Downward gradient in action potential duration along
conduction path in and around the sinoatrial node
M. R. BOYETT,1 H. HONJO,2 M. YAMAMOTO,2 M. R. NIKMARAM,3 R. NIWA2 AND I. KODAMA2
of Physiology, University of Leeds, Leeds LS2 9JT, United Kingdom;
2Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-01, Japan;
and 3Department of Physiology, Iran University of Medical Sciences, Tehran, Iran
1Department
heart; cardiac; pacemaking
is an extensive tissue (in the
rabbit, up to 10 mm in length and 8 mm in width)
located in the intercaval region between the openings of
the superior and inferior venae cavae. The action
potential is first initiated in just ,1% of the total area,
normally toward the center of the sinoatrial node (3,
14). From the center, the action potential propagates
preferentially in an oblique cranial direction through
transitional and peripheral regions of the sinoatrial
node to the atrial muscle of the crista terminalis (14). In
the rabbit, cat, and pig at least, conduction in the
opposite direction toward the atrial septum is blocked
(3, 22, 23). The sinoatrial node is an inhomogeneous
tissue; from the periphery to the center, there is a
decrease in upstroke velocity and peak of the action
potential, maximum diastolic potential, and intrinsic
pacemaker activity (14, 16). These differences in electrical activity have been attributed to regional differences
in the density of various ionic currents, Na1 current
(INa ) transient outward K1 current (Ito ), delayed rectifier K1 current (IK,r ), and hyperpolarization-activated
current (If ) (6, 7, 15, 20). The regional differences in
THE SINOATRIAL NODE
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electrical activity are physiologically important because 1) they are responsible for the sinoatrial node
being able to tolerate a wide range of conditions (via the
phenomenon of ‘‘pacemaker shift’’) (16); 2) they may
help the sinoatrial node drive, but not be suppressed by,
the surrounding atrial muscle (27); and 3) they may be
in part or in full responsible for the block of conduction
toward the atrial septum (4). Although much is known
about regional differences in electrical activity between
the periphery and center of the sinoatrial node (i.e., in
the lateral-medial direction), less is known about regional differences between the superior and inferior
parts of the sinoatrial node. Such differences are important because, for example, pacemaker shift almost
invariably involves a shift in the leading pacemaker
site in the superior-inferior direction as well as the
periphery-center direction (21); regional differences in
intrinsic membrane properties in the superior-inferior
direction may be one reason for this. In the present
study, we investigated such differences in both small
ball-like preparations of tissue from different regions of
the sinoatrial node and the intact sinoatrial node. We
have observed novel superior-inferior differences in
both action potential duration and intrinsic pacemaker
activity. We show that these superior-inferior differences are part of a complex two-dimensional pattern of
both action potential duration and intrinsic pacemaker
activity in the sinoatrial node. In the study, we also
discovered a novel region of inexcitable tissue in the
inferior part of the sinoatrial node.
The pattern of action potential duration in the sinoatrial node is such that action potential duration tends
to decrease down the conduction pathway. In the heart,
it appears to be a general rule that action potential
duration decreases down the conduction pathway. The
T wave is the same polarity as the R wave; this
demonstrates that in the ventricles repolarization occurs in the opposite direction to depolarization. The
corollary of this is that along the conduction pathway in
the ventricles there must be a downward gradient in
action potential duration. There is experimental evidence of this. The action potential spreads throughout
the ventricles via Purkinje fibers. The action potential
of Purkinje fibers is long compared with that of the
ventricular muscle (9, 19). The ventricular subendocardium of the apex is the first to be activated, and the
ventricular subepicardium of the base is the last. The
ventricular subendocardial action potential is longer
than that of the ventricular subepicardium, and the
apical action potential is longer than that of the base (2,
8). This rule is not restricted to the ventricles. Within
the right atrium, the atrial muscle of the crista termina-
0363-6135/99 $5.00 Copyright r 1999 the American Physiological Society
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Boyett, M. R., H. Honjo, M. Yamamoto, M. R. Nikmaram, R. Niwa, and I. Kodama. Downward gradient in
action potential duration along conduction path in and around
the sinoatrial node. Am. J. Physiol. 276 (Heart Circ. Physiol.
45): H686–H698, 1999.—Regional differences in electrical
activity in rabbit sinoatrial node have been investigated by
recording action potentials throughout the intact node or
from small balls of tissue from different regions. In the intact
node, action potential duration was greatest at or close to the
leading pacemaker and declined markedly in all directions
from it, e.g., by 74 6 4% (mean 6 SE, n 5 4) to the crista
terminalis. Similar data were obtained from the small balls.
The gradient is down the conduction pathway and will help
prevent reentry. In the intact node, a zone of inexcitable
tissue with small depolarizations of ,25 mV or stable resting
potentials was discovered in the inferior part of the node, and
this will again help prevent reentry. The intrinsic pacemaker
activity of the small balls was slower in tissue from more
inferior (as well as more central) parts of the node [e.g., cycle
length increased from 339 6 13 ms (n 5 6) to 483 6 13 ms (n 5
6) in transitional tissue from more superior and inferior
sites], and this may help explain pacemaker shift.
REGIONAL DIFFERENCES IN SINOATRIAL NODE
lis is the first to be activated by the action potential
arriving from the sinoatrial node, and the action potential then spreads to the right atrial appendage; the
action potential of the crista terminalis is longer than
that of the right atrial appendage (26). The downward
gradient in action potential duration along the conduction pathway is thought to be a protective mechanism
to help prevent reentry arrhythmias.
MATERIALS AND METHODS
included the whole sinoatrial node and some of the surrounding atrial muscle. The preparation (endocardial surface up)
was fixed in a tissue bath. A typical preparation is illustrated
in Fig. 1. The sinoatrial node in the intercaval region,
bordered by the superior and inferior venae cavae, the thick
bundle of atrial muscle, the crista terminalis, and the atrial
septum, can be seen. The tissue bath was superfused with
modified Krebs-Ringer solution at 32°C. Experiments were
carried out at 32°C because our experience is that all electrophysiological properties (including rate of spontaneous activity and action potential configuration) are stable for much
longer periods (.8 h) at 32°C than at 37°C. Modified KrebsRinger solution contained (in mM) 120 NaCl, 25.2 NaHCO3,
1.2 NaH2PO4, 4 KCl, 1.2 CaCl2, 1.3 MgSO4, and 4 glucose. The
solution was equilibrated with 95% O2-5% CO2 to give a pH of
7.4. Solution flowed under the action of gravity at a rate of
20–25 ml/min through a heat exchanger into the chamber.
The bath temperature was monitored using a miniature
thermistor to ensure that the temperature was constant.
At the start of an experiment an accurate drawing of the
preparation was made (see, e.g., Fig. 6) using a fine probe held
Fig. 1. Photograph of a typical preparation of
intact sinoatrial node of the rabbit. Typical
position from which 4 strands of tissue (1–4)
were cut and subsequently tied into a series of
balls (typically, A–E) is shown. CT, crista
terminalis; SVC, superior vena cava; SEP,
atrial septum; LSARB, left branch of sinoatrial ring bundle; IVC, inferior vena cava;
RSARB, right branch of sinoatrial ring bundle;
RA, right atrial appendage.
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Experiments were carried out on the intact sinoatrial node
and small ball-like preparations of sinoatrial node tissue.
Intact sinoatrial node. New Zealand White rabbits weighing 1.5–2 kg were anesthetized with intravenous pentobarbital sodium (30–40 mg/kg). The chest was opened, and the
heart was rapidly excised into modified Krebs-Ringer solution at 32°C. The right atrium was separated from the rest of
the heart and opened by a longitudinal incision in the free
wall to expose the endocardial surface. The right atrium was
then trimmed to leave a preparation ,15 3 15 mm, which
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REGIONAL DIFFERENCES IN SINOATRIAL NODE
(right of the RSARB in Fig. 1). The strands were cut around
the expected leading pacemaker site and were numbered 1–4.
The peripheral part of the sinoatrial node overlaps the atrial
muscle of the crista terminalis, and a razor blade was used to
remove this muscle from the strands as well as the lipid tissue
on the epicardial surface of the remainder of the sinoatrial
node. After they had been trimmed, the strands were ,0.3–
0.4 mm in width, ,0.2 mm in depth, and ,3–4 mm in length.
The strands were tied into a series of small balls (typically 5)
with diameters of ,0.3–0.4 mm. The ball closest to the crista
terminalis included the right branch of the sinoatrial ring
bundle on its surface and was named A. The remaining balls
were named B–E. The nomenclature used in relation to the
balls is shown in Fig. 1. Strand 1 was from the more superior
(or cranial) part of the sinoatrial node, whereas strand 4 was
from the more inferior (or caudal) part. Ball A, being closest to
the atrial muscle of the crista terminalis, was from the
periphery of the sinoatrial node, whereas balls D and E, being
distant from the crista terminalis, were from the center. The
intervening balls were from a transitional region between the
periphery and center. The dissection procedure took several
hours to complete because after each step the tissue was
allowed sufficient time to recover and resume spontaneous
activity. Once the dissection procedure was complete, a
strand of balls (endocardial surface up) was fixed in the tissue
bath. Although the balls of tissue were small, they were
unlikely to be significantly damaged by the dissection procedure (see Ref. 5). The procedure of using ties to separate balls
of tissue was developed by the late Professor H. Irisawa for
preparation of tissue specimens suitable for the two-microelectrode voltage-clamp technique. It was adequate to electrically
isolate the balls of tissue from each other: after preparation
each ball beat independently of the others, and there was no
evidence of electrotonic interaction (e.g., entrainment or a
small depolarization at the time of the action potential in a
neighboring ball).
The tissue bath was superfused with either modified
Krebs-Ringer solution (see Intact sinoatrial node) or Tyrode
solution. The Tyrode solution contained (in mM) 93 NaCl, 20
NaHCO3, 1 Na2HPO4, 5 KCl, 1.2 CaCl2, 1 MgSO4, 20 sodium
acetate, and 10 glucose with 5 U/ml insulin. The solution was
equilibrated with 95% O2-5% CO2 to give a pH of 7.4. The
results obtained using the two solutions were similar and
have been combined. There is a difference of 1 mM in the K1
concentration in the two solutions, but this is not sufficient to
have a substantial effect on electrical activity of rabbit
sinoatrial node tissue (14). Solution flowed under the action of
gravity or was pumped through a heat exchanger into the
chamber (flow rate 20–25 or ,4 ml/min). The bath temperature was monitored using a miniature thermistor to ensure
that the temperature remained at 32°C. Intracellular action
potentials were recorded as described in Intact sinoatrial
node; in some experiments a World Precision Instruments
high-input impedance amplifier (model 750, World Precision
Instruments, New Haven, CT) was used instead of the Nihon
Kohden amplifier. Data were recorded using the equipment
above or a chart recorder (Gould 2600S), tape (Store 7DS tape
recorder, Racal Recorders, Hythe, UK), and Signal Averager
software (Cambridge Electronic Design, Cambridge, UK).
Data are presented as means 6 SE. Statistical analysis
was carried out using SigmaStat (Jandel Scientific Software,
CA). An analysis of variance or a t-test was used as appropriate. An equivalent nonparametric test was used if the data
were not normally distributed. A difference was considered
significant if P , 0.05.
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in a calibrated XYZ micromanipulator with 0.1-mm precision
to establish the coordinates of various landmarks. A pair of
modified bipolar electrodes was used to record the extracellular potential from the atrial muscle as a reference signal. The
pair of modified bipolar electrodes consisted of two 100-µm
stainless steel wires (one wire 1 mm shorter than the other)
insulated to the tip and taped together. High-gain amplification (50–88 dB) and filtering (0.5- to 30-Hz bandpass filter
used) of the signal from the modified bipolar electrodes by a
Nihon Kohden dual-channel bioelectric amplifier (Tokyo,
Japan) resulted in a sharp negative deflection at the instant
of activation of the recording site (confirmed by action potential recording by conventional glass microelectrodes). Intracellular action potentials were recorded using conventional
glass microelectrodes (resistance, 30–40 MV; filling solution,
3 M KCl) and a Nihon Kohden microelectrode amplifier.
Intracellular action potentials were recorded from ,100 sites
(with 0.5- or 1-mm spacing) throughout the sinoatrial node
and some of the surrounding atrial muscle. The probe used to
help draw the preparation (see above) was also used to show
the position at which an intracellular recording was to be
made; in this way the drawing and recording sites shared
common coordinates. The coordinates of recording sites in the
intact sinoatrial node are given in some of the figures. The
x-axis was set roughly perpendicular to the crista terminalis,
the y-axis was set roughly parallel to the crista terminalis,
and the leading pacemaker site was set as the origin.
In all experiments an activation map was obtained (see,
e.g., Fig. 6A). This was either obtained from the intracellular
recordings or from extracellular recordings (from ,100 sites
throughout the preparation) made using a second pair of
modified bipolar electrodes. The time interval between the
time of activation at the recording site and the time of
activation at the reference site on the atrial muscle was
measured. The site showing the earliest activation (at which
this interval was longest) was taken to be the leading
pacemaker site. The time of activation of other sites with
respect to the time of initiation of the action potential at the
leading pacemaker site was shown as a series of isochrones at
5- to 10-ms intervals. The activation pattern was stable in all
experiments reported.
From the intracellular recordings, action potential duration and spontaneous cycle length (time interval between
successive spontaneous action potentials) were measured
using an electronic device (11). Action potential duration was
measured at ,30 mV as in our previous studies (5, 15, 16, 20).
Intracellular action potentials, action potential duration, and
spontaneous cycle length were recorded using a thermal
array recorder (RTA-1200, Nihon Kohden), tape (digital magnetic tape recorder, PC-108M, Sony; sampling rate, 5 kHz),
and Axoscope software (Axon Instruments, Burlingame, CA)
for later analysis.
Small ball-like preparations of sinoatrial node tissue. The
sinoatrial node was isolated as described in Intact sinoatrial
node (except that in some experiments the dissection was
carried out in Tyrode solution). Next, four strands of tissue
(,0.5 mm in width and 3–4 mm in length) were cut from the
sinoatrial node in a direction perpendicular to the crista
terminalis. A typical position of the strands in the intact
sinoatrial node is shown in Fig. 1. The crista terminalis runs
from top to bottom in Fig. 1. For much of its length, a thin flap
of tissue (a remnant of the venous valve in the embryo), the
right branch of the sinoatrial ring bundle (RSARB), runs
along the crista terminalis. The right branch of the sinoatrial
ring bundle marks the approximate border between the atrial
muscle (left of the RSARB in Fig. 1) and the sinoatrial node
REGIONAL DIFFERENCES IN SINOATRIAL NODE
RESULTS
periphery to the transitional zone there was a substantial increase in action potential duration. In this example, on going from the transitional zone to the center
there was a substantial decrease in action potential
duration. This novel finding was frequently but not
always observed for reasons evident later. Figure 2B
shows superimposed action potentials at a slower time
base (from balls A, B, and D from strand 2 from a
different heart). This shows the well-established increase in cycle length (reflecting a decrease in intrinsic
pacemaker activity), as well as the other changes
(including the biphasic change in action potential duration), on going from the periphery to the center.
As well as periphery-center differences in electrical
activity, we have now observed superior-inferior differences. Figure 2, C and D, shows superimposed action
potentials at fast and slow time bases. All recordings
were made from balls of tissue from the transitional
zone (ball B in all cases). The balls of tissue were from
strand 1 (Fig. 1) from a more superior part of the sinoatrial node and strand 4 (Fig. 1) from a more inferior
part of the sinoatrial node. In the more inferior part of the
sinoatrial node, both the action potential duration and the
cycle length were substantially greater (Fig. 2, C and D).
Fig. 2. Periphery-center and superior-inferior differences in intrinsic electrical activity in sinoatrial node. A and
B: superimposed action potentials recorded from small balls of tissue from the periphery, transitional zone, and
center of sinoatrial node at fast (A) and slow (B) time bases. In A, recordings were made from balls A, B, and E from
strand 3 of one heart, and in B, recordings were made from balls A, B, and D from strand 2 of another heart. C and
D: superimposed action potentials recorded from small balls of tissue from more superior and more inferior parts of
sinoatrial node at fast (C) and slow (D) time bases. Recordings were made from ball B from strands 1 and 4.
Recordings in C and D were obtained from tissue from different hearts.
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Periphery-center and superior-inferior differences in
action potential duration and other parameters in small
ball-like tissue preparations from different regions of
sinoatrial node. We previously studied differences in
electrical activity between the periphery and center of
the sinoatrial node using small ball-like tissue preparations (,0.35 mm in diameter) from the different regions. The advantage of this preparation is that regional differences in intrinsic electrical activity (i.e.,
electrical activity free of the influence of electrotonic
influences) can be studied. In one study (16) we observed a regional difference in action potential duration, but we did not study it systematically. Figure 2A
shows superimposed action potentials at a fast time
base recorded from small balls of tissue from the
periphery, transitional zone, and center of the sinoatrial node (balls A, B, and E, Fig. 1). All balls were
from the same strand (strand 3) from the same heart.
From the periphery to the center, there was a decrease
in the takeoff potential, upstroke velocity, action potential peak, and maximum diastolic potential as reported
before (14, 16). In addition, large changes in action
potential duration can be seen; on going from the
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REGIONAL DIFFERENCES IN SINOATRIAL NODE
Fig. 3. Summary of regional differences in intrinsic electrical activity
in sinoatrial node: action potential duration. A: action potential
duration for strands 1 and 4 plotted for balls A–D. B: action potential
duration for balls A, B, and D plotted for strands 1–4. Means 6 SE
are plotted. Ball 1A: n 5 4; ball 4D: n 5 5; other balls: n 5 6–9.
regional change shown in Fig. 2A. In all strands (1–4),
there are statistically significant differences among the
data for the different balls (ANOVA: strand 1, P 5
0.007; strand 2, P 5 0.047; strand 3, P 5 0.021; strand
4, P 5 0.009). Figure 3B shows that in all balls there
tended to be an increase in the mean action potential
duration from the more superior to the more inferior
part of the sinoatrial node, and the increase was
greatest in ball B from the transitional zone. In all balls
apart from balls D and E (i.e., balls A–C), there are
statistically significant differences among the data for
the different strands (ANOVA: ball A, P 5 0.014; ball B,
P 5 0.003; ball C, P 5 0.011).
Figure 4A shows that there were decreases in both
the mean action potential peak and the mean maximum diastolic potential from the periphery to the
center. There are statistically significant differences in
the action potential peak in balls A to D or E in all
strands apart from strand 1 (i.e., strands 2–4) (ANOVA:
strand 2, P 5 0.01; strand 3, P 5 0.005; strand 4, P 5
0.011), and there are statistically significant differences
in the maximum diastolic potential in balls A to D or E
in all strands apart from strand 4 (i.e., strands 1–3)
(ANOVA: strand 1, P 5 0.006; strand 2, P , 0.001;
strand 3, P 5 0.004). Figure 4B shows the mean action
potential peak and the mean maximum diastolic potential from the more superior to the more inferior part of
the sinoatrial node. There was no significant change in
either action potential peak or maximum diastolic
potential for any ball.
In all strands there was a decrease in the mean
maximum upstroke velocity from the periphery to the
center [Fig. 4C; statistically significant differences
among data for different balls in strands 1–4 (ANOVA):
strands 1–3, P , 0.001; strand 4, P 5 0.004], but Fig.
4C shows that in strand 4 from the more inferior part of
the sinoatrial node mean maximum upstroke velocities
were depressed compared with those in strand 1 from
the more superior part of the sinoatrial node. Figure 4D
shows that there tended to be a decrease in the mean
maximum upstroke velocity from the more superior to
the more inferior part of the sinoatrial node. However,
although there are statistically significant differences
among the data for ball A, there are no such differences
for data from the other balls (B–E) (ANOVA: ball A, P 5
0.038).
Figure 4E shows that there was an increase in cycle
length from the periphery to the center. There were
statistically significant differences among the data for
the different balls in all strands (1–4) (ANOVA: strands
1 and 2, P , 0.001; strand 3, P 5 0.018; strand 4, P 5
0.005). Finally, Fig. 4F shows that in all balls there
tended to be an increase in cycle length from the more
superior to the more inferior part of the sinoatrial node.
However, there are only statistical significant differences among the data for ball B (ANOVA: ball B, P 5
0.021).
Periphery-center and superior-inferior differences in
action potential duration and other parameters in intact sinoatrial node. In four preparations of the intact
sinoatrial node, action potentials were recorded from
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Mean data showing both periphery-center and superior-inferior differences in action potential duration
and other parameters are shown in Figs. 3 and 4. Data
for action potential duration are shown in Fig. 3, and
data for action potential peak and maximum diastolic
potential, maximum upstroke velocity, and cycle length
are shown in Fig. 4. In all cases, data for strands 1 and 4
are plotted for balls A–D in the top panels (data for
strands 2 and 3 and ball E are not shown for clarity),
and data for balls A, B, and D are plotted for strands
1–4 in the bottom panels (data for balls C and E not
shown for clarity).
In strand 1 from the more superior part of the
sinoatrial node, there was a monotonic increase in
mean action potential duration from the periphery to
the center, but in strand 4 from the more inferior part
mean action potential duration at first increased and
then declined (Fig. 3A). The latter pattern is the
REGIONAL DIFFERENCES IN SINOATRIAL NODE
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,100 sites throughout the sinoatrial node and some of
the surrounding atrial muscle. Marked and consistent
regional differences in action potential duration were
observed in the four preparations. Furthermore, in a
further five preparations in which a more restricted
number of actions potentials were recorded, consistent
results were obtained.
Superimposed action potential recordings from various sites in one preparation are shown in Fig. 5. Figure
5, C and D, shows action potentials recorded along a
line perpendicular to the crista terminalis and going
through the leading pacemaker site (see inset). Figure
5C shows the action potential at the leading pacemaker
site (0 mm) as well as action potentials recorded at sites
toward and into the atrial muscle (at increasing distances from the leading pacemaker site). In this direction there was a large decrease in action potential
duration. Figure 5D shows the action potential at the
leading pacemaker site again (0 mm) as well as action
potentials recorded at sites at increasing distances from
the leading pacemaker site toward the atrial septum (but
still in the sinoatrial node). There was also a large decrease
in action potential duration in this direction.
Figure 5, A and B, shows action potentials recorded
along another line perpendicular to the crista terminalis. This line was 7 mm superior to the leading pacemaker site (see inset). All the action potentials were
shorter than the corresponding action potentials at the
level of the leading pacemaker site (Fig. 5, C and D).
Despite this, the same pattern was evident. The action
potential at 0 mm in the top panels was recorded at the
same x coordinate (see METHODS ) as the leading pacemaker site. On going toward and into the atrial muscle
(Fig. 5A) or toward the atrial septum (but still in the
sinoatrial node) (Fig. 5B) there was a decrease in action
potential duration.
The results are summarized in the inset in Fig. 5.
The asterisk shows the position of the leading pacemaker site. The isochrones show action potential durations of a particular value and show that the action
potential was longest at the leading pacemaker site (it
was 186 ms in duration at this site) and declined
markedly and monotonically the further the recording
site was from the leading pacemaker site. The decline
in action potential duration continued across the sinoatrial node-atrial muscle border. The shortest action
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Fig. 4. Summary of regional differences in intrinsic electrical activity in sinoatrial node: action potential peak,
maximum diastolic potential, maximum upstroke velocity and cycle length. A: action potential peak (top) and
maximum diastolic potential (bottom) for strands 1 and 4 plotted for balls A–D. B: action potential peak (top) and
maximum diastolic potential (bottom) for balls A, B, and D plotted for strands 1–4. C: maximum upstroke velocity
(dV/dtmax) for strands 1 and 4 plotted for balls A–D. D: maximum upstroke velocity for balls A, B, and D plotted for
strands 1–4. E: cycle length for strands 1 and 4 plotted for balls A–D. F: cycle length for balls A, B, and D plotted for
strands 1–4. Means 6 SE are plotted. Ball 1A: n 5 2–3; ball 4D: n 5 4–6; other balls: n 5 5–9.
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REGIONAL DIFFERENCES IN SINOATRIAL NODE
potential recorded was 10 ms in duration (near the
superior vena cava/atrial septum). These data are
consistent with the data from the small balls as considered in the DISCUSSION. In four preparations, the maximum action potential duration in the sinoatrial node
was 170 6 18 ms and the minimum action potential in
the crista terminalis was 43 6 3 ms; this corresponds to
a decrease in action potential duration of 74 6 4%.
Figure 5 shows that there were regional differences
in the action potential peak, upstroke velocity, and
maximum diastolic potential as well as action potential
duration throughout the sinoatrial node. The slope of
the pacemaker potential also varied regionally and was
greatest at the leading pacemaker site (not illustrated).
Figures 6 and 7 summarize results from another experiment. Figure 6 shows activation time, action potential
duration, and repolarization time throughout the sinoatrial node and surrounding atrial muscle by isochrones. Figure 7 shows the maximum diastolic potential, maximum upstroke velocity, and slope of the
pacemaker potential by contours and action potential
peak by points of various sizes.
Figure 6A shows that the activation sequence of the
preparation was typical. The leading pacemaker site
was ,1.7 mm from the crista terminalis, and conduction preferentially occurred in an oblique cranial (superior) direction toward the atrial muscle of the crista
terminalis. It should be noted that although conduction
preferentially occurs in the oblique cranial direction,
conduction directly toward the crista terminalis still
occurs; the conduction velocity in the direction perpendicular to the crista terminalis is simply lower than
that roughly parallel to it. As a consequence of the
nonradial spread of the action potential from the
leading pacemaker site shown in Fig. 6A, the action
potential arrives at the crista terminalis over a broad
wave front. In all maps of the sinoatrial node in Figs. 6
and 7, the position of the leading pacemaker site
(asterisk) is shown.
Figure 6B shows the distribution of action potential
duration in the same preparation. The distribution of
action potential duration is similar to that in Fig. 5.
Comparison of panels A and B in Fig. 6 shows that the
distribution of action potential duration is roughly
similar to that of the activation sequence. In the
DISCUSSION, it is suggested that the primary purpose of
the pattern of action potential duration is that repolarization should occur in the opposite direction to depolarization, as occurs in the ventricles. Figure 6C shows the
time (after the action potential was first initiated at the
leading pacemaker site) at which repolarization occurred (calculated by summing the activation time and
action potential duration). This shows that repolarization first occurred in the atrial muscle and was last to
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Fig. 5. Periphery-center and superior-inferior differences in action potential duration in intact sinoatrial node. A
and B: action potentials recorded along a line perpendicular to crista terminalis 7 mm superior to leading
pacemaker site. C and D: action potentials recorded along a line perpendicular to crista terminalis through leading
pacemaker site. In each panel, action potential marked 0 mm was recorded either at leading pacemaker site (C and
D) or at same x-coordinate (see MATERIALS AND METHODS ) 7 mm superior (A and B). A and C: action potential at 0 mm
and action potentials at increasing distances from this in direction of atrial appendage. Action potentials not
followed by a pacemaker potential were recorded from atrial muscle. B and D: action potential at 0 mm and action
potentials at increasing distances from this in direction of atrial septum. All action potentials recorded were nodal.
Inset, map showing regional differences in action potential duration in intact sinoatrial node. Isochrones show
action potential durations of 180, 170, 160, 120, 80, 60, 50, and 40 ms. Dotted lines show levels along which
recordings in A–D were made. SARB, left branch of sinoatrial ring bundle.
REGIONAL DIFFERENCES IN SINOATRIAL NODE
H693
Fig. 6. Summary of regional differences in electrical activity in intact
sinoatrial node: activation time (A), action potential duration (B),
and repolarization time (C). Values of isochrones given in milliseconds. In A, w shows position of reference modified bipolar electrodes
(see MATERIALS AND METHODS ). Repolarization time is time taken for a
site to repolarize to 230 mV after action potential was first initiated
at leading pacemaker site; it was calculated as sum of activation time
and action potential duration.
occur close to the leading pacemaker site; depolarization and repolarization, therefore, do occur in opposite
directions.
Figure 7 shows that the action potential peak, maximum diastolic potential, and maximum upstroke velocity were least in the intercaval area and greatest in the
surrounding atrial muscle, whereas the slope of the
pacemaker potential was greatest in the intercaval
area and zero in the surrounding atrial muscle. In the
case of the action potential peak and maximum upstroke velocity, there was a long area down the center of
the intercaval area with a low action potential peak (24
to 11 mV in this example) and low maximum upstroke
velocity (,5 V/s). In the case of the slope of the
pacemaker potential, there was a long area down the
intercaval area with a steep pacemaker potential.
However, this area was shifted toward the crista terminalis compared with the area of low action potential
peak and maximum upstroke velocity. The distributions of the action potential peak, maximum diastolic
potential, maximum upstroke velocity, and slope of the
pacemaker potential (Fig. 7) were all different from
that of action potential duration (Fig. 6B): compared
Fig. 7. Summary of regional differences in electrical activity in intact
sinoatrial node: action potential (AP) peak (A), maximum diastolic
potential (B), maximum upstroke velocity (C), and slope of pacemaker potential (D). In A, size of points represents value of action
potential peak (scale given); closed symbols are used to denote
positive peak potentials, and open symbols are used to denote
negative peak potentials (positive and negative scales not the same
for clarity). In B–D, values of contours are given in mV (B), V/s (C), or
mV/s (D). Slope of pacemaker potential was measured as change in
membrane potential during the 100 ms following maximum diastolic
potential. All data are from the same preparation as Fig. 6.
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with the region in which action potential duration was
at a maximum, the region in which the action potential
peak and maximum upstroke velocity were at a minimum was further toward the atrial septum, the region
in which maximum diastolic potential was at a minimum was more superior, and the region in which the
slope of the pacemaker potential was at a maximum
extended further in both the superior and inferior
directions.
Inexcitable zone in periphery of sinoatrial node. Figure 6A shows the characteristic block of conduction of
the action potential from the leading pacemaker site
toward the atrial septum. As shown in Fig. 6A, excitation of the septal side of the intercaval region is the
result of conduction circumventing the block zone, i.e.,
conduction around the upper and lower margins of the
block zone. In Fig. 6A, the approximate position of the
block zone is shown by the solid black line; it is also
shown in the other maps of the sinoatrial node in Figs.
6 and 7. The leading pacemaker site (asterisk) was
located on the outside or edge of the area down the
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REGIONAL DIFFERENCES IN SINOATRIAL NODE
Fig. 8. Electrical activity recorded in inferior part of block zone.
A: superimposed action potentials recorded along a line perpendicular to crista terminalis 3 mm inferior to leading pacemaker site.
Action potentials were recorded at various distances away from
x-coordinate (see MATERIALS AND METHODS ) of leading pacemaker site
in direction of atrial septum. Action potential at 1.5 mm is a typical
sinoatrial node action potential, recordings at 2 and 4 mm are from
block zone, and action potential at 7 mm is from atrial muscle of atrial
septum. B: superimposed recordings of membrane potential made
along a line perpendicular to crista terminalis 1 mm inferior to
leading pacemaker site in another preparation. Recordings were
made 0 and 1.5 mm away from x-coordinate of leading pacemaker site
in direction of atrial septum. Recording at 0 mm is a typical sinoatrial
node action potential, and recording at 1.5 mm is from block zone.
tions). Figure 9A shows the activation sequence of the
preparation together with the position of six recording
sites arranged along the line of preferential conduction.
Figure 9B shows superimposed fast time base recordings of action potentials at these sites. The usual
marked gradient in action potential duration can be
seen. After the recordings, the preparation was stimulated at a cycle length of 400 ms (,18% shorter than
the spontaneous cycle length); the site of stimulation
(star in Fig. 9A) in the atrial muscle was such that the
activation sequence of the preparation was reversed.
Figure 9C shows superimposed action potentials recorded from the same six sites during stimulation. The
gradient in action potential duration was unchanged. It
was also unchanged after 4-h stimulation. It is con-
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middle of the intercaval region with a low action
potential peak (Fig. 7A) and a low maximum upstroke
velocity (Fig. 7C); it was located within the area with
the longest action potentials (Fig. 6B) and steepest
pacemaker potentials (Fig. 7D) instead. In contrast, the
block zone was located within the area down the middle
of the intercaval region with a low action potential peak
(Fig. 7A) and a low maximum upstroke velocity (Fig.
7C) and outside the area with the longest action
potentials (Fig. 6B) and steepest pacemaker potentials
(Fig. 7D). The small, slow, short action potentials in the
block zone show the tissue in this zone to be poorly
excitable, and this may be responsible for the blocking
of conduction.
In the block zone in the inferior part of the intercaval
region, in three of four preparations, zones of extremely
poor excitability were seen with depolarizations with
amplitudes of ,25 mV or stable resting potentials.
Figure 8A shows an example; it shows superimposed
action potentials recorded along a line perpendicular to
the crista terminalis and inferior to the leading pacemaker site. One recording was made 1.5 mm medial
(direction of the atrial septum) to the leading pacemaker site, whereas the others were further medial.
The site 7 mm medial to the leading pacemaker site
was within the atrial muscle of the septum. In Fig. 8A,
the action potentials are lined up by the simultaneously
recorded reference signal (extracellular action potential) from the atrial muscle (see MATERIALS AND METHODS ). This display allows the activation times of the
sites to be seen. The site to be activated first (site 1.5
mm medial to the leading pacemaker site) was closest
to the leading pacemaker site. At the sites 2 and 4 mm
medial to the leading pacemaker site, small, slow
depolarizations were recorded. The atrial action potential (7 mm medial to the leading pacemaker site) was
activated much earlier than the depolarizations in the
block zone, and it must have been activated as a result
of conduction around the side of the block zone.
Another example is given in Fig. 8B, which shows
two superimposed recordings made 0 and 1.5 mm
medial to the leading pacemaker site along a line
perpendicular to the crista terminalis and inferior to
the leading pacemaker site. At the site 1.5 mm medial
to the leading pacemaker site, there was no depolarization, only a stable resting potential of 275 mV. In the
three preparations in which depolarizations with amplitudes of ,25 mV or stable resting potentials were
recorded, the maximum diastolic potential was 267 6 5
mV at the sites at which the small depolarizations or
stable resting potentials were recorded.
Regional differences in action potential duration in
sinoatrial node are preserved when activity is driven
rather than stimulated. The observation that the distribution of action potential duration (Fig. 6B) is similar
to that of the activation sequence (Fig. 6A) raises the
possibility that it is the activation sequence that determines in some unknown way the action potential
duration. This hypothesis was tested in three preparations; Fig. 9 shows the result from one preparation
(similar results were obtained from the 2 other prepara-
REGIONAL DIFFERENCES IN SINOATRIAL NODE
H695
cluded that the activation sequence in the short term
does not control action potential duration.
DISCUSSION
The major new findings from the present study are
that 1) there is a marked downward gradient in action
potential duration along the conduction pathway in
and around the sinoatrial node; 2) there is a superior-toinferior gradient in intrinsic pacemaker activity in the
sinoatrial node; and 3) there can be an inexcitable zone
in the inferior part of the sinoatrial node. In addition,
this study has mapped the distributions of various
electrophysiological variables in the sinoatrial node.
Two-dimensional biophysically detailed models of the
rabbit sinoatrial node and surrounding atrial muscle
are being developed by us and others (see, e.g., Ref. 25),
and the detailed mapping of electrical activity described in this study will help in the development of
such models.
Comparison with previous studies. Our first clues of
changes in action potential duration in the small
ball-like preparations from different regions of the
sinoatrial node can be seen in our previous studies (5,
16). Evidence of the regional differences in action
potential duration in the intact sinoatrial node, although not reported, can be seen in the work of others
(see, e.g., Ref. 3). In the small ball-like preparations
from different regions of the sinoatrial node, the changes
in action potential peak, maximum diastolic potential,
maximum upstroke velocity, and cycle length in the
periphery-center direction in the present study (Figs. 3
and 4) are similar to those reported by us previously
(14, 16). We have now shown that these changes are
just one component of a complex two-dimensional variation in these parameters in both the periphery-center
and superior-inferior directions (Figs. 3 and 4). In the
intact sinoatrial node, the activation sequence and
distributions of maximum upstroke velocity and slope
of the pacemaker potential are similar to those published previously (see, e.g., Refs. 3, 14, and 18). The
distributions of the other action potential parameters
(action potential duration, repolarization time, action
potential peak, maximum diastolic potential) have not
been mapped before. A comprehensive survey of all
action potential parameters measured simultaneously,
as carried out in the present study, has not been carried
out before.
Comparison of regional differences in small ball-like
tissue preparations and intact sinoatrial node. The
results for maximum upstroke velocity, action potential
peak, action potential duration, and maximum diastolic potential from the small balls of tissue (Figs. 3
and 4) are consistent with those from the intact sinoatrial node (Figs. 5–7) in terms of both the absolute
values recorded and the pattern of changes. In the
small balls of tissue and the intact sinoatrial node,
values of the maximum upstroke velocity were comparable and, in both types of preparation, decreased from
the periphery to the center (Figs. 4C and 7C). In the
small balls of tissue (especially from the periphery),
there was a decrease in maximum upstroke velocity
from strand 1 (more superior) to strand 4 (more inferior) (Fig. 4D). The same tendency was observed in the
intact sinoatrial node on going from the superior part of
the sinoatrial node toward the leading pacemaker site
(Fig. 7C). In both the small balls of tissue (Fig. 4A) and
the intact sinoatrial node (Fig. 7, A and B), both the
action potential peak and the maximum diastolic potential decreased from the periphery to the center, but
there was little change from a more superior part of the
sinoatrial node to a more inferior part; absolute values
of the two parameters were similar in the two types of
preparation. In the small balls of tissue, action potential duration tended to increase from the periphery to
the center (Fig. 3A), and the same occurred in the intact
sinoatrial node (Figs. 5 and 6B) (comparison of Figs.
3A, 5, and 6B shows the values of action potential
duration to be comparable in the 2 types of preparation). In strand 4 from a more inferior part of the
sinoatrial node, from the periphery to the center, action
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Fig. 9. Regional differences in action potential duration
in sinoatrial node are preserved when activity is driven
rather than stimulated. A: activation map. Isochrones
show activation times (values given in ms). Sites 1–6 at
which action potentials were recorded from are shown
by filled circles. B: superimposed action potentials recorded from sites 1–6 during spontaneous activity of
sinoatrial node. Spontaneous cycle length was ,490 ms.
C: superimposed action potentials recorded from sites
1–6 during stimulation at a cycle length of 400 ms
(stimulus pulse duration and amplitude, 1 ms and
,20% above threshold, ,20 V, respectively). Site of
stimulation is identified by w in A. Throughout experiment, 0.6 µM propranolol and 2 µM atropine were
present to block effects of released neurotransmitters.
H696
REGIONAL DIFFERENCES IN SINOATRIAL NODE
Mackaay et al. (17) divided the rabbit sinoatrial node
into superior and inferior halves and observed that the
spontaneous activity of the inferior half was slower
than that of the superior half; this is consistent with
the data in Fig. 4F.
Physiological importance of downward gradient in
action potential duration along conduction pathway. As
stated in the introductory paragraphs, it appears to be
a general rule that there is a downward gradient in
action potential duration along the conduction pathway
in the heart, known examples being the atrial appendage versus the crista terminalis, the ventricular muscle
versus the Purkinje fibers, the ventricular subepicardium versus the ventricular subendocardium, and the
base versus the apex. The regional differences in action
potential duration in the sinoatrial node are another
example of this general rule. However, the gradient in
action potential duration in the sinoatrial node is
larger than that elsewhere in the heart. For example,
on going from the ventricular subendocardium to the
subepicardium there is an ,10% shortening of the
action potential (1), whereas Figs. 5 and 6B show that
on going from the sinoatrial node to the atrial muscle
there is a much greater shortening: in four preparations, there was a decrease in action potential duration
of 74 6 4% (on going from the site in the sinoatrial node
at which the action potential was longest to the site in
the crista terminalis at which the action potential was
shortest). A downward gradient in action potential
duration along the conduction pathway is expected to
help prevent reentry, and this is also expected to be the
case in the sinoatrial node. A possible example of this is
provided by Kirchhof and Allessie (12), who studied the
electrical activity of the sinoatrial node during atrial
fibrillation in rabbit hearts. They observed a minimal
degree of overdrive of the sinoatrial node (9%) during
atrial fibrillation, which they attributed to the longer
refractory period of the sinoatrial node than that of the
atrium. The longer refractory period of the sinoatrial
node must, in part at least, be the result of the longer
action potential in the sinoatrial node. The long action
potential in the sinoatrial node is not the only feature to
help prevent reentry; the block zone (see Nature of
conduction block on septal side of leading pacemaker
site) and slow conduction within the sinoatrial node
will also help. The long action potential in the sinoatrial node may have another purpose. There has been
much discussion about how the sinoatrial node may
drive the large mass of atrial muscle that surrounds it,
and various schemes have been proposed: a gradient in
electrical coupling at the boundary of the two tissues
(10), interdigitations of the two tissues at the boundary
(24), and the presence of Na1 channels in the periphery
of the sinoatrial node (27). The action potential can
take 20–40 ms to propagate out of the sinoatrial node
into the atrial muscle, and, because of the long action
potential in the center of the sinoatrial node, there will
always be an outwardly directed flow of depolarizing
current to facilitate propagation of the action potential.
At no point will the center of the sinoatrial node
repolarize and draw away the flow of depolarizing
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potential at first increased and then decreased (Fig.
3A). In the intact sinoatrial node, action potential
duration behaved in the same way near the leading
pacemaker site (Figs. 5 and 6B). Finally, action potential duration tended to be less in strand 1 (more
superior) than in strand 4 (more inferior) (Fig. 3B). In
the intact sinoatrial node the same change was observed on going from the superior part of the preparation to the leading pacemaker site.
The similar regional differences in maximum upstroke velocity, action potential peak, action potential
duration, and maximum diastolic potential in the small
balls of tissue and the intact sinoatrial node show that
the regional changes in these parameters in the intact
sinoatrial node must be the result of changes in the
intrinsic properties of the tissue rather than electrotonic influences. It could be argued that the changes in
action potential duration in the small balls of tissue
were the result of the differences in the rate of spontaneous activity in the different balls; however, this is
unlikely because similar regional differences in action
potential duration were observed in the intact sinoatrial node (in the intact sinoatrial node, the rate of
action potentials is of course the same for all regions).
Furthermore, similar regional differences in action
potential duration in the intact sinoatrial node were
observed during atrial stimulation at a constant rate
(Fig. 9C).
Figure 4, E and F, shows that, in the small ball-like
tissue preparations, cycle length tended to be greater in
both the center of the sinoatrial node compared with
the periphery (as has been reported before) and the
more inferior part of the sinoatrial node compared with
the more superior part. There are, of course, no regional
differences in cycle length in the intact sinoatrial node.
However, the regional differences in cycle length in the
small balls (Fig. 4, E and F) can be compared with the
regional differences in the slope of the pacemaker
potential (Fig. 7D). The two are different. The intrinsic
pacemaker activity of tissue from the periphery is
higher than that of tissue from the center (Fig. 4E).
However, in the intact sinoatrial node, the slope of the
pacemaker potential was less in the periphery than in
the center (Fig. 7D). This is explained by the suppression of the pacemaker potential in the periphery as a
result of the electrotonic influence of the atrial muscle
(see, e.g., Ref. 13). In the intact sinoatrial node, there
was no superior-inferior difference in the slope of the
pacemaker potential (Fig. 7D) equivalent to the superior-inferior difference in the cycle length (Fig. 4F). In
the intact sinoatrial node, it is possible that this
difference is masked by electrotonic effects. Regardless,
Fig. 4F shows that there tends to be a superior-inferior
difference in intrinsic pacemaker activity, and this may
be important for the phenomenon of pacemaker shift.
Pacemaker shift is a shift of the leading pacemaker site
in response to an intervention, and it almost invariably
involves a shift in the superior-inferior direction. Such
a shift could result from superior-inferior differences in
pacemaking (although there are other possible explanations such as regional differences in innervation).
REGIONAL DIFFERENCES IN SINOATRIAL NODE
has not been reported before, but it must contribute to
the conduction block.
Ionic mechanisms underlying regional differences in
electrical activity. Much is known of the peripherycenter differences. From the periphery to the center, it
has been proposed that 1) the decrease in maximum
diastolic potential is the result of a decrease in IK,r
density (15); 2) the decline in the maximum upstroke
velocity is the result of a decrease in INa density (7, 16);
and 3) the decrease in intrinsic spontaneous activity is
caused by a decrease in If density (7, 20), the switch
from INa to the L-type Ca21 current (ICa ) as the current
responsible for the action potential upstroke (16), and
the increase in action potential duration. The initial
increase in the action potential duration on going from
the periphery toward the center could be caused by a
decrease in the density of both Ito and IK,r (5, 15).
Little is known of the superior-inferior differences.
We previously showed (5) that the block of Ito by
4-aminopyridine causes a larger prolongation of the
action potential in the more inferior part of the sinoatrial node. A higher density of Ito in the inferior part of
the sinoatrial node, however, cannot explain the longer
action potential. We also showed (15) that partial block
of IK,r has greater effects on electrical activity of the
more inferior part of sinoatrial node than of the more
superior part. This suggests that the density of IK,r is
less in the more inferior part of the sinoatrial node, and
this could explain why the action potential is longer in
this region. The cause of the decrease in intrinsic
pacemaker activity (i.e., increase in cycle length) in the
more inferior part of the sinoatrial node is not known,
but it must in part be the result of the increase in action
potential duration.
The cause of the lack of excitability in the block zone
can be only speculated on, because there have been no
studies of such tissue. From the periphery to the center,
there is evidence for a decrease in the density of the
Na1 channel responsible for INa (7); this explains the
decrease in the upstroke velocity of the action potential
from the periphery to the center (16). We propose that
from the center to the block zone there is a decrease in
the density of the Ca21 channel responsible for ICa,
because this will explain the further decrease in the
action potential and, thus, cell excitability. This possibility is supported by computer modeling and preliminary
immunocytochemical data (Y. Takagishi, H. Zhang, H.
Honjo, M. R. Boyett, A. V. Holden and I. Kodama,
unpublished observations). In the inferior part of the
block zone (Fig. 8), the high resting potential suggests
the presence of inward rectifying K1 current. The
presence of inward rectifying K1 current (in the absence of INa ) is also expected to contribute to the
decrease in excitability.
Address for reprint requests: M. R. Boyett, Dept. of Physiology,
Univ. of Leeds, Leeds LS2 9JT, UK (E-mail: [email protected]).
Received 11 May 1998; accepted in final form 28 September 1998.
REFERENCES
1. Antzelevitch, C., S. H. Litovsky, and A. Lukas. Epicardium
versus endocardium: electrophysiology and pharmacology. In:
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
current from sites downstream, which would be expected to impede propagation. Furthermore, because of
the long action potential in the center of the sinoatrial
node, during the 20–40 ms it takes for the action
potential to propagate out of the sinoatrial node, inward current sources (e.g., L-type Ca21 channels) in the
center of the sinoatrial node are expected to be active
(i.e., not deactivated by repolarization) and thus an
important source of depolarizing current for propagation. Figure 6A shows that, as a result of the characteristic pattern of propagation from the leading pacemaker site in the sinoatrial node, the action potential
arrives at the atrial muscle on the crista terminalis as a
broad wave front. This may also have advantages for
the driving of the atrial muscle by the sinoatrial node,
because, if the action potential emerged into the atrial
muscle at a single point, the action potential could
perhaps be suppressed by the surrounding atrial muscle.
Nature of conduction block on septal side of leading
pacemaker site. Figure 6A illustrates the well-known
phenomenon of block of conduction from the leading
pacemaker site toward the atrial septum. Activation of
the atrial septum must await the spread of the action
potential around the upper and lower margins of the
block zone. The block zone is physiologically important
because it will be a further barrier to reentry by
preventing the invasion of the sinoatrial node from
action potentials from the direction of the atrial septum. The conduction block must be the result of poor
excitability of cells in the region or poor electrical
coupling between the cells. Bleeker et al. (4) found the
space constant of the block zone to be similar to that
elsewhere in the sinoatrial node and concluded that
conduction block is not the result of poor electrical
coupling. They suggested that it is the result of poor
excitability; when they prevented the action potential
from conducting around the block zone by cutting the
tissue superior and inferior to the block zone, the action
potential entering the block zone from the leading
pacemaker site gradually died out.
The results of the present study are consistent with
the possibility that the block is the result of poor
excitability. Figures 6 and 7 show that in this region the
maximum upstroke velocity is low, the action potential
peak is low, the maximum diastolic potential can be low
(although not necessarily so), and action potential
duration is less than maximum. All these features
reflect poor excitability and are expected to slow conduction. In the block zone, action potentials (albeit small
and slow) could be recorded, although they often had
two components as reported before (4) because of the
collision of two wave fronts (one directly from the
leading pacemaker site and the other around the
perimeter of the block zone). However, in three of four
preparations, a very marked loss of excitability was
seen in the block zone in the more inferior part of the
preparation. In this region, cells had high resting
potentials (e.g., 275 mV in Fig. 8B) and no action
potential (Fig. 8B) or a small, presumably passive
depolarization of the membrane (Fig. 8A). This region
H697
H698
2.
3.
4.
5.
7.
8.
9.
10.
11.
12.
13.
14.
Cardiac Electrophysiology. From Cell to Bedside, edited by D. P.
Zipes and J. Jalife. Philadelphia, PA: Saunders, 1990, p. 386–
395.
Antzelevitch, C., S. Sicouri, S. H. Litovsky, A. Lukas, S. C.
Krishnan, J. M. Di Diego, G. A. Gintant, and D.-W. Liu.
Heterogeneity within the ventricular wall. Electrophysiology
and pharmacology of epicardial, endocardial, and M cells. Circ.
Res. 69: 1427–1449, 1991.
Bleeker, W. K., A. J. C. Mackaay, M. Masson-Pevet, L. N.
Bouman, and A. E. Becker. Functional and morphological
organization of the rabbit sinus node. Circ. Res. 46: 11–22, 1980.
Bleeker, W. K., A. J. C. Mackaay, M. Masson-Pevet, T. Op’t
Hof, H. J. Jongsma, and L. N. Bouman. Asymmetry of the
sino-atrial conduction in the rabbit heart. J. Mol. Cell. Cardiol.
14: 633–643, 1982.
Boyett, M. R., H. Honjo, M. Yamamoto, R. Niwa, and I.
Kodama. Regional differences in effects of 4-aminopyridine
within the sinoatrial node. Am. J. Physiol. 275 (Heart Circ.
Physiol. 44): H1158–H1168, 1998.
Boyett, M. R., I. Kodama, R. Suzuki, and H. Honjo. A
4-aminopyridine-sensitive current controls action potential duration in the rabbit sinoatrial node (Abstract). J. Physiol. (Lond.)
497: 44P–45P, 1996.
Honjo, H., M. R. Boyett, I. Kodama, and J. Toyama. Correlation between electrical activity and the size of rabbit sinoatrial
node cells. J. Physiol. (Lond.) 496: 795–808, 1996.
Iwata, H., I. Kodama, R. Suzuki, K. Kamiya, and J. Toyama.
Effects of long-term oral administration of amiodarone on the
ventricular repolarization of rabbit hearts. Jpn. Circ. J. 60:
662–672, 1996.
Janse, M. J. The Effect of Changes in Heart Rate on the
Refractory Period of the Heart (PhD thesis). Amsterdam, The
Netherlands: University of Amsterdam, 1971.
Joyner, R. W., and F. J. L. van Capelle. Propagation through
electrically coupled cells: how a small SA node drives a large
atrium. Biophys. J. 50: 1157–1164, 1986.
Kentish, J. C., and M. R. Boyett. A simple electronic circuit for
monitoring changes in the duration of the action potential.
Pflügers Arch. 398: 233–235, 1983.
Kirchhof, C. J. H. J., and M. A. Allessie. Sinus node automaticity during atrial fibrillation in isolated rabbit hearts. Circulation
86: 263–271, 1992.
Kirchhof, C. J. H. J., F. I. M. Bonke, M. A. Allessie, and
W. J. E. P. Lammers. The influence of the atrial myocardium on
impulse formation in the rabbit sinus node. Pflügers Arch. 410:
198–203, 1987.
Kodama, I., and M. R. Boyett. Regional differences in the
electrical activity of the rabbit sinus node. Pflügers Arch. 404:
214–226, 1985.
15. Kodama, I., M. R. Boyett, M. R. Nikmaram, M. Yamamoto,
H. Honjo, and R. Niwa. Regional differences in the effects of
E-4031 within the sinoatrial node. Am. J. Physiol. In press.
16. Kodama, I., M. R. Nikmaram, M. R. Boyett, R. Suzuki, H.
Honjo, and J. M. Owen. Regional differences in the role of the
Ca21 and Na1 currents in pacemaker activity in the sinoatrial
node. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2793–
H2806, 1997.
17. Mackaay, A. J. C., T. Op’t Hof, W. K. Bleeker, H. J. Jongsma,
and L. N. Bouman. Interaction of adrenaline and acetylcholine
on cardiac pacemaker function. Functional inhomogeneity of the
rabbit sinus node. J. Pharmacol. Exp. Ther. 214: 417–422, 1980.
18. Masson-Pévet, M. A., W. K. Bleeker, E. Besselsen, B. W.
Treytel, H. J. Jongsma, and L. N. Bouman. Pacemaker cell
types in the rabbit sinus node: a correlative ultrastructural and
electrophysiological study. J. Mol. Cell. Cardiol. 16: 53–63, 1984.
19. Moore, E. N., J. B. Preston, and G. K. Moe. Durations of
transmembrane action potentials and functional refractory periods of canine false tendon and ventricular myocardium. Circ.
Res. 17: 259, 1965.
20. Nikmaram, M. R., M. R. Boyett, I. Kodama, R. Suzuki, and
H. Honjo. Variation in effects of Cs1, UL-FS-49, and ZD-7288
within sinoatrial node. Am. J. Physiol. 272 (Heart Circ. Physiol.
41): H2782–H2792, 1997.
21. Opthof, T. The mammalian sinoatrial node. Cardiovasc. Drugs
Ther. 1: 573–597, 1988.
22. Opthof, T., B. de Jonge, H. J. Jongsma, and L. N. Bouman.
Functional morphology of the pig sinoatrial node. J. Mol. Cell.
Cardiol. 19: 1221–1236, 1987.
23. Opthof, T., B. de Jonge, M. Masson-Pevet, H. J. Jongsma,
and L. N. Bouman. Functional and morphological organization
of the cat sinoatrial node. J. Mol. Cell. Cardiol. 18: 1015–1031,
1986.
24. Winslow, R. L., and H. J. Jongsma. Role of tissue geometry
and spatial localization of gap junctions in generation of the
pacemaker potential (Abstract). J. Physiol. (Lond.) 487: 126P,
1995.
25. Winslow, R. L., A. L. Kimball, A. Varghese, and D. Noble.
Simulating cardiac sinus and atrial network dynamics on the
Connection Machine. Physica D 3: 281–298, 1993.
26. Yamashita, T., T. Nakajima, H. Hazama, E. Hamada, Y.
Murakawa, K. Sawada, and M. Omata. Regional differences
in transient outward current density and inhomogeneities of
repolarization in rabbit right atrium. Circulation 92: 3061–3069,
1995.
27. Zhang, H., M. R. Boyett, A. V. Holden, H. Honjo, and I.
Kodama. Evidence that the Na1 current, INa, in the periphery of
the sinoatrial node helps the node to drive the surrounding atrial
muscle (Abstract). J. Physiol (Lond.) 506: 54P, 1998.
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REGIONAL DIFFERENCES IN SINOATRIAL NODE