Effect of galanin and galanin antagonists on peristalsis in
esophageal smooth muscle in the opossum
Shigeru
Yamato,
Ikuo
Hirano, and
Raj K.
Goyal
Center for Swallowing and Motility Disorders, Brockton/West Roxbury
Veterans Affairs Medical Center, West Roxbury 02132; and Harvard
Medical School, Boston, Massachusetts 02115
 |
ABSTRACT |
Galanin, a neuropeptide that is
widely distributed in the esophageal nerves, is known to exert a
neuromodulatory action in the gut. These studies examined the effect of
galanin and galanin antagonists on esophageal peristalsis in
anesthetized opossums in vivo. Intraluminal esophageal pressures were
recorded at 1, 3, 5, 7, and 9 cm above the lower esophageal sphincter.
Esophageal peristaltic contractions were induced by swallow and short-
(1-s) and long-train (10-s) vagal stimulation (VS). Galanin (1 nmol/kg) inhibited the amplitude of swallow-induced peristaltic contractions and
increased peristaltic velocity by enlarging the latency periods in the
upper part of the esophagus and reducing them in the lower part.
Galinin nearly abolished esophageal contractions caused by short-train
VS at 5 Hz and inhibited the contractions at 10 Hz. Galanin increased
latency periods induced by short-train VS with little change in the
velocity of peristalsis and reduced the amplitude of both A
(cholinergic) and B (noncholinergic) contractions due to long-train VS.
However, the decrease in amplitude of B contractions was more marked.
Galantide (3 nmol/kg) antagonized the inhibitory action of exogenous
galanin on esophageal contractions elicited by short-train VS, but by
itself galantide had no significant effect on esophageal contractions.
In conclusion, exogenous galanin inhibits the amplitude of
swallow-induced peristaltic contractions and converts them into
nonperistaltic contractions by inhibiting both the cholinergic and
noncholinergic components.
nonperistaltic contractions; cholinergic nerves; nonadrenergic,
noncholinergic nerves
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INTRODUCTION |
GALANIN IS A
NEUROPEPTIDE with 29 amino acids (30 in humans) that is widely
distributed in the central and peripheral nervous system, including the
enteric nervous system (9, 22, 26, 27). In the gut, it
binds to synaptosomes as well as to smooth muscle cells (5, 17,
23) and exerts diverse tissue-specific actions
(20). Galanin can have an inhibitory effect on myenteric neurons, but it often coexists with other neurotransmitters such as
ACh, vasoactive intestinal polypeptide (VIP), and nitric oxide synthase
in the nerve endings and acts presynaptically to inhibit the
neurotransmitter release (8, 12, 19, 25). On the other
hand, galanin may also serve as an excitatory mediator that causes
release of other neurotransmitters (4, 18). Galanin can
also exert an excitatory or an inhibitory effect on the smooth muscle.
For example, galanin causes contraction of the circular muscle but
causes relaxation of the longitudinal muscle of guinea pig ileum by
stimulating distinct excitatory and inhibitory receptors, respectively
(3, 10, 11).
In the esophagus, galanin is localized to myenteric and submucosal
neurons and in nerve fibers around the neurons and those innervating
esophageal smooth muscle (24). Galanin causes contraction of the lower esophageal sphincter by a direct action and inhibition of
relaxation by suppression of the activity of nonadrenergic, noncholinergic (NANC) inhibitory nerves (21). The purpose
of these studies was to investigate the effect of galanin on esophageal peristaltic contractions and study the action of galanin antagonists to
determine the possible physiological role of galanin in esophageal peristalsis.
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MATERIALS AND METHODS |
The study protocol was approved by the Animal Studies
Subcommittees of Beth Israel Hospital (Boston, MA) and the West Roxbury Veterans Affairs Medical Center (West Roxbury, MA). Studies were performed in anesthetized opossums (Didelphis virginiana)
weighing 2.3-3.9 kg. After an overnight fast, animals were
initially anesthetized with pentobarbital sodium (40 mg/kg ip).
Subsequently,
-chloralose (30-50 mg iv) was administered
slowly, as needed, to maintain anesthesia. Anesthetized animals were
strapped supine on an animal board and maintained at 37°C with a
heating pad. The brachial artery was cannulated to monitor blood
pressure, and the brachial vein was cannulated for administration of
test agents as needed.
Intraluminal esophageal pressures were measured with a catheter
assembly consisting of six polyvinyl catheters. Each catheter had a
side hole: the five proximal holes were situated 2 cm apart, and the
sixth, most distal, hole was 1 cm distal to the fifth so that
esophageal pressure was measured at 1, 3, 5, 7, and 9 cm above the
lower esophageal sphincter. The outside diameter of the assembly was 5 mm. Each catheter was continuously perfused with bubble-free distilled
water using a low-compliance pneumohydraulic system.
Swallowing was induced by stroking the pharynx with a cotton swab. The
onset of swallow-induced peristalsis was determined by the onset of
spike bursts in the mylohyoid muscle. Mylohyoid electromyography was
recorded using a conventional bipolar electrode as described previously
(14).
In some animals, the vagi were isolated in the neck and severed, and
the peripheral end of one decentralized vagus was used for electrical
stimulation with a bipolar electrode. Vagal stimulation of short (1-s)
and long (10-s) trains was applied with square-wave pulses of 60 V and
0.5-ms pulse duration at 5, 10, and 20 Hz using a Grass stimulator
(model S11; Quincy, MA).
In all animals, control responses were obtained first, followed by
responses after galanin. Galanin was dissolved in saline and
administered as an intravenous bolus followed by continuous intravenous
infusion. Intravenous bolus galanin increased blood pressure in a
dose-dependent manner. The increase in mean arterial pressure was
24.4 ± 4.4%, 26.8 ± 4.0%, 40.7 ± 5.9%, and
35.5 ± 1.5% with doses of 0.1, 0.3, 1, and 3 nmol/kg iv galanin
bolus, respectively. Galanin (1 nmol/kg iv) bolus increased mean
arterial pressure from 111.3 ± 4.2 to 154.6 ± 4.6 mmHg
(n = 12, P < 0.01). Earlier study
(21) showed that this dose of galanin also caused a
maximal increase in lower esophageal sphincter pressure in opossum. With intravenous bolus, galanin blood pressure reached a maximal value
within 2-3 min and returned to the control level after ~10 min.
Therefore, intravenous bolus was combined with continuous infusion of
galanin. With the combination of intravenous bolus (1 nmol/kg) followed
by intravenous infusion of 1 nmol · kg
1 · 2 min
1 of
galanin, blood pressure remained stable during the infusion. In these
periods, heart rate decreased from 162 ± 4 to 118 ± 2/min (n = 6, P < 0.01). Galanin antagonists
were also administered as intravenous boluses followed by intravenous
infusion. When the effect of galanin antagonist on galanin was
examined, galanin and galanin antagonist were administered as
intravenous bolus only. The dose of galanin antagonist was three times
higher than that of galanin. The galanin antagonist (galantide) only
transiently reduced blood pressure, which returned to the control level
in 3 to 5 min. Mean arterial pressure was 109 ± 2 and 114 ± 5 mmHg, respectively, before and after galantide.
Statistics
Quantitative data are expressed as means ± SE. Animals
served as their own controls. Statistics of effects of treatments were determined in each animal (3-5 observations in each animal)
separately and also cumulatively in all animals. Statistical analysis
were performed using paired or unpaired t-tests and ANOVA
for multiple comparisons.
Drugs
Galanin and galanin antagonists galantide (M15) and M40 were
purchased from Peninsula Laboratories.
N
-nitro-L-arginine methyl
ester (L-NAME),
-chloralose, and atropine sulfate
were purchased from Sigma Chemical (St. Louis, MO).
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RESULTS |
Influence of Galanin on Primary Peristalsis
Esophageal primary peristalsis (P contraction) was produced in
response to swallowing induced by pharyngeal stimulation. Figure 1 shows manometric tracing of the effect
of galanin on esophageal primary peristalsis. Galanin reduced the
amplitude of peristaltic contractions, and it increased peristaltic
velocity. Figure 2 shows that the
amplitude of contractions caused by swallowing varied from 53.0 ± 8.2 to 101.0 ± 13.2 mmHg at different esophageal sites. Galanin
treatment decreased the amplitude of contractions throughout the
esophagus, particularly at the distal sites. At the 5-cm site, galanin
decreased the amplitude of contractions from 101.0 ± 13.2 to
76.3 ± 14.2 mmHg (n = 6, P < 0.01).

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Fig. 1.
Manometric tracing of the effect of galanin on
swallow-induced esophageal peristalsis. SW, the onset of swallowing.
Note that galanin reduced the amplitude of peristaltic contractions.
Moreover, galanin increased peristaltic velocity by increasing the
latency of contraction in the upper esophagus and decreasing the
latency in the lower esophagus. LES, lower esophageal sphincter.
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Fig. 2.
Effect of galanin on the amplitude of swallow-induced
esophageal contractions. Note that galanin reduced the amplitude of the
contractions at all sites. The effect of galanin was significant at the
distal esophageal sites (* P < 0.05, ** P < 0.01). Bars show means ± SE of
observations in 6 animals.
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Galanin had different effects on the latency of peristaltic
contractions at different esophageal sites; it increased latencies at
the proximal sites and reduced them at the distal esophageal sites.
Figure 3 shows that the latencies of
primary peristalsis varied from 2.6 ± 0.1 to 5.1 ± 0.2 s depending on the esophageal sites. Galanin increased the latencies at
the 9- and 7-cm sites from 2.6 ± 0.1 to 3.1 ± 0.1 s
and from 3.0 ± 0.1 to 3.6 ± 0.1 s, respectively
(P < 0.0 1), and it decreased the latencies at the
1-cm site from 5.1 ± 0.2 to 4.2 ± 0.2 s
(P < 0.05). These modifications of latencies of
contractions resulted in an increase in the speed of peristalsis from
3.0 cm/s in control to 7.5 cm/s after galanin treatment.

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Fig. 3.
Effect of galanin on the latencies of swallow-induced
contractions. Note that galanin increased the latencies at 9- and 7-cm
sites but reduced those at 3- and 1-cm sites (n = 6, * P < 0.05, ** P < 0.01). The
speed of peristalsis during the control period was 3.0 cm/s, and after
galanin treatment it was 7.5 cm/s.
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Influence of Galanin on Esophageal Contractions Caused by Vagal
Stimulation
Vagal stimulation produces contractions in the esophageal body due
to peripheral mechanisms and excludes the central deglutitive reflex
pathways (16). Short trains of vagal stimulation produce esophageal peristaltic contractions (called S contractions) whose latencies, peristaltic velocities, amplitudes, and neurotransmitter mediators vary with the parameters of electrical stimulation
(7). Long trains of vagal stimulation (10 s) cause
contractions soon after the onset of the stimulus (A contraction) and
after cessation of the stimulus (B contraction) (7, 13,
16). The prevalence and quantitative features of A and B
contractions also depend on the parameters of electrical stimulation
and considerable interspecies variations. Moreover, the mediators of
these two responses are also different; A contractions are cholinergic
whereas B contractions are nonadrenergic, noncholinergic in nature
(15). B contractions were reported (1, 29) to
be mediated by nitric oxide, because a nitric oxide synthase inhibitor
abolished B contractions. We examined the effect of galanin on each of
these contractions.
Influence on S contractions.
Short-train vagal efferent stimulation produced peristaltic
contractions. With 1-s train stimulation at 5 Hz, the contractions were
almost abolished by galanin treatment (Figs.
4 and
5A). The amplitude of
contractions produced by 10 Hz of stimulation were also significantly
reduced (Fig. 5B), and latencies of contractions were
prolonged at all esophageal sites by ~0.4-1 s (n = 6, P < 0.05) (Fig. 6).

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Fig. 4.
Effect of galanin on S contractions due to short-train
vagal efferent stimulation (VS) at 5 Hz in 1 animal. Note that galanin
nearly abolished esophageal contractions due to short-train vagal
stimulation at 5 Hz.
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Fig. 5.
Effect of galanin on the amplitude of esophageal
contractions induced by short-train vagal stimulation. Note that with
5-Hz vagal stimulation, the contractions were nearly abolished at all
esophageal sites (A). Galanin partially inhibited the
contractions with 10-Hz vagal stimulation (B).
* P < 0.05, ** P < 0.01. Bars
are means ± SE of observations in 6 animals. Vagal efferent
stimulus parameters: 60 V with 0.5-ms pulse duration for 1-s train.
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Fig. 6.
Effect of galanin on the latencies of esophageal
contractions to 1-s vagal stimulation at 10 Hz. Note that galanin
increased the latencies of contractions at all esophageal sites
(n = 6; * P < 0.05, ** P < 0.01).
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Influence on A and B contractions.
Figure 7 shows the effect of galanin on A
and B contractions in response to long-train vagal efferent stimulation
at 5 Hz. As shown in Fig. 8A,
A contractions with 10-s vagal efferent stimulation at 5 Hz had
amplitudes varying from 20.8 ± 6.7 to 102.2 ± 11.4 mmHg,
and B contractions had amplitudes varying from 2.0 ± 1.3 to
82.5 ± 22.2 mmHg (n = 6). Galanin treatment
reduced the amplitude of both A and B contractions; however, the
reduction in the amplitude of B contractions was more significant.
Galanin completely abolished B contractions in three of six animals. A
contractions produced by long-train stimulation had latencies from the
onset of stimulus varying from 1.5 ± 0.1 to 2.4 ± 0.2 s. Galanin treatment caused a significant prolongation of the latencies
of A contractions at all esophageal sites by ~0.9-1.4 s.

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Fig. 7.
Influence of galanin on A and B contractions in response
to long-train vagal efferent stimulation at 5 Hz in 1 animal. Note that
galanin reduced the amplitude of both A and B contractions to
long-train vagal stimulation. The reduction of amplitude of B
contractions was more significant.
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Fig. 8.
Effect of galanin on the amplitude of A and B
contractions to 10-s vagal stimulation (5 and 10 Hz). Galanin treatment
reduced amplitude of both A and B contractions at 5 Hz; however, the
reduction of amplitude of B contractions was more significant
(A) (* P < 0.05, ** P < 0.01). At 10 Hz, galanin partially inhibited the amplitudes of A and
B contractions (B). Bars are means ± SE of
observations in 6 animals. Vagal efferent stimulus parameters: 60 V
with 0.5-ms pulse duration for 10-s train.
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At 10 Hz, galanin also inhibited the amplitudes of A and B contractions
(Fig. 8B), and it caused a significant prolongation of
latency periods of A contractions at all esophageal sites by 0.6-1.1 s (see Fig. 9). Effect of
galanin on latencies of B contractions could not be analyzed because
many of them were abolished by galanin.

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Fig. 9.
Effect of galanin on the latencies of A contractions to
10-s vagal stimulation at 10 Hz. Galanin caused a significant
prolongation of latencies of A contractions at all esophageal sites by
0.6-1.1 s (n = 6; * P < 0.05, ** P < 0.01).
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Influence of Galanin Antagonists
M15 (galantide) and M40, at a dose of one to six times that of
galanin, were reported (27, 28) to antagonize the effect of galanin. In our studies, M40 (3 nmol/kg iv) reduced the amplitude of
S contractions and acted like a galanin agonist rather than an
antagonist. On the other hand, M15 (galantide) antagonized the effect
of galanin. As shown in Fig. 10,
galantide (3 mnol/kg) antagonized the inhibitory effect of galanin on
esophageal contractions to short-train vagal efferent stimulation
(n = 3, P < 0.01). To examine a
possible inhibitory role of endogenous galanin on esophageal peristalsis, we examined the effect of galantide (3 nmol/kg) to see if
it augmented the esophageal contractions. Galantide slightly increased
the amplitude of swallow-induced primary peristalsis and S, A, and B
contractions (n = 4). However, the increases in the
amplitudes were not consistent or significant at all sites (Table
1). Galantide did not modify latency of
contractions induced by swallows or vagal stimulation.

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Fig. 10.
Effect of galanin and galanin antagonist (galantide) on
the amplitudes of contractions to 1-s vagal stimulation at 5 Hz.
Galanin (1 nmol/kg) nearly abolished the contractions induced by 1-s
vagal stimulation at 5 Hz (n = 3;
* P < 0.05, ** P < 0.01).
Galantide (3 nmol/kg) antagonized the inhibitory effect of galanin.
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 |
DISCUSSION |
These studies show that galanin causes a decrease in amplitude of
swallow-induced esophageal contractions. This effect of galanin may be
exerted on the central swallowing mechanism or the peripheral motor
mechanisms of peristalsis. Galanin reduced the amplitude of both the
contractions due to vagal efferent stimulation. These observations
suggest that the action of galanin is exerted on the peripheral
pathways for peristalsis. Galanin reduced amplitudes of both the A
contractions, which are cholinergic as they are atropine sensitive
(15), and B contractions, which are rebound contractions
due to the inhibitory neurotransmitter nitric oxide (1,
29).
Galanin had opposing effects on the latencies of primary peristalsis at
the proximal and the distal sites; it increased the latencies at the
proximal sites and decreased them at the distal sites. As a result of
these changes, the speed of peristalsis, 3.0 cm/s, increased to 7.5 cm/s. Galanin increased the latencies to vagal efferent stimulation (S
and A contractions) at all esophageal sites by ~1 s.
These seemingly confusing effects of galanin on the latencies of the
esophageal contractions to swallowing and vagal efferent stimulation
are due to differences in the mechanisms of the two types of contractions.
Esophageal contractions involve two overlapping phenomena, a period of
inhibition followed by rebound contraction due to NANC nerves and
excitation due to cholinergic nerves (7, 13). With vagal
efferent stimulation, NANC inhibitory nerves and the cholinergic
excitatory nerves are stimulated simultaneously. Under these
conditions, the cholinergic component of the contraction precedes the
NANC rebound contraction at all esophageal sites. The net result of
cholinergic and NANC nerve inhibition by galanin is to increase
latencies of the contractions at all esophageal sites. In contrast to
vagal efferent stimulation, swallowing first produces activation of the
NANC inhibitory pathways and the activation of the cholinergic
excitatory pathway occurs afterward, following a certain delay.
Moreover, the interval between the activation of the NANC inhibitory
pathway and the cholinergic excitatory pathway increases distally along
the esophagus (14). As a result, at the proximal
esophageal sites, the cholinergic component of the esophageal
contraction precedes the NANC rebound contraction. On the other hand,
at the distal sites, the cholinergic component of the contraction
overlaps the NANC rebound contraction. The effect of atropine on
swallow-induced peristalsis in the opossum was reported by Gilbert and
Dodds (15) and that of L-NAME and the
combination of L-NAME plus atropine on peristalsis was
reported by Yamato et al. (29). L-NAME causes
a decrease in the latencies of contractions at distal sites due to
suppression of NANC activity so that the contractions occur after a
latency of 2-3 s. On the other hand, atropine increases the
latencies of contractions, particularly in proximal esophageal sites.
Antagonism of both the inhibitory NANC and the excitatory cholinergic
nerves by a combination of L-NAME and atropine places the
latency gradient midway between that of L-NAME and atropine
treatment. With this combination treatment, the latency increased at
the proximal sites and decreased at the distal sites so that the
swallow-induced contractions occurred almost simultaneously. The effect
of galanin on the latencies of swallow-induced contractions was similar
to that of the combination of L-NAME and atropine (see Fig.
2). These observations are consistent with the inhibitory effect of
galanin on NANC inhibitory and cholinergic excitatory nerves. The
effects of the same agents on short-train vagal stimulation-induced
esophageal contractions were also reported (1, 29). In
contrast to swallow-induced peristalsis, decrease in latencies by
L-NAME with vagal stimulation is small and the combination
of L-NAME plus atropine prolongs the latencies in all the
esophageal sites. The effect of these combinations is also similar to
that of galanin (see Fig. 4).
Galanin can act presynaptically to inhibit the synaptic transmission,
myenteric neurons, or neuromuscular transmission. Galanin is localized
with ACh, VIP, and nitric oxide synthase in the myenteric neurons. It
is possible that galanin acts to inhibit the release of cholinergic and
noncholinergic neurotransmitters. Further studies are needed to
distinguish between these possibilities. The inhibitory action of
galanin could also be exerted directly on the smooth muscle. However,
such a direct effect on the muscle would not explain the changes in
latencies of contraction due to galanin. The possibility that the
observed actions of galanin in vivo are mediated indirectly via
systemic release of other mediators or hormones cannot be excluded by
these studies.
Wiesenfeld-Hallin et al. (28) found that the increase of
spinal cord excitability after stimulation of afferents was potentiated by the galanin antagonist M35 and speculated that endogenous galanin is
released to suppress nociceptic impulses on intense activation of
nociceptors. Our studies show that M15 (galantide) but not M40 is a
potent antagonist of the inhibitory action of galanin on esophageal
contractions. This may be due to participation of different galanin
receptor subtypes in the two responses (3, 20). Galantide,
in doses that markedly antagonized the inhibitory action of galanin on
the amplitude of esophageal contractions evoked by a short train of
vagal stimulation, had no consistently significant effect on esophageal
contractions evoked by swallowing or vagal stimulation. These
observations suggest that endogenous galanin may not exert a modulatory
role on esophageal contractions evoked by swallowing or vagal
stimulation. However, further studies using higher concentrations of
galantide are needed to fully exclude this possibility.
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ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant RO I DK-31092 and a Merit Review
Award from the Office of Research and Development, Medical Research
Service, Department of Veterans Affairs.
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FOOTNOTES |
Address for reprint requests and other correspondence: R. K. Goyal, Research and Development (151), Veterans Affairs
Medical Center, 1400 VFW Parkway, West Roxbury, MA 02132 (E-mail:
raj-goyal{at}hms.harvard.edu).
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.
Received 2 September 1999; accepted in final form 26 April 2000.
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