Vol. 273, Issue 4, H1800-H1806, October 1997
Parasympathetic inhibition of sympathetic effects on
atrioventricular conduction in anesthetized dogs
Yuji
Hoyano,
Yasuyuki
Furukawa,
Miho
Kasama, and
Shigetoshi
Chiba
Department of Pharmacology, Shinshu University School of Medicine,
Matsumoto 390, Japan
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ABSTRACT |
To investigate
the selective parasympathetic control of atrioventricular (AV)
conduction during sympathetic activation, we studied the effects of
cervical vagus nerve stimulation on the positive dromotropic responses
to sympathetic interventions before and after surgical dissection of
dual fatty tissues at the junction of the inferior vena cava and
inferior left atrium and at the right atrial side of the atrial
junctions of the right pulmonary veins in open-chest anesthetized dogs.
In atrial-paced hearts, vagus stimulation at low frequencies prolonged
atrio-His (A-H) interval and at high frequencies induced second- and
third-degree AV blocks. Vagus stimulation additively prolonged A-H
interval shortened by stimulation of the ansae subclaviae or
isoproterenol infusion. After dissection of dual fatty tissues, vagus
stimulation prolonged A-H interval by only 7%. However, during
sympathetic stimulation but not during isoproterenol infusion, vagus
stimulation prolonged the shortened A-H interval. Atropine abolished
the responses to vagus stimulation. These results suggest that even
during sympathetic activation, regional vagus inputs selectively
control A-H interval, and even after denervation of the regional
parasympathetic nerves, presynaptic parasympathetic inhibition of the
positive cardiac responses to sympathetic activation works in the heart
in situ.
atrioventricular node; autonomic nervous system; sinus node; sympathetic-parasympathetic interaction; intracardiac parasympathetic
nerve
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INTRODUCTION |
CARDIAC FUNCTION is regulated by tonic activity of the
sympathetic and parasympathetic nervous systems, i.e., activation of the sympathetic nerves normally facilitates cardiac function, whereas
activation of the parasympathetic nerves inhibits it. Parasympathetic
nerve stimulation decreases heart rate more in the presence of tonic
sympathetic nerve stimulation than in its absence (15, 19, 25). On the
other hand, the sympathetic-parasympathetic interactions in
atrioventricular (AV) conductivity observed in previous studies were
not consistent. In some studies in anesthetized dogs, the increase in
AV conduction time in response to vagus stimulation was not influenced
by sympathetic nerve stimulation (15, 24). In other studies, however,
vagus nerve stimulation during sympathetic stimulation produced either
a greater increase in AV conduction time in anesthetized dogs (20) or a
smaller increase in AV conduction time in anesthetized puppies (23). Thus the sympathetic-parasympathetic interactions in the AV
conductivity are different from those of the sinoatrial (SA) nodal
pacemaker activity.
The parasympathetic neural elements included in cardiac intrinsic
ganglionated plexus in the fatty tissue overlying the right atrial side
of the atrial junction of the right pulmonary veins mediate nearly all
parasympathetic control of sinus rate (1, 8, 16). Additionally, it is
well recognized that parasympathetic neural elements included in
cardiac intrinsic ganglionated plexus in the fatty tissue at the
junction of the inferior vena cava and inferior left atrium control AV
conduction (1, 8, 16). We refer to the former and latter
parasympathetic neural elements as the sinus rate-related
parasympathetic nerves (SRRPN) and the AV conduction-related
parasympathetic nerves (AVCRPN), respectively. Therefore, we refer to
surgical dissection of the right pulmonary vein fatty tissue including
SRRPN as SRRPN denervation and dissection of the inferior vena
cava-inferior left atrial fatty tissue including AVCRPN as AVCRPN
denervation, although these fatty tissues contain multiple neuronal
types in addition to the parasympathetic postganglionic nerves (10,
26). We recently observed that after SRRPN denervation, cervical vagus
stimulation did not decrease sinus rate itself but decreased the sinus
rate increased by infusion of isoproterenol in anesthetized dogs and
suggested that a small number of vagus nerves to the SA nodal area
different from the SRRPN decrease the sinus rate increased by
adrenergic interventions in the dog heart in situ (4). In the present
study, therefore, we investigated whether cervical nerve stimulation
after AVCRPN denervation also prolonged the AV conduction time
shortened by sympathetic interventions as does cervical vagus
stimulation on sinus rate in anesthetized dogs.
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MATERIALS AND METHODS |
Preparation.
Eleven mongrel dogs (10-19 kg body wt) were anesthetized with
pentobarbital sodium (30 mg/kg iv); supplemental doses of pentobarbital sodium were given as necessary to maintain stable anesthesia. A
tracheal cannula was inserted, and intermittent positive-pressure ventilation (tidal volume 20 ml/kg; frequency 14 strokes/min) was
started. The chest was opened transversely at the fifth intercostal space. Each cervical vagus nerve was crushed with a tight ligature, and
each stellate ganglion was ligated tightly at its junction with the
ansa subclavia. These maneuvers remove almost all tonic neural activity
to the heart (14).
Two bipolar electrodes were placed on the base of the epicardial
surface of the right atrial appendage to record the electrical activity
and to pace the atrium electrically. Atrial rate was derived from the
atrial electrogram with a tachometer (model AT-600G, Nihon Kohden,
Tokyo, Japan). A bipolar electrode catheter was inserted via the right
femoral artery and positioned in the noncoronary cusp of the aortic
valve to record His bundle electrical activity. The His bundle
electrogram was filtered with a band pass of 30-300 Hz (model
AP621G, Nihon Kohden). The electrograms were recorded on the
oscillograph (model RTA1200, Nihon Kohden) at paper speeds of 100 mm/s.
In these electrograms, the interval between the atrial deflection and
the His bundle deflection was determined as the atrio-His (A-H)
interval. Atrial rate and femoral arterial blood pressure were also
recorded on the oscillograph.
To stimulate cervical vagus nerves, two copper wire electrodes were
placed in each cardiac side of the cervical vagus complexes at the
crushed region and connected in parallel to an electrical stimulator
(model SEN7103, Nihon Kohden). The cervical vagus nerve fibers were
stimulated with a pulse amplitude of 10 V with 
0.03-ms pulse duration
and frequencies of 2, 5, 10, and 30 Hz or 1-ms duration and 30 Hz for
30 s. To stimulate bilateral efferent sympathetic nerve fibers, two
bipolar hook electrodes were placed on both sides of the ansa subclavia
and connected to an electrical stimulator (model SEN7103, Nihon
Kohden).
We removed the fatty tissue, including the intracardiac parasympathetic
neural elements, at the junction of the inferior vena cava and inferior
left atrium by careful trimming of the fatty tissue using a thermoknife
and 10% phenol (4). We refer to this procedure as AVCRPN denervation.
Cervical vagus stimulation with 1 ms, 10 V, and 30 Hz caused complete
AV block. Thus we thought that the AVCRPN were denervated almost
totally when cervical vagus stimulation with 1 ms, 10 V, and 30 Hz
hardly increased A-H interval (increases of <20 ms). We also removed
the fatty tissue, including the intracardiac parasympathetic neural
elements to the SA nodal area overlying the right atrial side of the
atrial junctions of the right pulmonary veins, because some of these
neural elements affect the negative dromotropic response to cervical
vagus stimulation (7, 8). We refer to this procedure as SRRPN
denervation. Thus we studied the dromotropic or chronotropic effects of
cervical vagus nerve stimulation before and after denervation of both
AVCRPN and SRRPN.
Protocols.
We investigated the effects of cervical vagus nerve stimulation, before
and after AVCRPN and SRRPN denervation, on the decrease in A-H interval
in response to sympathetic interventions in the atrial-paced heart of
the open-chest anesthetized dog and the effects of cervical vagus
stimulation on the increase in sinus rate in response to sympathetic
interventions in the unpaced heart of the open-chest dog.
First, we studied the effects of cervical vagus stimulation on the
decrease in A-H interval in response to sympathetic nerve stimulation
(n = 6) or isoproterenol infusion
(n = 6) before and after AVCRPN and
SRRPN denervation in the atrial-paced heart of open-chest anesthetized
dogs. To determine the A-H interval, the heart rate was held by
electrical atrial pacing. The right atrium was paced with 4 V and 1-ms
pulse duration at a rate of ~150 beats/min that was 40 beats/min
above intrinsic sinus rate but maintained 1:1 AV transmission without
Wenckebach-type AV block. Before denervation, we determined the effects
of cervical vagus stimulation on A-H interval in the absence or
presence of sympathetic nerve stimulation or isoproterenol infusion in
the atrial-paced heart as the vagus stimulation level was changed by
increasing the stimulation frequencies from 2 to 5, 10, and 30 Hz with
10 V and 0.03-ms pulse duration and by prolongation of the
stimulation pulse duration from 0.03 to 1 ms with 10 V and 30 Hz
(Fig. 1). The stimulation with 1 ms and 10 V at 30 Hz caused complete AV block. To confirm whether the sympathetic
interventions could cause similar cardiac effects before and after
denervation, we determined the increase in sinus rate in response to
sympathetic nerve stimulation in unpaced hearts. We stimulated the
cardiac sympathetic nerves with 10-12 V, 1 ms, and 2 Hz for 6 min,
and this stimulation increased the sinus rate ~70 beats/min. We also
determined the infusion rate of isoproterenol (0.2-0.4
µg · kg
1 · min1)
that similarly increased sinus rate 70 beats/min. While the right
atrium was paced at a rate of 220 beats/min, we determined the effects
of cervical vagus stimulation on A-H interval. After each sympathetic
intervention, at least 15 min were needed for recovery. Twenty minutes
after AVCRPN and SRRPN denervation, we had confirmed the minimum
response to cervical vagus stimulation with 1 ms, 10 V, and 30 Hz, and
we then studied the effects of cervical vagus stimulation on the
positive dromotropic response to sympathetic interventions. Nerve
stimulation and isoproterenol infusion with the same conditions were
repeated before and after denervation.
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Fig. 1.
Experimental protocol. We first determined changes in atrio-His (A-H)
interval in response to stimulation of cervical vagus nerves (Vagus
Stim; A) with 0.03-ms pulse
duration and 10-V amplitude at a frequency of 2, 5, 10, or 30 Hz and
with 1-ms duration and 10-V amplitude at a frequency of 30 Hz for 30 s
with a 30-s interval under electrical atrial pacing. We then tested
effects of sympathetic interventions (hatched areas), i.e., sympathetic
stimulation (Sym Stim; B) and
isoproterenol infusion (C) on
negative dromotropic responses to cervical vagus stimulation under
atrial pacing. We repeated experiment after both sinus rate- and
atrioventricular conduction-related parasympathetic nerve (SRRPN and
AVCRPN, respectively) denervation. Freq, frequency.
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In six animals, we tested the effects of atropine at a intravenous dose
of 0.2 mg/kg on the negative dromotropic responses to cervical vagus
stimulation during sympathetic intervention after AVCRPN and SRRPN were
denervated. Two minutes after atropine treatment, the effects of
cervical vagus stimulation on the responses to sympathetic intervention
were determined again.
In the second series of experiments, we investigated the effects of
cervical vagus stimulation on increases in sinus rate in response to
sympathetic nerve stimulation or isoproterenol infusion before and
after SRRPN and AVCRPN denervation in open-chest anesthetized dog
hearts. In these experiments, we also removed dual fatty tissues at the
right atrial side of the atrial junctions of the right pulmonary veins
and at the junction of the inferior vena cava and inferior left atrium.
First, we determined the changes in sinus rate in response to cervical
vagus stimulation as the stimulation level was changed by increasing
the stimulation frequencies from 2 to 30 Hz with 10 V and 0.03-ms
pulse duration and by prolongation of the stimulation pulse duration
from 0.03 to 1 ms with 10 V and 30 Hz. We then studied the effects of
cervical vagus stimulation on the positive chronotropic response to
stimulation of the ansae subclaviae or isoproterenol infusion. We
determined the level of sympathetic nerve stimulation or of infusion
rate of isoproterenol that is required to increase sinus rate by ~70
beats/min (to 200 beats/min or greater) before the start of the
experiment. The sympathetic nerves were stimulated with 2 Hz, 1-ms
pulse duration, and 10-12 V for 5 min. Isoproterenol was infused
at a rate of 0.2-0.4
µg · kg1 · min1
for 7 min. After each sympathetic intervention, at least 15 min of
recovery time were needed. When we clearly observed an increase in
sinus rate after cessation of cervical vagus stimulation, we stopped
further experiments. Twenty minutes after SRRPN and AVCRPN denervation,
we had confirmed the minimum response to cervical vagus stimulation
with 1 ms, 10 V, and 30 Hz, and we then studied the effects of cervical
vagus stimulation on the positive chronotropic responses to sympathetic
stimulation and isoproterenol infusion in SRRPN- and AVCRPN-denervated
hearts. Nerve stimulation and isoproterenol infusion with the same
conditions were repeated before and after SRRPN and AVCRPN denervation.
Statistical analysis.
All data are expressed as means ± SE, and the averages are for each
animal. We analyzed the absolute changes in A-H interval and rate in
response to interventions except where mentioned. Analysis
of variance with Bonferroni's test was used for the statistical analysis of multiple comparisons of data.
P values <0.05 were considered
statistically significant.
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RESULTS |
Cervical vagus stimulation before and after denervation of AVCRPN
and SRRPN.
Before removal of the fatty tissue at the junction of the inferior vena
cava and inferior left atrium including the intracardiac parasympathetic neural elements to the AV nodal region, i.e., AVCRPN,
and of the fatty tissue overlying the right atrial side of the atrial
junction of the right pulmonary veins including the intracardiac
parasympathetic neural elements to the SA nodal region, i.e., SRRPN,
cervical vagus nerve stimulation prolonged A-H interval in the
anesthetized dog hearts paced electrically (147 ± 9.5 beats/min)
(Fig. 2). Vagus stimulation at frequencies of 2 and 5 Hz with 0.01- to 0.03-ms pulse duration and 10-V amplitude prolonged A-H interval, and at 10 and 30 Hz it caused second- and
third-degree AV blocks (Fig. 2). When the level of stimulation was
increased to 1-ms duration at 30 Hz, vagus stimulation caused a
complete AV block. After careful denervation of the AVCRPN and SRRPN,
vagus stimulation prolonged A-H interval by only 8 ± 4.5 ms at 30 Hz with 0.01- to 0.03-ms pulse duration. Even when the level of the
vagus stimulation was increased by the prolongation of the stimulation
pulse duration to 1 ms at 30 Hz, vagus stimulation did not prolong A-H
interval (Fig. 2).
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Fig. 2.
Changes in A-H interval in response to cervical vagus nerve stimulation
before ( ) and after ( ) denervation of both SRRPN and AVCRPN in 6 open-chest anesthetized dog hearts under atrial pacing. Vertical bars,
SE. Dashed line, basal A-H interval (mean 101 ms). Cervical vagus
nerves were stimulated at frequencies of 2 (v2), 5 (v5), 10 (v10), and
30 Hz (v30) with 0.03-ms pulse duration and 30 Hz with 1-ms pulse
duration (vh) for 30 s. Pulse amplitude of stimulation was 10 V. Cont,
control.
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Before AVCRPN and SRRPN denervation, cardiac sympathetic nerve
stimulation and isoproterenol infusion similarly increased sinus rate
and decreased A-H interval in six unpaced hearts of anesthetized dogs
(Table 1). After denervation, sympathetic
stimulation and isoproterenol infusion increased sinus rate similarly
to stimulation before denervation. However, the decrease in A-H
interval induced by sympathetic stimulation was less than that by
isoproterenol infusion in denervated hearts and less than the decreases
in A-H interval induced by sympathetic interventions in intracardiac parasympathetic nerve-intact hearts.
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Table 1.
Cardiac values before and during sympathetic nerve stimulation or
isoproterenol infusion in AVCRPN- and SRRPN-intact and -denervated,
unpaced dog hearts
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Before and after AVCRPN and SRRPN denervation, resting A-H intervals
were not significantly different in six atrial-paced hearts of
autonomically decentralized, open-chest anesthetized dogs (Table 1).
The A-H intervals during sympathetic interventions in atrial-paced
hearts were not significantly different before and after denervation
(Table 2).
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Table 2.
AHI and HVI before and during sympathetic nerve stimulation or
isoproterenol infusion in AVCRPN- and SRRPN-intact and -denervated,
electrically paced dog hearts
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Parasympathetic inhibition of positive dromotropic responses to
sympathetic interventions before and after denervation of AVCRPN and
SRRPN.
Stimulation of the right and left ansae subclaviae decreased A-H
interval before and after AVCRPN and SRRPN denervation. However, the
positive dromotropic response to sympathetic nerve stimulation after
denervation was smaller (P < 0.05) than that before
denervation (Table 1).
During sympathetic nerve stimulation or isoproterenol infusion,
cervical vagus stimulation at 2 and 5 Hz with 0.03-ms pulse duration
and 10-V amplitude prolonged A-H interval, and at 10 and 30 Hz it
caused second- or third-degree AV block when AVCRPN and SRRPN were
intact (Figs. 3 and
4). The increases in A-H interval in
response to vagus stimulation during sympathetic interventions were not
significantly different from those in response to vagus stimulation
alone in intracardiac parasympathetic nerve-intact hearts of open-chest
anesthetized dogs (Fig. 4).
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Fig. 3.
Effects of cervical vagus stimulation at 5 different levels on positive
dromotropic responses to sympathetic nerve stimulation
(A) and isoproterenol infusion
(B) before () and after ()
denervation of SRRPN and AVCRPN in 6 open-chest anesthetized dog hearts
under atrial pacing. Vertical bars, SE. Dashed line, basal A-H interval
(mean 101 ms). Pulse amplitude of stimulation was 10 V.
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Fig. 4.
Effects of cervical vagus stimulation at 5 different levels on basal
A-H interval (), positive dromotropic responses to sympathetic nerve
stimulation ( ), and isoproterenol infusion ( ) before
(A) and after
(B) denervation of SRRPN and AVCRPN
in 6 open-chest anesthetized dog hearts under atrial pacing. Values are
percentage of A-H interval just before cervical vagus stimulation.
Vertical bars, SE. Pulse amplitude of stimulation was 10 V.
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After AVCRPN and SRRPN denervation, during sympathetic nerve
stimulation, cervical vagus stimulation prolonged A-H interval slightly
but significantly (P < 0.001); vagus
stimulation at 30 Hz significantly (P < 0.05) prolonged A-H interval during sympathetic stimulation (Figs.
3 and 4). On the other hand, however, during isoproterenol infusion
vagus stimulation did not prolong A-H interval significantly (Fig. 4).
The negative dromotropic response to vagus stimulation during
sympathetic stimulation was abolished by atropine at an intravenous
dose of 0.2 mg/kg in the atrial-paced heart (Fig.
5).
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Fig. 5.
Effects of atropine (0.2 mg/kg iv) on negative dromotropic responses to
cervical vagus stimulation during sympathetic nerve stimulation in 6 anesthetized dog hearts after both SRRPN and AVCRPN were removed.
Values are percent changes from level just before cervical vagus
stimulation. Vertical bars, SE. Cervical nerves were stimulated with 30 Hz, 1 ms, and 10 V.
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Parasympathetic inhibition of positive chronotropic responses to
sympathetic interventions in unpaced heart before and after SRRPN and
AVCRPN denervation.
Before and after SRRPN and AVCRPN denervation, sympathetic nerve
stimulation and isoproterenol infusion increased sinus rate similarly
in five unpaced hearts of open-chest anesthetized dogs (Table
3). Cervical vagus nerve stimulation
decreased sinus rate itself and sinus rate during sympathetic
interventions in a stimulation frequency-dependent manner (data not
shown). The decreases in sinus rate induced by vagus stimulation were
similar in the presence of sympathetic nerve stimulation or
isoproterenol infusion.
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Table 3.
Sinus rate before and during sympathetic nerve stimulation and
isoproterenol infusion in five SRRPN- and AVCRPN-intact and
-denervated dog hearts
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After SRRPN and AVCRPN denervation, vagus stimulation hardly decreased
sinus rate itself but attenuated the positive chronotropic response to
sympathetic stimulation and to isoproterenol infusion as we previously
reported (4). The inhibition by vagus stimulation of the positive
chronotropic response to sympathetic stimulation was greater
(P < 0.01) than that of the positive
chronotropic response to isoproterenol infusion.
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DISCUSSION |
In the dog heart, stimulation of the intracardiac parasympathetic
neural elements at the fatty tissue at the junction of the inferior
vena cava and inferior left atrium selectively prolongs AV conduction
time (6, 8), and denervation of the regional parasympathetic nerves
(AVCRPN) eliminates the prolongation of AV conduction time induced by
cervical vagus stimulation (1, 16). Stimulation of the intracardiac
parasympathetic neural elements at the fatty tissue overlying the
atrial junctions of the right pulmonary veins selectively decreases
sinus rate (6, 8), and denervation of the regional parasympathetic
nerves (SRRPN) eliminates the decrease in sinus rate in response to
cervical vagus stimulation (1, 16). Thus activation of AVCRPN and SRRPN
prolongs AV conduction time and decreases sinus rate, respectively.
In the present study, we demonstrated that after denervation of AVCRPN
and SRRPN, cervical vagus stimulation hardly prolonged A-H interval
itself or the A-H interval decreased by isoproterenol infusion in the
atrial-paced heart. However, vagus stimulation at a high stimulation
frequency, but not at low frequencies, prolonged the A-H interval
slightly but significantly when sympathetic stimulation shortened A-H
interval in the AVCRPN- and SRRPN-denervated hearts. These results
suggest that the negative dromotropic response to cervical vagus
stimulation is mediated almost totally by AVCRPN at rest and during
sympathetic activity in the heart in situ and that, in addition to the
postsynaptic parasympathetic inhibition of the sympathetic effects,
presynaptic parasympathetic inhibition works functionally although the
parasympathetic inhibition threshold for postsynaptic inhibition is
much lower than that for presynaptic inhibition.
AVCRPN denervation.
To elucidate the role of the AVCRPN on AV conduction when sympathetic
nerves are activated, we investigated the effects of cervical vagus
stimulation on A-H interval during sympathetic interventions, i.e.,
sympathetic nerve stimulation and isoproterenol infusion, before and
after AVCRPN and SRRPN denervation in the dog heart. To complete the
denervation of AVCRPN, we removed the fatty tissue at the junction of
the inferior vena cava and lower left atrium by using a thermoknife
with phenol. We considered that denervation had been completed when
cervical vagus nerve stimulation did not increase A-H interval 
20 ms,
although the same vagus stimulation caused complete AV block before
denervation. To elucidate the effects of the denervation procedures on
the responses to sympathetic interventions, we compared the changes in
sinus rate and in A-H interval in response to sympathetic interventions before and after denervation in spontaneously beating hearts. The
decrease in A-H interval in response to sympathetic stimulation after
AVCRPN and SRRPN denervation was less than that before the denervation,
although the decrease in A-H interval induced by isoproterenol and the
increase in sinus rate induced by sympathetic interventions were not
different before and after AVCRPN and SRRPN denervation (Table 1).
These results indicate that the AVCRPN denervation procedure removes
not only AVCRPN but also some of the sympathetic nerves to the AV nodal
region in the dog heart. The ventrolateral cardiac nerve is distributed
to the inferior atrial, AV junctional, and ventricular tissues, and its
stimulation causes shortening of AV conduction time and an induction of
AV junctional rhythm (9, 17, 18). Stimulation of AVCRPN decreases AV
conduction time and induces an AV junctional rhythm in atropine-treated anesthetized dogs (5, 21). Thus our denervation procedure allows us to
analyze the data of the sympathetic-parasympathetic interactions on AV
conduction before and after AVCRPN and SRRPN denervation qualitatively
but not quantitatively.
Sympathetic-parasympathetic interactions on AV conduction and sinus
rate.
In intracardiac parasympathetic nerve-intact hearts, vagus nerve
stimulation decreases sinus rate more in the presence than in the
absence of tonic sympathetic interventions in anesthetized dogs as
shown previously (4, 15, 19, 25), whereas the increase in AV conduction
time in response to vagus nerve stimulation was not significantly
influenced by sympathetic nerve stimulation (Figs. 3 and 4) as
previously reported (15, 24). On the other hand, after AVCRPN and SRRPN
denervation, vagus stimulation did not prolong A-H interval during
isoproterenol infusion, whereas it decreased sinus rate during
isoproterenol infusion. These results suggest that, although a very
small number of intracardiac parasympathetic neural elements might
exist after AVCRPN and SRRPN denervation, the denervation of
AVCRPN and SRRPN abolished the dromotropic effects of vagus stimulation
in the dog heart and that the AVCRPN almost totally mediate the
negative dromotropic response to cervical vagus stimulation in the
presence as well as the absence of adrenergic stimulation. However,
stimulation of a small number of parasympathetic neural elements
probably decreased sinus rate increased by isoproterenol because of the
parasympathetic inhibition of the sympathomimetic effects on sinus rate
at the postsynaptic site (4), suggesting that the parasympathetic
neural regulation of sinus rate and AV conduction is different and that
complex interactions exist in the heart.
After AVCRPN and SRRPN denervation, during sympathetic stimulation,
cervical vagus stimulation at a high frequency (30 Hz) increased A-H
interval slightly but significantly, but at low frequencies it did not
(Fig. 4). These results together with the lack of prolongation of the
A-H interval in response to vagus stimulation during isoproterenol
infusion suggest that presynaptic parasympathetic inhibition works
functionally, although the parasympathetic inhibition threshold for
postsynaptic inhibition is lower than that for presynaptic inhibition
in the heart in situ. Parasympathetic ganglionic cells as well as
postsynaptic parasympathetic nerve fibers exist in the fatty tissues at
the junction of the inferior vena cava and lower left atrium and at the
right atrial junctions of the right pulmonary veins (3, 6, 16). Because
we might have removed those neural elements, including parasympathetic ganglionic cells, the prolongation of A-H interval by vagus stimulation during sympathetic stimulation observed in the present study would be
induced at the site proximal to these parasympathetic ganglia. It is
well known that sympathetic-parasympathetic interactions on the heart
are evoked at both the presynaptic and postsynaptic sites (12, 13).
Sympathetic-parasympathetic interaction at the presynaptic site
involves interactions between the terminal postganglionic vagal and
sympathetic fibers, which often lie in close apposition to each other
in the heart (2, 11, 13). Therefore, it is likely that intraneuronal
mechanisms for sympathetic-parasympathetic interactions may partially
be an extracardiac neural interaction in addition to an intracardiac
neural interaction in the dog heart. However, it has been reported that
there are several intrinsic cardiac ganglionated plexuses other than
those we have removed, including not only cholinergic neurons but also
catecholamine-sensitive and/or -producing neurons and others
(10, 26). Thus we cannot rule out the possibility of the participation
of other innervation, from nerves that do not pass through the
intrinsic cardiac ganglia we have removed, in presynaptic inhibition of
the positive dromotropic response to sympathetic nerve activation.
We confirmed that in the SRRPN- and AVCRPN-denervated heart of the
anesthetized dog, cervical vagus stimulation hardly decreased sinus
rate, but it depressed the sinus rate increased by isoproterenol as
well as by sympathetic stimulation as previously reported (4). SRRPN
stimulation during sympathetic nerve stimulation decreases sinus rate
more than SRRPN stimulation alone in the anesthetized dog heart (22).
On the other hand, vagus stimulation after AVCRPN and SRRPN denervation
did not affect the A-H interval during isoproterenol infusion
significantly (Figs. 3 and 4). Thus the postsynaptic inhibition by
vagus stimulation of sinus rate would be more complex than that of AV
conduction in the dog heart in situ.
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FOOTNOTES |
Address for reprint requests: Y. Furukawa, Dept. of Pharmacology,
Shinshu Univ. School of Medicine, Matsumoto 390, Japan.
Received 16 September 1996; accepted in final form 12 June 1997.
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AJP Heart Circ Physiol 273(4):H1800-H1806
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Abstract
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