A shows that the
first beat of the train, occurring after a 3-second pause,
was initiated at a TOP of —79 mV, corresponding to the
resting potential. The second beat was the first to occur
at an interval of 600 msec and was initiated at a higher
TOP than the first. The next 10 beats demonstrated a
sequentially decreasing TOP. Concurrently, the interelectrode conduction times indicated a speeding of conducDownloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
E
100
-llllit
BCL
msec
=
300
600
FIGURE 4 Variation in TOP in canine Purkinje tissue by
acetylstrophanthidininduced OAP (1 X 10~7 g/ml). The top
trace is an intracellular recording and the bottom trace illustrates the pattern of stimulation. The BCL is indicated below
each train of 10 driven responses. OAP coupled to preceding
driven activity are apparent at both BCL. At long BCL, developing OAP caused a progressive loss in TOP. At short BCL,
each beat occurred at a high and almost constant TOP.
tion. Figure 5B illustrates a progressive loss of TOP, and
also a progressive decrease of maximum upstroke velocity
as the OAP developed. Reduction of TOP, whether
caused by digitalis-induced OAP or associated with late
phase 3 repolarization or phase 4 depolarization, is accompanied by acceleration of conduction at a time when the
maximum upstroke velocity is depressed.
One of the main advantages of using OAP to alter TOP
is that a large array of TOP with resultant conduction
times can be recorded within a very brief time. Statistical
analysis of values from several sequential trains allows an
estimate of the variability of the observed relationship
between conduction times and TOP. An example of such
an analysis of data collected from seven sequentially
recorded trains is shown in Figure 6. The data presented
in this figure are from the same experiment as that
illustrated in Figure 9. Both the horizontal and vertical
bars represent standard errors of the mean for values
associated with each member of the train. The regression
line was fitted ty the least squares method. The regression
coefficient (r) had a value of 0.506 and the corresponding
P value was less than 0.001. Thus the data suggest a
direct linear relationship between conduction time and
TOP. The occurrence and direction of this relationship
was confirmed in 25 experiments in which TOP was
varied by superimposition of test beats on OAP developing within trains of driven beats. In many experiments,
the same relationship also was demonstrated by superimposition of a test beat at different positions on a large
OAP following each of several sequential trains similar to
that illustrated on the right in Figure 4. In all cases, data
were collected only from preparations exhibiting maximum diastolic potentials greater than —75 mV during
exposure to acetylstrophanthidin (AS).
B
TOP •—•
CT * - *
65
TOP
•—
iMf/dt • - •
65
400
5.9
;70
E70
5.7
5.5
80
360
-
320
»
5.3
280
5
BEAT NUMBER
10
BCL = 800
1
5
BEAT NUMBER
10
15
BCL - 600 ( u e c )
FIGURE 5 Progressive changes in TOP, conduction time, and maximum upstroke velocity (dV/dt) caused by progressive increments
in amplitude of acetylstrophanthidin (AS)-induced OAP. The numbers on the abscissas indicate the numerical position of individual
driven beats within trains. Panel A shows that, after the first pair of driven responses, the progressive loss in TOP was associated
with a reduction in interelectrode conduction time. Panel B shows that, despite speeding of conduction, loss of TOP is associated
with depression of maximum upstroke velocity. BCL = basic cycle length.
CIRCULATION RESEARCH
130
In illustrations presented thus far, conduction velocity
was an inverse function of upstroke velocity and of TOP.
However, within the high range of membrane potentials
studied (-75 to -105 mV), a similar relation between
conduction velocity and TOP also could be demonstrated
when the maximum dv/dt remained constant. An example of this is shown in Figure 7A. The data were collected
from a preparation treated with AS and driven with trains
of stimuli at a BCL = 600 msec. Thus, the first beat was
initiated at the resting potential, the second beat at the
maximum diastolic potential, and the remaining beats
exhibit a progressive loss of TOP due to developing OAP.
3.2
r = 0.506
P = •= 0.001
\
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= 3.1
3.0
2.9 •-
90
85
95
"TAKE O F F " POTENTIAL (mv)
FIGUKE 6 Relationship between conduction time and TOP.
TOP was varied by AS-induced OAP developing during trains
of driven responses. The data were collected from seven sequentially recorded trains of nine members each. The horizontal and vertical bars are standard errors of the means.
VOL. 43, No. 1, JULY 1978
Conduction times show an initial lengthening corresponding to the change of TOP from resting levels to maximum
diastolic potential. Subsequently, conduction times
shortened as the OAP increased in amplitude and thereby
reduced the TOP. Maximum upstroke velocity, shown at
the top of the figure, remained essentially constant
throughout.
Because of the relationship between conduction times
and TOP, conduction time becomes rate dependent when
slow diastolic depolarization is enhanced (see Fig. 2).
Changes in TOP due to OAP are also rate dependent. At
moderate BCL, OAP asymptotically increase in amplitude with approximately the first 10 beats. Subsequently,
if intoxication is moderate, the TOP remains constant at
a value determined by the BCL, and the amplitude and
time course of the OAP. However, at short BCL, each
beat is initiated at close to the maximum diastolic potential (Fig. 7B; also see Fig. 4, right). Figure 7B shows that,
following the first beat which is initiated at the resting
potential, TOP show little variation, and the conduction
times remain almost constant. Furthermore, conduction
times are longer than observed at the end of the train at
BCL = 600 msec (Fig. 7A).
Abolition of OAP by Phenytoin: Effects on
Conduction
Clinically, digitalis arrhythmias are frequently suppressed with phenytoin (diphenylhydantoin, DPH). Rosen et al.15 have reported that they were able to decrease
the amplitude but did not abolish ouabain-induced OAP
with DPH. We have studied the effects of DPH on canine
false tendons treated with AS in a total of 17 experiments.
Figure 8 shows records from one of five experiments in
which both electrical and contractile activities were recorded. During the control period (Fig. 8, top), pauses in
B
-530
•°480
CT • - »
TOP • - •
CT
TOP
75
5.7
| 75
5.7
5.5
5.5
80
5.3
5.3
85
. - 85
5.1
1 2
3 4
BEAT NUMBER
5
6
7
8 9 10
BCL = 600
5.1
1 2
3 4
BEAT NUMBER
5
6
7
8 9 10
BCL = 3 5 0
FIGURE 7 Relationships of conduction times (CT), maximum upstroke velocity (dV/dt), and TOP to the numerical position of beats
within trains at either of two basic cycle lengths (BCL). The preparation, a false tendon exposed to acetylstrophanthidin (7.5 x I0~s
g/ml), demonstrated rate-dependent changes in conduction time and TOP. Maximum upstroke velocity of the driven action potentials
remained constant.
EXCITABILITY AND CONDUCTION/Peo/i et al.
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driven activity exposed only moderate slow diastolic depolarization. Following the first beat of the train, the
TOP of subsequent beats remained essentially constant
at close to the maximum diastolic potential. The second
panel was recorded after the preparation was exposed to
1 x 10~7 g/ml of AS for approximately 1 hour. Prominent
OAP followed the driven trains. In addition, the OAP
increased in amplitude during the first 8-10 beats of the
train and thereby caused a progressive reduction in TOP
at the BCL illustrated. The contractile record demonstrates a strong positive inotropic effect. Shortly after
these traces were recorded, DPH (1 X 10~6 g/ml) was
added to the perfusate. After 20 minutes of exposure to
the two agents (third panel), the OAP and the associated
progressive change in TOP were reduced in amplitude.
These effects were accompanied by a reversal of the
positive inotropic effect of AS. The bottom panel, recorded 9 minutes later, demonstrates further reversal of
the positive inotropic effect and complete abolition of
OAP. The TOP once again remained constant at near the
maximum diastolic potential after the first beat of the
train. Similar changes were observed in all five experiments.
In six other experiments, the effects of DPH were
assessed only after the development of spontaneous beats
L-
CONTROL
too
AS 66min
.juuuuub
AS88min
DPH 2lmin —
AS 97min
DPH 30min —
IllHlllllillllll
] lQOmg
BCL = 600 msec
FIGURE 8 Effects of phenytoin (diphenylhydantoin, DPH) on
electrical and contractile activity of a canine false tendon
superfused with a toxic concentration of AS (1 x 10~~' g/ml). In
each panel, the top trace is the electrical record, the middle
trace shows the corresponding contractions (resting tension 200
mg), and the bottom trace indicates the pattern of stimulation.
Abolition of OAP by phenytoin was accompanied by reversal of
most of the positive inotropic effect of acetylstrophanthidin.
131
attributable to OAP. Spontaneous activity was greatly
reduced by DPH in two preparations and was reversibly
abolished in the remaining four. In six additional preparations exhibiting AS-induced OAP, an appropriate concentration of the commercial solvent was tested and
found to be without effect.
The effects of DPH on OAP amplitude and the associated changes in TOP suggested that DPH might cause
related changes in conduction times in AS-treated preparations. We investigated this in seven experiments, one
of which is illustrated in Figure 9. Figure 9A shows the
TOP for each beat within trains of nine at a BCL = 600
msec. During the control period, the first beat was initiated at the resting potential achieved after a 3-second
pause in driven activity. All of the remaining members of
the train started from a constant maximum diastolic
potential. After exposure of the preparation to AS, the
TOP for the first two beats were similar to those of the
corresponding control beats. However, the remaining
members of the train demonstrated a conspicuous beatby-beat reduction of TOP because of the developing OAP.
Upon exposure of the preparation to DPH for 45 minutes,
the amplitude of the OAP observable at the end of the
train of driven responses was greatly reduced, as was the
slope of the curve relating TOP to beat number.
The above changes in TOP resulted in corresponding
alterations in conduction times of successive members of
the train of beats. This was confirmed in all seven experiments and is illustrated for the present example in Figure
9B. The first beat in the control period was initiated from
a lower TOP than the subsequent responses and was
conducted relatively quickly. Conduction times were constant for the remaining beats. In the presence of AS, a
progressive acceleration of conduction accompanied the
developing OAP. In this experiment, the later beats of
the train were conducted with conduction times briefer
than those of the control series. Speeding of conduction
relative to control was observed in several preparations
but was not a consistent effect of AS. Responses superimposed on OAP, however, always were conducted more
quickly than beats initiated at higher potentials either
preceding or following OAP. The remaining curve in
Figure 9B shows conduction times of beats recorded after
the amplitudes of OAP were greatly reduced by DPH.
The curve indicates an overall shift toward longer conduction times. This shift was not present in all experiments. However, DPH greatly reduced the slope of the
curve attributable to underlying OAP. This effect was
observed in all seven experiments. Thus the effects of
DPH on conduction in preparations exposed to digitalis
may be compounded by effects on TOP mediated via
actions on OAP.
The Relationship between Conduction Time and
Excitability as Measured by Intracellular
Stimulation
At membrane potentials greater than —70 mV, one
cannot reliably predict changes in conduction times from
changes in maximum upstroke velocity. Within the range
of membrane potentials tested, concurrent depression of
conduction and maximum upstroke velocity was observed
132
CIRCULATION RESEARCH
VOL. 43, No.
1, JULY
1978
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23
1 2
3
4
5
6
7
8
9
BEAT NUMBER
1 2
3
4
CBCl = 600 msec)
5
6
7
8
9
FIGURE 9 Changes in conduction time attributable to effects of phenytoin (DPH) on OAP. Open circles: control; filled circles:
acetylstrophanthidin (1 X 10~7 g/ml); filled squares: acetylstrophanthidin plus DPH (1 X 10'1' g/ml). "Beat number" indicates the
numerical position of a driven response within a train of 9.
only for beats initiated before complete repolarization of
a preceding action potential and then only for beats
earlier than the supernormal period of conduction.
Other possible determinants of conduction time were
considered in five experiments in which potassium and
calcium concentrations were varied. The results of one
experiment, representative of the series, are shown in
Figure 10. For each change in ionic concentration, data
from three responses are included. Each of the three
responses was initiated at an early, intermediate, or late
position during the diastolic interval accompanying a 3second pause in regular stimulation. Thus, variation of
TOP of measured responses was maximized, especially at
low concentrations of potassium. Changes in the concentrations of both ions were accompanied by variation in
maximum upstroke velocity. However, conduction times
demonstrated no uniform correlation with those variations (Fig. 10 A).
In other experiments described in this study, we
showed a direct relationship between conduction times
and TOP (e.g., Figs. 2 and 6). Figure 10B shows an
attempted correlation between changes in conduction
times and changes in TOP for variations in potassium
and calcium concentrations. A linear relationship well
describes the relationship between conduction time and
TOP for changes resulting from alterations of potassium
concentration, but when calcium concentrations were altered, equally large changes in conduction times occurred
with little or no change in TOP. Obviously, another
variable in addition to TOP must be important in determining speed of conduction.
Because calcium is known to affect threshold voltage,10
we considered excitation requirements to be a possible
determinant of conduction velocity. In the series of ex-
periments illustrated by Figure IOC, we determined the
relationship between intracellularly injected current required to initiate propagated responses (threshold current) and TOP. Threshold current clearly demonstrated
a linear correlation with changes in TOP induced by
alterations of potassium concentrations within the range
known to cause little variation of threshold voltage.8 In
contrast, changes in calcium concentration resulted in
large changes in threshold current with little variation in
TOP. Threshold current would be expected to be directly
proportional to the difference between threshold potential and TOP, when changes in membrane resistance are
not excessive. When calcium concentration is varied, the
membrane potential is little affected but threshold voltage varies inversely with the calcium concentration.10
Thus, our observed changes in threshold current in response to variations in calcium concentration are also
predictable on the basis of the difference between threshold voltage and TOP. The similarity between variations
of both conduction times and threshold current with TOP
is striking (Fig. 10, B and C, respectively). The close
similarity between these graphs suggests that conduction
times might better be expressed as a direct function of
threshold current. Figure 10D shows this to be true for
alterations of both potassium and calcium concentrations.
These results, similar in all five experiments, suggest that
excitation requirements are a major determinant of conduction time.
Discussion
The present results demonstrate that the maximum
upstroke velocity of action potentials cannot be used as
a reliable index of conduction velocity. Speeding of conduction was observed in the present study under circum-
EXCITABILITY AND CONDUCTION/Peo/i et al.
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FIGURE 10 Effects of changing potassium and calcium concentrations on conduction time, maximum upstroke velocity (dV/dt),
TOP, and threshold current. Threshold current was measured as the minimum current necessary to initiate a propagated response
when the current was delivered intracellularly via a microelectrode. A detailed explanation of the series of plots is given in the text.
All lines are hand drawn.
stances in which upstroke velocity increased, decreased,
and remained constant. Examples in which depression of
upstroke velocity was accompanied by slowing of conduction were restricted to beats initiated during phase 3
repolarization. These beats were initiated during the relatively refractory period.6 During the terminal phase of
repolarization and during diastole, maximum upstroke
velocity declined or remained constant as TOP decreased.
The TOP encountered and the precise voltage at which
the steep portion of the relation between TOP and upstroke velocity started for any given preparation most
probably determined which occurred in any given experiment. In either case, regardless of whether changes in
TOP were accomplished via premature and postmature
test beats, phase 4 depolarization, changes in potassium
concentrations, or superimposition of beats upon digitalisinduced oscillatory afterpotentials, conduction speeded
with loss in TOP.
In all of the above examples, excitability changed in a
direction appropriate to account for the observed changes
in conduction. Increased excitability associated with depolarization in response to elevation of potassium concentrations was tested directly in the present study and has
been called upon previously to explain this well known
example of speeding of conduction.8 Phase 4 depolarization also has been shown to be accompanied by increased
excitability. Weidmann10 measured excitability during
phase 4 with intracellular injection of current and found
that progressively less current was needed to initiate a
response as depolarization progressed. Block of conduction related to phase 4 depolarization and suggested as a
mechanism of arrhythmia would necessarily be restricted,
as Singer et al.3 suggested, to situations involving substantial depression of excitability and depolarization to
levels well below —70 mV. Phase 4 depolarization associated with normal pacemaker activity, because of increased excitability and more rapid conduction, would
tend to ensure invasion of all specialized conducting tissue
by a propagating wavefront. Digitalis-induced pacemaker
activity provides conditions similar to that of phase 4
depolarization. In a previous study, we demonstrated
increased excitability associated with the peak and ascending limb of oscillatory afterpotentials induceed by
acetylstrophanthidin in canine Purkinje tissue.16 As noted
in the results of the present study, increased conduction
velocity associated with oscillatory afterpotentials was on
several occasions of sufficient magnitude to reduce conduction times below control. Speeding of conduction in
response to exposure to digitalis is not without precedent.
Moe and Mendez17 observed speeding of intraventricular
conduction in in situ canine hearts exposed to moderate
doses of cardiac glycosides. Speeding of conduction was
accompanied by increased excitability. Swain and Weidner18 confirmed these observations in canine heart-lung
preparations treated with ouabain. It is, of course, not
known whether oscillatory afterpotentials were a part of
the mechanism underlying these earlier examples. It
should be emphasized that speeding of conduction in
134
CIRCULATION RESEARCH
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specialized conducting tissues was observed at an early
stage of digitalis intoxication. As confirmed in our previous study,16 later more advanced stages of intoxication
are characterized by block of conduction. This level of
intoxication was associated with very large oscillatory
afterpotentials and greatly depressed excitability as measured by intracellular current injection.
The effects of varying the concentration of calcium
were of special interest to us since conduction could be
related to excitability in the absence of changes in TOP.
The observation that conduction is related similarly to
threshold current requirements, whether the latter is
varied by changing TOP with different potassium concentrations or threshold potential with different calcium
concentrations, lends considerable support to the contention that excitability is an important variable in the
determination of conduction velocity.
In Purkinje tissue depolarized during diastole to potentials between approximately —70 and —55 mV, loss of
TOP and depression of maximum upstroke velocity is
accompanied by slowing of conduction.3 Singer et al.3
assigned the accompanying depression of excitability a
permissive rather than determinant role, but excitability
might also be a major determinant of conduction velocity
in this range of potentials. However, it would be difficult
to evaluate the relative importances of excitability and
maximum upstroke velocity because most agents or procedures would be expected to change both in parallel in
preparations depolarized to this level.
It may be instructive to compare our observations to
the behavior predicted by mathematical models of excitable tissues. Hunter et al.19 have recently considered the
relative influence of various determinants of conduction
velocity in several analytical models. Of the determinants
considered, the term most comparable to excitability was
safety factor. Their expressions for safety factor quantified the extent to which the ability of the tissue to be
excited and conduct exceeded the minimum conditions
necessary for these events. The analysis predicted that
conduction velocity would vary as a function of the square
root of the safety factor. Furthermore, the definition used
in their cubic model predicts that safety factor will increase greatly as membrane potential approaches threshold in the range of membrane potentials normally associated with phase 4 depolarization. Although the mathematical models considered by Hunter et al. were not
derived specifically for canine Purkinje tissue, the behavior predicted by these models is analogous to our experimental findings.
The phenomenon of supernormal conduction must be
considered in the context of the present study. Supernormal conduction has often been considered as a separate
entity distinctly different from "normal" conduction. In
light of the present study, supernormal conduction is
easily incorporated within a single relationship applying
equally well to beats later in diastole. In preparations
exhibiting phase 4 depolarization, one may consider the
point in time at which maximum diastolic potential is
reached as a reference. The membrane potential either
earlier or later than this point is less and is closer to
threshold. Excitability is greater during both terminal
VOL. 43, No. 1, JULY 1978
repolarization and diastolic depolarization, and conduction is more rapid than for beats initiated at the maximum
diastolic potential. A single continuous relationship to
excitability appears to govern conduction velocity
through terminal repolarization and diastole. Conduction
during terminal repolarization gives the greatest impression of being "supernormal" in those preparations in
which slow diastolic depolarization is suppressed by previous rapid activity. Diastolic potentials remain high and
conduction slow.
The effect on "supernormal" conduction of elevating
the potassium concentration provides a counterpart to
the last example. Elevation of potassium concentration
has been shown to eliminate the period of "supernormal"
conduction in isolated canine Purkinje tissues.6 The present results indicate that this effect is accomplished not
by antagonism of supernormal conduction but by elimination of subsequent slowing of conduction. This effect
can be seen in our results (Fig. 3) and in the illustrations
published by Spear and Moore.6 In both studies, phase 3
repolarization, in the presence of moderately elevated
potassium concentrations, proceeded to levels associated
with full recovery of excitability. Further repolarization
to higher membrane potentials and lower excitability was
antagonized by the effects of the higher levels of potassium on maximum diastolic potential. Thus, diastolic or
"normal" conduction velocity approached and frequently
equalled that previously labeled "supernormal." Strongly
supporting this interpretation is the observation of Spear
and Moore6 that supernormnal excitability also is eliminated by elevation of potassium, and this occurs by enhancement of diastolic excitability rather than by suppression of excitability during the period of supernormality.
In the course of our study of the effects of DPH on
Purkinje tissue treated with AS, we confirmed previous
observations that DPH reduced the amplitude of OAP.15
In addition, we frequently observed that DPH abolished
OAP and suppressed digitalis-induced automaticity.
These effects were accompanied by a marked reversal of
the positive inotropic effect of digitalis. Direct negative
inotropic effects of DPH in the absence of digitalis pretreatment have been reported in studies of isolated rabbit
atrial muscle20 and of left ventricular function in the
dog.21 In addition, although some reports suggest that
DPH may dissociate arrhythmic and inotropic effects of
digitalis,22 others indicate depression of left ventricular
function by DPH in patients receiving digitalis.23 Comparison of the present observations with those of previous
studies is impeded by differences in tissue studied, in drug
concentration, and criteria used in assessing inotropic and
antiarrhythmic effects. However, our observations are
consonant with the close association of oscillatory phenomena and inotropic actions of digitalis we previously
reported.24
Studies of the effects of DPH on conduction have also
provided a diversity of results. Bigger et al.25 observed
speeding of conduction in isolated preparations in which
conduction was depressed prior to exposure to DPH.
However, studies of the in situ canine heart demonstrated
little or no change in intraventricular conduction either
EXCITABILITY AND CONDUCTION/Peow et al.
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with26 or without27 pretreatment with digitalis. In addition, Katzung and Jensen20 reported that the effects of
DPH were dependent on the concentration of potassium
to which the tissue was exposed. They observed slowing
of conduction in the presence of high potassium concentrations (5.6 and 7.6 IDM) and no change in conduction at
low concentrations (2.6 IDM). In light of the present study,
one may speculate that slowing of conduction in high
potassium might be mediated by an action of DPH to
reverse the depolarizing effect of high potassium and thus
increase the difference between TOP and threshold potential. In the absence of other agents, DPH reportedly
increases excitability by shifting the threshold voltage of
canine Purkinje fibers to more negative values.2' In our
experiments, any negative shift in threshold potential
must have been more than counterbalanced by reduction
of the amplitude of OAP as evidenced by the cessation of
automatic activity in preparations intoxicated to that
level.
Previous studies of conduction velocity in depressed
cardiac tissues emphasized the importance of upstroke
velocity and action potential amplitude. In more completely polarized tissues, exceptions to a direct relationship between conduction velocity and these proposed
indices were attributed to opposing effects of changes in
excitability. The present study suggests that the exceptions are more likely the rule. Although upstroke velocity
and conduction velocity may both decrease in relatively
refractory tissues or in tissues in which membrane potentials of less than —70 mV are reached, over a broad range
of transmembrane potentials (—70 to —110 mV), conduction velocity was not observed to vary as a function of
upstroke velocity. Speed of conduction appeared to vary
more directly with changes in excitability as measured by
intracellular current injection. Thus, upstroke velocity
cannot be used as a reliable index of conduction velocity
in assessing new pharmacological agents for possible cardiac effects. Similarly, interpretation of previous studies
in which only upstroke velocity was measured must be
reserved until direct measurements of conduction velocity
are made.
5.
6.
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8.
9.
10.
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Erratum
In the paper by Ralph D. Tanz et al., ""Negative Chronotropic and Antiarrhythmic
Properties of Atropine and Other Tropane Analogues on Isolated Cat Heart Preparations," Circ. Res. 42: 467-473 (April) 1978, Figures 1 and 3 were inadvertently reversed.
The figure at the bottom of the page is Figure 1 and should have been placed at the top of
the page. The figure at the top of page 469 is Figure 3 and should have been placed at the
bottom of the page.
The relationship of excitability to conduction velocity in canine Purkinje tissue.
J Peon, G R Ferrier and G K Moe
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Circ Res. 1978;43:125-135
doi: 10.1161/01.RES.43.1.125
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