Vol. 283, Issue 6, H2687-H2691, December 2002
Disruption of vagal efferent axon and nerve terminal function
in the postischemic myocardium
Toru
Kawada1,
Toji
Yamazaki2,
Tsuyoshi
Akiyama2,
Hidezo
Mori2,
Kazunori
Uemura1,
Tadayoshi
Miyamoto1,
Masaru
Sugimachi1, and
Kenji
Sunagawa1
1 Departments of Cardiovascular Dynamics and
2 Cardiac Physiology, National Cardiovascular Center
Research Institute, Osaka 565 - 8565, Japan
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ABSTRACT |
Despite the importance of vagal
control over the ventricle, little is known regarding vagal
efferent conduction and nerve terminal function in the
postischemic myocardium. To elucidate postischemic
changes in the cardiac vagal efferent neuronal function, we measured
myocardial interstitial acetylcholine (ACh) levels by using in vivo
cardiac microdialysis and examined the ACh responses to electrical
stimulation of the vagi or local administration of ouabain in
anesthetized cats. Sixty-minute occlusions of the left anterior
descending coronary artery (LAD) followed by 60-min reperfusion
abolished electrical stimulation-induced ACh release (20.4 ± 3.9 vs. 0.9 ± 0.4 nmol/l; means ± SE, P < 0.01). In different groups of animals, 60-min LAD occlusion followed by
60-min reperfusion decreased but did not completely abolish
ouabain-induced release of ACh (9.2 ± 1.8 vs. 3.9 ± 0.7 nmol/l; P < 0.05). These results indicate that
function of the vagal efferent axon was completely interrupted, whereas
the local ACh release was partially suppressed in the
postischemic myocardium. The postischemic disruption of vagal efferent neuronal function might exert deleterious effects on
cardiac regulation.
cardiac microdialysis; vagal stimulation; ouabain; cats; acetylcholine
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INTRODUCTION |
AUTONOMIC DERANGEMENT
ASSOCIATED with acute myocardial ischemia or infarction
has deleterious effects on the heart (3, 6). The autonomic
derangement occurs during postischemic as well as
ischemic periods. Elucidating the underlying mechanisms of
autonomic disturbance during the postischemic period is
important to understand the pathophysiology of postischemic
events such as those occurring after thrombolytic therapies. In the
sympathetic nervous system, nerve terminal function as assessed by
tyramine-induced norepinephrine release recovers 60-120 min after
reperfusion of the coronary artery (1, 14). On the other
hand, the myocardial response to electrical stimulation of sympathetic
efferent neurons remains impaired up to 2 h after reperfusion,
despite a preserved myocardial response to exogenous norepinephrine
(5). Therefore, injury to sympathetic efferent axons
(4, 8) is considered to be responsible for sympathetic
denervation in the postischemic myocardium. However, conduction
of the postganglionic axons in response to electrical stimulation of
the epicardial sites was unaffected by regional ventricular
ischemia (9), suggesting that the intrinsic
cardiac fibers in the epicardial region were resistant to myocardial
ischemia. We speculate that changes in the environment
surrounding the postganglionic axons traveling through the midcardium
affected the axonal conduction (15) even if the axon
itself was not injured.
In contrast to the sympathetic efferent nervous system, little is
known regarding vagal efferent neuronal function in the postischemic myocardium in vivo. We have measured myocardial
interstitial acetylcholine (ACh) levels by using a cardiac
microdialysis technique in anesthetized cats (2,
10-13). The ACh levels measured by the cardiac
microdialysis were able to detect changes in the ACh kinetics in the
vagal nerve terminals induced by pharmacological interventions,
arterial baroreflex, or Bezold-Jarisch reflex (13). ACh
levels increased during 60-min occlusion of the left anterior descending coronary artery (LAD) and decreased toward preocclusion level after LAD reperfusion (12). Whether the reduction in
the ACh level on reperfusion indicated functional recovery of ACh release in the postischemic myocardium remains to be elucidated.
The purpose of the present study was to examine ACh release in the
postischemic myocardium. We employed two methods of vagal stimulation to induce myocardial ACh release: electrical stimulation of
the vagi and local administration of ouabain. We assumed that the ACh
response to electrical stimulation reflected efferent neuronal function
including both axonal conduction and local ACh release from the vagal
nerve terminals. In contrast, the ACh response to local ouabain
administration was considered to reflect the local ACh release from the
vagal nerve terminals alone. Results indicate that vagal efferent
axonal conduction was interrupted, and local ACh release was suppressed
in the postischemic myocardium 60 min after reperfusion after
60-min LAD occlusion.
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MATERIALS AND METHODS |
Surgical preparations.
Animal care was provided in accordance with the Guiding
Principles for the Care and Use of Animals in the Field of
Physiological Sciences approved by the Physiological Society of
Japan. A total of 37 adult cats was anesthetized via an intraperitoneal
injection of pentobarbital sodium (30-35 mg/kg) and ventilated
mechanically with room air mixed with oxygen. The depth of anesthesia
was maintained with a continuous intravenous infusion of pentobarbital
sodium (1-2
mg · kg
1 · h1)
through a catheter inserted from the right femoral vein. Systemic arterial pressure was measured from a catheter inserted into the right
femoral artery. Heart rate (HR) was determined by using a
cardiotachometer from an electrocardiogram. Esophageal temperature of
the animal was measured by using a thermometer (model CTM-303; Terumo)
and was maintained at around 37°C by using a heated pad and a lamp.
With the animal in the lateral position, the left fifth and sixth ribs
were resected to expose the heart. A dialysis probe was implanted by
inserting a fine guiding needle into the anterolateral free wall of the
left ventricle perfused by the LAD (1, 2, 10-13, 20,
21). Heparin sodium (100 U/kg) was administered intravenously to
prevent blood coagulation. When LAD occlusion was required, a 4-0 silk
suture was passed around the LAD just distal to the first diagonal
branch, and both of its ends were passed through a polyethylene tube to
make a snare for occlusion. The discoloration area on the LAD occlusion
was large enough to cover the full length of the implanted dialysis
fiber macroscopically. When vagal stimulation was required, the vagi
were exposed bilaterally in the neck. Bipolar platinum electrodes were
then attached to the cardiac end of each sectioned vagal nerve. The
nerves and electrodes were covered with warmed mineral oil for
insulation. A pair of stainless steel wire electrodes was attached to
the left ventricular apex removed from the implanted dialysis probe to
pace the heart during electrical stimulation of the vagi.
At the end of the experiment, the experimental animals were killed with
an overdose of pentobarbital sodium. Postmortem examination confirmed
that the dialysis probe had been implanted within the left ventricular myocardium.
Dialysis technique.
We measured the concentration of ACh in the dialysate sample as an
index of myocardial interstitial ACh level (10-13).
Materials and properties of the dialysis probe have been reported
previously (2). Briefly, we designed a transverse dialysis
probe. A dialysis fiber (13-mm length, 310 µm OD, 200 µm ID; 50,000 molecular weight cutoff) (model PAN-1200; Asahi Chemical, Japan) was
glued at both ends to polyethylene tubes (25-cm length, 500 µm OD,
200 µm ID). The dialysis probe was perfused at a rate of 2 µl/min
with Ringer solution containing a cholinesterase inhibitor, eserine
(100 µM). Experimental protocols were initiated 2 h after
implanting the dialysis probe. The dialysate sampling period was set at
15 min and was performed taking into account the dead space volume
between the dialysis membrane and the sample tube. Concentration of ACh in the dialysate was measured by high performance liquid chromatography with electrochemical detection (Eicom).
Protocols.
Acute myocardial ischemia was induced by LAD occlusion. The
study consisted of the following two different protocols (Fig. 1). In protocol 1, the
myocardial interstitial ACh response to electrical stimulation of the
vagi was examined (2, 13). Fifteen-minute vagal
stimulation (20 Hz, 1 ms pulse duration, 10 V pulse amplitude) was
performed under ventricular pacing at 200 beats/min in the following
groups of vagotomized animals: control (n = 7), 15-min
ischemia followed by 60-min reperfusion (CO15
group, n = 5), and 60-min ischemia followed by
60-min reperfusion (CO60 group, n = 5).
Pacing was applied only during the vagal stimulation and not during the
ischemic period.
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Fig. 1.
Experimental protocols. Protocol 1 (A) was
performed on vagotomized animals. Effects of electrical vagal
stimulation on myocardial interstitial ACh level were examined in three
groups of animals: control; 15-min ischemia followed by 60-min
reperfusion (CO15); and 60-min ischemia followed by
60-min reperfusion (CO60). Protocol 2 (B) was performed on animals different from those in
Protocol 1. Effects of local ouabain
administration on myocardial interstitial ACh level were examined in
three groups of animals: control (intact vagi); vagotomized (VX); and
60-min ischemia followed by 60-min reperfusion with intact vagi
(CO). occ, Occlusion of the left anterior descending coronary artery;
rep, reperfusion after occlusion; vs, vagal stimulation; bl, baseline
before ouabain administration.
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In protocol 2, the myocardial interstitial ACh response to
local ouabain administration was examined (13, 20). We
collected a baseline dialysate sample while perfusing the dialysis
probe with Ringer solution. We then replaced the perfusate with Ringer solution containing ouabain (100 µM), thereby locally administering ouabain through the dialysis probe. Local ouabain administration was
performed in control animals (n = 8), animals with
vagotomy (VX group, n = 6), and animals with intact
vagi subjected to 60-min ischemia followed by 60-min
reperfusion (CO group, n = 6).
Statistical analysis.
All data are presented as means ± SE. In protocol
1, differences in the electrical stimulation-induced ACh
release among control, CO15, and CO60 groups
were examined by using one-way ANOVA followed by Dunnett's test
(7). In protocol 2, changes in the
ACh concentration in the CO group were examined by using a
repeated-measures ANOVA. When there was significant difference,
Dunnett's test was applied to identify the difference relative to the
baseline ACh concentration. We also examined differences in the
baseline or maximum ACh responses among the control, VX, and CO groups
by using one-way ANOVA, followed by Dunnett's test. Differences were
considered significant when P < 0.05.
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RESULTS |
Figure 2 shows ACh
liberated into the myocardial interstitium in response to vagal
stimulation in protocol 1. The electrical stimulation-induced ACh response was suppressed in the CO15
group compared with the control group and abolished in the
CO60 group.
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Fig. 2.
Myocardial interstitial ACh response to electrical vagal
stimulation obtained from protocol 1. The ACh response was
attenuated in the CO15 group and abolished in the
CO60 group compared with the C (control) group.
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Figure 3 depicts changes in the
myocardial interstitial ACh level in response to local ouabain
administration in the CO group obtained from protocol 2. The
ACh level increased gradually on ouabain administration, reaching a
maximum at 15-30 min, after which it declined toward baseline.
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Fig. 3.
Myocardial interstitial ACh response to local ouabain
administration through the dialysis probe obtained in the CO group in
protocol 2. The ACh level was increased significantly from
the baseline value after 15-30 min of ouabain administration.
 P < 0.05.
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Figure 4A illustrates the
baseline ACh levels in protocol 2. There were no significant
differences in baseline ACh levels among control, VX, and CO groups.
Figure 4B illustrates the maximum ACh responses observed
during 15-30 min of ouabain administration. The CO group exhibited
a significantly reduced ACh response compared with the control group.
The VX group showed the maximum ACh response between the control and CO
groups.
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Fig. 4.
Effects of local ouabain administration on the myocardial
interstitial ACh levels obtained from protocol 2. A: baseline ACh levels for control, VX, and CO groups.
B: maximum ACh levels obtained after 15-30 min of
ouabain administration for control, VX, and CO groups.
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Table 1 summarizes mean arterial pressure
(MAP) and HR obtained from the CO group in protocol 2.
Changes in MAP and HR 60 min after LAD occlusion and 60 min after
reperfusion were insignificant compared with preocclusion values.
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DISCUSSION |
To our knowledge, this is the first report on in vivo ACh release
in the postischemic myocardium. The finding is in marked contrast to observations of ischemia-induced ACh release in our previous studies (10-13). The following discussion
will focus on two aspects: postischemic deterioration of axonal
conduction and nerve terminal function of the vagal efferent nerve.
Interruption of vagal efferent neuronal function.
Myocardial interstitial ACh release in response to electrical
stimulation of the vagi was suppressed markedly 60 min after reperfusion after LAD occlusion in the presence of occlusions lasting
15 or 60 min (Fig. 2). The attenuation of the ACh response to
electrical stimulation in the CO60 group was similar to
that achieved by pretreatment with a voltage-sensitive Na+
channel inhibitor, tetrodotoxin (13), suggesting complete
damage to vagal efferent neuronal function in the postischemic
myocardium. Because ouabain-induced ACh release was not abolished in
the CO group in protocol 2 (Fig. 3), the disruption of vagal
efferent neuronal function can be attributed mainly to damage to vagal axons. Inoue and Zipes (8) demonstrated that the vagal
efferent neuronal function, assessed by the lengthening of the
effective refractory period in the nonischemic myocardium
apical to the ischemic region, is impaired heterogenously
5-20 min after coronary artery occlusion. The present results
indicate that the disruption of the vagal efferent axons in the
postischemic myocardium persists for at least 60 min after LAD
reperfusion began.
It is unlikely that the LAD occlusion exerted mechanical damage to the
intracardiac vagal efferent axons. The reasons are as follows. First,
most vagal efferent fibers cross the atrioventricular groove dive
intramurally and are located in the subendocardium in the ventricle
(22). Therefore, the vagal efferent fibers run apart from
the LAD ligation snare. Second, the suppression of electrical
stimulation-induced ACh release depended on the duration of LAD
occlusion (Fig. 2). If the vagal efferent fibers were mechanically
damaged by the ligation procedure, an abrupt interruption of electrical
stimulation-induced ACh release should have resulted. The fact that
5-min brief LAD occlusion followed by 20-min reperfusion did not
suppress the ACh release in response to subsequent 5-min brief LAD
occlusion in a previous study (11) is also in opposition
to the possible mechanical damage to the intracardiac vagal efferent
axons by the ligation procedure.
Impaired local ACh release.
Our previous studies indicated that acute myocardial ischemia
increases myocardial interstitial ACh levels in the ischemic region (10, 12). In those studies, vagotomy did not
abolish ischemia-induced ACh release, suggesting that a local
release mechanism independent of the centrally mediated vagal control plays a significant role in the ischemia-induced ACh release. Whereas no significant differences were observed in MAP and HR 60 min
after ischemia and reperfusion compared with
preischemic baseline values (Table 1), marked ACh release
evoked by acute myocardial ischemia might have caused depletion
of ACh stores or structural membrane abnormalities in the vagal
efferent nerve terminals. Although the baseline ACh levels were similar
between the control and CO groups (Fig. 4), this does not guarantee
functional recovery of the vagal nerve terminals in the
postischemic myocardium. To assess the functional recovery of
the vagal nerve terminals more precisely, we examined the effect of
local ouabain administration on the myocardial interstitial ACh levels.
Integrity of the axoplasmic membrane may be judged by normal
Na+-K+-ATPase activity. Ouabain inhibits the
membrane Na+-K+-ATPase and induces
intracellular Na+ accumulation, which leads to exocytotic
ACh release via the reversal of Na+/Ca2+
exchanger, activation of voltage-sensitive Ca2+ channels,
and/or intracellular Ca2+ mobilization (16,
18). Because Na+-K+-ATPase is the major
target for ATP at the nerve terminal, ischemia induces a
progressive failure of Na+-K+-ATPase activity
by depletion of ATP. If the integrity of the axoplasmic membrane had
been lost due to ischemia and the
Na+-K+-ATPase remained inactive after
reperfusion, ouabain would not be able to evoke ACh release in the
postischemic myocardium. Similarly, if the ACh stores were
depleted by ischemia-induced ACh release, ouabain would also
fail to induce ACh release. However, ouabain increased ACh levels in CO
group (Fig. 3), indicating that membrane function was restored within
60 min after reperfusion. The observed result is consistent with the
fact that the Na+-K+-ATPase becomes active on
reperfusion, leading to restoration of the Na+ gradient
across the axoplasmic membrane in isolated rat hearts (19).
Whereas ouabain administration evoked myocardial interstitial ACh
release, the ACh levels so induced were lower in the CO than in the
control group (Fig. 4). To examine whether the difference in
ouabain-induced ACh release is associated with the absence of baseline
vagal activity, we performed local ouabain administration in
vagotomized animals. As shown in Fig. 4B, the VX group
showed that ACh levels were in between the control and CO groups.
Therefore, absence of the baseline vagal activity due to the
interruption of axonal conduction, on top of the impaired local ACh
release, could contribute to the suppression of ouabain-induced ACh
release in the CO group. According to a study by Schmid et al.
(17), changes in the activity of choline acetyltransferase
in ischemic myocardial tissue are insignificant 2.5 and 5 h after coronary artery occlusion. The discrepancy between ACh
synthesis and ouabain-induced ACh release suggests that nerve terminal
function depends not only on axoplasmic enzyme activity but also on
extraneuronal circumstances, such as extracellular ion content.
Limitations.
Methodological limitations associated with anesthesia and eserine
administration have been described previously
(10-13). Other limitations to the present study are
as follows. First, we did not examine whether vagal efferent function
after LAD occlusion was reversible in the long term. To answer this
question, further studies focusing on the recovery of vagal efferent
function by using chronic experimental models are required. Second, we
did not assess the impact of disruption of the vagal efferent neuronal function on the arrhythmogenesis. Vagal nerve activity is known to
exert both antiarrhythmic and proarrhythmic effects on the heart
(6). Further studies are clearly needed to elucidate the
functional significance of the disruption of the vagal control on the
postischemic cardiac events.
In conclusion, we found interruption of the myocardial ACh release in
response to vagal stimulation as well as suppression of local ACh
release in the postischemic myocardium 60 min after reperfusion
after 60-min LAD occlusion. The disruption of vagal control in the
postischemic myocardium might have deleterious effects on the heart.
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ACKNOWLEDGEMENTS |
This study was supported by Ministry of Health and Welfare of
Japan, Cardiovascular Diseases Research Grants 9C-1, 11C-3, 11C-7; a
Health Sciences Research Grant for Advanced Medical Technology; a
National Space Development Agency of Japan and Japan Space Forum Grant;
a Ground-Based Research Grant for the Space Utilization; a Science and
Technology Agency of Japan Grant; a Bilateral International Joint
Research Grant; Ministry of Education, Science, Sports and Culture of
Japan Grants; Scientific Research Grants-in-Aid B-11694337, C-11680862,
C-11670730; Encouragement of Young Scientists Grants-in-Aid 11770390 and 11770391; and by a Japan Science and Technology Corporation, Research and Development Grant for Applying Advanced Computational Science and Technology.
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FOOTNOTES |
Address for reprint requests and other correspondence: T. Kawada, Dept. of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (E-mail: torukawa{at}res.ncvc.go.jp).
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. Section 1734 solely to indicate this fact.
August 29, 2002;10.1152/ajpheart.00291.2002
Received 25 February 2002; accepted in final form 22 August 2002.
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Am J Physiol Heart Circ Physiol 283(6):H2687-H2691
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ABSTRACT
INTRODUCTION
