A teaching module on cellular control of small intestinal motility

Article (PDF Available)inNeurogastroenterology and Motility 17 Suppl 3(s3):4-19 · November 2005with13 Reads
DOI: 10.1111/j.1365-2982.2005.00712.x · Source: PubMed
A teaching module on cellular control of small intestinal
motility
THE VARENNA GROUP (M. COSTA,* K. M. SANDERS,** M. SCHEMANN, T. K. SMITH,** I. J. COOK, R. DE GIORGIO,à
J. DENT,§ D. GRUNDY, *T. SHEA-DONOHUE,àà M.TONINI§§&S.J.H.BROOKES*)
*Department of Human Physiology and Centre for Neuroscience, Flinders University, Bedford Park, South Australia
Department of Gastroenterology, The St George Hospital, University of New South Wales, Kogarah, New South Wales, Australia
àDepartment of Internal Medicine and Gastroenterology, University of Bologna, Italy
§Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, South Australia, Australia
Department of Biomedical Science, The University of Sheffield, Sheffield, UK
**Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno Nevada, USA
Department of Human Biology, Center of Life and Food Sciences, Technical University Munich, Freising-Weihenstephan,
Germany
ààMucosal Biology Research Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
§§Department of Physiological and Pharmacological Sciences, University of Pavia, Pavia, Italy
INTRODUCTION
Motility plays an important role in the digestive
process. This lecture/review illustrates a little of the
extensive literature of human and animal recording of
motility in a few figures which are designed to be used
as teaching tools. It is limited to the small intestine and
aims to show how the complex patterns of behaviour of
the small intestine can be explained on the basis of the
properties of the different types of intestinal cells and
tissues.
Address for correspondence
Professor Simon Brookes, Department of Physiology, School of Medicine, Flinders University, PO Box 2100, Adelaide 5001, SA,
Australia.
Tel: 61 8 8204 4201; fax:61 8 8204 5768; e-mail: simon.brookes@flinders.edu.au
Slides shown in this article will be available, from late September 2005, via links at http://www.gastrosource.com.
Figure 1 The small intestine (duodenum, jejunum and
ileum) receives content from the stomach and is
involved in ensuring its appropriate mixing and pro-
pulsion to the large intestine allowing time for digestion
and absorption of nutrients to take place. In humans,
the small intestine is approximately 4 m long and motor
activity is highly coordinated between longitudinal and
circular muscle layers.
Neurogastroenterol Motil (2005) 17(Suppl. 3), 4–19
4 Ó 2005 Blackwell Publishing Ltd
described in the literature: they include a variety of
mixing and propulsive movements and characteristic activity that takes place during fasting.
simultaneously excited by enteric neurons, the ampli-
tude of slow waves exceeds a threshold, sufficient to generate Ca
2+
dependent smooth muscle action potentials.
Fig. 4 shows a series of slow waves with action potentials superimposed at the peak of each slow wave. The second
trace shows that the action potentials are blocked by the drug, nifedipine, indicating that they are primarily due to
entry of Ca
2+
via L-type channels. When slow waves trigger Ca
2+
action potentials, they are associated with powerful
contractions. Inhibition of the Ca
2+
action potentials blocks most of the contractile response.
Figure 4 The musculature of the small intestine is
composed of a functional syncytium of smooth muscle
cells organized in different layers, namely the longi-
tudinal, circular and the muscularis mucosae. Record-
ings of electrical activity from the muscle reveal
underlying mechanisms of the spontaneous phasic
contractions of the muscle. Human intestinal muscles
generate spontaneous slow waves, which are small
depolarizations in membrane potential. These oscilla-
tions have also been called Ôbasic electrical rhythmÕ,
Ôpacesetter potentialsÕ, Ôcontrol potentialsÕ and Ôelectrical
control activityÕ. Slow waves occur continuously,
regardless of whether the small intestine is in the fed or
fasting state. When small intestinal smooth muscle is
Figure 2 In order to ensure an appropriate progress of
chyme along the small intestine, coordinated contrac-
tion and relaxation of the gastrointestinal (GI) muscu-
lature is required. The digestion and absorption of
macromolecular nutrients requires adequate contact
with the mucosa and mixing with enzymes and bile
acids. This requires significant mixing. The absorption
of digestion products requires stirring to maximize
contact between nutrient molecules and epithelial cell
membranes. Finally, slow propulsion of chyme in an
overall aboral direction must occur to deliver the con-
tents to the large intestine, but at a pace that allows the
completion of digestion and absorption. Motor patterns
optimized to achieve these requirements have been
Figure 3 Since the late 1800s, recordings from living
animals and humans showed that the small intestine is
seldom at rest. Phasic changes of intraluminal pressure
have been repeatedly described. Subsequent
investigations established that these were due to con-
tractions and relaxations of the muscular wall of the
intestine, suggesting that the intestinal muscle is
spontaneously active. Frequencies of contractions range
from 3–50 min
)1
, depending of the species and region of
GI tract studied.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
contractions. Fig. 5 shows typical slow wave activity
recorded from canine circular muscles from different regions of gut. Slow waves consist of a relatively rapid upstroke
depolarization, partial repolarization and a sustained plateau depolarization before full repolarization. Note
differences in frequency and waveform in the various organs, but also note that the maximum level of depolarization
reaches approximately the same level in each tissue.
rhythmic contraction of the muscle. In the longitudinal
muscle, these contractions are associated with phasic shortening or changes in tension. In the circular muscle, these
contractions result in the reduction in the diameter or in phasic increases in intraluminal pressure. The literature is
full of recordings of these phasic contractions generated by myogenic mechanisms.
1,3–5
In some cases, sufficient
calcium may enter during slow waves even in the absence of action potentials to produce small contractions.
Figure 5 Other regions of the GI tract, beside the small
intestine, also typically show phasic contractile activ-
ity, which is organized by the electrical slow waves.
Slow waves result in an oscillation in membrane
potential from quite negative values, to less negative
(i.e. )40 to )25 mV), where the open probability for
voltage-dependent Ca
2+
channels increases. During the
period of increased Ca
2+
channel opening, Ca
2+
enters
smooth muscle cells and causes transient contraction.
During the period of membrane repolarization to more
negative values, Ca
2+
is removed from cells or seques-
tered into intracellular stores and the muscle cells relax.
Thus, slow waves force the mechanical behaviour of
phasic GI muscle into a series of transient (phasic)
Figure 6 The relationship between smooth muscle
membrane-potential and contraction has been clarified
in recent years. If a slow wave depolarizes cells above a
threshold membrane potential (usually about )40 mV),
this activates enough L-type Ca
2+
channels to produce
Ômechanically-productiveÕ entry of Ca
2+
. In some regions
of the GI tract, Ca
2+
-dependent action potentials can be
initiated by supra-threshold depolarization. If the slow
wave fails to reach threshold, for example when smooth
muscle is inhibited by enteric inhibitory motor neurons,
then calcium entry is minimal and little or no con-
traction ensues (fig. 6). In the small intestine when the
slow waves reach threshold, bursts of action potentials
occur within a limited time window
1,2
The result is
6
Ó 2005 Blackwell Publishing Ltd
The Varenna Group Neurogastroenterology and Motility
have been identified in various layers of the gut wall. In
the small intestine, ICC near the myenteric plexus are important pacemakers. They have prominent fusiform nuclei
and multiple thin processes running in each direction. The ICC in fig. 8 were fluorescently labelled using antibodies
raised against the kit receptor tyrosine kinase.
Figure 8 Over previous decades, it was realized that
the propagation of slow waves could not be readily
explained by the conduction properties of the smooth
muscle syncytium. It was established that action pot-
entials only propagated for very short distances, whereas
slow waves often propagated for several intestinal
diameters. One or more additional mechanisms had to
be involved. The Interstitial Cells of Cajal (ICC) have, in
the last decade, been identified as an important pace-
maker system. The ICC form mesh-like networks in the
pacemaker layers of the GI tract. The cells are coupled
together by gap junctions and also electrically coupled
to the adjacent smooth muscle cells. Several popula-
tions of ICC with different morphology and properties
Figure 7 The pattern of motor activity in the small
intestine depends on the spatio-temporal spread of slow
waves. There is a broad consensus that slow waves
propagate along the gut. Mapping the origin and spread
of slow-wave electrical activity demonstrates this very
elegantly.
6
The mapping in this case was achieved by
recording slow waves with an array of 240 silver wires
positioned on the serosal surface of the duodenum. By
joining all electrodes in the array recording a slow-wave
peak at a particular time, the pattern of conduction in
the intestine is reconstructed. Reprinted from Lammers
et al. (1993),
6
with permission from the American
Physiological Society.
Figure 9 The roles of other types of ICC in pacing
small intestinal smooth muscle is yet to be ascertained.
Fig. 9 is a scanning electron micrograph showing some
of the cell types in the region of the myenteric plexus.
Myenteric ganglia (MG) form an extensive network of
nerve cell bodies and interganglionic processes. Inter-
stitial Cells of Cajal also form an extensive network in
this region. Fibroblast-like cells and macrophages (not
shown) are also common in this region. Smooth muscle
cells of the circular muscle layer can be seen beneath
the cells of the myenteric plexus region.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
other and with adjacent smooth muscle cells (inset).
Smooth muscle cells are also coupled to ICC (arrow head). Thus, ICC and smooth muscle cells form an extensive,
electrically coupled syncytium. Gap junctions between ICC form a means for pacemaking activity to be coordinated
and to propagate. Gap junctions with smooth muscle cells form a means for slow waves to spread to smooth muscle
cells.
This brief description of the muscular apparatus of the small intestine, comprised of the smooth muscle
syncytium and interconnected ICC, enables us to consider how the overall motor behaviour of the small intestine is
determined.
of irregular activity, where only some of the slow waves
are associated with action potential (phase II; grey areas in the figure). This is then followed by a period of intense
regular activity, in which every slow wave is associated with a burst of action potentials (phase III; black areas in the
figure). Finally there is a return to quiescence (sometimes called phase IV). Recording at multiple sites also reveals
the migratory character of the cyclic activity. Migrating myoelectric complex is also called the migrating motor
complex. Reprinted from Code and Marlett (1975),
8
with permission from Blackwell Publishing.
Figure 10 The location of pacemaker ICC varies along
the GI tract, with myenteric ICC playing a key role in
the small intestine, but submucosal ICC being import-
ant in the colon. Nevertheless, the fundamental struc-
ture of these cells and their connections with smooth
muscle cells share many characteristics. Fig. 10 shows
an electron micrograph of ICC at the submucosal border
of the circular layer in the canine proximal colon.
Smooth muscle cells are shown along the bottom left-
most region of the slide in cross-section adjacent to a
thin band of ICC, identified by their ultrastructural
features. They contain an abundance of mitochondria, a
prominent basal lamina, caveolae, rough endoplasmic
reticulum (RER), and form gap junctions with each
Figure 11 Studies over the last few decades have
revealed a striking pattern of behaviour, which occurs in
the preprandial (fasting) gut of omnivores and carnivores
but more or less continuously in herbivores. First des-
cribed by Szurszweski (1969), the migrating myoelectric
complex (MMC) can be revealed by recording myoelec-
trical or mechanical activity at multiple sites along the
small intestine.
7
Fig. 11 shows the fundamental features
of this behaviour in the stomach and small intestine, in
the fasted conscious dog.
8
Its key features are that it is
cyclic and it migrates (propagates) along the intestine.
There is a quiescent phase, during which slow waves are
present but with no associated action potentials (phase
I; flat line in the schematic figure), followed by a phase
8
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The Varenna Group Neurogastroenterology and Motility
phase III, all bursts propagate over at least three
recording sites. Reprinted from Summers and Dusdieker (1981),
11
with permission from the American
Gastroenterological Association.
Figure 14 One can ask what kind of patterns of
electrical and contractile activity occurs during the
different phases of the MMC. The issue was addressed
by Summers and Dusdieker (1981)
11
, using computer-
ized graphics to display the occurrence of bursts of
action potentials at multiple points along the intestine.
The top panel shows all action potential bursts; the
middle shows bursts that occurred only at a single site
(non-propagating); the bottom panel shows only bursts,
which propagated over three or more sites. The dark
oblique band in the top and bottom panels reflects phase
III of the MMC propagating aborally. In phase II, a
variable but significant proportion of bursts of action
potentials propagate aborally for significant distances,
but some are highly localized (middle panel). In
Figure 12 This cyclic electrical and mechanical activity
sweeps the small intestine at intervals of about
80–125 min in humans, with variable durations of the
different phases. The quiescent phase, in which none of
the slow waves is associated with action potentials,
lasts between 45–60 min, phase II lasts 30–45 min and
the phase III, in which all slow waves are associated
with action potentials, lasts only 5–10 min.
Figure 13 The MMC migrates slowly (about
10 cm min
)1
in human): calculations suggest that
when the regular motor activity of phase III reaches the
distal ileum, a new ÔfrontÕ starts in the duodenum. Thus
each phase occupies a significant portion of the length of
the small intestine. Fig. 13 shows the approximate
portions of the small intestine occupied by the three
phases as the complex migrates aborally. Phase III is
often referred to as the ÔfrontÕ of the complex, but is
actually preceded by the irregular activity of phase II. As
phase III passes, it leaves behind a trail of mechanical
quiescence (phase I) or irregular contractions (phase IV)
before quiescence.
9,10
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Volume 17, Supplement 3, October 2005 Small intestinal motility
phase II and III can thus be described as ÔperistalticÕ.
Figure 17 The pattern of phase III motor activity
occupies several tens of centimetre of small intestine at
any one moment. It consists of regular contractions (see
broken lines in fig. 17) occurring at the same frequency,
direction and speed as the slow waves (10–15 min
)1
propagating aborally at several centimetres per second
depending on species and region). The entire area, occu-
pied by this phase III activity also propagates aborally at a
slow rate (few cm min
)1
) (dotted line). In this way, the
entire area occupied by phase III is swept by highly
regular, propulsive waves of contractions which push
residual secretory and digestive contents aborally. This is
supplemented by the less intense and less coordinated
activity in phase II. Propagating contractions in
Figure 16 During phase II and III of the MMC, spike
bursts propagate for considerable distances and are often
associated with outflow of contents. Fig. 17 shows a
representation of spike burst propagation with associ-
ated outflow associated with bursts that progress along
the length of the recorded region (bottom trace).
Reprinted from Summers and Dusdieker (1981),
11
with
permission from the American Gastroenterological
Association.
Figure 15 In the same study, detailed analysis at higher
temporal resolution of phase II, recorded at 3-cm inter-
vals along the small intestine, showed that action
potentials (ÔspikesÕ) in phase III occur in synchrony with
the underlying slow waves. Spike bursts appearing in
adjacent electrodes are shaded to show their propaga-
tion. Note that the bursts propagate for varying distan-
ces along the intestine. Because smooth muscle action
potentials generate contraction, it would be expected
that shaded bands also correspond closely to propagated
(peristaltic) contractions. Reprinted from Summers and
Dusdieker (1981),
11
with permission from the American
Gastroenterological Association.
10
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The Varenna Group Neurogastroenterology and Motility
rise to intermittent and discontinuous areas being
suprathreshold for smooth muscle action potentials. Overall, peristaltic contractions generated in the MMC
depend on neural activity interacting with myogenic activity. How enteric motor neurons are activated in this cyclic
and migrating fashion is yet to be determined. As the MMC occurs in absence of nutrients, it is likely that this
pattern may be an intrinsic property of enteric neural circuits, rather than being triggered by physical or chemical
stimuli. If this were so, MMCs would be expected to occur in isolated preparations of small intestine. Marzio et al.
14
reported this in rabbit tissue. Preparations of stomach and initial part of the small intestine showed spontaneous
cyclic motor activity that slowly propagated aborally. In the mouse, long segments of distal small intestine and
attached large intestine show cyclic contractions which migrate aborally.
15
Similarly, in the rat isolated intestine,
migrating motor complexes were demonstrated in spatio-temporal maps of motor activity.
16
Fig. 19 shows an
example of slowly propagating areas of motor activity in the rat isolated small intestine as a spatio-temporal map.
White areas correspond to circular muscle contractions, darker areas correspond to dilation. The complexes consist
of circular muscle contractions (white areas) slowly propagating aborally (blue broken arrows) probably due to
activity in enteric neural circuits. Within the active areas, phasic regular contractions can be seen to propagate
rapidly aborally (yellow arrows) at the frequency and speed of the underlying slow waves.
Figure 19 Extensive literature demonstrates that the
initiation and migration of the MMC depend on the
neural circuits embedded in the gut wall, i.e. the enteric
nervous system. Extrinsic nerves also play an important
modulatory role.
12,13
The simplest explanation for
MMC activity is that excitatory motor neurons fire
tonically in the area occupied by phase III. This brings
slow waves above the threshold for action potentials
and thus causes contraction. The regular patterning
within the phase III region is thus due to myogenic
properties (muscle and pacemaker cells). In phase II, the
excitation by motor neurons is less intense, giving
Figure 18 The propagating contractions during phase III
of the interdigestive period clean the intestinal segment
from accumulated chyme. Because every wave starts
and ends a bit more distal to the previous one, the whole
area occupied by phase III slowly migrates in an aboral
direction.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
Figure 20 Peristalsis is a commonly used word to
describe intestinal propulsive behaviour. As there are
different possible mechanisms underlying such beha-
viour, a working definition should be inclusive of diverse
mechanisms. These include:
1. Any propagating, propulsive contraction of intestinal
circular muscle
2. Propagating, propulsive contraction of intestinal
circular muscle driven by content
3. Intermittent, propagating, propulsive contraction of
intestinal circular muscle, driven by content
4. Intermittent, propagating, propulsive contraction of
intestinal circular muscle, driven by content and
preceded by a region of relaxation.
Figure 22 The enteric nervous system in addition to
the myenteric plexus, also includes ganglionated
plexuses in the submucosa (from 1–3 distinguishable
submucous plexuses, varying between species) and
non-ganglionated plexuses of nerve fibres supplying the
muscle layers, blood vessels, glands and epithelium.
Figure 21 Having seen how complex activity during
MMCs arises from an interaction between myogenic
and neurogenic mechanisms, it is necessary to consider
the workings of the enteric neural circuits. The enteric
nervous system is composed of ganglionated plexuses
embedded within the gut wall. The myenteric plexus is
located between the external longitudinal muscle and
circular muscle layers and can be readily seen in a whole
tissue preparation stained by a simple histochemical
reaction for NADPH-diaphorase, which stains a large
proportion of enteric neurons and was found to be
identical to the nitric oxide synthase (NOS) enzyme.
12
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The Varenna Group Neurogastroenterology and Motility
Figure 24 Within each MG there are different
functional classes of enteric neurons, including motor
neurons, interneurons and primary afferent neurons,
organized in functional circuits that span several ganglia
along the small intestine. One of the major excitatory
transmitter of enteric neurons is acetylcholine. Neurons
that synthesize acetylcholine contain the enzyme
choline acetyltransferase (ChAT). Immunoreactivity for
ChAT reveals numerous cell bodies and some axons in a
preparation of human intestine.
Figure 25 In addition to acetylcholine, other transmit-
ters have been discovered in enteric neurons. Immu-
nohistochemical techniques have been used to reveal
the extraordinary range of chemicals contained in each
class of enteric neurons. Among these, in addition to
ChAT, are NOS, several neuropeptides, aminoacids and
amines. Multiple labelling immunohistochemistry
enables visualization of the several histochemical
classes of enteric neurons. Fig. 25 shows an example
of multiple labelling showing four classes distinguished
by pseudocolour according to the combination of
chemicals they contain.
Figure 23 The myenteric plexus forms a continuous net
along the small intestine. Using simple staining (in this
case, methylene blue), myenteric ganglion (MG) are
revealed in the guinea pig small intestine. The ganglia,
orientated circumferentially occur in somewhat irregu-
lar rows, spaced just under 500 lm apart. Longitudinally
running internodal strands join ganglia and a combina-
tion of faintly labelled secondary branches (running cir-
cumferentially) and fine tertiary plexus (irregularly lined
nerve trunks on the longitudinal muscle) are also visible.
There are up to 100 neurons in a ganglion and 500–1500
axons per internodal strand, with 1500 cells per square
millimetre.
17
The exact patterns and density of enteric
ganglia vary considerably between regions of gut and
between species.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
Recent work shows however that additional pathways,
including descending excitation are also involved in small intestinal peristalsis.
19,20
Figure 28 The enteric nervous system is involved not
just in generating the MMC, which generally occurs
when the upper gut is empty, but is also involved in
patterns of motor activity for the propulsion of nutrients
after a meal. In normal conditions, the MMC starts in
the stomach and propagates to the small intestine. In
carnivores and omnivores, feeding interrupts the MMC
for periods that depend on the caloric intake. Post-
prandial gastroduodenal motility is characterized by low
amplitudes antral contractions occurring at maximal
frequency, rhythmic opening and closing of the pyloric
sphincter and co-ordinated duodenal contractions
occurring in sequence with the antral waves.
Figure 27 The presence of enteric neurons with speci-
fic projections, particularly excitatory and inhibitory
motor neurons and some interneurons, provide the
basis for polarized (i.e. oral or aboral) responses to local
distension. Thus inflating a balloon in a region of the
small intestine evokes oral excitation and anal inhibi-
tion, resulting in oral contraction and anal relaxation
of the circular muscle respectively. Bayliss and Starling
(1899) suggested that these nerve mediated reflex re-
sponses are involved in peristalsis.
18
As the bolus
advances, pushed by the oral contraction into a relaxed
area, it activates similar new reflex pathways. The
propulsion of contents could be the result of sequential
activation of the polarized enteric reflex pathways.
Figure 26 In a few areas of the enteric nervous system,
systematic studies have been carried out to determine
the combinations of histochemical markers and
morphological features, which identify the different
classes of enteric neurons. A reasonably complete
identification of most functional classes has been
achieved in the guinea-pig small intestine and combined
with electrophysiological and structural data. The
fig. 26 shows a summary of the classes in the enteric
nervous system based on studies from several
laboratories.
14
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The Varenna Group Neurogastroenterology and Motility
On a longer timescale, motor activity of the small
intestine after feeding is often described as being similar to that seen in phase II of the MMC (see left side of fig. 14,
middle panel). Slow wave dependent contractions are indeed irregular (i.e. do not occur on all slow waves) and
propagate aborally for varying distances along the small intestine. However this is a simplification. Reprinted from
Andrews et al. (2001),
21
with permission from the American Physiological Society.
when excitatory motor neurons are activated over a
longer region of gut. If the enteric neural activity migrates aborally, migrating clusters of contractions will result.
Nutrients have been shown to modulate enteric neural pathways. The presence of food appears to fragment the
regular cycle of the MMC, thereby slowing the rate of emptying of the small intestine to allow digestion and
absorption to occur optimally.
Figure 30 The postprandial pattern in dog small intes-
tine includes stationary, segmenting contractions
(white arrowheads), stationary and migrating clusters of
contractions (red horizontal lines) and short peristaltic
waves (dotted lines) visible in this recording with a
faster timebase. These patterns can be readily explained
by the same basic processes that have been described for
the MMC. Stationary contractions probably occur in
small areas where excitatory motor neurons are active,
triggering contractions as the slow waves pass through.
Such stationary contractions occur at the slow wave
frequency. Segmenting contractions could be generated
Figure 29 Intraluminal manometry from multiple
recording sites along the human duodenum reveals
various patterns of contractile activity. Some
contractions propagate aborally but some propagate
orally for short distances. It is currently not clear which
patterns depend on slow wave propagation, as in the
MMC, and which depend on nutrients-stimulated
activity in enteric neural circuits.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
Combinations of just these three types of control
mechanism can explain most of the patterns of activity in the small intestine. Thus myogenic activity, spontaneous
cyclical, migrating activity of the MMC and the neurally mediated responses to luminal contents give rise to a
repertoire of patterns required for digestion and absorption of food with a wide range of nutrient compositions.
Reprinted from Schemann and Ehrlein (1986),
10
with permission from the American Gastroenterological Association.
more traditional multi-channel mechanical recordings.
essentially non-intrusive on the isolated specimen of gut.
Figure 31 In fig. 31, postprandial patterns of contractile
activity in the dog jejunum are revealed by multiple
intraluminal pressure recordings. Short aborally
propagated pressure waves occur in an irregular fashion,
probably advancing the contents in small spurts.
Foods with different nutrient composition generate
different amounts of each pattern.
10
Ileal flow is more
pulsatile and empties into the colon in boluses.
Figure 33 One method to create spatio-temporal maps is
shown in Fig.32.
24,25
Eachsingleframeof a videorecording
is digitized and converted to a silhouette by thresholding.
The diameter at each point along the silhouette is calcu-
lated and expressed as a greyscale pixel. Thus a row of
pixels represents the profile of intestinal diameter at one
point in time; when multiple rows are aligned in sequence,
the resulting maps graphically represents the patterns of
contraction at hundreds of points along the intestine. The
patterns of motor activity become readily detectable by
visual inspection, no matter how complex. Maps are not
restricted to gut diameter; equivalent maps can be created
for longitudinal muscle activity, volume (and hence flow)
at each point and can be combined with electrophysio-
logical recording methods. Spatio-temporal mapping is
Figure 32 An accurate, quantitative picture of irregular
motor activity cannot be readily obtained from record-
ings at a few points or even by watching video or films of
gut movements. However, over the past few years a
number of laboratories have developed methods to plot
intestinal motility in the form of spatio-temporal
maps.
22–25
Fig. 32 shows on the left an example of such a
spatio-temporal map of intestinal diameter (circular
muscle contraction) during segmentation. As in fig. 19,
white areas represent contractions of the circular mus-
cle. The right panel shows reconstructed Ôisotonic
recordingsÕ taken from four points along the segment
corresponding to the dotted lines. The spatial temporal
map reveals features of motor coordination that are not
apparent from the closely spaced recording points in the
16
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The Varenna Group Neurogastroenterology and Motility
Figure 35 Using this method, intraluminal pressure and
longitudinal muscle activity can be easily recorded.
Slow infusion of fluid slowly distends the segment,
evoking a neurally mediated gradual shortening of the
longitudinal muscle, but without emptying the fluid
content (often called the Ôpreparatory phaseÕ). At a
particular threshold volume, a sudden increase in
intraluminal pressure is associated with a propagating
circular muscle contraction, which empties the fluid
(often called the Ôemptying phaseÕ).
Figure 36 Visual inspection of peristalsis indicates that
during the preparatory phase, the overall diameter of
the intestine increases (distension) and that during the
emptying phase a lumen-occlusive contraction of
the circular muscle occurs at the oral end of the segment
which propagates aborally, expelling the fluid.
Figure 34 Intestinal peristalsis initiated by mechanical
luminal stimuli can be studied in isolated specimens
of small intestine using a preparation originally
developed by Trendelenburg
26
which has since been
widely modified. Briefly, a segment of small intestine
(usually guinea-pig) is cannulated at both ends. Fluid
(usually a physiological solution) is infused in a
controlled way at the oral end and the gut empties via
the aboral cannula against a fixed back pressure, via a
non-return valve.
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Volume 17, Supplement 3, October 2005 Small intestinal motility
neural peristalsis, with a purely mechanical stimulus. It
is unclear exactly how often this dramatic pattern of activity actually occurs under physiological conditions in the
small intestine. Most probably it occurs very seldom, unless the gut is inflamed or infected. Reprinted from Hennig
et al. (1999),
25
with permission from Blackwell Publishing.
Figure 38 This simple behaviour is known to involve
several classes of enteric neurons and multiple, parallel
mechanisms for initiation, propagation and termin-
ation. Investigating the cellular basis of neurogenic
peristalsis will require cellular electrophysiology to be
combined with simultaneous mechanical recording of
muscle activity, during the behaviour. Fig. 38 shows
such a preparation.
28
Figure 37 This figure shows a spatio-temporal map
representation of fluid-induced peristalsis in the guinea-
pig small intestine. During the preparatory phase, the
gradual darkening of the map indicates the gradual
distension of the gut. Research shows that during this
phase enteric inhibitory neural pathways are active,
actively relaxing the circular muscle.
27
At the end of the
preparatory phase, the whitening of the map at the oral
end marks the beginning of contraction of the circular
muscle. Enteric neural activity has been shown to be
essential for this kind of peristalsis. The slope of the
white streak represents the speed of propagation of the
peristaltic contraction. Peristalsis elicited in vitro in
this manner is an example of a content-dependent
CONCLUSIONS
This brief overview illustrates how a basic understand-
ing of simple motility in one region of GI tract involves
the interaction of several different cellular systems. Up
to date, these systems (smooth muscle, pacemaker cells
and enteric neurons) have largely been studied sepa-
rately, by laboratories specializing in specific cell types.
It is clear that motility patterns arise from the integrated
activity of these control systems and future research in
this field must take this on board. Already it is clear that
just a few basic mechanisms (myogenic pacemaking and
smooth muscle activity, content-independent cyclical
enteric neuronal activity and content-dependent enteric
activity) can explain much of the normal repertoire of GI
motor behaviour. There are enormous opportunities for
a new generation of researchers to characterize the
patterns of motility in the gut and identify their key
determinants in both health and disease. This will allow
the rational testing, and perhaps design of novel phar-
maceuticals to treat disorders of GI motility. We hope
that this attempt to provide materials for the teachers of
the next generation of researchers in our field will
contribute to future progress.
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19
Volume 17, Supplement 3, October 2005 Small intestinal motility
    • "An interesting way to downregulate macrophages is to interfere with the cholinergic anti-inflammatory pathway ; for instance, by the use of a7 nicotinic acetylcholine receptors agonists, direct vagal stimulation or the use of acetylcholine esterase inhibitors [40,69] . Electrical stimulation of the vagal nerve attenuates systemic inflammation in rodent models of endotoxemia, cecal ligation and puncture, and intestinal manipulation76777879 . Pretreatment with the a7 nAChR, AR-R17779, prevented postoperative ileus and the inflammatory reaction in mice [80] . "
    [Show abstract] [Hide abstract] ABSTRACT: Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system.
    Full-text · Article · Nov 2010
    • "An interesting way to downregulate macrophages is to interfere with the cholinergic anti-inflammatory pathway ; for instance, by the use of a7 nicotinic acetylcholine receptors agonists, direct vagal stimulation or the use of acetylcholine esterase inhibitors [40,69] . Electrical stimulation of the vagal nerve attenuates systemic inflammation in rodent models of endotoxemia, cecal ligation and puncture, and intestinal manipulation76777879 . Pretreatment with the a7 nAChR, AR-R17779, prevented postoperative ileus and the inflammatory reaction in mice [80] . "
    [Show abstract] [Hide abstract] ABSTRACT: Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system.
    Article · Jan 2010
    • "The stomach generates myogenic activity in which electrical slow waves generate rings of contraction that spread from the corpus towards the pyloric sphincter (Hirst & Edwards, 2006). Slow waves generated by interstitial cells of Cajal (ICC) conduct into smooth muscle cells and depolarize the membrane, causing a transient contraction due to mechanically productive Ca 2+ entry via voltage-gated (L-type) Ca 2+ channels (Costa et al. 2005). Removal of Ca 2+ from the cytoplasm by the plasma membrane Ca 2+ -ATPase and the sarcoplasmic reticulum (SR) membrane Ca 2+ -ATPase (SERCA) repolarizes the membrane and relaxes the smooth muscle cells (Sanders, 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: We investigated intracellular Ca(2+) waves, spontaneous transient outward currents (STOCs), and membrane potentials of gastric antrum smooth muscle cells from wild-type and phospholamban-knockout mice. The NO donor sodium nitroprusside (SNP) increased intracellular Ca(2+) wave activity in wild-type antrum smooth muscle cells, but had no effect on the constitutively elevated intracellular Ca(2+) wave activity of phospholamban-knockout cells. STOC activity was also constitutively elevated in phospholamban-knockout antrum smooth muscle cells relative to wild-type cells. SNP or 8-bromo-cGMP increased the STOC activity of wild-type antrum smooth muscle cells, but had no effect on STOC activity of phospholamban-knockout cells. Iberiotoxin, but not apamin, inhibited STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells. In the presence of SNP, STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells was inhibited by ryanodine, but not 2-APB. The cGMP-dependent protein kinase inhibitor KT5823 reversed the increase in STOC activity evoked by SNP in wild-type antrum smooth muscle cells, but had no effect on STOC activity in phospholamban-knockout cells. The resting membrane potential of phospholamban-knockout antrum smooth muscle cells was hyperpolarized by approximately -6 mV compared to wild-type cells. SNP hyperpolarized the resting membrane potential of wild-type antrum smooth muscle cells to a greater extent than phospholamban-knockout antrum smooth muscles. Despite the hyperpolarized membrane potential, slow wave activity was significantly increased in phospholamban-knockout antrum smooth muscles compared to wild-type smooth muscles. These results suggest that phospholamban is an important component of the mechanisms regulating the electrical properties of gastric antrum smooth muscles.
    Article · Sep 2008
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