Neurogastroenterol Motil (2005) 17 (Suppl.
1), 13–21
The lower oesophageal sphincter
G. E. BOECKXSTAENS
Division of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
Abstract The lower oesophageal sphincter (LOS) is a
specialized segment of the circular muscle layer of the
distal oesophagus, accounting for approximately 90%
of the basal pressure at the oesophago-gastric junc-
tion. Together with the crural diaphragm, it functions
as an antireflux barrier protecting the oesophagus
from the caustic gastric content. During swallowing
or belching, the LOS muscle must relax briefly in
order to allow passage of food or intragastric air.
These swallow-induced and prolonged transient lower
oesophageal sphincter relaxations (TLOSRs) respect-
ively result from activation of the inhibitory motor
innervation of the sphincter. Both in man and ani-
mals, the main neurotransmitter released by the
inhibitory neurones is nitric oxide.The two typical
examples of dysfunction of the LOS are achalasia and
gastro-oesophageal reflux disease (GORD). Achalasia
is characterized by reduction or even absence of the
inhibitory innervation to the LOS, leading to
impaired LOS relaxation with dysphagia and stasis of
food in the oesophagus. On the contrary, GORD
results from failure of the antireflux barrier, with
increased exposure of the oesophagus to gastric acid.
This leads to symptoms such as heartburn and
regurgitation, and in more severe cases to oesophagi-
tis, Barrett’s oesophagus and even carcinoma. To date,
TLOSRs are recognized as the main underlying
mechanism, and may represent an important target
for treatment. More insight in the pathogenesis of
both diseases will undoubtedly lead to new treat-
ments in the near future.
Keywords gastro-oesophageal reflux disease, lower
oesophageal sphincter, transient lower oesophageal
sphincter relaxation.
Address of correspondence
G. E. Boeckxstaens, Division of Gastroenterology, Academic
Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The
Netherlands.
Tel.: +31 20 566 3632; Fax: +31 20 691 7033;
e-mail: g.e.boeckxstaens@amc.uva.nl
Ó 2005 Blackwell Publishing Ltd
INTRODUCTION
The junction between the oesophagus and the stomach
is a specialized region, composed of the lower oeso-
phageal sphincter (LOS) and its adjacent anatomic
structures, the gastric sling and the crural diaphragm.1
Together these structures function to prevent reflux of
gastric contents across the oesophago-gastric junction
(OGJ) into the oesophagus while at the same time the
passage of ingested food into the stomach must be
guaranteed. Somewhat related to the latter, the LOS
high-pressure zone should also allow retrograde pas-
sage of gastric contents into the oesophagus during
belching or vomiting. This complicated task is
achieved by a high-pressure zone, which keeps the
junction between the oesophagus and the stomach
continuously closed, but which is still able to relax
briefly via input from inhibitory neurones to permit
passage through the sphincter. This manuscript will
mainly focus on the LOS, however, it is important to
stress that in particular the crural diaphragm also plays
a crucial role in the physiology and pathophysiology of
the OGJ.
ANATOMY/INNERVATION
The LOS is a specialized thickened region of the
circular muscle layer of the distal oesophagus, in
humans extending over an axial distance of 2–3 cm.
Sensory information from the LOS to the brain is
conveyed by both spinal and vagal sensory afferents.2,3
The spinal afferents have their cell bodies in the dorsal
root ganglia at T1 to L3,4 and are believed to detect
mainly nociceptive stimuli. The vagal afferents with
their cell bodies in the nodose ganglia transmit non-
painful sensory information to the brain stem where
the central terminations synapse in the nucleus tractus
solitarius. The neurones of this nucleus tractus solita-
rius are closely connected with the dorsal motor
nucleus of the vagal nerve. The latter provides the
motor innervation to the LOS and contains the efferent
neurones that can either increase or decrease LOS tone
by stimulation of inhibitory or excitatory motor
13
G. E. Boeckxstaens
neurones in the myenteric plexus of the LOS. The
rostral neurones in the dorsal motor nucleus of the
vagal nerve preferentially innervate the excitatory
myenteric neurones whereas the neurones in the caudal
regions innervate inhibitory motor neurones.5,6 The
excitatory myenteric neurones in the LOS are choliner-
gic in nature and act to stimulate muscarinic receptors
on the smooth muscle.7 Inhibitory motor neurones to
the LOS are abundant and receive powerful cholinergic
nicotinic inputs from the vagal efferents.7 Although
the vagal nerve innervates both inhibitory and excita-
tory myenteric motor neurones, vagal stimulation in
experimental protocols generally results in LOS
relaxation.8–10 In some species however, a complex
motor response consisting of three phases (a brief
relaxation followed by a brief contraction and a pro-
longed relaxation) has been reported in response to
vagal nerve stimulation.11,12 On the contrary, splanch-
nic nerve stimulation relaxes the LOS by activation of
adrenergic neurones probably via nicotinic and non-
nicotinic mechanisms of neural transmission, which in
turn elicit b-adrenergic inhibitory effects on the LOS.11
The inhibitory myenteric neurones innervating the
LOS are nitrergic in nature. Both in vitro and in vivo
studies in many different species have shown that LOS
relaxation to electrical field stimulation (EFS), vagal
nerve stimulation or swallowing are blocked by inhib-
itors of nitric oxide synthase (NOS) or the NO/cGMP
pathway.9,10,13–15 However, other neurotransmitters
including ATP, vasoactive intestinal peptide (VIP) and
carbon monoxide may be involved. For example, in the
opossum, EFS induces a biphasic relaxation with a
rapid initial and a slower sustained relaxation. The first
phase is clearly nitrergic, however the second one is
mediated by an as yet unidentified neurotransmitter.
Although VIP has been suggested as inhibitory neuro-
transmitter in the LOS, VIP antagonists or VIP anti-
serum did not antagonize the second phase of the
relaxation,16,17 suggesting that other mediators are
released. Not only in animals, but also in humans
evidence has been reported illustrating the importance
of NO in the LOS.18–21
HIGH-PRESSURE ZONE AT THE
OESOPHAGO-GASTRIC JUNCTION
The LOS is a specialized part of the circular smooth
muscle of the distal oesophagus, with a length of
approximately 4 cm. In healthy volunteers, this part
of the sphincter complex generates a tonic pressure of
15–30 mmHg above the intragastric pressure,22
strongly varying during the day,23 and accounting for
approximately 90% of the basal pressure at the OGJ.
14
Neurogastroenterology and Motility
The basal resting tone most likely results from the
relatively depolarized resting membrane potential of
the smooth muscle cells compared with the adjacent
tissue.7 In the opossum LOS, the depolarized resting
membrane potential contributes to the spontaneous
release of Ca2+ from the sarcoplasmatic reticulum
activating Ca2+-activated Cl) currents that in turn lead
to continuous spike-like action potentials and the
generation of basal tone.24 Other studies suggest
regional electrophysiological differences in ion-chan-
nel diversity as underlying mechanism.25 In addition to
the myogenic properties of the LOS, neurogenic mech-
anisms can contribute as well.
As reflux mainly occurs when LOS pressure is below
5 mmHg, basal LOS pressure should be sufficient to
protect against the pressure gradient between the
stomach and the oesophagus.26 However, with increas-
ing abdominal pressure, such as during inspiration and
straining an additional compensatory mechanism is
required. This function is fulfilled by the crural
diaphragm or the ÔexternalÕ component of the oesoph-
ago-gastric sphincter which encloses the proximal
2 cm of the LOS and contracts during each inspira-
tion.27–29 The crural diaphragm will not only prevent
ÔstressÕ reflux, but also reflux during periods of absent
LOS pressure. Elegant studies show that even in the
absence of basal LOS pressure, manoeuvres that
increase abdominal pressure fail to induce gastro-
oesophageal reflux.27,30 Moreover, additional studies
showed that reflux mainly occurs when the crural
diaphragm is inhibited during LOS relaxation, illustra-
ting the importance of the crural diaphragm.31
Together, the internal and external components of
the sphincter complex generate the typical pressure
profile at the OGJ. When the two sphincters are
separated however, as in patients with a hiatal hernia,
the pressure profile changes significantly into two
separated low-pressure zones.32 These findings further
imply that the smooth muscle and the crural-striated
muscle components strengthen each other and func-
tion as a well coordinated and efficient sphincter
region, a condition very similar to the sphincter
complex at the anorectum.
SWALLOW-INDUCED RELAXATION AND
TRANSIENT LOWER OESOPHAGEAL
RELAXATION
One of the main functions of the LOS is to create a
high-pressure zone to protect the oesophagus against
reflux from caustic gastric contents. However, the LOS
withdraws from this function temporarily and relaxes
during swallowing and belching in order to allow
Ó 2005 Blackwell Publishing Ltd
Volume 17, Supplement 1, June 2005 Lower oesophageal sphincter

passage of ingested food or intragastric content (mainly
air) in appropriate directions.
Swallow-induced relaxation is part of primary peri-
stalsis, a complex reflex generated by the swallowing
program generator in the swallowing centre in the
brain stem.33 It involves activation of sensory afferents
in the pharyngeal area (superior laryngeal nerve, glos-
sopharyngeal nerves) connected to the neurones of the
swallowing centre. These neurones also receive input
from other areas of the central nervous system, partic-
ularly from the cerebral cortex and regional afferents
from the pharyngo-oesophageal tube.2,3 Although the
brain stem neurones that constitute the swallowing
centre are not well understood, they are most likely
located in the nucleus of the solitary tract and the
adjoining reticular formation.3 Stimulation of the
superior laryngeal nerve at high frequencies elicits
either a full swallowing response and lower frequency
stimulation results in isolated small LOS relaxation.34
In addition to swallowing, the LOS relaxes also as part
of secondary peristalsis. The pathways and brain
centres involved are described in more detail else-
where.2,3
Electrical stimulation of afferent vagal fibres (ventral
branch of the subdiaphragmatic vagus nerve) arising
from the stomach rather induces isolated, i.e. in the
absence of peristalsis, frequency-dependent relaxation
of the LOS.35 Most likely, this neural pathway is
involved in the generation of the so-called transient
lower oesophageal relaxations (TLOSRs). These are
prolonged relaxations of the LOS in the absence of
swallowing, believed to underlie belching and to
constitute the main mechanism during which gastro-
oesophageal reflux occurs36,37 (Fig. 1). Mainly from
animal studies, it is believed that TLOSRs are medi-
ated by a vagovagal reflex pathway as they are
abolished by vagal cooling.38 The TLOSRs are triggered
by activation of gastric vagal afferents resulting from
distension of the stomach, in particular the subcardiac
region. These vagal afferents synapse in the nucleus of
the solitary tract to activate motor neurones in the
dorsal motor nucleus of the vagal nerves relaxing the
LOS. Interestingly, the crural diaphragm is also inhib-
ited during TLOSRs. This observation has led to the
assumption that TLOSRs are mediated by a pattern
generator in the brain stem not only sending projec-
tions to the dorsal nucleus of the vagus nerve, but also
to the nucleus of the phrenic nerve located in the
cervical spinal cord1 (Fig. 2). However, no immunoh-
istochemical studies are yet available providing ana-
tomical evidence for this pathway.
LOS DYSFUNCTION IN DISEASE
In the following paragraphs, two typical examples of
dysfunction of the LOS will be described. Achalasia is
chosen as example of impaired relaxation of the LOS,
whereas gastro-oesophageal reflux disease (GORD) is
selected to illustrate the consequences of an impaired
antireflux capacity of the oesophago-gastric region.
Achalasia
As described above, the LOS pressure decreases upon
swallowing in order to allow passage of the ingested
food to the stomach. In patients with achalasia how-
ever, manometry typically shows an incomplete relax-
ation of the LOS upon deglutition39,40 (Fig. 3A). In
addition, oesophageal peristalsis is absent and resting
tone of the LOS will often be elevated. The net result of
these motor abnormalities is that saliva and food will
be retained in the oesophagus leading to the typical
symptoms of achalasia: dysphagia for both solids and
liquids, regurgitation of undigested food, respiratory
complications (nocturnal cough and aspiration), chest
pain and weight loss.41 In clinical practice, the

7
pH 4
1
140

Pharynx 0
140

0
140

Oesoph. 0
140
body
0
140

0
70
Figure 1 Manometric tracing showing a
typical example of a transient lower
LOS 0
70
oesophageal sphincter relaxation TLOSR Swallow
Stomach 0
(TLOSR) accompanied by a reflux epi-
sode and a swallow-induced relaxation. 30 s 25 mmHg

Ó 2005 Blackwell Publishing Ltd 15

G. E. Boeckxstaens Neurogastroenterology and Motility

not elsewhere in the gastrointestinal tract remains

Efferent Vagal
Pattern
limb nerve
generator
Afferent
Phrenic nerve
limb
Figure 2 Schematic representation of the neural pathway
involved in the triggering of transient lower oesophageal
sphincter relaxations (TLOSRs).
diagnosis is made preferably by manometry, after
exclusion of organic causes of dysphagia. Endoscopy
is diagnostic in about one-third and radiology in about
two-third of the patients; diagnostic certainty is
provided by manometry in over 90% of cases.42
Although achalasia is the best characterized oeso-
phageal motor disorder, its pathogenesis is still incom-
pletely elucidated.43 Histological examination reveals
a significant decrease in the number of myenteric
neurones, especially inhibitory NO releasing neurones
in the distal oesophagus and at the level of the LOS.44
Why exactly these neurones disappear at this level and
unclear. Detailed examination of resection specimens
shows infiltration of myenteric ganglia with CD3-/
CD8-positive lymphocytes expressing activation mark-
ers.45,46 In addition, immunoglobulin M (IgM) antibod-
ies and evidence of complement activation was shown
within myenteric ganglia.47 Finally, antibodies against
myenteric neurones have been repeatedly shown in
serum of achalasia patients,48,49 especially in patients
with a specific human leucocyte antigen (HLA) geno-
type, namely those carrying the DQA1*0103 and
DQB1*0603 alleles.50 These findings all point towards
an autoimmune origin of the myenteric ganglionitis.
The exact stimulus initiating this autoimmune
response or the antigen targeted remain, however to
be identified. Some studies suggest a previous viral
infection as possible trigger, however others fail to
confirm this.47,51–53 Other investigators have also
demonstrated antineuronal antibodies in serum from
GORD patients, suggesting that the antineuronal
antibodies are generated in response to tissue damage
and thus rather represent an epiphenomenon and not a
causative factor.49
The loss of the nitrergic neurones results in the
absence of relaxation of the LOS in response to various
stimuli both in vitro and in vivo. Muscle strips taken
from the LOS of patients with achalasia fail to relax in
response to EFS54,55 (Fig. 3B). In addition, infusion of
cholecystokinin, known to relax the LOS in healthy
volunteers, contracts the LOS in patients with achal-
asia56 and LOS relaxation to oesophageal distension is
reduced.57 Finally, gastric distension fails to induce
TLOSRs in achalasics,58 further illustrating the
absence of inhibitory innervation to the LOS.

A B

Control
EFS NO

Figure 3 (A) Manometric tracing of

swallow-induced peristalsis and lower
oesophageal sphincter (LOS) relaxation
in a healthy control subject. Note the
absence of peristalsis and LOS relaxation
2 10 20 40 in a tracing obtained from a patient with
Hz 3.10–7 10–6 M
achalasia. (B) Representative tracings
Achalasia from muscle strips of the LOS of a con-
EFS NO trol subject and a patient with achalasia.
In control tissue, electrical field stimu-
Control Achalasia lation (EFS) results in frequency-
dependent relaxations, mimicked by ni-
2 10 20 3.10–7 M
Hz tric oxide (NO). In contrast, EFS-induced
relaxation is significantly impaired in
achalasia, whereas the response to NO is
similar to that in control tissue.

16 Ó 2005 Blackwell Publishing Ltd

Volume 17, Supplement 1, June 2005
Treatment of achalasia is aimed at improving bolus
transport across the LOS. As the damage to the
neurones is irreversible, the only therapeutic option
is reduction of LOS pressure to decrease the resistance
to flow at the OGJ. At present, treatment options in
achalasia are pharmacotherapy, pneumatic dilation,
surgery or injection of botulinum toxin.59–64 Although
several studies have reported some degrees of success
using calcium-channel blockers or nitrates, these types
of treatment are only useful in less severe types of
achalasia. They are associated with cardiovascular
side-effects and they are generally less efficacious.
Pneumatic dilation aims at disruption of the LOS by
forceful dilatation using an air-filled balloon. Follow-
up studies have indicated that the best predictor for a
long-term remission is a residual sphincter pressure
below 10 mmHg.65 Pneumatic dilation yields good to
excellent results in 70–80% of patients, especially in
patients over 45 years old, in patients with a longer
standing history (>5 years of symptoms) and in patients
with a slightly dilated oesophagus. An alternative to
pneumatic dilation is per-endoscopic injection of bot-
ulinum toxin in the LOS, an easy and patient-friendly
procedure.64 The mechanism of action consists of a
temporarily blockade of release of acetylcholine from
excitatory motor neurones at the level of the LOS.
Although the initial rate of symptomatic benefit may
be comparable with that of pneumatic dilations, the
effect wears off quickly in many patients,63 making
this treatment less attractive. Surgical myotomy, now
performed via a laparoscopic approach, is increasingly
performed and has become the treatment of choice in
many centres. Via laparoscopic route, a myotomy
combined with an antireflux procedure is applied
leading to reported success rates of 80–90%.62 Whether
this rather new approach is superior to pneumatic
dilation is still unclear and needs further study.
Unfortunately, none of these therapies corrects the
underlying abnormality. Recent studies in mice how-
ever, suggest that transplantation of neuronal stem
cells may be a therapeutical option. Indeed, neuronal
stem cells injected in the pylorus survived and even
expressed NO synthase.66 The advantage of such a
technique would be that not only sphincter function
will be restored, but perhaps even peristalsis. Clearly, a
lot of research remains to be done further exploring
this approach.
Gastro-oesophageal reflux disease
Gastro-oesophageal reflux disease is one of the most
common gastrointestinal disorders resulting from
abundant exposure of the oesophagus to gastric
Ó 2005 Blackwell Publishing Ltd
Lower oesophageal sphincter
components such as acid, pepsin and bile. Especially
with increasing acid and/or bile reflux, GORD can be
complicated by oesophageal intestinal metaplasia
(Barrett’s oesophagus), dysplasia and ultimately oeso-
phageal carcinoma. It was commonly believed that a
defective LOS pressure was the main mechanism
underlying reflux in GORD patients. However, especi-
ally in patients with non-erosive GORD, LOS pres-
sures are in the normal range.67 It was not until 1982
that Dodds et al. unravelled this discrepancy and
showed that the majority (65%) of GORD patients
have reflux episodes during a TLOSR.26 As mentioned
above, a TLOSR is a vagovagal reflex-mediated motor
pattern generated in the brain stem and triggered by
distension of the stomach with free air, inflation of an
intragastric balloon, or ingestion of a meal.37 Most
likely, stretch receptors rather than tension receptors
in the subcardiac region mediate this response to
distension.68,69
As TLOSRs account for the majority of reflux
episodes, one would assume that GORD patients have
more TLOSRs. However, studies have reported con-
flicting results with both increased and normal
TLOSRs rates in GORD patients.70 A more consistent
finding is that the probability of reflux during TLOSRs
is doubled in patients with GORD.70 In addition,
studies using intraluminal impedance have character-
ized the patterns of gas and liquid reflux during a
TLOSR71 and provided evidence that the air-liquid
composition of the refluxate differs between patients
with GORD and controls.72,73 Why patients have an
increased percentage of TLOSRs accompanied by reflux
or which factors actually determine the composition of
the refluxate remain however, unclear. Possibly, a
difference in compliance of the OGJ,74 differences in
the meal distribution or the localization of the acid
pocket on top of the meal75 may be involved.
Another important factor leading to incompetence of
the antireflux barrier is the presence of a hiatal
hernia.76 This anatomic abnormality may promote
reflux via several mechanisms.1 Acid may be trapped in
the hiatal sac ready to reflux when the LOS relaxes
after swallowing or when the LOS pressure is low.77 In
addition, in the presence of a larger hiatal hernia, the
two components of the sphincter complex, namely the
LOS and crural diaphragm are disrupted leading to a
significant change in pressure profile and reduced basal
pressures.32
Based on the knowledge that TLOSRs are an import-
ant mechanism underlying GOR, it is now considered
an important target to treat GORD. The first evidence
that pharmacological blockade of TLOSRs is indeed
feasible and results in reduction of reflux episodes was
17
G. E. Boeckxstaens
reported in 1995.78 By now, several pharmacological
agents, such as cholecystokinin A antagonists,79 mor-
phine,80 glutamate antagonists,81 cannabinoids82 and
NOS inhibitors21 have been shown to reduce the
triggering of TLOSRs. So far, these drugs have not
reached clinical development mainly due to their
undesirable pharmacological profile and/or side-effects.
Recently, baclofen, a c-aminobutyric acid (GABAB)
receptor agonist clinically used in the management of
spasticity, was reported to reduce TLOSRs in animals83
and humans.84,85 c-Aminobutyric acid is an important
inhibitory neurotransmitter in the central nervous
system and is abundantly present in the medullary
centres controlling swallowing, oesophageal motility
and respiration.86 In particular, GABAB receptors are
expressed in LOS-projecting neurones of the motor
nucleus of the vagal nerve, and in the subnucleus
centralis of the nucleus tractus solitarius,87 both
important nuclei in the control of TLOSRs. In addition,
activation of peripheral GABAB receptors inhibits
gastric vagal mechanoreceptors and impairs vagal
motor outflow, further explaining the effect of baclofen
on TLOSRs.88,89 Unfortunately, baclofen has central
side-effects compromising its clinical use in GORD.
Therefore, the development of new analogues with a
different profile are certainly warranted.90
The TLOSRs are also reduced by antireflux surgery
most likely due to changes in the distensibility or
compliance of the cardiac region and/or damage to the
afferent innervation.91 Recently, several new endo-
scopic techniques have been developed to treat
GORD.92 The Stretta technique delivers radiofrequency
energy at the OGJ in order to remodel the OGJ or
achieve neurolysis of the LOS region. This method
improved the antireflux barrier by slightly increasing
LOS pressure and reducing the number of postprandial
TLOSRs.93 A randomized placebo-controlled study
however, failed to confirm this.94 Other techniques
such as Enteryx95 or Gatekeeper96 aim at bulking or
reinforcing of the LOS by submucosal delivery of an
inert material. Placebo-controlled studies evaluating
the efficacy of these techniques are, however still
lacking.
CONCLUSION
The LOS is a specialized segment of the circular
muscle layer of the distal oesophagus. Together with
the crural diaphragm, it creates a high-pressure zone
functioning as an antireflux barrier protecting the
oesophagus from the caustic gastric content. In order
to allow passage of food or intragastric air across this
barrier, the LOS muscle must relax briefly. The brief
18
Neurogastroenterology and Motility
relaxation is achieved by activation of the inhibitory
motor innervation of the sphincter. These inhibitory
neurones receive a prominent vagal input and mediate
the swallow-induced and the prolonged TLOSR. In the
past decades, insight into the physiology and patho-
physiology of the LOS has led to a better understanding
of diseases such as achalasia and GORD, and will
undoubtedly lead to new treatments in the near future.
REFERENCES
1 Mittal RK, Balaban DH. The esophagogastric junction.
N Engl J Med 1997; 336: 924–32.
2 Hornby PJ, Abrahams TP, Partosoedarso ER. Central
mechanisms of lower esophageal sphincter control. Gast-
roenterol Clin North Am 2002; 31(Suppl. 4): S11–S20.
3 Goyal RK, Padmanabhan R, Sang Q. Neural circuits in
swallowing and abdominal vagal afferent-mediated lower
esophageal sphincter relaxation. Am J Med 2001;
111(Suppl. 8A): 95S–105S.
4 Collman PI, Tremblay L, Diamant NE. The distribution of
spinal and vagal sensory neurons that innervate the
esophagus of the cat. Gastroenterology 1992; 103: 817–22.
5 Hyland NP, Abrahams TP, Fuchs K et al. Organization and
neurochemistry of vagal preganglionic neurons innervat-
ing the lower esophageal sphincter in ferrets. J Comp
Neurol 2001; 430: 222–34.
6 Rogers RC, Hermann GE, Travagli RA. Brainstem path-
ways responsible for oesophageal control of gastric motil-
ity and tone in the rat. J Physiol 1999; 514(Pt 2): 369–83.
7 Yuan S, Costa M, Brookes SJ. Neuronal pathways and
transmission to the lower esophageal sphincter of the
guinea pig. Gastroenterology 1998; 115: 661–71.
8 Paterson WG, Anderson MA, Anand N. Pharmacological
characterization of lower esophageal sphincter relaxation
induced by swallowing, vagal efferent nerve stimulation,
and esophageal distention. Can J Physiol Pharmacol 1992;
70: 1011–5.
9 Sivarao DV, Mashimo HL, Thatte HS et al. Lower eso-
phageal sphincter is achalasic in nNOS()/)) and hypo-
tensive in W/W(v) mutant mice. Gastroenterology 2001;
121: 34–42.
10 Yamato S, Saha JK, Goyal RK. Role of nitric oxide in lower
esophageal sphincter relaxation to swallowing. Life Sci
1992; 50: 1263–72.
11 Blackshaw LA, Haupt JA, Omari T et al. Vagal and sym-
pathetic influences on the ferret lower oesophageal
sphincter. J Auton Nerv Syst 1997; 66: 179–88.
12 Kawahara H, Blackshaw LA, Lehmann A et al. Responses
of the rat lower oesophageal sphincter (LOS) to vagal
efferent activation. Neurogastroenterol Motil 1997; 9: 85–
97.
13 De Man JG, Pelckmans PA, Boeckxstaens GE et al. The
role of nitric oxide in inhibitory non-adrenergic non-cho-
linergic neurotransmission in the canine lower oesopha-
geal sphincter. Br J Pharmacol 1991; 103: 1092–6.
14 Tottrup A, Svane D, Forman A. Nitric oxide mediating
NANC inhibition in opossum lower esophageal sphincter.
Am J Physiol 1991; 260(3 Pt 1): G385–9.
15 Conklin JL, Du C, Murray JA et al. Characterization and
mediation of inhibitory junction potentials from opossum
Ó 2005 Blackwell Publishing Ltd
Volume 17, Supplement 1, June 2005
lower esophageal sphincter. Gastroenterology 1993; 104:
1439–44.
16 Park H, Clark E, Conklin JL. Effects of phosphodiesterase
inhibitors on oesophageal neuromuscular functions. Neu-
rogastroenterol Motil 2003; 15: 625–33.
17 Uc A, Oh ST, Murray JA et al. Biphasic relaxation of the
opossum lower esophageal sphincter: roles of NO, VIP, and
CGRP. Am J Physiol 1999; 277(3 Pt 1): G548–54.
18 Preiksaitis HG, Tremblay L, Diamant NE. Nitric oxide
mediates inhibitory nerve effects in human esophagus
and lower esophageal sphincter. Dig Dis Sci 1994; 39:
770–5.
19 Tottrup A, Ny L, Alm P et al. The role of the L-arginine/
nitric oxide pathway for relaxation of the human lower
oesophageal sphincter. Acta Physiol Scand 1993; 149:
451–9.
20 Murray JA, Ledlow A, Launspach J et al. The effects of
recombinant human hemoglobin on esophageal motor
functions in humans. Gastroenterology 1995; 109: 1241–8.
21 Hirsch DP, Tiel-Van Buul MM, Tytgat GN et al. Effect of
L-NMMA on postprandial transient lower esophageal
sphincter relaxations in healthy volunteers. Dig Dis Sci
2000; 45: 2069–75.
22 Richter JE, Wu WC, Johns DN et al. Esophageal manom-
etry in 95 healthy adult volunteers. Variability of pressures
with age and frequency of ÔabnormalÕ contractions. Dig Dis
Sci 1987; 32: 583–92.
23 Schoeman MN, Tippett MD, Akkermans LM et al.
Mechanisms of gastroesophageal reflux in ambulant heal-
thy human subjects. Gastroenterology 1995; 108: 83–91.
24 Zhang Y, Paterson WG. Role of sarcoplasmic reticulum in
control of membrane potential and nitrergic response in
opossum lower esophageal sphincter. Br J Pharmacol 2003;
140: 1097–107.
25 Salapatek AM, Ji J, Diamant NE. Ion channel diversity in
the feline smooth muscle esophagus. Am J Physiol 2002;
282: G288–99.
26 Dodds WJ, Dent J, Hogan WJ et al. Mechanisms of gastr-
oesophageal reflux in patients with reflux esophagitis.
N Engl J Med 1982; 307: 1547–52.
27 Mittal RK, Rochester DF, McCallum RW. Sphincteric
action of the diaphragm during a relaxed lower esophageal
sphincter in humans. Am J Physiol 1989; 256(1 Pt 1):
G139–44.
28 Mittal RK. The crural diaphragm, an external lower eso-
phageal sphincter: a definitive study. Gastroenterology
1993; 105: 1565–7.
29 Mittal RK, Fisher M, McCallum RW et al. Human lower
esophageal sphincter pressure response to increased intra-
abdominal pressure. Am J Physiol 1990; 258(4 Pt 1): G624–
30.
30 Mittal RK, Fisher MJ. Electrical and mechanical inhibition
of the crural diaphragm during transient relaxation of the
lower esophageal sphincter. Gastroenterology 1990; 99:
1265–8.
31 Mittal RK, Chiareli C, Liu J et al. Characteristics of lower
esophageal sphincter relaxation induced by pharyngeal
stimulation with minute amounts of water. Gastroenter-
ology 1996; 111: 378–84.
32 Kahrilas PJ, Lin S, Chen J et al. The effect of hiatus hernia
on gastro-oesophageal junction pressure. Gut 1999; 44:
476–82.
Ó 2005 Blackwell Publishing Ltd
Lower oesophageal sphincter
33 Jean A. Brain stem control of swallowing: neuronal net-
work and cellular mechanisms. Physiol Rev 2001; 81: 929–
69.
34 Sang Q, Goyal RK. Swallowing reflex and brain stem
neurons activated by superior laryngeal nerve stimulation
in the mouse. Am J Physiol 2001; 280: G191–200.
35 Sang Q, Goyal RK. Lower esophageal sphincter relaxation
and activation of medullary neurons by subdiaphragmatic
vagal stimulation in the mouse. Gastroenterology 2000;
119: 1600–9.
36 Mittal RK, McCallum RW. Characteristics of transient
lower esophageal sphincter relaxation in humans. Am J
Physiol 1987; 252(5 Pt 1): G636–41.
37 Hirsch DP, Tytgat GN, Boeckxstaens GE. Transient lower
oesophageal sphincter relaxations–a pharmacological tar-
get for gastro-oesophageal reflux disease? Aliment Phar-
macol Ther 2002; 16: 17–26.
38 Martin CJ, Patrikios J, Dent J. Abolition of gas reflux
and transient lower esophageal sphincter relaxation by
vagal blockade in the dog. Gastroenterology 1986; 91:
890–6.
39 Hirano I, Tatum RP, Shi G et al. Manometric heterogen-
eity in patients with idiopathic achalasia. Gastroenterol-
ogy 2001; 120: 789–98.
40 Richter JE. Oesophageal motility disorders. Lancet 2001;
358: 823–8.
41 Vantrappen G, Hellemans J, Deloof W et al. Treatment of
achalasia with pneumatic dilatations. Gut 1971; 12: 268–
75.
42 Howard PJ, Maher L, Pryde A et al. Five year prospective
study of the incidence, clinical features, and diagnosis of
achalasia in Edinburgh. Gut 1992; 33: 1011–5.
43 Paterson WG. Etiology and pathogenesis of achalasia.
Gastrointest Endosc Clin N Am 2001; 11: 249–66, vi.
44 Mearin F, Mourelle M, Guarner F et al. Patients with
achalasia lack nitric oxide synthase in the gastro-oeso-
phageal junction. Eur J Clin Invest 1993; 23: 724–8.
45 Clark SB, Rice TW, Tubbs RR et al. The nature of the
myenteric infiltrate in achalasia: an immunohistochemi-
cal analysis. Am J Surg Pathol 2000; 24: 1153–8.
46 Goldblum JR, Rice TW, Richter JE. Histopathologic fea-
tures in esophagomyotomy specimens from patients with
achalasia. Gastroenterology 1996; 111: 648–54.
47 Storch WB, Eckardt VF, Junginger T. Complement com-
ponents and terminal complement complex in oesopha-
geal smooth muscle of patients with achalasia. Cell Mol
Biol (Noisy-le-grand) 2002; 48: 247–52.
48 Storch WB, Eckardt VF, Wienbeck M et al. Autoantibodies
to Auerbach’s plexus in achalasia. Cell Mol Biol (Noisy-le-
grand) 1995; 41: 1033–8.
49 Moses PL, Ellis LM, Anees MR et al. Antineuronal anti-
bodies in idiopathic achalasia and gastro-oesophageal
reflux disease. Gut 2003; 52: 629–36.
50 Ruiz-de-Leon A, Mendoza J, Sevilla-Mantilla C et al.
Myenteric antiplexus antibodies and class II HLA in
achalasia. Dig Dis Sci 2002; 47: 15–9.
51 Robertson CS, Martin BA, Atkinson M. Varicella-zoster
virus DNA in the oesophageal myenteric plexus in
achalasia. Gut 1993; 34: 299–302.
52 Castagliuolo I, Brun P, Costantini M et al. Esophageal
achalasia: is the herpes simplex virus really innocent?
J Gastrointest Surg 2004; 8: 24–30.
19
G. E. Boeckxstaens
53 Birgisson S, Galinski MS, Goldblum JR et al. Achalasia is
not associated with measles or known herpes and human
papilloma viruses. Dig Dis Sci 1997; 42: 300–6.
54 Tottrup A, Forman A, Funch-Jensen P et al. Effects of
postganglionic nerve stimulation in oesophageal achalasia:
an in vitro study. Gut 1990; 31: 17–20.
55 Boeckxstaens GE, Mebis J, Janssens J et al. Clinical rele-
vance of nitric oxide in the gut. Lancet 1994; 344: 129.
56 Dodds WJ, Dent J, Hogan WJ et al. Paradoxical lower
esophageal sphincter contraction induced by chole-
cystokinin-octapeptide in patients with achalasia.
Gastroenterology 1981; 80: 327–33.
57 Paterson WG. Esophageal and lower esophageal sphincter
response to balloon distention in patients with achalasia.
Dig Dis Sci 1997; 42: 106–12.
58 Holloway RH, Wyman JB, Dent J. Failure of transient
lower oesophageal sphincter relaxation in response to
gastric distension in patients with achalasia: evidence for
neural mediation of transient lower oesophageal sphincter
relaxations. Gut 1989; 30: 762–7.
59 Vakil N, Kadakia S, Eckardt VF. Pneumatic dilation in
achalasia. Endoscopy 2003; 35: 526–30.
60 West RL, Hirsch DP, Bartelsman JF et al. Long term
results of pneumatic dilation in achalasia followed
for more than 5 years. Am J Gastroenterol 2002; 97:
1346–51.
61 Zaninotto G, Annese V, Costantini M et al. Randomized
controlled trial of botulinum toxin versus laparoscopic
heller myotomy for esophageal achalasia. Ann Surg 2004;
239: 364–70.
62 Zaninotto G, Costantini M, Molena D et al. Minimally
invasive surgery for esophageal achalasia. J Laparoendosc
Adv Surg Tech A 2001; 11: 351–9.
63 Vaezi MF, Richter JE, Wilcox CM et al. Botulinum toxin
versus pneumatic dilatation in the treatment of achalasia:
a randomised trial. Gut 1999; 44: 231–9.
64 Pasricha PJ, Ravich WJ, Hendrix TR et al. Intrasphincteric
botulinum toxin for the treatment of achalasia. N Engl J
Med 1995; 332: 774–8.
65 Eckardt VF, Gockel I, Bernhard G. Pneumatic dilation for
achalasia: late results of a prospective follow up investi-
gation. Gut 2004; 53: 629–33.
66 Micci MA, Learish RD, Li H et al. Neural stem cells
express RET, produce nitric oxide, and survive transplan-
tation in the gastrointestinal tract. Gastroenterology 2001;
121: 757–66.
67 Kahrilas PJ, Dodds WJ, Hogan WJ et al. Esophageal peri-
staltic dysfunction in peptic esophagitis. Gastroenterology
1986; 91: 897–904.
68 Penagini R, Carmagnola S, Cantu P et al. Mechanorecep-
tors of the proximal stomach: role in triggering transient
lower esophageal sphincter relaxation. Gastroenterology
2004; 126: 49–56.
69 Franzi SJ, Martin CJ, Cox MR et al. Response of canine
lower esophageal sphincter to gastric distension. Am J
Physiol 1990; 259(3 Pt 1): G380–5.
70 Mittal RK, Holloway RH, Penagini R et al. Transient
lower esophageal sphincter relaxation. Gastroenterology
1995; 109: 601–10.
71 Sifrim D, Silny J, Holloway RH et al. Patterns of gas and
liquid reflux during transient lower oesophageal sphincter
relaxation: a study using intraluminal electrical imped-
ance. Gut 1999; 44: 47–54.
20
Neurogastroenterology and Motility
72 Sifrim D, Holloway R, Silny J et al. Composition of the
postprandial refluxate in patients with gastroesophageal
reflux disease. Am J Gastroenterol 2001; 96: 647–55.
73 Sifrim D, Holloway R, Silny J et al. Acid, nonacid, and gas
reflux in patients with gastroesophageal reflux disease
during ambulatory 24-hour pH-impedance recordings.
Gastroenterology 2001; 120: 1588–98.
74 Pandolfino JE, Shi G, Trueworthy B et al. Esophagogastric
junction opening during relaxation distinguishes nonher-
nia reflux patients, hernia patients, and normal subjects.
Gastroenterology 2003; 125: 1018–24.
75 Fletcher J, Wirz A, Young J et al. Unbuffered highly acidic
gastric juice exists at the gastroesophageal junction after a
meal. Gastroenterology 2001; 121: 775–83.
76 Kahrilas PJ. The role of hiatus hernia in GERD. Yale J Biol
Med 1999; 72: 101–11.
77 Sloan S, Kahrilas PJ. Impairment of esophageal emptying
with hiatal hernia. Gastroenterology 1991; 100: 596–605.
78 Mittal RK, Holloway R, Dent J. Effect of atropine on the
frequency of reflux and transient lower esophageal
sphincter relaxation in normal subjects. Gastroenterology
1995; 109: 1547–54.
79 Boeckxstaens GE, Hirsch DP, Fakhry N et al. Involvement
of cholecystokinin A receptors in transient lower esopha-
geal sphincter relaxations triggered by gastric distension.
Am J Gastroenterol 1998; 93: 1823–8.
80 Penagini R, Bianchi PA. Effect of morphine on gastro-
esophageal reflux and transient lower esophageal sphincter
relaxation. Gastroenterology 1997; 113: 409–14.
81 Hirsch DP, Tytgat GN, Boeckxstaens GE. Is glutamate
involved in transient lower esophageal sphincter relaxa-
tions? Dig Dis Sci 2002; 47: 661–6.
82 Lehmann A, Blackshaw LA, Branden L et al. Cannabinoid
receptor agonism inhibits transient lower esophageal
sphincter relaxations and reflux in dogs. Gastroenterology
2002; 123: 1129–34.
83 Lehmann A, Antonsson M, Bremner-Danielsen M et al.
Activation of the GABA(B) receptor inhibits transient
lower esophageal sphincter relaxations in dogs. Gastroen-
terology 1999; 117: 1147–54.
84 Zhang Q, Lehmann A, Rigda R et al. Control of transient
lower oesophageal sphincter relaxations and reflux by the
GABA(B) agonist baclofen in patients with gastro-oeso-
phageal reflux disease. Gut 2002; 50: 19–24.
85 Lidums I, Lehmann A, Checklin H et al. Control of tran-
sient lower esophageal sphincter relaxations and reflux by
the GABA(B) agonist baclofen in normal subjects. Gas-
troenterology 2000; 118: 7–13.
86 Blackshaw LA. Receptors and transmission in the brain-
gut axis: potential for novel therapies: IV. GABA(B)
receptors in the brain-gastroesophageal axis. Am J Physiol
2001; 281: G311–5.
87 McDermott CM, Abrahams TP, Partosoedarso E et al. Site
of action of GABA(B) receptor for vagal motor control of
the lower esophageal sphincter in ferrets and rats. Gas-
troenterology 2001; 120: 1749–62.
88 Smid SD, Young RL, Cooper NJ et al. GABA(B)R expressed
on vagal afferent neurones inhibit gastric mechanosensi-
tivity in ferret proximal stomach. Am J Physiol 2001; 281:
G1494–501.
89 Partosoedarso ER, Young RL, Blackshaw LA. GABA(B)
receptors on vagal afferent pathways: peripheral and
central inhibition. Am J Physiol 2001; 280: G658–68.
Ó 2005 Blackwell Publishing Ltd
Volume 17, Supplement 1, June 2005
90 Boeckxstaens GE, Tytgat GN. More pathophysiologically
oriented treatment of GORD? Lancet 2002; 359: 1267–8.
91 Ireland AC, Holloway RH, Toouli J et al. Mechanisms
underlying the antireflux action of fundoplication. Gut
1993; 34: 303–8.
92 Lehman GA. The history and future of implantation
therapy for gastroesophageal reflux disease. Gastrointest
Endosc Clin N Am 2003; 13: 157–65, xi.
93 Tam WC, Schoeman MN, Zhang Q et al. Delivery of
radiofrequency energy to the lower oesophageal sphincter
and gastric cardia inhibits transient lower oesophageal
sphincter relaxations and gastro-oesophageal reflux in
patients with reflux disease. Gut 2003; 52: 479–85.
Ó 2005 Blackwell Publishing Ltd
Lower oesophageal sphincter
94 Corley DA, Katz P, Wo JM et al. Improvement of gastr-
oesophageal reflux symptoms after radiofrequency energy:
a randomized, sham-controlled trial. Gastroenterology
2003; 125: 668–76.
95 Johnson DA, Ganz R, Aisenberg J et al. Endoscopic
implantation of Enteryx for treatment of GERD: 12-month
results of a prospective, multicenter trial. Am J Gast-
roenterol 2003; 98: 1921–30.
96 Fockens P. Gatekeeper Reflux Repair System: technique,
pre-clinical, and clinical experience. Gastrointest Endosc
Clin N Am 2003; 13: 179–89.
21