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Ebook Gastrointestinal Physiology Mosby Physiology Series PDF Full Chapter PDF
Ebook Gastrointestinal Physiology Mosby Physiology Series PDF Full Chapter PDF
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The first edition of Gastrointestinal Physiology appeared In editions one through seven, the motility chapters
in 1977. It developed as a result of the authors’ teaching were written by Dr. Norman W. Weisbrodt, who has since
experiences and the need for a book on gastrointestinal retired. I am grateful to him for allowing me to use his
physiology written and designed for medical students material as I saw fit.
and beginning graduate students. This ninth edition is I would like to thank H.J. Ehrlein and Michael Schemann
directed to the same audience. New to this edition are end- for generously allowing us to link the videos referenced
of-chapter self-study problems. in Chapters 4 and 5, which appear on the website of the
Major changes in the eighth edition were the addition Technische Universität München (http://humanbiology.
of a list of “Objectives” at the beginning of each chapter wzw.tum.de/index.php?id=4&L=1). The videofluoroscopy
and “Clinical Applications” boxes within chapters. I hope on gastrointestinal motility of dogs, pigs, and sheep was
that the learning objectives will provide a guide to the performed during the scientific studies of H.J. Ehrlein and
important concepts and be an aid to understanding them. his colleagues over a period of 25 years. This video proj-
The material presented as clinical applications is meant to ect was supported by an educational grant from Janssen
emphasize the significance of some of the basic science, Research Foundation.
provide some perspective, and increase student interest. Finally, I thank Ms. Marybeth Thiel of Elsevier for sug-
I am grateful to my own students for pointing out ways gestions and for helping with the communications and
to improve the book. Numerous colleagues in other med- organizational work that are a necessary part of such a
ical schools and professional institutions have added their project.
suggestions and criticisms as well. I am thankful for their Leonard R. Johnson
interest and help, and I hope that anyone having criticisms
of this edition or suggestions for improving future editions
will transmit them to me.
v
Regulation: Peptides of the
Gastrointestinal Tract
OBJECTIVES
• Describe the four major functions ofthe gastrointesti • Identify the important paracrines and their functions
nal (GI) tract. in the GI tract.
• Understand the differences between and significance of • Understand the causes and resulting physiology ofgas
endocrine, paracrine, and neurocrine agents. trinoma (Zollinger-Ellison,syndrome) and pancreatic
• Identify the major GI hormones, their functions, sites cholera (Werner Morris�drome).
ofrelease, and stimuli for release.
• Identify the important neurocrines and their functions
in the GI tract.
The functions of the gastrointestinal (GI) tract are regu release or inhibit the release of an endocrine substance,
lated by peptides, derivatives of amino acids, and a variety thereby ultimately regulating a process remote from its
of mediators released from nerves. All GI hormones are origin. Histamine, a derivative ofthe amino acid histidine,
peptides, but it is important to realize that not all peptides is an important regulatory agent that acts as a paracrine.
found in digestive tract mucosa are hormones. The GI trac Some GI peptides are located in nerves and may act
peptides can be divided into endocrines, paracrines, an as neurocrines or neurotransmitters. A neurocrine is
neurocrines, depending on the method by which the pep released near its target tissue and needs only to diffuse
tide is delivered to its target site. across a short synaptic gap. Neurocrines conceivably may
Endocrines, or hormones, are released into he general stimulate or inhibit the release ofendocrines or paracrines.
circulation and reach all tissues ( unless these substances Acetylcholine (ACh), although not a peptide, is an import
are excluded from the brain by the blood- rain barrier). ant neuroregulator in the GI tract. One of its actions is to
Specificity is a property of the tauget tissue itself. Specific stimulate acid secretion from the gastric parietal cells.
receptors, which recognize ana bind the hormone, are
present on its target tissues and abse t from others. There
GENERAL CHARACTERISTICS
are five established GI hormones; in addition, some GI
peptides are released from endocrine cells into the blood The GI tract is the largest endocrine organ in the body, and
but have no known physiologic function. Conversely, sev its hormones were the first to be discovered. The word hor
eral peptides have been isolated from mucosal tissue and mone was coined by W. B. Hardy and used by Starling in
have potent GI effects, but no mechanism for their physi 1905 to describe secretin and gastrin and to convey the con
ologic release has been found. Members ofthese latter two cept ofbloodborne chemical messengers. The GI hormones
groups are classified as candidate hormones. are released from the mucosa ofthe stomach and small intes
Paracrines are released from endocrine cells and dif tine by nervous activity, distention, and chemical stimulation
fuse through the extracellular space to their target tissues. coincident with the intake of food. Released into the portal
Their effects are limited by the short distances necessary for circulation, the GI hormones pass through the liver to the
diffusion. Nevertheless, these agents can affect large areas heart and back to the digestive system to regulate its move
of the digestive tract by virtue of the scattered and abun ments, secretions, and growth. These hormones also regulate
dant distributions ofthe cells containing them. A paracrine the growth ofthe mucosa ofthe stomach and small and large
agent can also act on endocrine cells. Thus a paracrine may intestines, as well as the growth ofthe exocrine pancreas.
1
2 CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract
The GI peptides have many different types of actions. cells of the mucous membrane which, passing into the blood
Their effects on water, electrolyte, and enzyme secretion are or lymph, later stimulates the secretory cells of the stomach
well known, but they also influence motility, growth, and to functional activity.” For 43 years investigators were pre-
release of other hormones, as well as intestinal absorption. occupied by the controversy over the existence of gastrin.
Many of these actions overlap; two or more GI peptides The debate intensified when Popielski demonstrated that
may affect the same process in the same direction, or they histamine, a ubiquitous substance present in large quantities
may inhibit each other. Many of the demonstrated actions throughout the body (including the gastric mucosa), was a
of these peptides are pharmacologic and do not occur powerful gastric secretagogue. In 1938 Komarov demon-
under normal circumstances. This chapter is concerned strated that gastrin was a polypeptide and was different from
primarily with the physiologic effects of the GI peptides. histamine. By 1964 Gregory and his colleagues had extracted
The actions of the GI peptides also may vary in both and isolated hog gastrin; Kenner and his group synthesized
degree and direction among species. The actions discussed in it the same year. After 60 years all of the criteria for establish-
the remainder of this chapter are those occurring in humans. ing the existence of a GI hormone had been satisfied.
In 1928 Ivy and Oldberg described a humoral mechanism
for the stimulation of gallbladder contraction initiated by
DISCOVERY the presence of fat in the intestine. The hormone was named
Four steps are required to establish the existence of a GI cholecystokinin after its primary action. The only controversy
hormone. First, a physiologic event such as a meal must involving CCK was a mild one over nomenclature. In 1943
be demonstrated to provide the stimulus to one part of Harper and Raper described a hormone released from the
the digestive tract that subsequently alters the activity in small intestine that stimulated pancreatic enzyme secretion
another part. Second, the effect must persist after all ner- and accordingly named it pancreozymin. As Jorpes and Mutt
vous connections between the two parts of the GI tract carried out the purification of these two substances in 1968,
have been severed. Third, from the site of application of the it became obvious that both properties resided in the same
stimulus a substance must be isolated that, when injected peptide. For the sake of convenience and because it was the
into the blood, mimics the effect of the stimulus. Fourth, first action described, this hormone is called CCK.
the substance must be identified chemically, and its struc- In 1969 Brown and his coworkers described the purifi-
ture must be confirmed by synthesis. cation of a powerful enterogastrone from intestinal mucosa.
Five GI peptides have achieved full status as hormones. Enterogastrone literally means a substance from the intestine
They are secretin, gastrin, cholecystokinin (CCK), gastric (entero-) that inhibits (-one) the stomach (gastr-). By 1971 this
inhibitory peptide (GIP), and motilin. There is also an peptide had been purified, isolated, sequenced, and named
extensive list of “candidate” hormones whose significance gastric inhibitory peptide for its ability to inhibit gastric secre-
has not been established. This list includes several chemi- tion. Released from the intestinal mucosa by fat and glucose,
cally defined peptides that have significant actions in phys- GIP also stimulates insulin release. Following proof that the
iology or pathology but whose hormonal status has not release of insulin was a physiologic action of the peptide, GIP
been proved. These are pancreatic polypeptide, neuroten- became the fourth GI hormone. The insulinotropic effect of
sin, and substance P. In addition, two known hormones, GIP requires elevated amounts of serum glucose. For this rea-
glucagon and somatostatin, have been identified in GI tract son, and because it is doubtful whether the inhibitory effects
mucosa; their possible function as GI hormones is cur- of the peptide on the stomach are physiologic, it has been sug-
rently being investigated. Some of these peptides function gested that its name be changed to glucose-dependent insulino-
physiologically as paracrines or neurocrines. Another GI tropic peptide. In either case, it is still referred to as GIP.
peptide, Ghrelin, is released from the body of the stomach Brown and his coworkers also described the purifica-
and functions as a hormone to regulate food intake. This tion of motilin in the early 1970s. Motilin is a linear 22–
topic is covered in Chapter 13. amino acid peptide purified from the upper small intestine.
Secretin, the first hormone, was discovered in 1902 During fasting it is released cyclically and stimulates upper
by Bayliss and Starling and was described as a substance, GI motility. Its release is under neural control and accounts
released from the duodenal mucosa by hydrochloric acid, for the interdigestive migrating myoelectric complex.
that stimulated pancreatic bicarbonate and fluid secretion.
Jorpes and Mutt isolated it and identified its amino acid
CHEMISTRY
sequence in 1966. It was synthesized by Bodanszky and
coworkers later the same year. The GI hormones and some related peptides can be divided
Edkins discovered gastrin in 1905, stating to the Royal into two structurally homologous families. The first consists
Society that “in the process of the absorption of digested of gastrin (Fig. 1.1) and CCK (Fig. 1.2). The five carboxyl-
food in the stomach a substance may be separated from the terminal (C-terminal) amino acids are identical in these two
CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract 3
* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Secretin (27) His – Ser – Asp – Gly – Thr – Phe –Thr – Ser – Glu – Leu– Ser – Arg – Leu – Arg – Asp –
VIP (28) Ala – Val – Asp – Asn – Tyr – Thr – Lys –
GIP (42) Tyr – Ala – Glu – Ile – Asp – Tyr – Ile – Ala – Met
Glucagon (29) Gln – Asp – Tyr – Lys – Tyr – Leu
16 17 18 19 20 21 22 23 24 25 26 27 28 29
Secretin Ser – Ala – Arg – Leu – Gln – Arg – Leu – Leu – Gln – Gly – Leu – Val – NH2 –
VIP Gln – Met – Ala – Val – Lys – Lys – Tyr – Asn – Ser – Ile – Leu – Asn – NH2 –
GIP Lys – Ile Gln – Asp– Phe – Val – Asn – Trp – Leu – Ala – Gln – 14 more
Glucagon Arg – Ala – Asp – Phe – Val – Trp – Met – Asp –Thr
Fig. 1.3 Structures of the secretin family of peptides. GIP, Gastric inhibitory peptide; VIP, vasoactive intesti-
nal peptide.
Yalow and Berson demonstrated heterogeneity by showing The nature of this distribution makes it virtually impossible
that the major component of gastrin immunoactivity in the to remove the source of one of the GI hormones surgically
serum was a larger molecule that they called big gastrin. and examine the effect of its absence without compromis-
On isolation, big gastrin was found to contain 34 amino ing the digestive function of the animal.
acids; hence it is called G 34. Trypsin splits G 34 to yield The endocrine cells of the gut are members of a widely
G 17 plus a heptadecapeptide different from G 17. Therefore distributed system termed amine precursor uptake decar-
G 34 is not simply a dimer of G 17. An additional gastrin boxylation (APUD) cells. These cells all are derived from
molecule (G 14) has been isolated from tissue and contains neuroendocrine-programmed cells originating in the
the C-terminal tetradecapeptide of gastrin. Current evi- embryonic ectoblast.
dence indicates that most G 17 is produced from pro G 17 The distributions of the individual GI hormones are
and most G 34 is derived from pro G 34. Thus G 34 is not a shown in Fig. 1.4. Gastrin is most abundant in the antral
necessary intermediate in the production of G 17. and duodenal mucosa. Most of its release under physio-
During the interdigestive (basal) state, most human logic conditions is from the antrum. Secretin, CCK, GIP,
serum gastrin is G 34. Unlike those of other species, the and motilin are found in the duodenum and jejunum.
duodenal mucosa of humans contains significant amounts Ultrastructurally, GI endocrine cells have hormone-
of gastrin. This is primarily G 34 and is released in small containing granules concentrated at their bases, close to the
amounts during the basal state. After a meal, a large capillaries. The granules discharge, thereby releasing their
quantity of antral gastrin, primarily G 17, is released and hormones in response to events that are either the direct or
provides most of the stimulus for gastric acid secretion. the indirect result of neural, physical, and chemical stim-
Smaller amounts of G 34 are released from both the antral uli associated with eating a meal and the presence of that
and the duodenal mucosa. G 17 and G 34 are equipotent, meal within the digestive tract. These endocrine cells have
although the half-life of G 34 is 38 minutes and that of microvilli on their apical borders that presumably contain
G 17 is approximately 7 minutes. The plasma concentration receptors for sampling the luminal contents.
of gastrin in fasting humans is 10 to 30 pmol/L, and it dou- Table 1.1 lists the stimuli that are physiologically
bles or triples during the response to a normal mixed meal. important releasers of the GI hormones. Gastrin and
motilin are the only hormones shown to be released
directly by neural stimulation. Protein in the form of
DISTRIBUTION AND RELEASE peptides and single amino acids releases both gastrin and
The GI hormones are located in endocrine cells scattered CCK. Fatty acids containing eight or more carbon atoms
throughout the GI mucosa from the stomach through the or their monoglycerides are the most potent stimuli for
colon. The cells containing individual hormones are not CCK release. Fat must be broken down into an absorbable
clumped together but are dispersed among the epithelial cells. form before release of CCK, thus providing evidence that
CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract 5
Gastrin
CCK
Secretin
GIP
Motilin
Fig. 1.4 Distribution of the gastrointestinal hormones. Shaded areas indicate where the most release occurs
under normal conditions. CCK, Cholecystokinin; GIP, gastric inhibitory peptide.
the receptors for release are triggered during the process releases gastrin. During a meal the pressure of ingested food
of absorption. initiates this response. The magnitude of the response is not
Evidence indicates that intestinal releasing factors as great as originally believed, however, and the contribu-
secreted into the intestine of certain species, including tion of distention to the total amount of gastrin released in
humans, stimulate the release of CCK. Pancreatic enzymes humans probably is minor. Gastrin also can be released by
inactivate these releasing factors. The ingestion and pres- calcium, decaffeinated coffee, and wine. Pure alcohol in the
ence of a meal in the intestine result in temporary binding same concentration as that of wine does not release gastrin
of trypsin and other proteases and allow the releasing fac- but does stimulate acid secretion. Motilin is released cyclically
tors to remain active and stimulate CCK secretion. Thus (approximately every 90 minutes) during fasting. This release
this mechanism acts as a negative feedback control on pan- is prevented by atropine and ingestion of a mixed meal. Acid
creatic enzyme secretion. and fat in the duodenum, however, increase motilin release.
Carbohydrate, the remaining major foodstuff, does not In addition to releasing secretin, acid exerts an important
alter the release of gastrin, secretin, or CCK to a significant negative feedback control of gastrin release. Acidification
extent but does stimulate GIP release. GIP also is released by of the antral mucosa below a pH of 3.5 inhibits gastrin
fat and protein. The strongest stimulus for secretin release is release. Patients with atrophic gastritis, pernicious anemia,
H+. Secretin is released when the pH in the duodenum falls or other conditions characterized by the chronic decrease
below 4.5. Secretin also is released by fatty acids. This may of acid-secreting cells and hyposecretion of acid may have
be a significant mechanism for secretin release because the extremely high serum concentrations of gastrin because of
concentration of fatty acids in the lumen is often high. CCK the absence of this inhibitory mechanism.
can also be released by acid, but except during hypersecre- Hormones alter the release of GI peptides in several
tion of acid, the physiologic significance of this mechanism instances. Both secretin and glucagon, for example, inhibit
of release has not been established. The purely physical stim- gastrin release. CCK has been shown to stimulate gluca-
ulus of distention activates antral receptors and causes gas- gon release, and four GI hormones (secretin, gastrin, CCK,
trin release; for example, inflating a balloon in the antrum and GIP) increase insulin secretion. Elevated serum calcium
6 CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract
0, No effect; blank spaces, not yet tested; CCK, cholecystokinin; GIP, gastric inhibitory peptide; HCO3–, bicarbonate; I, inhibits; S,
stimulates;
stimulates both gastrin and CCK release. It is doubtful whether every target tested. Even though large doses of hormone
any of these mechanisms, with the exception of release of sometimes are necessary to produce an effect, either stim-
insulin by GIP, play a role in normal GI physiology. Some ulatory or inhibitory, these tests indicate that receptors
mechanisms, however, may become important when circu- for each hormone are present on most target tissues. The
lating levels of hormones or calcium are altered by disease. myriad activities possessed by these peptides are summa-
rized in Table 1.2.
The important physiologic actions of the GI hormones
ACTIONS AND INTERACTIONS are depicted in Table 1.3. Numerous guidelines have been
The effects of pure GI hormones have been tested on proposed for determining whether an action is physiologic.
almost every secretory, motor, and absorptive function The action should occur in response to endogenous hor-
of the GI tract. Each peptide has some action on almost mone released by normal stimuli (i.e., those present during
CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract 7
a meal). In other words, an exogenous dose of hormone Both CCK and secretin also stimulate the growth of the
should produce the effect in question without elevating exocrine pancreas. CCK exerts a stronger effect than secretin,
serum hormone levels above those produced by a meal. but the combination of the two hormones produces a poten-
An acceptable guideline for exogenous infusion is a dose tiated response in rats that is truly remarkable. It is likely that
that produces 50% of the maximal response (D50) of the the effects of these two hormones on pancreatic growth are
primary action of the hormone. The hormone should be as important as their effects on pancreatic secretion.
administered as a continuous intravenous infusion rather In addition to its effects on the pancreas, secretin stimu-
than as a single bolus because a bolus produces transient, lates biliary secretion of fluid and bicarbonate. This action
unphysiologically high serum levels. is shared by CCK, but secretin is the most potent choleretic
The primary action of gastrin is the stimulation of gas- of the GI hormones. In dogs, secretin is a potent inhibitor
tric acid secretion. It does this by causing the release of of gastrin-stimulated acid secretion. This action is proba-
histamine (a potent acid secretagogue) from the enter- bly not physiologically important in humans. The ability of
ochromaffin-like (ECL) cells of the stomach and by direct secretin to inhibit acid secretion may be important in some
action on the parietal cells. Gastrin is the most important human diseases, however, and students should be aware of
regulator of gastric acid secretion. There is considerable this action. Secretin has been nicknamed “nature’s antacid”
debate on the role of gastrin in regulating the tone of the because almost all its actions reduce the amount of acid in
lower esophageal sphincter, and the bulk of the evidence the duodenum. The only known exception to this statement
indicates no normal role for gastrin in regulation. is secretin’s pepsigogic activity. Secretin is second only to
One of the most important and more recently dis- ACh in promoting pepsinogen secretion from the chief cells
covered actions of GI hormones is their trophic activity. of the stomach. Because only small amounts of secretin are
Gastrin stimulates synthesis of ribonucleic acid (RNA), released under normal circumstances, it is doubtful whether
protein, and deoxyribonucleic acid (DNA), as well as secretin stimulates pepsin secretion physiologically.
growth of the mucosa of the small intestine, colon, and In addition to its physiologic actions on pancreatic and
oxyntic gland area of the stomach. If most endogenous biliary secretion, CCK regulates gallbladder contraction
gastrin is removed by antrectomy, these tissues atrophy. and gastric emptying. Of the GI peptides, CCK is the most
Exogenous gastrin prevents this atrophy. Patients with potent regulator of gallbladder contraction; it is approxi-
tumors that constantly secrete gastrin exhibit hyperpla- mately 100 times more effective than the gastrin tetrapep-
sia and hypertrophy of the acid-secreting portion of the tide in contracting the gallbladder. CCK causes significant
stomach. Gastrin also stimulates the growth of ECL cells. inhibition of gastric emptying in doses equal to the D50 of
Continued hypersecretion of gastrin results in ECL cell pancreatic secretion. Gastrin also inhibits gastric emptying,
hyperplasia, which may develop into carcinoid tumors. but the effective dose is approximately 6 times the D50 for
The trophic effects of gastrin are restricted to GI tissues and stimulation of acid secretion by gastrin. These data support
are counteracted by secretin. The trophic action of gastrin the conclusions that CCK physiologically inhibits gastric
is a direct effect that can be demonstrated in tissue culture. emptying and gastrin does not.
As mentioned previously, G-Gly also has trophic effects. CCK also functions to regulate food intake. It was the
G-Gly is far less potent (by at least four orders of magni- first satiety hormone to be discovered, and this action is
tude) than gastrin in stimulating gastric acid secretion. fully covered in Chapter 13.
However, G-Gly is stored in gut tissues, is secreted with Several peptides, including secretin and GIP, are
gastrin from antral G cells, and reaches concentrations enterogastrones. GIP was originally discovered because of
in plasma equal to those of gastrin. Although antagonists its ability to inhibit gastric acid secretion, and it may well
of the CCK-B/gastrin receptor block the trophic effects have been the original enterogastrone described by Ivy
of gastrin, they have no effect on the growth-promoting and Farrell in 1925. Its action has not been established as
actions of G-Gly. Additional evidence suggests that the physiologically significant in the innervated stomach. GIP,
growth-related receptors for G-Gly work in concert with however, is a strong stimulator of insulin release and is
gastrin to regulate the functional development of the gut. responsible for the fact that an oral glucose load releases
The primary effect of secretin is the stimulation of pan- more insulin and is metabolized more rapidly than an
creatic fluid and bicarbonate secretion; one of the primary equal amount of glucose administered intravenously.
actions of CCK is the stimulation of pancreatic enzyme Motilin stimulates the so-called migrating motility or
secretion. In addition, CCK has a physiologically import- myoelectric complex that moves through the stomach and
ant interaction in potentiating the primary effect of secre- small bowel every 90 minutes in the fasted GI tract. Its
tin. Thus CCK greatly increases the pancreatic bicarbonate cyclic release into the blood is inhibited by the ingestion
response to low circulating levels of secretin. of a meal. This is the only known function of this peptide.
8 CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract
TABLE 1.4 Candidate Hormones gastric secretion and emptying and thus qualifies as an
enterogastrone. Its effects do not appear to be direct in that
Peptide Released By Action(s) it does not inhibit secretion in response to gastrin or hista-
Pancreatic Protein ↓Pancreatic HCO3– and
mine. It does inhibit neurally stimulated secretion, but its
polypeptide Fat enzyme secretion
final status as an enterogastrone has not been determined.
Glucose
Peptide YY also inhibits intestinal motility, and this effect
Peptide YY Fat ↓Gastric secretion
is believed by some investigators to enhance luminal nutri-
↓Gastric emptying
ent digestion and absorption.
Enteroglucagon Hexose ↓Gastric secretion
The enteroglucagons are products of the same gene
Fat ↓Gastric emptying
processed in the pancreatic alpha cell to form glucagon.
↑lnsulin release
The intestinal L cell makes three forms of glucagon, one
of which, glucagon-like peptide-1 (GLP-1), may have
↓, Inhibits; ↑, stimulates; HCO3–, bicarbonate. important physiologic actions. This 30–amino acid pep-
tide is a potent insulin releaser, even in the absence of
hyperglycemia, and it also inhibits gastric secretion and
CANDIDATE HORMONES
emptying. GLP-1 may mediate the so-called ileal brake—
Earlier in this chapter, certain peptides isolated from the inhibition of gastric and pancreatic secretion and
digestive tract tissue were mentioned that may, at a later motility that occurs when lipids and/or carbohydrates
date, qualify as hormones. These often are referred to as are infused into the ileum in amounts sufficient to cause
candidate, or putative, hormones. Many have been pro- malabsorption.
posed, but interest is greatest for those listed in Table 1.4.
Enteroglucagon belongs to the secretin family. Pancreatic
polypeptide and peptide YY (tyrosine-tyrosine) belong
NEUROCRINES
to a separate family and are unrelated to either gastrin or All GI peptides were once believed to originate from endo-
secretin. crine cells and therefore to be either hormones or candidate
Pancreatic polypeptide was first identified as a minor hormones. With the advent of sophisticated immunocyto-
impurity in insulin. It was then isolated and found to be a chemical techniques for tissue localization of peptides, it
linear peptide with 36 amino acid residues. From a phys- became apparent that many of these peptides were con-
iologic viewpoint the most important action of pancreatic tained within the nerves of the gut.
polypeptide is the inhibition of both pancreatic bicarbon- Numerous peptides have been found in both the brain
ate and enzyme secretion because this effect has the low- and the digestive tract mucosa. The first of these to be
est dose requirement. Most constituents of a meal release isolated was substance P, which in the GI tract stimulates
pancreatic polypeptide, and the serum levels reached are intestinal motility and gallbladder contraction. The only
sufficient to inhibit pancreatic secretion. Because the peak other peptide isolated from both the brain and gut and
rate of pancreatic secretion during a meal is less than the known to have an identical structure in both sites is neu-
maximal rate that can be achieved with exogenous stimuli, rotensin. Neurotensin increases blood glucose by stimu-
it is possible that pancreatic polypeptide modulates this lating glycogenolysis and glucagon release and inhibiting
response under normal conditions. Before it can be con- insulin release. Other peptides have been isolated from
cluded that pancreatic polypeptide is responsible for the one site and identified by radioimmunoassay in the
physiologic inhibition of pancreatic secretion, it must be other. These include motilin, CCK, and VIP, which were
shown that this actually occurs and that pancreatic poly- first isolated from the gut. Enkephalin, somatostatin,
peptide is the causative agent. The fact that the peptide is and thyrotropin-releasing factor were first isolated from
located in the pancreas and cannot be removed without the brain and later found in the gut. Gastrin, VIP, soma-
also removing its target organ makes this evidence difficult tostatin, and enkephalin also are present in the nerves of
to obtain. the gut.
Peptide YY was discovered in porcine small intestine Three peptides have important physiologic functions
and was named for its N-terminal and C-terminal amino in the gut as neurocrines (listed in Table 1.5). Originally
acid residues—both tyrosines. Of its 36 amino acid resi- investigators thought that VIP was found in gut endo-
dues, 18 are identical to those of pancreatic polypeptide. crine cells, but VIP is now known to be localized within
Peptide YY is released by meals, especially by fat. It may the gut exclusively within nerves. It physiologically medi-
appear in plasma in concentrations sufficient to inhibit ates the relaxation of GI smooth muscle. Smooth muscle
CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract 9
TABLE 1.5 Neurocrines Absent from Table 1.5 is pituitary adenylate cyclase–
activating peptide (PACAP), the newest member of the
Peptide Location Action secretin family. If somatostatin is blocked, injection of
VIP Mucosa and muscle Relaxation of gut
PACAP stimulates the release of histamine from ECL cells
of gut smooth muscle
and therefore stimulates acid secretion. PACAP also stim-
GRP or Gastric mucosa ↑Gastrin release
ulates ECL cell growth, so its actions are similar to those of
bombesin
gastrin. It may be a significant neural mediator of ECL cell
Enkephalins Mucosa and muscle ↑Smooth muscle tone
function, but direct evidence that ECL cells are innervated
of gut
by PACAP-containing fibers is missing.
CLINICAL APPLICATIONS
Non–beta cell tumors of the pancreas or duodenal contributes to the diarrhea. Steatorrhea is produced
tumors may produce gastrin and continually release it by inactivation of pancreatic lipase and precipitation of
into the blood. This disease is known as gastrinoma or bile salts at a low luminal pH. Because the tumors are
Zollinger-Ellison syndrome. The tumors are small and difficult to resect and the clinical manifestations are
difficult to define and resect; if metastasizing, they grow caused by hypersecretion of gastric acid, the preferred
slowly. Gastrin is released from these tumors at a high surgical treatment is removal of the target organ (the
spontaneous rate that is not altered by feeding. The stomach). Although gastrin levels remain elevated, total
hypergastrinemia results in hypersecretion of gastric gastrectomy stops the ulceration and diarrhea. This dis-
acid through two mechanisms. First, the trophic action ease also may be treated nonsurgically with some of
of gastrin leads to increased parietal cell mass and acid the powerful new drugs that inhibit acid secretion (see
secretory capacity. Second, increased serum gastrin lev- Chapter 8).
els constantly stimulate secretion from the hyperplastic The only other clinical condition attributed to the over-
mucosa. The complications of this disease—fulminant production of a GI peptide concerns VIP. Pancreatic chol-
peptic ulceration, diarrhea, steatorrhea, and hypokale- era, or watery diarrhea syndrome, is a frequently lethal
mia—are caused by the presence of large amounts of disease resulting from the secretion of a peptide by a pan-
acid in the small bowel. The continual presence of acid creatic islet cell tumor. This peptide is a potent stimulus
in the duodenum overwhelms the neutralizing ability of for intestinal secretion of the fluid and electrolytes that
the pancreas, erodes the mucosa, and produces ulcers. produce the copious diarrhea. VIP has been identified in
In large amounts, gastrin inhibits absorption of fluid and both the tumor tissue and the serum of these patients.
electrolytes by the intestine and thereby adds to the The ability of VIP to stimulate cholera-like fluid secretion
large volumes of fluid (up to 10 liters [L]/day) entering from the intestine indicates that it is responsible for this
the intestine. Increased intestinal transit probably also disease.
CLINICAL TESTS
Gastrin is routinely measured by radioimmunoassay in run by infusing 5 milligrams (mg) of ionizable calcium/
clinical laboratories. Normal serum gastrin values must kilogram (kg)/hour as calcium gluconate for 3 hours while
be set by each laboratory for its particular assay. If the simultaneously measuring acid secretion and collecting
normal mean serum gastrin concentration is taken as blood samples at hourly intervals for gastrin determina-
50 picograms (pg)/milliliter (mL), serum gastrin in fasting tion. Peak gastrin responses are usually obtained 3 hours
patients with gastrinoma usually exceeds 200 pg/mL. The after calcium infusion is begun. In most patients with gas-
degree of overlap between patients with gastrinoma and trinoma, serum gastrin concentrations will at least dou-
those with ordinary duodenal ulcer disease means that ble, so the gastrin values will be more than 500 pg/mL.
specific tests are required to diagnose the gastrinoma. Patients with ordinary ulcer disease may show moderate
The tests most widely used in the evaluation of hyper- increases in serum gastrin with calcium infusion, but
gastrinemia include stimulation with protein meals, intra- absolute gastrin values after stimulation seldom exceed
venous calcium infusion, and secretin infusion. Patients 200–300 pg/mL.
with Zollinger-Ellison syndrome may not release gastrin in The most specific and easiest test to administer for
detectable amounts in response to food. The reason may gastrinoma is secretin injection. Secretin inhibits antral
be the low pH of gastric contents that is caused by ongo- gastrin release, yet it stimulates tumor gastrin release in
ing acid secretion stimulated by preexisting high serum almost all patients with gastrinoma. Secretin (1 unit [U]/kg)
gastrin levels. Acid in the antrum inhibits gastrin release, is given as a rapid intravenous injection and causes a
and any gastrin that could be released would be difficult peak increase in serum gastrin 5–10 minutes later. In
to detect against the already high serum levels. a patient with definitely increased basal serum gastrin
Patients with gastrinoma may have an exaggerated acid and acid hypersecretion, a doubling of serum gastrin
secretory response to calcium infusions that is caused at 5–10 minutes strongly indicates the presence of a
by the release of gastrin from tumor tissue. This test is gastrinoma.
CHAPTER 1 Regulation: Peptides of the Gastrointestinal Tract 11
S U M M A R Y
• The functions of the GI tract are regulated by mediators act- • The GI peptides have many pharmacologic actions, but
ing as hormones (endocrines), paracrines, or neurocrines. only a few of these are physiologically significant.
• Two chemically related families of peptides are respon- • Gastrin, CCK, secretin, GIP, and motilin are important
sible for much of the regulation of GI function. These GI hormones.
are gastrin/CCK peptides and a second group contain- • Somatostatin and histamine have important functions
ing secretin, VIP, GIP, and glucagon. as paracrine agents.
• The GI hormones are located in endocrine cells scat- • VIP, bombesin (or GRP), and the enkephalins are
tered throughout the mucosa and released by chemicals released from nerves and mediate many important
in food, neural activity, or physical distention. functions of the digestive tract.
K E Y W O R D S A N D C O N C E P T S
Endocrines/hormones Glucagon
Paracrines Enteroglucagon
Neurocrines G-Gly
Acetylcholine CCK-B receptor
Secretin Amine precursor uptake decarboxylation
Gastrin Enterochromaffin-like cells
Cholecystokinin Pancreatic polypeptide
Enterogastrone Peptide YY
Gastric inhibitory peptide Glucagon-like peptide-1
Motilin Somatostatin
Gastrin II Histamine
Vasoactive intestinal peptide
S E L F - S T U D Y P R O B L E M S
1. What determines which cells are acted upon by hor- what changes from normal would you expect? Serum
mones, paracrines, and neurocrines? gastrin; stool fat content; parietal cell number; antral
2. You diagnose a patient with severe duodenal ulcers as somatostatin release; histamine release from gastric
having a gastrinoma (Zollinger-Ellison syndrome). If ECL cells; serum gastrin following a rapid injection of
it were possible to measure the following parameters, secretin (1 U/kg).
OBJECTIVES
• Understand the anatomy and functions of the enteric • Explain the role of calcium ion in the contraction and
nervous system and its relationship with the parasym relaxation of smooth muscle cells.
pathetic and sympathetic systems. • Understand the roles of the interstitial cells of Cajal and
• Describe the anatomy and types of contractions of slow waves in the contraction of smooth muscle cells.
smooth muscle cells.
Secretory, motility, and absorptive functions of the gas Parasyrnpatftetic innervation is supplied primarily by the
trointestinal (GI) system are integrated to digest food and vagus and --p dvic nerves. Long preganglionic axons arise from
absorb nutrients and to maintain homeostasis between cell bodies witfiin the medulla of the brain and the sacral
meals. This integration is mediated by regulatory systems region of the spinal cord. These preganglionic nerves enter
that monitor events within the body (primarily the GI th various organs of the GI tract, where they synapse mainly
tract) and in the external environment. In Chapter 1, the with cells of the enteric nervous system (Fig. 2.2). In addi
important mediators released from endocrine, paracrine, tion, these same nerve bundles contain many afferent nerves
and neurocrine cells were discussed. In this chapter, the whose receptors lie within the various tissues of the gut. These
role of the nervous system is considered in more detai . nerves project to the brain and spinal cord to provide sensory
Although the regulatory systems act to integrate th_e input for integration. Approximately 75% of the fibers within
activities of the GI system, most secretory, absor tive, and the vagus nerve are afferent. Thus information can be relayed
muscle cells possess intrinsic activities that giv.e.J.h_em a from the GI tract to the medulla and integrated, and a mes
degree of autonomy. Thus function arise out of the inter sage can be sent back to the tract that may influence motility,
action of regulatory systems and local intrinsic properties. secretion, or the release of a hormone. These long or vagov
The basic properties and intrinsic �v.ities of each type agal reflexes play important roles in regulating GI functions.
of secretory and absorptive cell are discussed in separate Sympathetic innervation is supplied by nerves that
chapters that deal with the secretion and absorption of spe run between the spinal cord and the prevertebral gan
cific chemicals. The basic properties and intrinsic activities glia and between these ganglia and the organs of the gut.
of the smooth muscle cells are discussed in this chapter. Preganglionic efferent fibers arise within the spinal cord
and end in the prevertebral ganglia. Postganglionic fibers
ANATOMY OF THE AUTONOMIC NERVOUS from these ganglia then innervate primarily the elements
of the enteric nervous system (see Fig. 2.1). Few fibers end
SYSTEM directly on secretory, absorptive, or muscle cells. Afferent
The GI tract is innervated by the autonomic nervous sys fibers also are present within the sympathetic division.
tem (ANS). It is called the ANS because, under normal These nerves project back to the prevertebral ganglia and/
circumstances, people neither are conscious of its activities or the spinal cord. Thus an abundance of sensory informa
nor exert any willful control over them. The ANS can be tion also is available via these nerves.
divided into the extrinsic nervous system and the intrinsic, Elements of the intrinsic, or enteric, nervous system
or enteric, nervous system. are grouped into several anatomically distinct networks,
The extrinsic nervous system is in turn divided into of which the myenteric and submucosal plexuses (see
parasympathetic and sympathetic branches (Fig. 2.1). Fig. 2.2) are the most prominent. These plexuses consist
12
CHAPTER 2 Regulation: Nerves and Smooth Muscle 13
CG
SM
G
IM
G
A B
Fig. 2.1 Extrinsic branches of the autonomic nervous system. (A) Parasympathetic. Dashed lines indicate the
cholinergic innervation of striated muscle in the esophagus and external anal sphincter. Solid lines indicate the
afferent and preganglionic efferent innervation of the rest of the gastrointestinal tract. (B) Sympathetic. Solid
lines denote the afferent and preganglionic efferent connections between the spinal cord and the prevertebral
ganglia. Dashed lines indicate the afferent and postganglionic efferent innervation. CG, Celiac ganglion; IMG,
inferior mesenteric ganglion; SMG, superior mesenteric ganglion.
of nerve cell bodies, axons, dendrites, and nerve endings. neurons contained within the prevertebral ganglia and
Processes from the neurons of the plexuses do not just enteric nervous system. Norepinephrine is found in many
innervate target cells such as smooth muscle, secretory cells, nerve endings of the postganglionic efferent nerves of the
and absorptive cells. They also connect to sensory receptors sympathetic nervous system. This transmitter also exerts
and interdigitate with processes from other neurons located its effects primarily on neurons of the enteric nervous sys-
both inside and outside the plexus. Thus pathways within tem. Within the enteric nervous system, ACh, serotonin,
the enteric nervous system can be multisynaptic, and inte- vasoactive intestinal peptide (VIP), nitric oxide (NO),
gration of activities can take place entirely within the enteric and somatostatin have been localized to interneurons.
nervous system (see Fig. 2.2), as well as in the ganglia of the ACh and the tachykinins (TKs) (e.g., substance P) have
extrinsic nerves, the spinal cord, and the brainstem. been localized to nerves that are excitatory to the muscle;
Many chemicals serve as neurocrines within the ANS. VIP and NO have been localized to inhibitory nerves to the
Several of these chemicals have been localized within spe- muscle. In many instances, more than one transmitter can
cific pathways, and a few have defined physiologic roles. be localized to the same nerve. The goals of mapping neu-
Most of the extrinsic, preganglionic, efferent fibers contain ral circuits within the extrinsic and enteric nervous system
acetylcholine (ACh). This transmitter exerts its action on and elucidating their functions are far from complete.
14 CHAPTER 2 Regulation: Nerves and Smooth Muscle
Endocrine
Cell
Vagus
Nerve
Mechano-
receptors
Parasympathetic Chemo-
System receptors
Secretory
Cells
Sympathetic
Ganglia
Preganglionic
Nerves Postganglionic
Nerves
kinase
MLCK MLCK
(active) (inactive)
Ca .CaM
2
MLCK.Ca2.CaM
ATP
MLCP MLCP
(inactive) (active)
ADP Pi
kinase, other?
Contraction
Fig. 2.5 Biochemical events in smooth muscle contraction. An increase in the levels of calcium (Ca2+) acti-
vates the enzyme myosin light chain kinase (MLCK), which phosphorylates myosin. Phosphorylated myosin
(Myosin P) interacts with actin to cause muscle contraction and adenosine triphosphate (ATP) consumption.
When Ca2+ levels fall, the kinase becomes inactive, and the activity of myosin light chain phosphatase (MLCP)
dominates. Myosin P is dephosphorylated, and the muscle relaxes. The activities of both MLCK and MLCP
can be modulated by kinases and/or second messengers to influence calcium sensitivity of the contractile
process. ADP, Adenosine diphosphate; CaM, calmodulin; Pi, inorganic phosphate.
of seconds (phasic contractions). Other smooth muscles, which is fueled by the splitting of adenosine triphosphate
such as those found in the lower esophageal sphincter, orad (ATP). When the intracellular levels of Ca2+ fall, the myosin
stomach, and ileocecal and internal anal sphincters, show is dephosphorylated by a specific phosphatase. This leads
sustained contractions that last from minutes to hours. to a cessation of the interaction between the contractile
These muscles exhibit what are called tonic contractions. proteins, and muscle relaxation occurs. In smooth mus-
As discussed in subsequent chapters, the type of contraction, cles that contract tonically, the exact mechanism for the
whether phasic or tonic, is governed by the smooth muscle maintenance of tone is not known. What is known is that
cells themselves or by ICCs in association with smooth mus- tone can be maintained at low levels of phosphorylation of
cle cells. It does not depend on neural or hormonal input. myosin and of ATP utilization. In addition, it is becoming
Neurocrines, endocrines, and paracrines are important apparent that smooth muscle contraction is regulated not
because they modulate the basic contractile activity, so that only by levels of Ca2+ but also by processes that regulate the
the amplitude of the contractions of phasic muscles varies activity of the phosphatase(s) that dephosphorylates myo-
and the tone of the tonic muscles increases or decreases. sin, thereby altering the Ca2+ sensitivity of the contractile
As in striated muscle, contractile activity of smooth process.
muscle, especially those muscles that contract phasically, The exact source of the Ca2+ that participates in the con-
is modulated by fluctuating levels of free intracellular cal- tractile process is not certain and appears to vary from one
cium (Ca2+). At low levels (less than 10–7 molar [M]) of muscle to another. In many muscles (e.g., muscle from the
Ca2+, interaction of the contractile proteins does not occur. body of the esophagus), Ca2+ enters the cells from the extra-
At higher levels of Ca2+, proteins interact and contractions cellular fluid or from pools of Ca2+ that are tightly bound
occur. The prevailing theory to explain how Ca2+ brings to the smooth muscle cell membranes or contained in cav-
about contraction is that the Ca2+, combined with the Ca2+- eolae (see Fig. 2.3). Influx of Ca2+ from these sites is regu-
binding protein calmodulin, activates a protein kinase that lated by permeability changes of the membrane that also
brings about the specific phosphorylation of one of the cause characteristic electrical activities (see the following
components of myosin (Fig. 2.5). Myosin in its phosphor- paragraph). In other muscles (e.g., muscle from the lower
ylated form then interacts with actin to cause contraction, esophageal sphincter), Ca2+ is sequestered in intracellular
CHAPTER 2 Regulation: Nerves and Smooth Muscle 17
Spontaneous activation of
Interstitial cell pacemaker current
network in
pacemaker region
Electrotonic conduction
of slow waves
Smooth muscle
cells
Intramuscular ICC
Enteric
motorneuron
Varicosity
28
mV
62
A
58 mV
5 sec
B
Fig. 2.6 Top, Interactions among interstitial cells of Cajal (ICCs), smooth muscle cells, and nerves. Pacemak-
er current leading to slow waves appears to originate in the ICC network. Slow waves actively propagate
within the ICC network and are passively conducted into the smooth muscle. Other ICCs appear to be inter-
posed between nerve endings and smooth muscle cells; they may be involved in neuromodulation. Bottom,
Recordings of electrical activity from the small intestine of a normal mouse (A) and a mouse deficient in
ICCs (B). Note the absence of slow waves in B. (Modified from Horowitz B, Ward SM, Sanders KM: Cel-
lular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu Rev Physiol 61:19-43,
1999.)
structures called the sarcoplasmic reticulum (see Fig. 2.4) many physically active muscles, these spike potentials do
and is released in response to electrical events of the plasma not arise from a stable resting membrane potential. Rather,
membrane or to agonist-induced increases in inositol tri- they are superimposed on relatively slow (3 to 12 cycles/
phosphate, or to both. In addition to these sources for Ca2+, minute) but regular oscillations in membrane potential.
mechanisms also exist for the expulsion of Ca2+ from the These potential changes, called slow waves, do not in
cells and for reuptake into the sarcoplasmic reticulum. themselves cause significant contractions. They set the tim-
Increases in free intracellular Ca2+ most often are related ing, however, for when spike potentials can occur, because
to electrical activities of the smooth muscle cell membranes. spikes are seen only during the peak of depolarization of
In phasically active muscle, Ca2+ enters the cell by way of the slow wave.
voltage-dependent Ca2+ channels. When these channels are The genesis of slow waves appears to lie in complex
activated, rapid transients in membrane potential occur; interactions among smooth muscle cells and specialized
these are called action or spike potentials (see Fig. 5.6). In cells called interstitial cells of Cajal (ICCs) (Fig. 2.6). In all
18 CHAPTER 2 Regulation: Nerves and Smooth Muscle
regions of the GI tract from which slow waves are recorded, of spike potentials depends heavily on neural and hor-
ICCs are present and are connected to one another to form monal activities.
a three-dimensional network within and/or between the An excitatory endocrine, paracrine, or neurocrine acts
smooth muscle layers. These cells not only communicate on a receptor on the smooth muscle cell membrane to
with one another but also form gap junctions with smooth induce spike potentials in those cells and in adjacent cells
muscle cells. Some ICCs appear to be interposed between that are coupled to one another. The spike potentials lead
enteric nerve endings and smooth muscle cells and may be to an increase in intercellular free Ca2+ levels. The Ca2+ then
involved in neural modulation of smooth muscle activity acts via myosin light chain kinase to induce contraction. In
rather than in slow wave generation. Isolated ICCs exhibit contrast, an inhibitory mediator acts with its receptor on
membrane properties that could provide the pacemaker that same membrane. In this case, however, the response
activity responsible for the generation of slow waves. This is an inhibition of spike potentials or a hyperpolarization
activity spreads into and affects the smooth muscle cells. of the cell membrane, or both. This results in a decrease in
Both slow waves and spike potentials are recorded from intracellular free Ca2+ and subsequent relaxation. In addi-
smooth muscle cells that are coupled to ICCs, but slow tion, evidence indicates that activation of cell receptors
waves are absent from intestinal smooth muscle devoid of also can modulate contractile activity through mechanisms
ICCs (see Fig. 2.6). not involving the Ca2+-myosin phosphorylation pathway.
Slow waves are extremely regular and are only min- Whatever the mechanism, it is the interplay of these excit-
imally influenced by neural or hormonal activities, atory and inhibitory mediators on the basal activity of the
although they are influenced by body temperature and muscle that determines the motility functions of the vari-
metabolic activity. The higher the activity, the higher is ous organs of the gut.
the frequency of slow waves. Conversely, the occurrence
S U M M A R Y
• The regulation of GI function results from an interplay sphincter. Smooth muscle makes up the musculature of
of neural and hormonal influences on effector cells that the rest of the GI tract.
have intrinsic activities. • Adjacent smooth muscle cells are electrically coupled to
• The GI tract is innervated by the ANS, which is com- one another and contract synchronously when stimu-
posed of nerves that are extrinsic and nerves that are lated. Some smooth muscles contract tonically, whereas
intrinsic to the tract. others contract phasically.
• Extrinsic nerves are distributed to the GI tract through • In phasically active muscle, stimulation induces a rise
both parasympathetic and sympathetic pathways. in intracellular Ca2+, which in turn induces phosphor-
• Intrinsic nerves are grouped into several nerve plexuses, ylation of the 20,000-dalton light chain of myosin.
of which the myenteric and submucosal plexuses are the ATP is split, and the muscle contracts as the phosphor-
most prominent. Nerves in the plexuses receive input ylated myosin (myosin P) interacts with actin. Ca2+
from receptors within the GI tract and from extrinsic levels fall, myosin is dephosphorylated, and relaxation
nerves. This input can be integrated within the intrinsic occurs. In tonically active muscles, contraction can be
nerves such that coordinated activities can be effected. maintained at low levels of phosphorylation and ATP
• ACh is one of the major excitatory neurotransmitters, and utilization.
NO and VIP are two of the major inhibitory neurotrans- • Periodic membrane depolarizations and repolariza-
mitters at effector cells. Serotonin and somatostatin are two tions, called slow waves, are major determinants of the
important neurotransmitters of intrinsic interneurons. phasic nature of contraction. Slow wave activity results
• Striated muscle comprises the musculature of the phar- from ionic currents initiated through the interactions of
ynx, the oral half of the esophagus, and the external anal the ICCs with smooth muscle cells.
K E Y W O R D S A N D C O N C E P T S
Autonomic nervous system Intrinsic/enteric nervous system
Extrinsic nervous system Myenteric/submucosal plexuses
Parasympathetic innervation Neurocrines
Vagovagal reflexes Acetylcholine
Sympathetic innervation Norepinephrine
CHAPTER 2 Regulation: Nerves and Smooth Muscle 19
S E L F - S T U D Y P R O B L E M S
1. What is meant by the terms “long and short reflexes,” frequencies, yet slow waves set the maximal rates of
and why are they significant? contraction for each.
2. Explain the observation that gastrin and intesti-
nal smooth muscles can each contract at different
OBJECTIVES
• Describe the oral and pharyngeal events taking place • Understand the process of receptive relaxation of the
during a swallow. oral stomach, its function, and regulation.
• Describe the pressures within the esophagus and oral • Understand gastric esophageal reflux disease (GERD)
stomach at rest and during a swallow. and its causes.
• Explain the regulation involved during a swallow,
including its initiation and peristalsis through the
esophagus.
Swallowing consists of chewing, a pharyngeal phase, move is initia�by propulsion of material into the orophar
ment of material through the esophagus, and the relaxation ynx primari y By ovements of the tongue. The portion
of the stomach to receive the ingested material. Swallowing o�olid material to be swallowed is separated from other
is almost purely a motility function. Digestion and absorp mate,rial in the mouth so it lies in a chamber created by
tion are minimal, in part because transport of the bolus placing the tip of the tongue against the hard palate (Fig.
into the stomach takes only seconds. 3.1 ). The material is propelled by elevation and retrac
tion of the tongue against the palate. As the material passes
from the oral cavity into the oropharynx, the nasophar
CHEWING ynx is closed by movement of the soft palate and contrac
Chewing has three major functions: (1) it facilitates swal tion of the superior constrictor muscles of the pharynx
lowing by reducing the size of ingested particles and thus (Fig. 3.lB). Simultaneously, respiration is inhibited, and
also prevents damage to the lining of the pharynx and contraction of the laryngeal muscles closes the glottis and
esophagus; (2) it mixes food with saliva, w'hich exposes raises the larynx. The bolus is propelled through the phar
the food to digestive enzymes and lu6ricates it; and (3) it ynx by a peristaltic contraction that begins in the superior
increases the surface area of ingested material and thereby constrictor and progresses through the middle and infe
increases the rate at which it can be digested. rior constrictor muscles of the pharynx (Fig. 3.lC). These
The act of chewing is both voluntary and involuntary, contractions, along with relaxation of the upper esopha
and most of the time it proceeds by reflexes void of con geal sphincter (UES), propel the bolus into the esophagus
scious input. The chewing reflex is initiated by food in the (Fig. 3.lD).
mouth that inhibits muscles of mastication and causes the The oral and pharyngeal phases of swallowing are rapid,
jaw to drop. A subsequent stretch reflex of the jaw muscles taking less than 1 second. Swallowing can be initiated vol
produces a contraction that automatically raises the jaw untarily, but these efforts fail unless something, at least a
and closes the teeth on the bolus of food. Compression of small amount of saliva, triggers the swallowing reflex. Once
the bolus on the mucosal surface of the mouth inhibits the initiated, however, swallowing proceeds as a coordinated
jaw muscles to repeat the process. involuntary reflex. Coordination is central in origin, and
an area within the reticular formation of the brainstem has
been identified as the swallowing center. Afferent impulses
PHARYNGEAL PHASE from the pharynx are directed toward this center, which
Normally liquids are propelled immediately from the serves to coordinate the activity of other areas of the brain
mouth to the oropharynx and are swallowed. Swallowing such as the nuclei of the trigeminal, facial, and hyp oglossal
20
CHAPTER 3 Swallowing 21
Hard Soft
palate palate
Upper
constrictors
F
T
Ep Middle
constrictors
Lower
constrictors
Tr
A E B
C D
Fig. 3.1 Oral and pharyngeal events during swallowing. (A) The food bolus (F) to be swallowed is propelled
into the pharynx by placement of the tongue (T) on the roof of the hard palate. E, Esophagus; Ep, epiglottis;
Tr, trachea. (B) Further propulsion is caused by movement of the more distal regions of the tongue against
the palate. Contraction of the upper constrictors of the pharynx and movement of the soft palate separate the
oropharynx from the nasopharynx. (C) Propulsion through the upper esophageal sphincter is accomplished
by contraction of the middle and lower constrictors of the pharynx and by relaxation of the cricopharyngeal
muscle. Upward movement of the glottis and downward movement of the epiglottis seal off the trachea. (D)
The bolus is now in the esophagus and is propelled into the stomach by a peristaltic contraction.
nerves, as well as the nucleus ambiguus (Fig. 3.2). Efferent is located in the thorax, where the pressure is lower than
impulses from the center are distributed to the pharynx via in the pharynx and stomach, the esophagus also must
nerves from the nucleus ambiguus. The impulses appear to withstand the entry of air and gastric contents. The barrier
be sequential, so the pharyngeal musculature is activated in functions of the esophagus are accomplished by the pres-
a proximal-to-distal manner. This sequencing accounts for ence of sphincters at each end of the organ.
the peristaltic nature of the pharyngeal contractions. The Anatomically the esophageal muscle is arranged in
center also appears to interact with other areas of the brain two layers: an inner layer with the muscle fibers orga-
involved with respiration and speech. Injury to the swal- nized in a circular axis and an outer layer with the fibers
lowing center produces abnormalities in the pharyngeal organized in a longitudinal axis. The UES consists of
component of swallowing. a thickening of the circular muscle and can be identi-
fied anatomically as the cricopharyngeal muscle. This
muscle, like the musculature of the proximal third of
ESOPHAGEAL PERISTALSIS the esophageal body, is striated. The distal third of the
The esophagus propels material from the pharynx to the esophagus is composed of smooth muscle; although the
stomach. This propulsion is accomplished by coordi- terminal 1 to 2 centimeters (cm) of the musculature
nated contractions of the muscular layers of the body of acts as a lower esophageal sphincter (LES), no sepa-
the esophagus. Because a large segment of the esophagus rate sphincter muscle can be identified anatomically.
22 CHAPTER 3 Swallowing
Swallowing
center
A B C
A Nonvagal nuclei
B Nucleus ambiguus
UES
C Dorsal motor nucleus
Myenteric ganglia
Striated
muscle UES Upper esophageal
sphincter
Smooth
muscle
Longitudinal
layer Myenteric
Circular plexus
layer
Fig. 3.2 Control of pharyngeal and esophageal peristalsis. Sensory input from the pharynx activates an area
in the medulla (the swallowing center). This center serves to coordinate activation of the vagal nuclei with
other centers such as the respiratory centers. Muscles of the pharynx and striated areas of the esophagus
are activated by the center via the nucleus ambiguus. Areas of the smooth muscle are activated via the dorsal
motor nucleus. Peristalsis results from sequential activation of the muscles of the pharynx and esophagus
by sequential neural impulses from the center. The area enclosed within the circle is shown in more detail in
Fig. 3.4.
CHAPTER 3 Swallowing 23
A B
UES
1 0
2 0
3 0
4 0
Diaphragm
5 0
LES
6 0
7 Fundus
Swallow
Fig. 3.3 Manometric recordings from the esophagus and the orad portion of the stomach. Intraluminal pres-
sures from the upper esophageal sphincter (UES), four areas of the esophagus, the lower esophageal sphinc-
ter (LES), and the gastric fundus are shown. (A) Between swallows, both the upper and the lower sphincters
are closed, as indicated by the greater than atmospheric pressures recorded there. Pressures in the body of
the esophagus reflect intrathoracic or intraabdominal pressures. Pressures in the fundus reflect intraabdom-
inal pressure plus tonic contractions of the fundus. (B) On swallowing, the upper sphincter relaxes before
passage of the bolus. After bolus passage it contracts, followed by a peristaltic contraction in the body of the
esophagus. To allow passage of the bolus into the stomach, the lower sphincter and the orad stomach relax
before the peristaltic contraction reaches them.
The middle third of the body of the esophagus is com- a few centimeters, and the pressure may be 20 to 40 mm
posed of a mixture of muscle types with a descending Hg higher than on either side. Pressures in the body of the
transition from striated to smooth fibers. esophagus are similar to those within the body cavity in
The events that occur in the esophagus between and which the esophagus lies. In the thorax the pressures are
during swallowing are often monitored by placing pres- subatmospheric and vary with respiration; they drop with
sure-sensing devices at various levels in the esophageal inspiration and rise with expiration. These fluctuations in
lumen. Such devices indicate that between swallows, both pressure with respiration reverse below the diaphragm,
the UES and the LES are closed and the body of the esoph- and intraluminal esophageal pressure reflects intraabdom-
agus is flaccid (Fig. 3.3A). In the region of the UES, pres- inal pressure, which is slightly higher than atmospheric
sure is as much as 60 millimeters of mercury (mm Hg) pressure.
higher than that in the pharynx or body of the esophagus. During a swallow the sphincters and the body of the
A zone of elevated pressure also is found at the LES. The esophagus act in a coordinated manner (Fig. 3.3B). Shortly
length of this zone may range from several millimeters to before the distal pharyngeal muscles contract, the UES
24 CHAPTER 3 Swallowing
CLINICAL APPLICATIONS
Contractions of pharyngeal muscle are controlled solely component of swallowing can occur as part of a variety
by extrinsic nerves. Therefore certain neurologic diseases of systemic diseases. Examples are diabetes mellitus,
(e.g., cerebrovascular accident) can have an adverse chronic alcoholism, and scleroderma.
effect on this phase of swallowing. Aspiration often Motor dysfunction also can play an important contribu-
occurs because contractions in the pharynx and upper tory role in the pathogenesis of other esophageal diseases.
esophageal sphincter (UES) are no longer coordinated. A The most common symptom associated with esopha-
similar clinical picture can be seen in diseases that affect geal dysfunction is heartburn. This burning sensation is
striated muscle or the myoneural junction. caused by the reflux of gastric acid into the esophagus
Diseases affecting the smooth muscle portion of the and the resulting injury to the esophageal mucosa. This
esophagus predictably cause abnormalities in peristalsis condition may be produced by motor abnormalities that
and in the tone of the lower esophageal sphincter (LES). result in abnormally low pressures in the LES or by the
In achalasia, for example, the LES often fails to relax com- failure of secondary peristalsis to empty the esophagus
pletely with swallowing. This may be coupled with a loss of effectively. Reflux may also occur if intragastric pressure
peristalsis in the esophageal body, a complete absence of increases, as may occur after a large meal, during heavy
contractions, or the appearance of simultaneous rather than lifting, or during pregnancy. Persistent reflux and the
sequential contractions, with resulting impaired transit. resulting inflammation lead to gastroesophageal reflux
Patients with this disorder have considerable difficulty disease (GERD). This condition is usually treated effec-
swallowing, often aspirate retained esophageal content, tively with inhibitors of gastric acid secretion. In some
and may become severely malnourished. This disor- cases a region of the proximal stomach moves through
der has been attributed to abnormalities in the enteric the diaphragm into the thorax and produces severe gas-
nerves. In another disorder, diffuse esophageal spasm, tric reflux. This condition is termed hiatal hernia and is
simultaneous contractions of a long duration and high often treated by surgery. Reflux itself is not abnormal, and
amplitude can occur. Affected persons have difficulty it occurs several times a day. Under normal conditions
swallowing and may complain of chest pain. Although the refluxed acid is cleared from the esophagus, and no
not always symptomatic, abnormalities in the esophageal symptoms develop.
CLINICAL TESTS
Swallowing is assessed clinically by x-ray examination are passed through the nose or mouth so that their tips lie
with barium and by esophageal manometry. In the x-ray in various regions of the esophagus. Pressures detected
study, the patient swallows a bolus of liquid barium by the catheters then are recorded between and during
sulfate. Because this material is radiopaque, it can be swallowing small sips of water. These recordings pro-
observed fluoroscopically and recorded on the x-ray film vide a quantitative description of events occurring in the
as it traverses the esophagus, thereby providing a qualita- sphincters and body of the esophagus.
tive description of motor events in both the pharynx and A useful test for episodes of acid reflux is 24-hour moni-
the esophagus. toring of intraesophageal pH. A small pH probe is inserted
If a more detailed description of events is required, or nasally and positioned 5 cm above the lower esophageal
if motor disorders such as those just described are sus- sphincter. A small battery-powered computer is used for
pected, esophageal manometry is often useful. Catheters continuous recordings of pH.
S U M M A R Y
• Swallowing is initiated voluntarily, but once initiated, it • Peristaltic contraction of the pharyngeal muscles, relax-
proceeds as an involuntary reflex. ation of the UES, and peristaltic contraction of the stri-
• Swallowing is accomplished by peristaltic contraction of ated muscle of the upper esophagus are regulated by
pharyngeal muscles, during which time the UES relaxes. pathways within the central nervous system. Peristaltic
This is followed by peristaltic contraction of the esoph- contraction of the smooth muscle of the lower esoph-
ageal musculature, during which time the LES and the agus and relaxation of the LES are regulated by path-
orad region of the stomach relax. ways within the central nervous system and by pathways
within the intrinsic nerves.
CHAPTER 3 Swallowing 27
• Contraction of the pharynx and esophagus can be initi- release a transmitter (perhaps NO or VIP) to cause
ated by swallowing (primary peristalsis). Contraction of muscle relaxation.
the esophagus can be initiated by stimulation of recep- • Contraction of the orad stomach is the result of an inter-
tors within the esophagus (secondary peristalsis). play of excitatory and inhibitory neural and hormonal
• Tonic contraction of the LES between swallows is the influences acting on an intrinsic myogenic contraction.
result of an interplay of excitatory and inhibitory neural During a swallow, the orad stomach relaxes (recep-
and hormonal influences acting on an intrinsic myo- tive relaxation) in response to activation of inhibitory
genic contraction. During a swallow, intrinsic nerves nerves in the vagus.
K E Y W O R D S A N D C O N C E P T S
Oral ingestion Lower esophageal sphincter
Chewing reflex Primary peristalsis
Oropharynx Secondary peristalsis
Tongue Vagotomy
Oral cavity Orad portion
Nasopharynx Caudad portion
Glottis Receptive relaxation
Larynx Vasovagal reflex
Peristaltic contraction Achalasia
Pharynx Diffuse esophageal spasm
Upper esophageal sphincter Heartburn
Swallowing center Gastroesophageal reflux disease
Esophagus Hiatal hernia
S E L F - S T U D Y P R O B L E M S
1. What is the difference between the innervation of the 2. How does the body cope with the fact that much of the
striated and smooth muscle portions of the esophagus esophagus lies within the thorax?
and its physiologic consequences?
OBJECTIVES
• Describe the contractions of the orad and caudad • Understand the role of duodenal receptors in the regu-
regions of the stomach. lation of gastric emptying.
• Explain the regulation of the contractile activity of the • Describe the changes in motility that regulate gastric
stomach, including the role of slow waves. emptying.
• List the components of the gastric contents that affect • Describe the disorders that may result in an impair-
the rate of gastric emptying. ment of gastric emptying.
Motility of the stomach and upper small intestine is orga- longitudinal and circular muscle layers and throughout
nized to accomplish the orderly emptying of contents the circular muscle layer. The myenteric plexus receives
into the duodenum in the presence of ingested material nerve endings from other intrinsic plexuses, as well as from
of variable quantity and composition. Accommodation extrinsic nerves. Axons from neurons within the myenteric
and temporary storage of ingested material result from plexus synapse with the muscle fibers and with glandular
receptive relaxation of the orad stomach (see Chapter 3). cells of the stomach. Extrinsically the stomach is innervated
Emptying, which also requires mixing ingested material by branches of the vagus nerves and by fibers originating in
with gastric juice and reducing the particle size of any sol- the celiac plexus of the sympathetic nervous system.
ids that have been swallowed, results from integrated con- The pylorus, or gastroduodenal junction, is charac-
tractions of the orad stomach, caudad stomach, pylorus, terized by a thickening of the circular muscle layer of the
and duodenum. distal antrum. Separating this bundle of muscle from the
duodenum is a connective tissue septum; however, some
of the longitudinal muscle fibers pass from the antrum to
ANATOMIC CONSIDERATIONS connect with muscle cells of the duodenum. The pylorus is
Gastric contractions result from activity of smooth muscle richly innervated with both extrinsic and intrinsic nerves,
cells that are arranged in three layers: an outer longitudinal and nerve endings within the thickened circular muscle
layer, a middle circular layer, and an inner oblique layer. layer are abundant. Many of these endings contain neu-
The longitudinal layer is absent on the anterior and poste- ropeptides, especially enkephalin, and many produce and
rior surfaces of the stomach. The circular layer is the most release nitric oxide (NO).
prominent and is present in all areas of the stomach except The anatomy of the proximal duodenum is similar to
the paraesophageal region. The oblique layer, the least that of the rest of the intestine (described in Chapter 5).
complete, is formed from two bands of muscle lying on A significant difference is the larger number of intrinsic
the anterior and posterior surfaces. These two bands meet nerves present in this area compared with the rest of the
at the gastroesophageal sphincter and fan out to fuse with small bowel. These nerves may be involved in the regula-
the circular muscle layer in the caudad part of the stom- tion of gastric emptying (described in a later section).
ach. Both the circular and the longitudinal muscle layers In addition to the muscle cells and nerves, interstitial
increase in thickness toward the duodenum. cells of Cajal (ICCs) also are prominent in all regions and
The stomach is richly innervated with both intrinsic appear to play a prominent role in regulating motility.
and extrinsic nerves. The intrinsic nerves lie in various Many ICCs form gap junctions with smooth muscle cells,
plexuses, the most prominent being the myenteric plexus, whereas others appear to create a bridge between nerve
which lies in a three-dimensional matrix between the endings and smooth muscle cells.
28
CHAPTER 4 Gastric Emptying 29
2 ± 2 mV
3
2
3
4
5 4
8 7 6
Fig. 4.3 Electrical activity of smooth muscle cells of the stomach. Electrodes placed on the serosal surface
record no changes from the orad region. In the midregion, however, slow waves occur continuously at inter-
vals of 12 to 20 seconds. Slow waves give the appearance of moving through the caudad region at increasing
velocities. Compare this with Fig. 4.1. mV, Microvolts. (Adapted from Kelly KA, Code CF, Elveback LR: Pat-
terns of canine gastric electrical activity. Am J Physiol 217:461-471, 1969.)
(See videos: http://www.wzw.tum.de/humanbiology/mot- are therefore controlled by the frequency and velocity of
vid01/movie_11_1mot01.wmv; http://www.wzw.tum.de/hu- spread of the slow wave.
manbiology/motvid01/movie_13_1mot01.wmv; accessed Nervous and humoral factors are not necessary for the
March 2018). presence of slow waves, but they do alter slow wave behav-
Contractions of the caudad area of the stomach are ior. Vagotomy disorganizes the slow waves so that the
controlled by interactions among smooth muscle cells phase lag varies in both duration and direction. The hor-
and ICCs, as well as by nervous and humoral elements. mone gastrin increases the frequency of gastric slow waves,
Smooth muscle cells in this area have a membrane poten- although it has little effect on the apparent propagation of
tial that fluctuates rhythmically with cyclic depolarizations the waves through the musculature.
and repolarizations. These fluctuations are called slow Simultaneous recordings of both electrical and
waves (also referred to as basic electric rhythm, paceset- mechanical activities have shown that slow waves initi-
ter potentials, and control activity). Slow waves have two ate significant contractions of the musculature only when
components: an initial upstroke potential and a secondary the plateau potential exceeds a threshold (Fig. 4.4). Once
plateau potential. In the stomach, slow waves can initiate the threshold is exceeded, the greater the amplitude of the
significant contractions; thus some investigators refer to plateau, the greater will be the force of contraction. The
them as action potentials. However, slow waves are always plateau potential may or may not be accompanied by
present, regardless of the presence or absence of con- superimposed rapid oscillations called spike potentials
tractions. Their frequency is constant, and humans have or spike bursts. These oscillations also appear to initiate
approximately 3 cycles/minute (cpm). When slow waves contractions and are seen more frequently in muscle of
are recorded from multiple sites between the midstom- the caudad antrum. Threshold values for contraction are
ach and the gastroduodenal junction, they have the same not reached by every slow wave. Therefore not every slow
frequency at all sites (Fig. 4.3). However, slow waves do wave is accompanied by a contraction. If the threshold
not occur simultaneously at all points along the stomach. is reached, it is only during a specific phase of the slow
Rather, a phase lag occurs; thus they seem to pass from wave cycle. Thus the phasic and peristaltic nature of gas-
an area in the midstomach toward the gastroduodenal tric contractions results from the presence of slow waves.
junction. This phase lag between slow waves at equi- Whether an individual slow wave results in a contrac-
distant points lessens as the gastroduodenal junction is tion and the amplitude of contractions are determined by
neared. The frequency and velocity of the peristaltic waves hormonal and neural activity, which in turn depends on
CHAPTER 4 Gastric Emptying 31
(mm Hg)
80
Antrum 0
80
0
Pylorus 80
(sleeve)
0
80
Duodenum 0
80
1 min
Fig. 4.5 Intraluminal pressures recorded from two areas of the stomach (antrum), the pylorus, and two areas
of the proximal duodenum during the intraduodenal infusion of lipid. Note the regular isolated contractions,
and the elevated pressures (0 indicates atmospheric pressure in each tracing) between contractions, in the
pylorus. This activity is occurring at a time when no contractions are present in the stomach and duodenum.
(Adapted from Heddle R, Dent J, Read NW, et al: Antropyloroduodenal motor responses to intraduodenal lipid
infusion in healthy volunteers. Am J Physiol 254:G671-G679, 1988.)
A B C
Fig. 4.6 Regulation of gastric emptying. (A) Hypothetic conditions immediately after the rapid ingestion of
a meal and before the onset of any contractile activity. This outline is superimposed in B and C to illustrate
changes. (B) Conditions favoring emptying are increased tone of the orad region of the stomach, forceful
peristaltic contractions of the caudad region of the stomach, relaxation of the pylorus, and absence of seg-
menting contractions of the duodenum. As nutrients emptied from the stomach are further digested and
absorbed in the small intestine, they excite receptors located in the intestinal mucosa. Activation of these
receptors results in C. (C) Relaxation of the orad region of the stomach, a decrease in the number and force of
contractions of the caudad region of the stomach, contraction of the pylorus, and an increase in segmenting
contractions of the duodenum. These actions result in a slowing of gastric emptying.
of the caudad stomach, and increases in the diameter and Regulation of emptying results from the presence of
inhibition of segmenting contractions of the proximal receptors that lie in the upper small bowel. These recep-
duodenum all lead to an increased rate of gastric emptying. tors respond to the physical properties (e.g., osmotic
Inhibition of emptying occurs on reversal of one or more pressure) and chemical composition (e.g., H+, lipids)
of these contractile activities (see Fig. 4.6). of the intestinal contents. As contents empty from the
CHAPTER 4 Gastric Emptying 33
1.0
0.8
Fraction in stomach
0.6 Solid
0.4
Liquid
0.2
stomach, intestinal receptors located in the duodenum The pattern of motility of the gastroduodenal area
are activated. Receptor activation triggers several neural changes after the nutrient components of the meal have
and hormonal mechanisms that inhibit gastric emptying. been digested and absorbed. Any large particles of undi-
For example, fats release CCK, which increases the dis- gested residue that remain in the stomach are emptied by
tensibility of the orad stomach. Acid, when placed in the a burst of peristaltic contractions (phase 3) as part of the
duodenum, inhibits motility and emptying with a latent migrating motor complex (MMC) (Fig. 4.8). During this
period as short as 20 to 40 seconds, a finding indicat- short burst, powerful contractions begin in the previously
ing that the inhibition is the result of neural reflex. This inactive orad region and sweep the entire length of the stom-
reflex appears to be entirely intrinsic, with information ach. The pylorus dilates and the duodenum relaxes during
from the duodenal receptors to the gastric smooth mus- each sweep so that the resistance to emptying is minimal.
cle carried by neurons of the intramural plexus. Other Then duodenal contractions sweep the contents onward
hormones such as secretin and GIP also inhibit emptying (see Chapter 5). (See video: http://www.wzw.tum.de/hu-
but do not appear to do so in physiologic concentrations. manbiology/motvid02/movie_06_1mot02.wmv; accessed
Neural input that activates the sympathetic system, such March 2018). After a burst of activity, the region remains
as that produced by pain, anxiety, fear, or even exercise, relaxed for an hour or more. Then intermittent contrac-
may slow gastric emptying. Much of the regulation of gas- tions begin and lead to another burst. This cycle repeats
tric emptying is mediated by as yet undefined pathways, every 90 minutes or so until ingestion of the next meal.
but it is obvious that regulation allows time for osmotic Premature bursts can be initiated by injection of the hor-
equilibration, acid neutralization, and solubilization and mone motilin and by drugs (e.g., erythromycin) thought to
digestion of lipids. act on motilin receptors.
34 CHAPTER 4 Gastric Emptying
Proximal
stomach
Transitional
area
Antrum
(orad)
Antrum
(mid)
Antrum
(caudad)
Duodenum
Fig. 4.8 Schematic of intraluminal pressures recorded from the stomach and proximal duodenum during
an active phase of a migrating motor complex. Phasic contractions begin in the orad region of the stomach
and propagate over the caudad region. As contractions of the caudad region approach the gastroduodenal
junction, the pylorus relaxes (not shown) and duodenal contractions are momentarily inhibited. This process
allows contents to be swept into the duodenum. Contents are then propelled toward the colon, as described
in Chapter 5. (Adapted from Malagelada JR, Azpiroz F: Determinants of gastric emptying and transit in the
small intestine. In Schultz SG, Wood JD, Rauner BB [eds]: The Gastrointestinal System, vol 1. Bethesda, MD,
American Physiological Society, 1989.)
CLINICAL APPLICATIONS
Disorders of gastric motility generally are manifested by outlet (gastroenterostomy) in an attempt to avoid this
a rate of gastric emptying that is either too slow or too complication. After such an operation, emptying of liquids
fast. This condition may reflect an abnormality in one or generally is accelerated, but even with alteration of the
all of the major motor functions of the stomach. When gastric outlet, emptying of solids still may be slowed.
the stomach fails to empty properly, the affected person Most patients undergoing this type of surgical procedure
experiences nausea, loss of appetite, and early satiety, experience no other symptoms. However, some may
and gastric contents often may be vomited. The most experience diarrhea, sweating, palpitations, cramps, and
common cause of impaired emptying is obstruction at a variety of other unpleasant symptoms, which may be
the gastric outlet. Examples of disorders that may result the result of rapid emptying that constitutes dumping
in obstruction are gastric cancer and peptic ulcer disease. syndrome. This in turn causes the rapid entry of large
In the latter, the gastric lumen at the pylorus may actu- volumes of fluid into the upper small bowel to bring the
ally become occluded from inflammation and scarring hypertonic contents to isotonicity.
associated with the ulcer. Impaired emptying also can be It is speculated that motility abnormalities may underlie
caused by the absence or disorganization of motor events or contribute to other diseases of the upper gastrointesti-
in the caudad stomach. These phenomena occur with a nal tract. For example, gastric emptying is accelerated in
variety of metabolic disorders, such as diabetes mellitus patients with a duodenal ulcer. This accelerated emptying
and potassium depletion. may enhance the delivery of gastric acid to the duodenum
Vagus nerve section (vagotomy) invariably leads to a and perhaps may overwhelm the ability of the duodenal
delay in gastric emptying of solids. Consequently, vagot- mucosa to defend itself against injury. Alternatively, for
omy (e.g., performed to decrease acid secretion in pep- patients with a gastric ulcer, gastric emptying appears to
tic ulcer disease) is coupled with surgical alterations of be slowed. This slowing may render the stomach more
the pylorus (pyloroplasty) or creation of a new gastric susceptible to injury.
CHAPTER 4 Gastric Emptying 35
CLINICAL TESTS
A qualitative assessment of gastric motility and empty- function of time (see Fig. 4.7). In certain laboratories,
ing can be obtained by x-ray and fluoroscopic evaluation manometry similar to that used in assessing esopha-
of a barium-filled stomach. Aspiration of the stomach at geal motility can be employed. Compliance of the orad
specific intervals after instillation of an isotonic saline stomach can be assessed using a “barostat,” a large
solution also gives information on gastric emptying. A bag placed in the stomach that monitors changes in
more quantitative test involves gamma scintigraphy. volume under set pressures. More recently, magnetic
For this test, radiolabeled liquid or solid food, or both, resonance imaging and ultrasonography have been
is ingested, and gamma cameras are used to scan the employed as noninvasive methods to assess gastric
stomach at various times afterward. The fraction of motility and emptying.
material remaining in the stomach is then plotted as a
S U M M A R Y
• Contractile activity of the orad stomach varies with the and number of contractions of the caudad stomach,
digestive state. After the orad region has accommodated increased tone and phasic contractions of the pylorus,
a meal, it exhibits low-amplitude, long-lasting con- and increased segmenting contractions of the upper
tractions as the meal empties. After the meal has been duodenum.
digested and absorbed, the orad stomach undergoes • Rhythmic membrane depolarizations and repolariza-
periodic bursts of high-amplitude contractions as part tions called slow waves occur in smooth muscle cells
of the MMC. of the caudad stomach. These waves are omnipresent,
• Contractions of the caudad stomach are mostly peri- occurring at a frequency of approximately three per
staltic, beginning in the midstomach and progressing minute. Each depolarization appears to be initiated first
toward the duodenum. During emptying of a meal, in the midstomach and then to propagate toward the
contractions are of variable amplitude and are more or pylorus. Slow waves appear to set the timing and the
less continuous at a frequency of approximately 3 cpm. peristaltic nature of contractions; however, not every
During the interdigestive period, forceful peristaltic slow wave initiates a contraction. Those that do are of
contractions are grouped into periodic bursts as part of large amplitude and may exhibit superimposed spike
the MMC. potentials.
• Gastric emptying is highly regulated and involves feed- • Vagotomy results in a decrease in the number and
back inhibition from receptors located in the upper force of contractions of the caudad stomach and a
small intestine. Receptors are stimulated by osmotic decrease in gastric emptying of solids. Motilin induces
pressure, H+, and fatty acids. Stimulation results in contractions that are part of the gastric phase of the
patterns of motility that slow emptying: decreased MMC.
tonic contraction of the orad stomach, decreased force
K E Y W O R D S A N D C O N C E P T S
Longitudinal layer Spike potentials/spike bursts
Circular layer Intestinal receptors
Oblique layer Duodenal contractions
Pylorus Vagotomy
Peristaltic contraction Pyloroplasty
Retropulsion Gastroenterostomy
Slow waves Dumping syndrome
36 CHAPTER 4 Gastric Emptying
S E L F - S T U D Y P R O B L E M S
1. Nutrients enter the duodenum, causing the release of Isotonic NaCl
cholecystokinin, CCK. What changes in gastroduode- HCl pH 3
nal motility might you expect to record? A solution of amino acids
2. You have a patient with a significant decrease in Isotonic starch
pancreatic enzyme secretion. Which of the following Hypertonic NaCl
would be expected to empty from the stomach abnor- A solution of fatty acids
mally fast?
SUGGESTED READINGS Hunt JN, Knox MT. Regulation of gastric emptying. In: Code
CF, ed. Handbook of Physiology. Vol. 4. Baltimore: Williams &
Ehrlein HJ, Akkermans LMA. Gastric emptying. In: Wilkins; 1968.
Akkermans LMA, Johnson AG, Read NW, eds. Gastric and Rayner CK, Hebbard GS, Horowitz M. Physiology of the antral
Gastroduodenal Motility. New York: Praeger; 1984. pump and gastric emptying. In: Johnson LR, ed. Physiology of
Hasler WL. The physiology of gastric motility and gastric emp- the Gastrointestinal Tract. 5th ed Vol. 1. San Diego: Elsevier;
tying. In: Yamada T, Alpers DH, Laine L, et al., eds. Textbook 2012.
of Gastroenterology. 3rd ed. Vol. 1. Philadelphia: Lippincott
Williams & Wilkins; 1999.
5
Motility of the Small Intestine
OBJECTIVES
• Compare the motility patterns of the small intestine • Explain the peristaltic reflex and the intestino-
during feeding and fasting. intestinal reflex.
• Describe the functions of slow waves and spike poten- • Describe the motility changes that result in vomiting,
tials in regulating contractions of the small intestine. and discuss the primary factors controlling it.
• Describe the functions and control of the migrating
motility complex.
Motility of the small intestine is organized to optimize the to smooth muscle cells of both muscle layers, to epithelial
processes of digestion and absorption of nutrients and cells, and perhaps to endocrine and immune cells. Many
the aboral propulsion of undigested material. Thus con- neurotransmitters are present in the enteric nervous system,
tractions perform at least three functions: (1) mixing of including acetylcholine, norepinephrine, vasoactive intesti-
ingested foodstuffs with digestive secretions and enzymes, nal peptide, enkephalin, and other peptides. Furthermore,
(2) circulation of all intestinal contents to facilitate contact many nerves express nitric oxide synthase activity.
with the intestinal mucosa, and (3) net propulsion of the Interstitial cells of Cajal (ICCs) also are prominent in
intestinal contents in an aboral direction. and adjacent to the enteric nerves and muscular layers of
the intestine. At least two major classes of ICCs have been
identified: those responsible for generating slow waves and
ANATOMIC CONSIDERATIONS those involved in mediating neural input to the smooth
Contractions of the small intestine are effected by the activ- muscle cells.
ities of two layers of smooth muscle cells: an outer layer Extrinsic innervation is supplied by the vagus nerve and
with the long axis of the cells arranged longitudinally and by nerve fibers from the celiac and superior mesenteric
an inner layer with the long axis of the cells arranged cir- ganglia (see Fig. 2.1). Many of the fibers within the vagus
cularly. In general, the circular muscle layer is thicker, and are preganglionic, whereas many from the abdominal gan-
both layers are more abundant in the proximal intestine; glia are postganglionic. Some of the fibers within the vagus
they decrease in thickness distally to the level of the ileo- are cholinergic, whereas some from the abdominal plex-
cecal junction. uses are adrenergic. In addition, nerves that contain soma-
The small intestine is richly innervated by elements of the tostatin, substance P, cholecystokinin (CCK), enkephalin,
autonomic nervous system. Within the wall of the intestine neuropeptide Y, and other transmitters have been identi-
itself lie neurons, nerve endings, and receptors of the enteric fied in afferent and efferent vagal and splanchnic nerves.
nervous system. These neural elements tend to be concen- The exact pathways and physiologic roles of these nerves
trated in several plexuses. The most prominent, the myenteric are being elucidated.
or Auerbach plexus, lies between the circular and longitu-
dinal layers of smooth muscle cells. Plexal neurons receive
TYPES OF CONTRACTIONS
input from other neurons within the plexus, from receptors
located in the mucosa and muscle walls, and from the central Between contractions, pressures within the lumen of the
nervous system by way of the parasympathetic and sympa- small intestine approximately equal the intraabdominal
thetic nerve trunks. Plexal neurons provide integrated output pressure. When the musculature contracts, the lumen is
37
38 CHAPTER 5 Motility of the Small Intestine
30 s
Fig. 5.1 Intraluminal pressure changes recorded from the duodenum of a conscious human. Sensors placed
1 cm apart record changes in pressure that are phasic, lasting 4 to 5 seconds. Note that a rather large contrac-
tion can take place at one site while nothing is recorded 1 cm away on either side.
occluded partially or totally, and the pressure increases. placement of a solid bolus of material in the lumen), the
Most contractions are local events and involve only 1 to bowel responds with contraction orad and relaxation
4 centimeters (cm) of bowel at a time. The contractions aborad to the point of stimulation. These events tend to
usually produce intraluminal pressure waves that appear as move the material in an aboral direction (Fig. 5.3B), and if
nearly symmetric peaks of uniform shape (Fig. 5.1). In the they occur sequentially, they can propel a bolus the entire
human upper small bowel, contractions occur at any one length of the gut in a short time. This peristaltic response,
site at multiple intervals of 5 seconds (Fig. 5.2). first described by Bayliss and Starling, is known as the
Occasionally other types of pressure waves can be law of the intestines. Often it is invoked to explain how
recorded. One such type consists of an elevated baseline material is normally propelled through the small bowel.
pressure that lasts from 10 seconds to 8 minutes. This wave However, peristalsis involving long segments of intestine
seldom occurs alone and is usually accompanied by super- is seldom seen in normal persons, although peristaltic con-
imposed phasic changes in pressure. tractions involving short segments (1 to 4 cm) of intestine
The effect of any contraction on the intestinal contents have been described.
depends on the state of the musculature above and below
the point of the contraction. If a contraction is not coor-
PATTERNS OF CONTRACTIONS
dinated with activity above and below, intestinal contents
are displaced both proximally and distally during the con- Not only are there differences in individual contractions of
traction and may flow back during the period of relaxation. the intestine, but there also are different patterns of con-
This serves to mix and locally circulate the contents (Fig. tractions. In fasting humans, contractions do not occur
5.3A). Such contractions appear to divide the bowel into evenly over time. Rather, at each locus cycles consisting of
segments, and this feature accounts for the name given phases of no or few contractions are followed by a phase
to this process—segmentation. If, however, the con- of intense contractions (phase 3) that ends abruptly (Fig.
tractions at adjacent sites occur in a proximal-to-distal 5.4). The duration of each cycle is the same at adjacent loci
sequence, aboral propulsion will result. (See http://ww- of the bowel; however, the 5- to 10-minute phase of intense
w.wzw.tum.de/humanbiology/motvid01/movie_65_ contractions does not occur simultaneously at all loci.
1mot01.wmv; accessed March 2018). Instead, this phase appears to migrate aborally, and it takes
The small intestine is also capable of eliciting a highly approximately 1.5 hours to sweep from the duodenum
coordinated contractile response that is propulsive in through the ileum. The characteristics of this pattern have
function. When an area of bowel is stimulated (e.g., by earned it the title of migrating motor complex (MMC).
CHAPTER 5 Motility of the Small Intestine 39
Occurrence (%) 3
0
0 5 10 15 20 25 30 35 40 45
Time (s)
Fig. 5.2 Frequency distribution of 7572 contractions recorded at one site in the human small intestine. Note
that the contractions are most frequent at multiples of 5 seconds, the approximate interval between slow
waves in this region. (From Christensen J, Glover JR., Macagno EO, et al: Statistics of contractions at a point
in the human duodenum. Am J Physiol 221:1818-1823, 1971.)
Proximal duodenum
100 mm Hg
Distal duodenum
100 mm Hg
Jejunum
100 mm Hg
1 min
Fig. 5.4 Contractions at three loci in the small bowel. Note that at each locus, phases of no or intermittent
contractions are followed by a phase of continuous contractions that ends abruptly. Also note that the phase
of continuous contractions appears to migrate aborally along the bowel. Such a pattern is called the migrating
motor complex. (From Rees WD, Malagelada JR, Miller H: Human interdigestive and postprandial gastroin-
testinal motor and gastrointestinal hormone patterns. Dig Dis Sci 27:321-329, 1982.)
12
4
Number of contractions/min
0
12
0
12
0
0 50 100 150 200 250 300
Minutes
Fig. 5.5 Graphic presentation of the number of contractions at three loci in the small bowel. The number of
contractions during each minute of the recording was counted and plotted against the time of recording. The
resulting histogram indicates cycles of activity at each locus. Note that migrating motor complexes recur at
each locus at intervals of approximately 100 minutes and that the phases of intense contractions appear to
migrate aborally. (From Vantrappen G, Janssens J: The interdigestive motor complex of normal subjects and
patients with bacterial overgrowth of the small intestine. J Clin Invest 59:1158-1166, 1977.)
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discovered. But even the victims of that malady find atmospheric and other
conditions friendly to a prolongation of life in the salubrious air and sunshine of
the South African tablelands.
On the whole, there can be no question as to the general good effect upon
health of the South African climate. Europeans and Americans living therein
pursue their athletic sports with all the zest experienced in their native climates,
and the descendants of the original Dutch and Huguenot settlers—now in the
sixth and seventh generations—have lost nothing of the stature nor of the
physical energy that characterized their forefathers.
South Africa used to be the habitat of an unusually rich fauna. The lion, leopard,
elephant, giraffe, rhinoceros, hippopotamus, antelope in thirty-one species,
zebra, quagga, buffalo and various other wild creatures—some of them savage,
and all of them beautiful after their kind—abounded. But of late years all this has
been changed. Since firearms have been greatly improved and cheapened and
the country has been opened to the Nimrods of the world and the [269]swarming
natives have procured guns and learned to use them, the wild animals have
been thinned out. There are now but two regions in South Africa where big
game can be killed in any great numbers—the Portuguese territory from the
Zambesi to Delagoa Bay, and the adjoining eastern frontier of the Transvaal.
Snakes of various kinds and sizes, from the poisonous black mamba to the
python that grows to over twenty feet in length, used to infest many parts of the
country, but they have almost disappeared from the temperate regions inhabited
by the whites.
The farmers’ worst enemies are not now the great beasts and reptiles of former
years, but the baboons, which gather in the more rocky districts and kill the
lambs, and two species of insects—the white ants and the locusts—which
sometimes ravage the eastern coast.
Beyond that of most countries in the world of equal extent the flora of South
Africa is rich in both genera and species. The neighborhood of Cape Town and
the warm, sub-tropical regions of eastern Cape Colony and Natal are specially
affluent in beautiful flowers. In the Karoo district, and northeastward over the
plateau into Bechuanaland and the Transvaal, vegetation presents [270]but little
variety of aspect, owing in part to the general sameness of geological formations
and in part to the prevailing dryness of the surface.
In general, South Africa is comparatively bare of forests—a fact for which
denudation by man cannot account, for it is yet a country new to civilization.
Some primitive forests are to be found on the south coast of Cape Colony and in
Natal. These have been put under the care of a Forest Department of the
government. In the great Knysna forest wild elephants still roam at large. The
trees, however, even in the preserved forests, are small, few of them being more
than fifty or sixty feet in height. The yellowwood grows the tallest, but the less
lofty sneezewood is the most useful to man. Up the hillsides north of Graham’s
Town and King William’s Town are immense tracts of scrub from four to eight
feet high, with occasional patches of prickly pear—a formidable invader from
America, through which both men and cattle make their passage at the cost of
much effort and many irritating wounds from the sharp spines. A large part of
this region, being suitable for little else, has been utilized for ostrich farming.
The largest political division of South Africa is Cape Colony. The area is about
292,000 square miles and the population, white and native, is 2,011,305. The
whites number about 400,000. But little of it is suitable for agriculture, and
considerable portions of it are too arid for stock raising. Including the natives the
population is only about seven to the square mile. On the lowlands skirting the
sea on the south and west are some fruitful regions that give a profitable yield of
grapes and corn. On the tableland of the interior there is a rainfall of only from
five to fifteen inches in the year. As a consequence the surface is dry and
unfriendly to vegetable life. In an area of three hundred miles by one hundred
and fifty there is not a stream having a current throughout the year, nor is there
any moisture at all in the dry season except some shallow pools which are soon
dried up by evaporation. Nevertheless, in this desert, bare of trees and of
herbage, there is abundance of prickly shrubs, which are sufficiently succulent
when they sprout under the summer rains to afford good browsing for goats and
sheep. In the northwestern part of the interior and northward to Kimberley and
Mafeking, the country is better watered than the more westerly regions, and
[273]grazing animals find a generous growth of grass as well as nutritious shrubs.
In the southeastern part the rainfall is still heavier. The foothills of the
Quathlamba Range toward the sea are covered in places with forests, the grass
is more abundant and much of the land can be tilled to profit without artificial
irrigation. In 1899 there were about 3,000 miles of railway and nearly 7,000
miles of telegraph open in the colony. The number of vessels entering the ports
of Cape Colony in 1897 was 1,093, with a total tonnage of 2,694,370 tons; in
addition to this there were 1,278 vessels engaged in the coastwise trade, with a
tonnage of 3,725,831 tons. The foreign commerce of Cape Colony is large,
including, as it does, the bulk of the import and export trade of all South Africa.
The total importation of merchandise for 1897 was $80,127,495, and the
exports, including a large proportion of the gold and diamond products of
Kimberley and the Transvaal, amounted, in 1898, to $123,213,458.
Natal, beyond any other part of South Africa, is favored by natural advantages. It
lies on the seaward slope of the Quathlamba Mountains, and its scenery is
charmingly diversified by some of the lesser peaks and the foothills of that
range. It is well watered by perennial streams [274]fed by the snows and springs
of the mountains. While the higher altitudes to the west are bare, there is
abundance of grass lower down and toward the coast there is plenty of wood.
The climate in general is much warmer than that of Cape Colony; in the low strip
bordering the sea it is almost tropical. This high temperature is not caused so
much by latitude as by the current in the Mozambique Channel, which brings
from the tropical regions of the Indian Ocean a vast stream of warm water, which
acts on the climate of Natal as does the Gulf Stream on that of Georgia and the
Carolinas. Nearly the whole of Natal may be counted temperate; the soil is rich,
the scenery is beautiful, and, with the exception of certain malarious districts at
the north, the climate is healthful. Foreigners from Europe and America may
reasonably hope to enjoy long life and prosperity in it. The principal crop for
export is sugar, but cereals of all kinds, coffee, indigo, arrowroot, ginger,
tobacco, rice, pepper, cotton and tea are grown to profit. The coal fields of the
colony are large, the output in 1897 being 244,000 tons. There are 487 miles of
railway, built and operated by the government. The imports in 1897 amounted to
nearly $30,000,000. Pop. 828,500; whites, 61,000. [275]
The Orange Free State, in its entire area of 48,000 square miles, is on the great
interior plateau at an altitude of from 4,000 to 5,000 feet above the sea level.
The surface is mostly level, but there are occasional hills—some of them rising
to a height of 6,000 feet. The land is, for the most part, bare of trees, but affords
good grazing for two-thirds of the year. The air is remarkably pure and bracing.
There are no blizzards to encounter. There are, however, occasional violent
thunderstorms, which precipitate enormous hailstones—large enough to kill the
smaller animals, and even men. Notwithstanding the generally parched
appearance of the country, the larger streams do not dry up in winter. The
southeastern part of the Free State, particularly the valley of the Caledon River,
is one of the best corn-growing regions in Africa. In the main, however, with the
exception of the river valleys, the land is more suitable for pasture than for
tillage. The grazing farms are large and require the services of but few men; as a
consequence the population increases slowly. The Free State, corresponding in
size to the State of New York, has only about 80,000 white inhabitants and
130,000 natives. The chief industry is agriculture and stock-raising. A railway,
[276]constructed by the Cape Colony government, connects Bloemfontein, the
capital of the Orange Free State, with the ports of Cape Colony and Natal, and
with Pretoria, the capital of the South African Republic.
The South African Republic, commonly called the Transvaal, is 119,139 square
miles in area. The white population, numbering 345,397, is largely concentrated
in the Witwatersrand mining district. The native inhabitants number 748,759. All
the Transvaal territory belongs to the interior plateau, with the exception of a
strip of lower land on the eastern and northern borders. This lower section is
malarious. It is thought, however, that drainage and cultivation will correct this,
as they have done in other fever districts. Like the Free State, the Transvaal is
principally a grazing country. The few trees that exist in the more sheltered parts
are of little value, except those in the lower valleys. The winters are severely
cold, and the burning sun of summer soon dries up the moisture and bakes the
soil, causing the grass to be stunted and yellow during most of the year. Until
about sixteen years ago there was little in the surface appearance and known
resources of the Transvaal to attract settlers, and nothing to make it a desirable
[277]possession to any other people than its Africander inhabitants. In 1884
discoveries of gold were made, the first of which that excited the world being
some rich auriferous veins on the Sterkfontein farm. In a little time it became
known that probably the richest deposit of gold in the world was in the
Witwatersrand district of the Transvaal. Later, in 1897, diamonds were
discovered in the Transvaal, the first stone having been picked up at Reitfontein,
near the Vaal River, in August of that year. Since then the precious crystals have
been found in the Pretoria district, in Roodeplaats on the Pienaars River, at
Kameelfontein and at Buffelsduff. The output of gold in 1898 was $68,154,000,
and of diamonds $212,812.01. The total output of gold since it was first
discovered amounts to over $300,000,000, with $3,500,000,000 “in sight,” as
valued by experts. The commerce of the South African Republic, while
necessarily great because of the large number of people employed by the
mining industries, cannot be as accurately stated as that of states whose imports
are all received through a given port or ports. Foreign goods reach it through
several ports in Cape Colony, Natal, Portuguese East Africa, and in smaller
quantities from other ports on the coast. [278]The total imports for 1897 are
estimated at $107,575,000.
The British protectorate of Bechuanaland, lying to the north of Cape Colony and
Griqualand and to the west of the Transvaal, has an [279]area of about 213,000
square miles, with a population of 200,000—mostly natives. A railway and
telegraph line connect it with Cape Colony on the south and Rhodesia on the
north.
Rhodesia includes the territory formerly known as British South Africa and a
large part of that known as British East Africa. The area is about 750,000 square
miles—equal to about one-fourth of the area of the United States of America,
excluding Alaska. No exact statement of population can be made; estimates
range from 1,000,000 to 2,000,000, of which only about 6,000 are whites. The
entire territory is under the administration of the British South African Company,
organized and incorporated in 1889, subject to the British High Commissioner at
Cape Town. Rhodesia lies chiefly within the tablelands of South Africa and has
large but yet undeveloped resources, including grazing and agricultural lands
and important mining districts. Owing to the newness of the country to civilization
no definite statement can be made relative to its commerce. In all probability
Rhodesia will open a field wherein enterprise along the lines favored by its
natural resources and conditions will be richly rewarded.
The End.
[281]
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