Cephalic Phase

Related terms:

Secretion (Process), Acid, Acid Secretion, Food, Meal, Stomach, Insulin Release,
Pancreas Secretion, Odor, Vagus Nerve

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The Stomach
Joseph Feher, in Quantitative Human Physiology, 2012

The Cephalic Phase Is Mediated by the Vagus Nerve through

Acetylcholine and Gastrin
The cephalic phase of gastric secretion is mediated entirely through the vagus nerve.
A variety of sensory stimuli including the sight, smell, and taste of food elicits acid
secretion in the stomach. It contributes about 30–50% to the total postprandial
acid production. The vagus nerve is the sole neural link between the brain’s higher
functions and gastric secretion. It exerts its effects through two separate pathways:
direct stimulation by acetylcholine and indirect through gastrin.

Parietal cells possess M3 cholinergic receptors that turn on acid secretion. Stimu-
lation of the vagus excites postganglionic parasympathetic neurons in the stomach,
which then release acetylcholine onto parietal cells to stimulate acid secretion.

Cephalic efferents in the vagus nerve release gastrin-releasing peptide (GRP) onto
G-cells in the pyloric glands and these release gastrin. Atropine, a muscarinic
cholinergic antagonist, blocks the direct effects of vagal stimulation on parietal cells,
but it does not block the release of gastrin. Figure 8.2.6 illustrates the cephalic phase
of gastric acid secretion.
Figure 8.2.6. The cephalic phase of gastric acid secretion. Sensory stimuli such as the
sight, smell, and taste of food produce efferent activity from the brain (the nucleus
tractus solitarius and dorsal motor nucleus of the vagus) to stimulate parietal cells
to secrete acid. The mediator in this pathway is acetylcholine (ACh), which exerts
its effects on the parietal cells through a muscarinic (M3) cholinergic receptor. In
a second pathway, vagal stimulation releases gastrin from G-cells in the antrum,
which then stimulates acid secretion. Gastrin stimulation of the parietal cells is both
direct and indirect. In the direct pathway, parietal cells respond to gastrin through
gastrin receptors on their membranes. In the indirect pathway, gastrin stimulates
histamine (H) release from enterochromaffin-like (ECL) cells. Vagal stimulation also
relieves inhibition of acid secretion by somatostatin, SST, secreted by D-cells in the
body and antrum. Parietal cells thus have receptors for acetylcholine (ACh), gastrin
(G), histamine (H), and somatostatin (SST).

Gastrin is a polypeptide hormone secreted by G-cells in pyloric glands in the

antrum of the stomach and in the duodenum. It circulates in two forms: Gastrin-17
and Gastrin-34, referring to the number of amino acids in their sequences. The
circulating half-life of Gastrin-17 is just 7 min, whereas Gastrin-34 has a half-life of
30 min. Both forms are equally potent in stimulating acid secretion by the parietal
cells. Gastrin has structural similarities to CCK and, in fact, exerts its effects through
the CCK-2 receptor.

Gastrin released from the G-cells during the cephalic phase stimulates parietal cells
directly and indirectly through histamine released from enterochromaffin-like cells
(ECL cells) in the lamina propria nearby the parietal cells. Thus, histamine is a
paracrine hormone that affects nearby cells rather than traveling through the blood.
Mast cells in the stomach also release histamine, but they are not closely apposed to
the parietal cells. The histamine diffuses through the extracellular fluid to the parietal
cells where it binds to H2 receptors. These receptors are blocked by cimetidine.

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The Stomach
Joseph Feher, in Quantitative Human Physiology (Second Edition), 2017

The Cephalic Phase Is Mediated by the Vagus Nerve Through

Acetylcholine and Gastrin
The cephalic phase of gastric secretion is mediated entirely through the vagus nerve.
A variety of sensory stimuli including the sight, smell, and taste of food elicits acid
secretion in the stomach. It contributes about 30–50% to the total postprandial
acid production. The vagus nerve is the sole neural link between the brain’s higher
functions and gastric secretion. It exerts its effects through two separate pathways:
direct stimulation by acetylcholine and indirect through gastrin.

Parietal cells possess M3 cholinergic receptors that turn on acid secretion. Stimu-
lation of the vagus excites postganglionic parasympathetic neurons in the stomach,
which then release acetylcholine onto parietal cells to stimulate acid secretion.

Cephalic efferents in the vagus nerve release gastrin-releasing peptide (GRP) onto
G-cells in the pyloric glands and these release gastrin. Atropine, a muscarinic
cholinergic antagonist, blocks the direct effects of vagal stimulation on parietal cells,
but it does not block the release of gastrin. Figure 8.2.7 illustrates the cephalic phase
of gastric acid secretion.

Figure 8.2.7. The cephalic phase of gastric acid secretion. Sensory stimuli such as the
sight, smell, and taste of food produce efferent activity from the brain (the nucleus
tractus solitarius and dorsal motor nucleus of the vagus) to stimulate parietal cells
to secrete acid. The mediator in this pathway is acetylcholine (ACh), which exerts
its effects on the parietal cells through a muscarinic (M3) cholinergic receptor. In
a second pathway, vagal stimulation releases gastrin from G-cells in the antrum,
which then stimulates acid secretion. Gastrin stimulation of the parietal cells is both
direct and indirect. In the direct pathway, parietal cells respond to gastrin through
gastrin receptors on their membranes. In the indirect pathway, gastrin stimulates
histamine (H) release from enterochromaffin-like (ECL) cells. Vagal stimulation also
relieves inhibition of acid secretion by somatostatin, SST, secreted by D-cells in the
body and antrum. Parietal cells thus have receptors for acetylcholine (ACh), gastrin
(G), histamine (H), and somatostatin (SST).

Gastrin is a polypeptide hormone secreted by G-cells in pyloric glands in the

antrum of the stomach and in the duodenum. It circulates in two forms: Gastrin-17
and Gastrin-34, referring to the number of amino acids in their sequences. The
circulating half-life of Gastrin-17 is just 7 minutes, whereas Gastrin-34 has a half-life
of 30 minutes. Both forms are equally potent in stimulating acid secretion by the
parietal cells. Gastrin has structural similarities to CCK and, in fact, exerts its effects
through the CCK-2 receptor.

Gastrin released from the G-cells during the cephalic phase stimulates parietal
cells directly and indirectly through histamine released from enterochromaffin-like
cells (ECL cells) in the lamina propria nearby the parietal cells. Thus histamine is a
paracrine hormone that affects nearby cells rather than traveling through the blood.
Mast cells in the stomach also release histamine, but they are not closely apposed to
the parietal cells. The histamine diffuses through the extracellular fluid to the parietal
cells where it binds to H2 receptors. These receptors are blocked by cimetidine.
> Read full chapter

Volume 2
Rodger A. Liddle, in Physiology of the Gastrointestinal Tract (Sixth Edition), 2018

40.2.1 Cephalic Phase

The cephalic phase of secretion results from inputs including the sight, smell,
taste, and act of eating food and can account for up to 25% of the pancreatic
exocrine secretion of a meal. Although we commonly think of these processes as
stimulating pancreatic secretion they may also generate inhibitory signals when
eating is associated with unpleasant features such as unattractive, malodorous, or
bad tasting food. The cephalic phase of secretion has been produced in humans
by presenting them with food that they see, smell, and taste but not swallow (a
process known as modified sham feeding). In animals, food can be diverted from the
esophagus by a surgically prepared esophageal or gastric fistula, and sham feeding
can occur by allowing these animals to eat and swallow while preventing food from
entering the stomach. In both dogs and humans, sham feeding stimulates low
volumes of pancreatic secretions that are rich in enzymes but low in bicarbonate.
The total pancreatic secretory response to sham feeding is approximately 25%–50%
of maximal.9,10,32 Secretion of the islet hormone, pancreatic polypeptide, increases
with sham feeding and has been used as an indicator of vagal innervation of
the pancreas.33 In humans, the duration of pancreatic response to modified sham
feeding is brief, lasting approximately 60 min, and ceases at the conclusion of sham
feeding. If swallowing is included in sham feeding, the pancreatic secretory response
is much greater. In contrast, in dogs, the pancreatic enzyme response to sham
feeding lasts > 4 h.34

There is substantial experimental data to support the concept that cephalic stimula-
tion of pancreatic secretion is mediated by the vagus nerve. First, cholinergic ago-
nists produce a pancreatic secretory response similar to that of cephalic stimulation.
Second, the vagus nerve is the major source of cholinergic neurotransmitters to the
pancreas. Third, electrical nerve stimulation to the vagus nerve or administration of
2-deoxyglucose (2-DG) which causes hypoglycemia (and initiates a vagal response)
stimulated pancreatic juice flow similar to that of sham feeding.35 Finally, vagotomy
blocked these responses. In anesthetized rats, pancreatic fluid and protein output
following electrical nerve stimulation or 2-DG was partially blocked by atropine.36
Thus, although the vagus nerve carries fibers that bear peptidergic transmitters
as well as acetylcholine, these data indicate that acetylcholine is the dominant
neurotransmitter. The role of peptidergic efferent fibers in sham feeding is largely
unknown.

Sham feeding is also a major stimulus of gastric secretion which may contribute to
stimulation of pancreatic secretion through the release of secretin.9 Interestingly, it
has been shown that mental stress produced by intense problem-solving can also
stimulate pancreatic enzyme secretion in humans.37

The regions of the dorsal and ventral anterior hypothalamus, including the me-
dial hypothalamus, dorsomedial and ventromedial nuclei, and mammillary bodies,
appear to generate signals for pancreatic secretion.38 Determination of the neu-
rotransmitters and peptides that are involved in regulating these processes has
been approached by examining effects of substances administered into the central
nervous system. In rats, central administration of beta-endorphin, CGRP, and CRF
inhibit pancreatic secretion.39–41 In contrast, TRH stimulates pancreatic secretion
through the vagus nerve and involves both muscarinic and VIP receptors.41

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Regulation of Pancreatic Secretion

Rodger A. Liddle, in Physiology of the Gastrointestinal Tract (Fifth Edition), 2012

52.2.1 Cephalic Phase

The cephalic phase of secretion results from inputs including the sight, smell, taste,
and the act of eating food, which can account for up to 25% of the pancreatic
exocrine secretion of a meal. Although we commonly think of these processes as
stimulating pancreatic secretion, they may also generate inhibitory signals when
eating is associated with unpleasant features such as unattractive, malodorous, or
bad tasting food. The cephalic phase of secretion has been produced in humans
by presenting them with food that they see, smell, and taste but not swallow (a
process known as modified sham feeding). In animals, food can be diverted from the
esophagus by a surgically prepared esophageal or gastric fistula, and sham feeding
can occur by allowing these animals to eat and swallow while preventing food from
entering the stomach. In both dogs and humans, sham feeding stimulates low
volumes of pancreatic secretions that are rich in enzymes but low in bicarbonate.
The total pancreatic secretory response to sham feeding is approximately 25–50%
of maximal.9,10,32 Secretion of the islet hormone, PP, increases with sham feeding
and has been used as an indicator of vagal innervation of the pancreas.33 In humans,
the duration of pancreatic response to modified sham feeding is brief, lasting ap-
proximately 60 minutes, and ceases at the conclusion of sham feeding. If swallowing
is included in sham feeding, the pancreatic secretory response is much greater. In
contrast, with dogs the pancreatic enzyme response to sham feeding lasts more than
4 hours.34

There is substantial experimental data to support the concept that cephalic stimula-
tion of pancreatic secretion is mediated by the vagus nerve. First, cholinergic ago-
nists produce a pancreatic secretory response similar to that of cephalic stimulation.
Second, the vagus nerve is the major source of cholinergic neurotransmitters to the
pancreas. Third, electrical nerve stimulation to the vagus nerve or administration of
2-deoxyglucose (2-DG), which causes hypoglycemia (and initiates a vagal response),
stimulated pancreatic juice flow similar to that of sham feeding.35 Finally, vagotomy
blocked these responses. In anesthetized rats, pancreatic fluid and protein output
following electrical nerve stimulation or 2-DG was partially blocked by atropine.36
Although the vagus nerve carries fibers that bear peptidergic transmitters as well as
acetylcholine, these data indicate that acetylcholine is the dominant neurotransmit-
ter. The role of peptidergic efferent fibers in sham feeding is largely unknown.

Sham feeding is also a major stimulus of gastric secretion, which may contribute to
stimulation of pancreatic secretion through the release of secretin.9 Interestingly, it
has been shown that mental stress produced by intense problem solving can also
stimulate pancreatic enzyme secretion in humans.37

The regions of the dorsal and ventral anterior hypothalamus, including the medial
hypothalamus, dorsomedial and ventromedial nuclei, and mammillary bodies, ap-
pear to generate signals for pancreatic secretion.38 Determining the neurotrans-
mitters and peptides that are involved in regulating these processes has been ap-
proached by examining effects of substances administered into the central nervous
system. In rats, central administration of -endorphin, calcitonin gene-related pep-
tide (CGRP), and chronic renal failure inhibit pancreatic secretion.39–41 In contrast,
thyrotropin-releasing hormone (TRH) stimulates pancreatic secretion through the
vagus nerve and involves both muscarinic and vasoactive intestinal peptide (VIP)
receptors.41

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THE STOMACH
Margaret E. Smith PhD DSc, Dion G. Morton MD DSc, in The Digestive System
(Second Edition), 2010

Secretion
During the cephalic phase, gastric acid and pepsinogen secretion is activated by
the thought, sight or smell of food, and by food in the mouth. The mechanisms
of control of gastric secretion during the cephalic phase are summarized in Figure
4.11. Emotions also influence gastric secretion. The response to the sight and smell
of food is a conditioned reflex; a learned response based on previous experiences of
eating food. The release of acid at the sight and smell (approach) of food was first
demonstrated by sampling of the gastric contents through a gastrostomy (fistula)
in subjects who could not swallow food and had therefore been provided with a
permanent fistula so that food could be placed directly in the stomach. Emotions
were found to elicit increased or decreased acid secretion. This was shown by Wolff a
nd Wolff, physicians who studied a patient with a closed oesophagus who was
provided with a gastrostomy. They showed that hostility and resentment tended to
increase gastric secretion whilst depression tended to reduce it.

Fig. 4.11. Cephalic phase of control of gastric secretion.

The taste and the touch of food in the mouth also elicits secretion of gastric juice
(before the food reaches the stomach). This is a non-conditioned reflex. It was studied
by the physician Janowics, in a patient who had had a gastrostomy because she could
not swallow food. It was found that if the patient placed some food in her mouth and
chewed it, there was an increased secretion of gastric juice. Furthermore, food that
the patient enjoyed elicited a more copious secretion than food which she merely
tolerated. The secretion in response to palatable food is known as ‘appetite juice’.
This gives some physiological justification for starting a meal with a savoury course
(hors d’oeuvre).

The gastric juice secreted during the cephalic phase is rich in pepsinogen, but also
contains some acid. The secretion of both pepsinogen and acid is due to impulses
in the vagus nerve. Stimulation of the nerves releases acid both directly from the
oxyntic cell and indirectly via the release of gastrin (Fig. 4.11). Less than half the acid
produced in response to a meal is secreted during the cephalic phase. Vagotomy
(section of the vagus nerve, see Cases 4.1 and 4.2: 1) reduces the secretion of
gastric juice mainly because its effect during the cephalic phase is abolished. When
acid is secreted during the cephalic phase, that is while the stomach is still empty,
there is very little protein present in the stomach to buffer the acid. Therefore a
small amount of acid will produce a marked fall in pH. This results in the feedback
control mechanism coming into operation, whereby acid secretion is inhibited. The
secretion of pepsinogen during the cephalic phase is due both to direct stimulation
of the chief cells by the vagal impulses, and to the release of gastrin, which also
stimulates the chief cells.

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Gastrointestinal Functions☆
E.M.M. Quigley, in Reference Module in Neuroscience and Biobehavioral Psychol-
ogy, 2017

Gastric Secretion
Gastricsecretion is stimulated by the act of eating (cephalic phase) and the arrival of
food in the stomach (gastric phase). Arrival of the food in the intestine also controls
gastric secretion (intestinal phase). The secreted fluid contains hydrochloric acid,
pepsinogen, intrinsic factor, bicarbonate, and mucus. Gastric secretion of acid and
pepsinogen follows stimulation of the oral and gastric vagal afferents. Efferent vagal
pathways synapse with submucous plexus neurons, which innervate secretory cells
via several important bioactive molecules, including gastrin, histamine, and somato-
statin. In the stomach, there is some digestion of carbohydrate and protein but very
little absorption, except for some fat-soluble substances. The mucus–bicarbonate
layer protects the stomach lining from auto digestion by acid.

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Gastrointestinal Function
Michael Camilleri, in Primer on the Autonomic Nervous System (Third Edition), 2012

Gastric Secretion
Gastric secretion is stimulated by the act of eating (cephalic phase) and the arrival
of food in the stomach (gastric phase). Arrival of the food in the small intestine also
controls gastric secretion (intestinal phase). The secreted fluid contains hydrochloric
acid, pepsinogen, intrinsic factor, bicarbonate and mucus. Gastric secretion of acid
and pepsinogen follows stimulation of oral and gastric vagal afferents. Efferent vagal
pathways synapse with submucous plexus neurons which innervate secretory cells
via several important bioactive molecules including gastrin, histamine, and somato-
statin. In the stomach, there is some digestion of carbohydrate and protein, but
very little absorption except for some fat-soluble substances. The mucus-bicarbonate
layer protects the stomach lining from auto digestion by acid.

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Chemical Regulation of Feeding, Diges-
tion and Metabolism
David O. Norris Ph.D., James A. Carr Ph.D., in Vertebrate Endocrinology (Fifth
Edition), 2013

C Hormonal and Neural Regulation of Gastric Digestion

Neural control of gastric secretion occurs at two levels. The cephalic phase involves
stimulation of secretion via parasympathetic discharges elicited by the same stimuli
that cause salivation—that is, sight, smell, taste, thought, or presence of food. In
the gastric phase of secretory control, the presence of food in the stomach elicits
secretion through vagovagal reflexes and/or through the gastrin mechanism. In
addition, neural factors can stimulate secretion of a hormone produced in the
gastric epithelium that stimulates certain aspects of gastric secretion. It has not
been possible to determine which of these mechanisms is the more important in
controlling gastric secretion; probably all of these mechanisms operate in the normal
digestive process.

1 The Gastrin Theory and Acid Secretion

Edkins in 1905 showed that extracts prepared from the most posterior portion of
the stomach, the antrum, stimulated acid secretion by the gastric glands, and he
suggested the name of gastrin for the active substance in these extracts. He found
no gastrin activity in extracts prepared from other portions of the stomach. Edkin’s
gastrin hypothesis temporarily lost credibility with the discovery of histamine, a
potent stimulator of gastric acid secretion, and the demonstration of histamine
in extracts of the gastric mucosa. It was almost 30 years before it was shown
that histamine-free extracts from the mucosa of the antral portion of the stomach
possessed the ability to stimulate the acid-secreting parietal cells of the gastric
glands. Nevertheless, it was not until gastrin was finally isolated almost 60 years later
and characterized chemically by Gregory and Tracey that the term “gastrin theory”
finally was discarded, and the hormone gastrin was confirmed.

There are two peptide forms of gastrin, each composed of 17 amino acids: gastrin I
and a sulfated form, gastrin II, which has a sulfate group attached at position 6 near
the C-terminal end. A larger form of gastrin called big gastrin also has been found in
the circulation. Big gastrin consists of gastrin I or II plus a different 17-amino-acid
peptide component. Only about 5% of the circulating gastrin occurs as big gastrin,
however. The preprohormone for gastrin is composed of 104 amino acids and is
cleaved several times to release big and little gastrins. Most of the biological activity
of these gastrins resides in the four carboxy-terminal amino acids consisting of
Trp–Met–Asp–Phe–NH2. Several peptides that possess this terminal sequence (see
Figure 12-11) have been shown to stimulate acid secretion. A synthetic pentapeptide
(pentagastrin) incorporating the terminal tetrapeptide sequence is frequently used
for experimental studies.

FIGURE 12-11. Peptides that stimulate gastric acid secretion.Caerulein is a peptide

isolated from frog skin that has the common amino-terminal pentapeptide and
hence similar activity to gastrin II. The same sequence occurs in all CCKs, although
only CCK8 is shown. Y indicates that a sulfate group is attached to that tyrosine in
each of these peptides. See Appendix C for an explanation of the letters coding for
individual amino acids.(Adapted with permission from Walsh, J.H. and Dockray, G.J.,
“Gut Peptides,” Raven, New York, 1994.)

The control mechanism for acid secretion combines the observations that parasym-
pathetic stimulation, acetylcholine (ACh), histamine, gastrin, and some other pep-
tides all cause acid secretion (see Figure 12-12). In contrast, atropine (a muscarinic
cholinergic receptor antagonist), procaine (an anesthetic), sympathetic stimulation,
and certain antihistamines tend to reduce acid secretion under some experimental
conditions. Cephalic stimulation through the parasympathetic system (ACh) can
release gastrin from the G cell in the mucosa of the antral portion of the stomach.
Gastrin travels via the blood through the systemic circulation to the body of the
stomach, where it stimulates the release of histamine from enterochromaffin-like
(ECL) cells situated in the mucosa. Gastrin also activates the synthesis of histidine
decarboxylase, the enzyme responsible for histamine synthesis. Histamine in turn
stimulates release of HCl from the parietal cells. Gastrin also stimulates parietal
cells directly without employing histamine as an intermediate. Vagal stimulation or
application of ACh may stimulate the parietal cells directly to secrete HCl. Gastrin
acts on the CCK receptor 2 (CCKR2) on parietal cells and ECL cells to stimulate acid
and histamine secretion, respectively.

FIGURE 12-12. Neurocrine, endocrine, and paracrine mechanisms controlling acid

secretion by the stomach.Release of gastrin from G cells in the antral stomach can
be induced by nutrients in the gut lumen or by the neuropeptide gastrin-releasing
peptide (GRP) or by acetylcholine (ACh). Gastrin travels through the blood and by
acting on CCKR2 receptors directly stimulates the parietal cell in the corpus to
secrete H+ into the stomach lumen. Gastrin also stimulates histamine secretion from
enterochromaffin-like (ECL) cells. Histamine in turn acts on histamine H2 receptors
(HRH2) to stimulate HCl secretion from parietal cells. The parietal cell is also
stimulated by ACh and GRP. D cells in the antrum and corpus secrete somatostatin
(SST), which blocks gastrin release and parietal cell secretion, respectively, by acting
on somatostatin subtype 2 receptors (SSTR2). D cells may be stimulated by H+ and
inhibited by neurotransmitters. H+ in the stomach lumen also inhibits the G cell
directly. ENK, enkephalins; Sub-P, substance P.
2 Somatostatin
During active digestion the pH of the human stomach may be between 1 and 2.
Low pH in the antral portion of the stomach (especially near the pyloric sphincter)
reduces gastrin release (feedback), probably acting through local paracrine release of
somatostatin (SST) by D cells in the antral stomach. SST acts on the somatostatin
receptor subtype 2 (SSTR2) to directly inhibit gastrin secretion from G cells and to
directly inhibit acid secretion from parietal cells. In the 1930s, the term enterogas-
trone was coined to designate humoral inhibitors of intestinal origin that reduced
gastric secretion and/or motility. Several peptides secreted by the small intestine may
be candidates as enterogastrones either by evoking SST release or through more
direct inhibitory actions (Figure 12-13).

FIGURE 12-13. Enterogastrones.Several peptides released from the small intestine

inhibit acid secretion and slow processing of food in the stomach.(Adapted with
permission from Lloyd, K.C.K. and Walsh, J.H., in “Gut Peptides” (J.H. Walsh and
G.J. Dockray, Eds.), Raven, New York, 1994, pp. 147–173.)

3 Gastrin-Releasing Peptide
A novel peptide isolated from the mammalian stomach and intestine stimulates
gastrin release and hence was named gastrin-releasing peptide (GRP). This peptide
of 27 amino acids bears a remarkable structural similarity to the 14-amino-acid
peptide bombesin (BBS) that previously was isolated from the skin of frogs in
the genus Bombina. In the stomach, immunoreactive GRP appears exclusively in
post-ganglionic parasympathetic neurons, but the axonal tips of these neurons do
not contact the G cells directly, implying that this neurocrine behaves in a paracrine
fashion, whereas intestinal GRP acts in the manner of a true hormone. In addition
to its action on gastrin release, GRP stimulates the secretion of pancreatic enzymes,
contraction of gastric, intestinal, and gallbladder smooth muscle, and release of
several gastrointestinal and pancreatic hormones. GRP also produces mitogenic
effects resulting in hyperplasia of pancreatic, intestinal, and other tissues; thus, GRP
may play multiple roles in modulating GI physiology. Administration of GRP or BBS
into the ventricles of the brain causes a dramatic cessation of gastric acid secretion
regardless of the stimulus used to evoke gastric secretion. This effect appears to be
mediated via sympathetic nerves and suggests another level for the involvement of
this peptide in gastric function.

4 Secretion of Pepsinogen
The major gastric enzyme in adult humans and carnivorous vertebrates is the
protease pepsin, which is secreted by the chief cells of the gastric mucosa in an
inactive form called pepsinogen. Conversion of inactive pepsinogen to pepsin is
accomplished by the presence of an excess of H+ supplied by the parietal cells. The
optimum pH for vertebrate pepsins lies between 1 and 2, the normal pH range
observed in the stomach following stimulation of acid secretion. Pepsin is inactive
above a pH of about 4.5. The presence of acid on the surface of the gastric mucosa
may activate a cholinergic reflex that evokes pepsinogen release. Parasympathetic
stimulation via the vagus nerve causes release of pepsinogen, and hormonal control
of pepsinogen secretion may be absent. Gastrin causes release of pepsinogen only
when applied in doses large enough to inhibit acid secretion by the parietal cells,
implying that gastrin is not the normal factor causing pepsinogen release from the
chief cells. Several other GI peptides can invoke pepsinogen release but do so only
when applied in pharmacological doses. However, one duodenal peptide, motilin
(see ahead), has been implicated in regulating pepsinogen secretion at physiological
levels. Inhibition of pepsinogen release is caused by SST or by sympathetic stimula-
tion.

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Regulation of Gastric Acid Secretion

Mitchell L. Schubert, in Physiology of the Gastrointestinal Tract (Fifth Edition), 2012

47.4.1 Central Regulation of Gastric Acid Secretion

The central nervous system’s influence on gastric acid secretion was first recognized
by William Beaumont and Ivan Pavlov in the nineteenth century.80,81 The cephalic
phase of acid secretion is induced by sensory inputs driven by the thought, sight,
smell, and taste of food. Pavlov established a model of sham feeding in dogs
equipped with esophagostomy and demonstrated that anticipation of eating stimu-
lated gastric acid secretion.82 More recently, the cephalic phase has been studied
using 2-deoxy-d-glucose-induced hypoglycemia and sham feeding. In humans,
sham feeding is performed by measuring gastric acid output in volunteers who chew
food and spit it out before swallowing. Results of these experiments indicate that the
cephalic phase contributes ~50% to the overall acid response to a meal.24,25

It is also possible that peptides produced peripherally in the gut can signal the
brain directly by traversing the blood–brain barrier or indirectly by activating af-
ferent neurons that terminate in the spinal cord or brainstem.83,84 Although the
blood–brain barrier generally prevents the unrestricted movement of regulatory
peptides produced on one side of the barrier with those produced on the other, some
peptides (e.g., leptin and ghrelin) are capable of traversing the barrier via diffusion
or transporters.

The vagus nerve is primarily composed of afferent fibers (rat vagus: ~16,000 afferents
and ~6000 efferents) that monitor the mechanical/chemical milieu of the gut and
convey this sensory information to the nucleus of the solitary tract in the medulla
and the paraventricular nucleus in the hypothalamus.85–87 From there, information
is relayed to the vagal efferent neurons that originate from two brainstem nuclei: the
nucleus ambiguus and the dorsal motor nucleus of the vagus (DMV). The latter is
the source of vagal efferents innervating the stomach. Vagal efferents demonstrate
a gradient of decreasing innervation such that vagal influence is highest in stomach
and proximal duodenum and decreases in mid and distal gut. The vagal pregan-
glionic fibers synapse with postganglionic neurons within the wall of the stomach
that stimulate acid secretion directly as well as indirectly by inhibiting somatostatin
secretion and stimulating histamine and gastrin secretion. In rats, electrical stimula-
tion of the DMV as well as intracisternal injection of thyrotropin-releasing hormone
(TRH) or orexin-A, two peptides in the dorsal vagal complex, ultimately activate gas-
tric intramural cholinergic neurons that stimulate acid secretion.82,88,89 The actions
of orexin-A are mediated via two closely related G-protein-coupled receptors termed
orexin receptor 1 (OXR1) and OXR2.90 Intracerebroventricular injection of other
brain neurotransmitters such as neuropeptide Y, corticotropin-releasing factor, GRP,
and neuromedin U inhibit gastric acid secretion in rats.91–93

Sham-feeding-induced acid secretion is blocked by a TRH-1 receptor antisense

oligodeoxynucleotide, an OXR1 antagonist, or a GRP receptor antagonist. The acid
stimulatory effect of the central vagal stimulant, 2-deoxy-d-glucose, is blocked by a
PACAP receptor antagonist. These studies suggest that endogenously released TRH,
orexin-A, GRP, and PACAP contribute to the cephalic phase of acid secretion.64,89,94–96

Emotional stress, such as that experienced during the London air raids in 1940–1941
and during the devastating Hanshin-Awaji earthquake in 1995, has been associ-
ated with an increased incidence of peptic ulcer disease. Well-controlled studies in
humans, however, have produced disparate results regarding the effect of mental
or psychological stress on gastric acid secretion.97–99 Persons expressing emotions
(impulsivity high) have been reported to react with an increase whereas those with
low scores on the impulsivity scale react with a decrease in gastric acid output.97

> Read full chapter

Hormones of the Gastrointestinal Tract

H. Maurice Goodman, in Basic Medical Endocrinology (Fourth Edition), 2009
Regulation of Gastrin Secretion
Gastrin concentrations in blood increase about two- to threefold with food intake
and decline during interdigestive (between meal) periods. In the initial cephalic
phase, gastrin secretion is triggered by sensations of smell and taste, or even just
thoughts of food, and results from parasympathetic stimu-lation of the oxyntic mu-
cosa. Vagal input to secretomotor fibers in the antral mucosa stimulates release of
a 27 amino acid neurotransmitter called gastrin-releasing peptide (GRP). Gastrin-re-
leasing peptide belongs to a large family of neuropeptides that are widely expressed
in peripheral and central neurons in mammals and in the skin of amphibia. The
sequence of 13 out of the 14 amino acids at the C terminus is identical to the
amino acid sequence of the peptide bombesin, found in the skin of the frog Bombina
bombina.

In the gastric phase, food entering the stomach neutralizes the acid in the previously
empty stomach. The resulting increase in pH and distention of the stomach are
detected by chemo- and mechanoreceptors that signal G cells to release gas-
trin through vago–vagal reflexes. Partially degraded proteins, small peptides, and
amino acids, particularly phenylalanine and tryptophan, in the antral lumen directly
stimulate G cells to secrete gastrin. Calcium ions are also potent stimulants of
gastrin secretion. There is little direct information concerning how G cells detect
these metabolites. The G protein-coupled calcium sensing receptor expressed by
parathyroid and other cells (see Chapter 10) is also expressed in G cells, and may
be involved. Amino acids and peptides bind to the calcium receptor and increase
its sensitivity to calcium, which in turn activates the intracellular signaling pathways
that may culminate in gastrin secretion.

Passage of chyme into the duodenum begins the intestinal phase. Although the
duodenal mucosa contains some G cells, their contribution to gastrin secretion is
normally very small. Inhibition of gastrin secretion is more characteristic of the
intestinal phase. The acidic pH, lipid content, and high osmolarity of the chyme
that enters the duodenum trigger hormonal and neural responses that directly and
indirectly decrease secretion of both gastrin and gastric acid. Intestinal secretions
that inhibit acid secretion and stomach motility are called enterogastrones. Several in-
testinal hormones (see later) behave as enterogastrones, and produce their inhibitory
effects indirectly by stimulating D cells in the gastric mucosa to secrete somatostatin.
In addition, vago-vagal reflexes triggered by the same stimuli shut down GRP release
in the antral mucosa, and relieve vagal inhibition of somatostatin secretion in the
oxyntic mucosa (Figure 6.9).

Figure 6.9. Direct and indirect feedback regulation of gastrin secretion. Gastrin
secretion is positively regulated by luminal nutrients and gastrin releasing peptide
(GRP), and is negatively regulated by somatostatin (SST). Gastrin reaches D cells
in both the antral and oxyntic mucosae by paracrine or endocrine pathways and
stimulates them to secrete SST. Increased luminal H+ concentrations stimulate antral
and duodenal D cells to secrete SST. Increased H+ concentrations in the duodenum
and luminal nutrients in the intestine increase secretion of enteric hormones, which
stimulate D cells in the gastric and duodenal mucosae to secrete SST. Increased
luminal H+ concentrations are sensed by neuronal chemoreceptors and initiate
vago–vagal reflexes, which result in decreased release of GRP and decreased cholin-
ergic inhibition of D cells.

Somatostatin
Somatostatin (SST) is the most important negative feedback inhibitor of both gastrin
and gastric acid secretion. It was discovered as the hypothalamic peptide that inhibits
growth hormone secretion (see Chapters 2 and 11), but subsequent studies revealed
that its production and actions are not limited to the hypothalamus. Somatostatin is
synthesized and secreted by enteric neurons and by D cells that are widely distributed
throughout the mucosa of the stomach and intestines, and also by delta cells in
the pancreatic islets (see Chapter 7). Somatostatin secreted by enteroendocrine cells
acts both as a local paracrine factor and a circulating hormone. Two biologically
active forms consisting of 14 (SST-14) or 28 (SST-28) amino acids are produced in
the normal processing of the 116 amino acid preprosomato-statin gene product.
Both contain the same 14 amino acid sequence at the carboxyl terminus. A disulfide
bond links the carboxyl terminal cysteine with the cysteine residue 11 amino acids
upstream to produce a cyclized molecule. For most responses SST-14 and SST-28
have similar potencies, although SST-28 has a longer half-life in blood (15 min vs.
~2 min). Consistent with its widespread distribution, somatostatin serves a variety
of functions mediated by five distinct receptor isoforms, all of which are G-protein
coupled and activate multiple signaling pathways including inhibition of adenylyl
cyclase and activation or inhibition of specific ion channels.

The D cells that are present in the oxyntic and antral mucosae differ somewhat in
their anatomical and physiological characteristics. The D cells of the oxyntic mucosa
have long cytoplasmic processes that extend from the perikarial regions to end in
close proximity to parietal cells, chief cells, and ECL cells. Somatostatin secreted by
these cells is thought to act in a purely paracrine manner to inhibit histamine release
from ECL cells and acid secretion by parietal cells, but has little impact on gastrin
secretion by G cells in the antrum. D cells in the oxyntic mucosa have no direct
contact with the stomach contents and cannot monitor luminal pH. Secretion of
somatostatin by these cells is inhibited by vagal cholinergic input that is coordinated
with stimulation of ECL and parietal cells. Somatostatin secretion is stimulated by
 catecholamines released from sympathetic nerves and by intestinal hormones as
discussed later.

D cells in the antral mucosa are in contact with chyme in the antral lumen and secrete
somatostatin in response to low pH. Somatostatin acts as a paracrine inhibitor of
gastrin secretion from nearby G cells, and travels through the blood to reach distant
cells in the antral and oxyntic mucosae. Blood concentrations of somatostatin may
increase six- to ten-fold after eating a mixed meal, but the relative contributions of
intestinal, oxyntic, and antral D cells to the circulating pool of somatostatin have
not been determined. It is likely that increased hydrogen ion concentration directly
stimulates antral D cells. Peptides, amino acids, and fat in the intestinal lumen may
require neural or humoral intervention to stimulate antral, oxyntic mucosal, and
intestinal D cells (Figure 6.10).

Figure 6.10. Effects of somatostatin (SST) and control of its secretion in the gastric
mucosa. D cells in the oxyntic mucosa have no access to the luminal contents and
are stimulated to secrete SST by hormones secreted by endocrine cells downstream
in the GI tract, and inhibited by vagal cholinergic nerves. SST secreted by these cells
acts mainly as a paracrine factor. D cells in the antral mucosa are stimulated by
increases in H+ concentrations and circulating enteric hormones, and are inhibited
by vagal cholinergic neurons.

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