Vol. 276, Issue 2, H686-H698, February 1999
Downward gradient in action potential duration along
conduction path in and around the sinoatrial node
M. R.
Boyett1,
H.
Honjo2,
M.
Yamamoto2,
M. R.
Nikmaram3,
R.
Niwa2, and
I.
Kodama2
1 Department of Physiology,
University of Leeds, Leeds LS2 9JT, United Kingdom;
2 Research Institute of
Environmental Medicine, Nagoya University, Nagoya 464-01, Japan;
and 3 Department of Physiology,
Iran University of Medical Sciences, Tehran, Iran
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ABSTRACT |
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 ± 4% (mean ± SE, n = 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 ± 13 ms
(n = 6) to 483 ± 13 ms
(n = 6) in transitional tissue from
more superior and inferior sites], and this may help explain
pacemaker shift.
heart; cardiac; pacemaking
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INTRODUCTION |
THE SINOATRIAL NODE 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,
Na+ current
(INa) transient
outward K+ current
(Ito), delayed
rectifier K+ current
(IK,r), and
hyperpolarization-activated current
(If) (6, 7, 15,
20). The regional differences in 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 terminalis 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.
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MATERIALS AND METHODS |
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 × 15 mm, which 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 Krebs-Ringer 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.
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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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At the start of an experiment an accurate drawing of the preparation
was made (see, e.g., Fig. 6) using a fine probe held 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 M
;
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 (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
K+ 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 ± 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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RESULTS |
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 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.
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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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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).
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).
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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 ± SE are plotted.
Ball 1A:
n = 4; ball
4D: n = 5; other
balls: n = 6-9.
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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 ± SE are plotted.
Ball 1A:
n = 2-3; ball
4D: n = 4-6;
other balls: n = 5-9.
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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 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 = 0.007; strand
2, P = 0.047;
strand 3,
P = 0.021; strand
4, P = 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 = 0.014; ball
B, P = 0.003;
ball C,
P = 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 = 0.01; strand
3, P = 0.005;
strand 4,
P = 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 = 0.006; strand
2, P < 0.001;
strand 3,
P = 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 = 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 = 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 = 0.018; strand
4, P = 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 = 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 ~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.
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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.
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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 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 ± 18 ms and the minimum action potential in the crista terminalis
was 43 ± 3 ms; this corresponds to a decrease in action potential
duration of 74 ± 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.
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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,  shows position
of reference modified bipolar electrodes (see
MATERIALS AND METHODS).
Repolarization time is time taken for a site to repolarize to  30
mV after action potential was first initiated at leading pacemaker
site; it was calculated as sum of activation time and action potential
duration.
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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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|
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 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
(4 to +1 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 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 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.
View larger version (15K):
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|
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.
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|
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 75 mV. In the three preparations
in which depolarizations with amplitudes of <25 mV or stable resting
potentials were recorded, the maximum diastolic potential was 67 ± 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 preparations). 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 concluded that the activation
sequence in the short term does not control action potential duration.
View larger version (29K):
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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 in
A. Throughout experiment, 0.6 µM
propranolol and 2 µM atropine were present to block effects of
released neurotransmitters.
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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-to-inferior 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 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).
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 ± 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 Na+ 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 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 Ca2+ 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., 75 mV in Fig.
8B) and no action potential (Fig.
8B) or a small, presumably passive
depolarization of the membrane (Fig.
8A). This region 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 periphery-center 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
Ca2+ 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 Na+ 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
Ca2+ 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
K+ current. The presence of inward
rectifying K+ current (in the
absence of INa)
is also expected to contribute to the decrease in excitability.
| |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: M. R. Boyett, Dept. of Physiology,
Univ. of Leeds, Leeds LS2 9JT, UK (E-mail: m.r.boyett{at}leeds.ac.uk).
Received 11 May 1998; accepted in final form 28 September 1998.
| |
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Copyright © 1999 the American Physiological Society
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Abstract
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