Baclofen blocks LES relaxation and crural
diaphragm inhibition by esophageal and gastric distension in
cats
Jianmin
Liu,
Nonko
Pehlivanov, and
Ravinder
K.
Mittal
Division of Gastroenterology, San Diego Veterans Affairs
Medical Center and University of California San Diego, San Diego,
California 92161
 |
ABSTRACT |
Esophageal distension and transient
lower esophageal sphincter (LES) relaxation (TLESR) are accompanied by
simultaneous relaxation of the LES and inhibition of crural diaphragm.
Recent studies indicate that baclofen decreases the frequency of TLESR;
however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in
cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of
their EMG activity, respectively. One week after the surgery, animals
were lightly sedated and recordings were performed using a manometry
catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 µmol/kg iv) on the graded esophageal distension and gastric
distension-induced LES and crural diaphragm responses were studied.
Distension of the esophagus and stomach induces relaxation of the LES
and inhibition of the crural diaphragm, simultaneously. Baclofen blocks
both the esophageal and the gastric distension-induced relaxation of
the LES and inhibition of the crural diaphragm. The magnitude of
response to baclofen was significantly larger for the crural diaphragm
inhibition than for the LES relaxation. Baclofen, a GABAB
receptor agonist, blocks the reflex inhibitory pathway to the LES and
crural diaphragm. The reflex inhibitory pathway to the crural diaphragm
is more sensitive to blockade by baclofen than the reflex LES
inhibitory pathway.
transient lower esophageal sphincter relaxation; gastroesophageal
reflux; crural diaphragm; GABAB agonist
 |
INTRODUCTION |
TRANSIENT LOWER
ESOPHAGEAL sphincter (LES) relaxation (TLESR) is the major
mechanism of gastroesophageal reflux in normal subjects and patients
with reflux disease (8, 23). Recent studies in animals and
humans reveal that baclofen, a GABAB agonist, inhibits
TLESR (3, 11, 13, 28). Studies (10)
documenting the blockade of TLESR by baclofen used the LES relaxation
criteria to identify TLESR. During TLESR, along with LES, there
is also inhibition of the other major component of the antireflux
barrier, i.e., the crural diaphragm (21). Distension of
the stomach in dogs induces TLESR, which is also associated with
inhibition of the crural diaphragm (17). Simultaneous
relaxation of the LES and inhibition of crural diaphragm also occurs
during distension of the esophagus in cats (1). The effect
of baclofen on the crural diaphragm inhibition during TLESR and
esophageal distension is not known. The goals of our study were
twofold: 1) to determine the effects of baclofen on the
gastric distension-mediated LES relaxation and crural diaphragm
inhibition, the two important components of the TLESR, and
2) to determine the effects of baclofen on the esophageal
distension-mediated relaxation of the LES and inhibition of the crural diaphragm.
 |
MATERIALS AND METHODS |
Diaphragm electrodes implantation.
These studies were conducted in five female adult cats, weighing
between 3 and 3.7 kg. The protocol for the study was approved by The
Animal Ethics Committee of the University of California, San Diego, and
San Diego Veterans Affairs Hospital. Under general anesthesia induced
by xylazine (1.5 mg/kg im) and maintained by isoflurane (2-3%
inhalation), a midline laparotomy was performed. Six stainless steel
wire electrodes (model MYO/WIRE, A & E Medical, Farmingdale, NJ) were
implanted into the left diaphragm (3 into the crural and 3 into the
costal diaphragm) in each cat. These electrodes have a 1-cm bare wire
embedded into the muscle. The wire electrodes were parallel to each
other and spaced 1 cm apart. The other ends of the electrodes were
tunneled through the abdominal wall and exited outside the body on the
left side of the abdomen. The laparotomy incision was closed, and
animals were allowed to recover for at least 1 wk before the actual
recording sessions.
Data recordings.
Animals were fasted overnight before each recording session. On the
study day, telazol (10 mg/kg Fort Dodge Animal Health, Fort Dodge,
Iowa) was given intramuscularly to induce anesthesia. An
intravenous line was established for maintenance of anesthesia and the
injection of baclofen. Anesthesia was maintained with telazol (5 mg/kg
iv) administered every 20 min. Animals were placed on a heating pad for
maintenance of body temperature. Animals breathed spontaneously during
the experiments. A manometric catheter was placed through the mouth
into the esophagus and stomach for measurement of the esophageal, LES,
and stomach pressures. The manometry catheter was equipped with a
6-cm-long reverse-perfused sleeve sensor to measure the LES pressure
and side holes to measure pressure in the stomach (2 cm below the LES)
and esophagus at 2 and 8 cm above the LES. A 2-cm-long balloon with a
diameter of 2.5 cm (with 10 ml of air) was placed with its center at 4 cm above the LES. Each of the side holes and the sleeve sensor was
perfused at a rate of 0.5 ml/min, using a pneumohydraulic infusion
system (Arndorfer, Milwaukee, WI). The diaphragm electromyogram (EMG) signals were recorded using an amplifier (J & J
Electronics). The integrated EMG output from the amplifier was recorded
along with the pressures on a computer using a PC-Polygraph (Medtronic, Minneapolis, MN). Distension of the esophagus was performed by manually
inflating the balloon with 4, 6, 8, and 10 ml of air, each for 30 s using a hand-held syringe. Each balloon volume was tested three times
with a 1-min resting period between the distensions. Baclofen (Sigma,
St. Louis, MO) bolus (10 µmol/kg) was injected intravenously, and
2-3 min after the injection of baclofen, esophageal distensions
were repeated. Effects of gastric distension on the LES and crural
diaphragm were studied on a separate day in each animal, by injecting
60 ml of air into the stomach. The air injections were completed over a
period of 5-10 s using a hand-held syringe. Our preliminary
studies revealed that gastric distension with 60 ml of air consistently
induced long periods of LES relaxation. The air was kept in the stomach
for a period of 60 s and then withdrawn by using a syringe. The
volume of withdrawn air was measured. Eighty to ninety percent of the
injected air was recovered from the stomach after each gastric
distension. Gastric distensions were repeated three times in each
animal. A 2-min interval was allowed between gastric distensions. If an
esophageal contraction occurred immediately after the air injection,
gastric distension was terminated by withdrawing air from the stomach.
Data analysis.
LES pressure was referenced to the end-expiratory gastric pressure
before the injection of air into the stomach. Basal LES pressure was
measured over a 10-s period before each esophageal and gastric
distension. The basal diaphragmatic EMG was measured as the mean
inspiratory oscillations over a 10-s period before the distension in
reference to the end-expiratory baseline. The diaphragmatic EMG was
measured in arbitrary units (au). Percent LES relaxation and the
percentage of crural diaphragmatic EMG inhibition during esophageal and
gastric distension were calculated. Incidence of LES relaxation and
crural diaphragm inhibition were also calculated. For incidence
calculations, LES relaxation and crural diaphragm inhibition were said
to occur only if the drop in pressure and EMG activity was >50% of
the baseline values, respectively. Duration of LES relaxation and
crural diaphragm EMG inhibition were measured from the 50% values.
Esophageal contraction amplitude, proximal to the balloon (8 cm above
the LES) was measured during esophageal distension. Data were analyzed
using paired Student's t-tests and are presented as
means ± SE.
 |
RESULTS |
Effect of esophageal distension on LES and crural diaphragm.
Esophageal distension by the balloon induced simultaneous relaxation of
the LES and inhibition of the crural diaphragm. LES relaxation was
observed for tonic LES pressure as well as for inspiration-induced LES
pressure oscillations. Along with LES relaxation, esophageal distension
also induced inhibition of the inspiratory crural diaphragm EMG
activity. LES relaxation during esophageal distension ranged from 80 to
96%. We did not observe a graded response of LES relaxation with the
graded increase in the balloon volume in the range of balloon volumes
tested. Crural diaphragm inhibition was of the magnitude of
60-78% and was also not related to balloon volume. LES relaxation
during esophageal distension lasted 21.8 ± 0.4 s, and crural
diaphragm inhibition lasted 21.0 ± 0.6 s. An esophageal
contraction proximal to the site of esophageal distension (Fig.
1) was also observed, the amplitude of
which was directly related to the volume of air injected into the
balloon.

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Fig. 1.
Effects of esophageal distension on the lower esophageal
sphincter (LES) and crural diaphragm. This record shows 2 periods of
esophageal distension. Each distension induced relaxation of the LES
and inhibition of the crural diaphragm electromyogram (EMG) activity.
Note an esophageal contraction proximal to the balloon at the onset of
distension and an esophageal contraction distal to the balloon after
deflation of the balloon.
|
|
Effects of baclofen on LES pressure and crural diaphragm EMG during
baseline and esophageal distension.
Basal LES pressure was not significantly affected by baclofen. The
animal's breathing or the inspiratory pattern was significantly altered by baclofen. All animals showed an increase in the amplitude of
inspiratory crural and costal EMG activity. Mean inspiratory crural
diaphragm EMG increased from 91.3 ± 4.8 to 119.0 ± 7.5 au
in five cats (P < 0.002) (Figs.
2 and 3).
Some of the animals developed cyclic but brief periods of apnea in
inspiration after baclofen administration. Percent LES relaxation and
crural diaphragm inhibition were significantly reduced by baclofen. The
incidence of LES relaxation (>50% drop in LES pressure) was 100% for
all the distension volumes in the control period and was not
significantly altered by baclofen (78, 100, 82, and 81% with 4, 6, 8, and 10 ml distensions, respectively). Pooled data revealed that the
magnitude of LES relaxation was significantly reduced by baclofen at
all volumes of esophageal distensions (Fig.
4). Baclofen also reduced the incidence
and magnitude of crural diaphragm EMG inhibition during esophageal
distension (77 ± 1 vs. 13 ± 2% during esophageal distension with 10 ml, P < 0.001). After baclofen
administration, it was more difficult to elicit crural diaphragm
inhibition than it was to elicit LES relaxation. In other words, the
blockade of crural diaphragm inhibition was more sensitive to baclofen than the blockade of LES relaxation. Duration of LES relaxation was
significantly reduced by baclofen (21 ± 0.6 vs. 16.5 ± 0.6 s, P < 0.001). The amplitude of esophageal
contraction proximal to the distension site was reduced by baclofen
(from 38 ± 4 to 22 ± 8 mmHg during 10-ml distension).
However, the difference in the contraction amplitude before and after
baclofen was not statistically significant (P = 0.10).

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Fig. 2.
Effect of baclofen on the LES pressure and crural
diaphragm EMG. The inspiratory EMG activity increased after baclofen
administration. Also note periods of apnea in inspiration. Esophageal
distension after baclofen administration induced partial LES relaxation
and no inhibition of the crural diaphragm EMG.
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Fig. 3.
Effect of baclofen on the LES pressure (A) and crural
diaphragm EMG activity (B). Basal LES pressure was not
affected by baclofen. On the other hand, baclofen caused an
increase in the inspiratory crural diaphragm EMG activity.
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Fig. 4.
Pooled data of the effects of baclofen on the LES relaxation
(A) and crural diaphragm inhibition (B). LES
relaxation and crural diaphragm EMG inhibition were both reduced by
baclofen. However, the magnitude of reduction of crural diaphragm
inhibition by baclofen was significantly greater than its effect on the
reduction of LES relaxation.
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|
Effect of gastric distension on the LES and crural diaphragm.
Gastric distension with 60 ml of air induced a prolonged period of LES
relaxation (mean 48 s) and an increase in the esophageal pressure
(a common cavity phenomenon). The latter was defined as an increase in
intraesophageal pressure of >2 mmHg. LES relaxation occurred within
30 s of the completion of air injection into the stomach. LES
relaxation was accompanied by inhibition of the crural but not the
costal diaphragm EMG activity and was usually terminated by a
peristaltic esophageal contraction (Fig.
5). LES relaxation and crural diaphragm
inhibition were observed during 91% of gastric distensions. The
percent LES relaxation and crural diaphragm inhibition during all
gastric distensions in five cats were 76 ± 1 and 77 ± 1%,
respectively (see Fig. 8). Durations of LES relaxation and crural
diaphragm inhibition were 48 ± 3 and 41 ± 3 s,
respectively.

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Fig. 5.
Effects of gastric distension on the LES pressure and
crural diaphragm EMG activity. Air (60 ml) was injected slowly into the
stomach with the help of a hand-held syringe. Note relaxation of LES
and inhibition of crural diaphragm EMG activity. Costal diaphragm
activity increased during periods of LES relaxation. Also note an
increase in esophageal pressure or a common cavity during LES
relaxation. LES relaxation was terminated by a peristaltic esophageal
contraction.
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Effect of baclofen on the LES relaxation and crural diaphragm
inhibition induced by gastric distension.
Gastric distension-induced LES relaxation and crural diaphragm
inhibition was blocked by baclofen (Fig.
6). Baclofen reduced the incidence of LES
relaxation response from 91 to 28% (P < 0.01) (Fig.
7). Similarly, the incidence of crural
diaphragm inhibition, in response to gastric distension, was reduced by
baclofen (91 vs. 11%). Duration of LES relaxation and crural diaphragm
inhibition were significantly reduced by baclofen as well (48.5 ± 2.8 vs. 19 ± 0.9 s for LES and 41.1 ± 3.1 vs. 3 ± 0 s for crural diaphragm; P < 0.05). Pooled
data show that the magnitudes of LES relaxation during gastric
distension in the control and postbaclofen periods were 76 ± 0.8 and 30 ± 1.3%, respectively. The magnitude of crural diaphragm
inhibition was also significantly reduced by baclofen (77 ± 1 vs.
17 ± 1%) (P < 0.01, Fig.
8).

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Fig. 6.
Effect of baclofen on gastric distension-induced LES
relaxation and crural diaphragm inhibition. Note absence of LES
relaxation and crural diaphragm inhibition in response to distension.
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Fig. 7.
Incidence of LES relaxation (A) and crural diaphragm
inhibition (B) before and after baclofen, in response to
gastric distension with 60 ml of air. Relaxation/inhibition was said to
occur if the reduction in LES pressure and inhibition in crural
diaphragm EMG activity was >50% of the baseline activity. The
incidence of both LES relaxation and crural diaphragm inhibition was
significantly reduced by baclofen.
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Fig. 8.
Pooled data on effects of baclofen on gastric distension-induced
LES relaxation (A) and crural diaphragm inhibition
(B). Note that the LES relaxation and crural diaphragm
inhibition were significantly reduced by baclofen. *P < 0.01.
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|
 |
DISCUSSION |
Our data indicate that distension of the esophagus and stomach
elicits simultaneous relaxation of the LES and inhibition of crural
diaphragm in the lightly anesthetized cat. Baclofen, a GABAB agonist, antagonizes LES relaxation and crural
diaphragm inhibition induced by esophageal and gastric distensions. Our (3, 11, 13, 27) findings in cats of the effects of
baclofen on LES relaxation and crural diaphragm inhibition are in
agreement with the inhibitory effect of baclofen on the TLESR observed
in other animal species and humans. Most importantly, we find that, despite the differences in the pathways that may mediate LES and crural
diaphragm inhibition during esophageal and gastric distensions, baclofen can target both components of the antireflux barrier function,
i.e., LES and crural diaphragm, which are crucial in preventing reflux
of gastric contents into the esophagus (20).
TLESR was first reported (8) in humans using a sensor that
allowed continuous monitoring of the LES pressure over extended periods
of time, i.e., sleeve device. Although the majority of studies on TLESR
have been conducted in humans, the phenomenon has been recorded in dogs
(6, 11, 18), cats, and ferrets (3). The LES
relaxation is the major criterion for identification of TLESR in the
human as well as animal studies (10). It is now clear,
however, that along with the LES, several other regions i.e., the
esophagus (27), stomach, and crural diaphragm, are inhibited during TLESR. Crural diaphragm inhibition during TLESR has
been reported in humans (21) and dogs (17,
24). It seems that the inhibition of the crural diaphragm is
essential for the occurrence of gastroesophageal reflux during TLESR,
because in the absence of LES tone, gastroesophageal reflux does not
occur unless there is inhibition of the crural diaphragm (12, 20, 22).
In human studies (13), the frequency of spontaneous TLESR
is reduced by >50% with a single oral dose of baclofen (40 mg). Baclofen has also been reported to inhibit TLESR in dogs
(11) and ferrets (3). In all of the studies
that documented the inhibition of TLESR by baclofen, the LES relaxation
criterion was used to identify TLESR. From the literature, it is not
clear whether baclofen has any influence on the crural diaphragm
inhibition that accompanies LES relaxation during TLESR. Our study, for
the first time, shows that baclofen blocks both components of TLESR, i.e., LES relaxation and crural diaphragm inhibition. Furthermore, we
found that LES relaxation and crural diaphragm inhibition induced by
esophageal distension (1, 6) is also blocked by baclofen.
Our data show quantitative differences in the baclofen-induced
blockade of the LES relaxation and crural diaphragm inhibition caused
by esophageal distension. We found that the incidence as well as the
magnitude of crural diaphragm inhibition was much more affected by
baclofen than the incidence and magnitude of LES relaxation, a finding
that may have clinical relevance. GABAB agonists, because
of their inhibitory effect on the TLESR frequency, may have a role in
the treatment of reflux disease. However, the blockade of esophageal
distension-induced LES relaxation by baclofen is undesirable and can
impede esophageal transit, thus resulting in symptoms of dysphagia. Our
finding that the blockade of esophageal distension-induced LES
relaxation is less sensitive to baclofen is actually desirable, because
such an effect is likely to protect against dysphagia.
Several studies (18, 20) indicate that TLESR is a neural
reflex, which is mediated via vagal afferent, brain stem, and vagal
efferent pathways. It appears that gastric distension stimulates mechanoreceptors located in the fundus and the lesser curvature of the
stomach (9). The afferent signals from these
mechanoreceptors traverse via vagal afferent pathways and relay in the
nucleus tractus solitarii (NTS) of the vagal complex. The NTS in turn stimulates motor neurons of the dorsomotor nucleus of the vagus nerve
(DMV), which in turn sends efferent signals via the vagus nerve to the
LES. The mechanism by which gastric distension elicits crural diaphragm
inhibition is not known. The esophageal distension-mediated relaxation
of the LES and inhibition of the crural diaphragm is also mediated via
esophageal mechanoreceptors, vagal afferents, and NTS. How NTS mediates
crural diaphragm inhibition is also not known. One possibility is that
signals from NTS cause inhibition of crural diaphragm motor neurons
(central mechanism). However, Altschuler et al. (2) failed
to find inhibition of inspiratory medullary motor neurons and suggested
that the cervical spinal motor neuron may be the site of inhibition. We
recently reported evidence for a peripheral mechanism of esophageal
distension-mediated crural diaphragm inhibition (distal to the spinal
cord) (16). The precise nature of this peripheral
mechanism of inhibition, however, is not clear. How does baclofen block
LES relaxation and crural diaphragm inhibition? Baclofen acts at
several sites in the reflex pathway of TLESR. It inhibits the gastric
distension-mediated mechanoreceptor activity and vagal afferent
discharge (25). GABAB receptors are present in
the DMV complex and may have a central site of action, thus influencing
the efferent discharges to the LES (19, 26).
GABAB may also reduce the peripheral preganglionic
discharges that mediate LES relaxation (4). Our study does
not address the mechanism and site of action of baclofen. However, it
is interesting that there are similarities in the two pathways that
bring about LES relaxation and crural diaphragm inhibition during
esophageal distension and gastric distension that can be targeted by
baclofen. Besides baclofen, general anesthesia (7, 14) and
a blocker of nitric oxide synthase (nitro-L-arginine methyl
ester) (5, 15) have also been shown to inhibit
gastric distension, as well as esophageal distension-induced relaxation of the LES and inhibition of the crural diaphragm.
In summary, our study shows that gastric distension in lightly
anesthetized cats elicits simultaneous relaxation of LES and inhibition
of crural diaphragm, a response resembling TLESR. Our observation that
baclofen can block LES relaxation and crural diaphragm inhibition
induced by esophageal and gastric distension suggests the existence of
a commonality in the two distinct pathways, one that mediates LES
relaxation and the other crural diaphragm inhibition during TLESR.
Further studies are needed to understand the nature of this commonality
in the LES and crural diaphragm inhibitory pathways.
 |
ACKNOWLEDGEMENTS |
This study was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant 1RO1-DK-51604-02.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
R. K. Mittal, Division of Gastroenterology 111-D, Veterans
Affairs Medical Center, San Diego, 3350 La Jolla Village Drive, San
Diego, CA 92161 (E-mail:
rmittal{at}ucsd.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.
May 1, 2002;10.1152/ajpgi.00080.2002
Received 23 February 2002; accepted in final form 29 April 2002.
 |
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