Lecture 10: Gastric secretion & its regulation

1. Correlate between structure and functions of stomach

2.Explain the functions of different innervation of stomach
3.Relate components of gastric secretion to their functions
4.Discuss mechanism of gastric acid secretion and factors affecting
5.Differentiate between nerve reflexes controlling gastric secretion
6.Discuss role of the different hormones affecting gastric functions
7.Deduce how stomach is protected from its secretion
The stomach is the most dilated part of GIT; a storage sac between the oesophagus and the
duodenum. It consists of 3 regions: the fundus, the body; and the antrum. Functionally, the
fundus is a part of the body.
The wall of the stomach is similar to that present throughout the GIT. The lining mucosa
comprises the gastric pits into which the deeply lying gastric glands empty their secretions. Its
muscle has in addition an oblique layer. This facilitates distension and the storage of food.
The circular muscle layer is relatively thick in the antrum, where strong muscular contractions
aid the mixing of food. In addition, it is highly developed in the pylorus where it becomes a
functional sphincter that regulates stomach emptying. A ring of connective tissue separates the
pylorus from the duodenum.
The lining epithelial cells secrete mucus and alkaline fluid and have well developed tight
junctions all to protect the gastric mucosa.
The secretory mucosa of the stomach can be considered as two separate regions: the upper region
comprising the fundus and the body, known as the oxyntic glandular area, and the lower antral
and pyloric region which secretes the hormone gastrin.
The secretory cells of the oxyntic area produce most of the exocrine gastric digestive juice. The
major secretory cells present are oxyntic (or parietal) secrete acid and intrinsic factor, and chief
(or peptic) cells secrete pepsinogen. The stomach also contains enterochromaffin (ECL)-like
cells that secrete histamine, and D cells which secrete somatostatin.
Mucus- secreting cells are located in the neck region of gastric glands.
The endocrine cells are located in the deeper aspect of the gastric pits.

Functions of stomach:

The primary function of the stomach is to store the food ingested during a meal and to regulate
its release into the duodenum.
Its other functions are to churn and mix the food with the gastric secretions producing a thick
mixture known as ‘chyme’.
The exocrine secretions; gastric juice released into the stomach lumen
The major paracrine secretion is histamine, that stimulates gastric acid secretion.
The major endocrine secretion is the hormone gastrin, which acts on the stomach to stimulate
gastric motility and acid secretion, and distally on the intestines, pancreas and liver.
Absorption in the stomach: stomach is virtually impermeable to water. Aspirin and alcohol can
be absorbed at stomach. Alcohol is lipid soluble and aspirin becomes more lipid soluble in acid
pH of the stomach.
Composition of gastric juice
The adult human secretes approximately 2-3 L /day. Gastric juice is isotonic with plasma. During
a meal the acidity can reach pH 1.0.
The stomach produces two different secretions:
 an acid secretion known as parietal juice which is released from the oxyntic (parietal)
cells,
 an alkaline mucous
The composition of gastric juice changes with increase in flow rate when the stomach is
stimulated during a meal. The concentration of H ions increases with, as does that of Cl and K
ions, while the concentration of Na ions decreases.
The secretion of alkaline fluid is a passive process and so its rate is relatively unaffected. Thus
dilution of the chyme by the alkaline juice is therefore less at high flow rates.

1- Hydrochloric acid secretion

The secretion of H and Cl ions by the stomach are both active processes. The energy is derived
from the hydrolysis of ATP.
Carbon dioxide diffuses into the cell from the plasma. It combines with water to form carbonic
acid. This reaction is catalysed by the carbonic anhydrase. The carbonic acid dissociates to give
H and HCO3 ions. The HCO3 ions are transported into the blood, down a concentration gradient,
in exchange for Cl ions which also move down their concentration gradient. The secretion of
HCO3 ions into the blood during secretion of acid into the lumen results in transient alkalinity
of plasma; the ‘alkaline tide’.
Hydrogen ion secretion into the canaliculus of the oxyntic cell, is accomplished by proton pumps
which contains an ATPase, secretes H ions in exchange for K ions, in a ratio of 1:1. Na/K
coupled pumps.
Chloride ions are also secreted against a concentration and electrical gradient. The proton and
chloride pumps on the mucosal surface are coupled in the secreting cell so that H and Cl ions are
secreted in a ratio of 1:1. The coupling mechanism is not yet understood.
Functions of HCl
1. Activates the proteolytic enzyme pepsinogen to form, pepsin, and gives the optimum pH
needed for its action.
2. Has an antibacterial action by killing microorganisms.
3. Facilitates the absorption of calcium and iron. The acid environment the more soluble and
absorbable ferrous form.
4. Helps the hydrolysis of some food materials as disaccharides.
5. Acid chyme stimulates the release of secretin hormone from the duodenum and thus initiates
the enterogastric reflex which regulates the rate of emptying of the stomach.

2- Intrinsic factor
It is a glycoprotein which complexes with vitamin B 12 (cobalamin). So, it is resistant to
digestion and undergoes a specialized absorption mechanism in the distal ileum

3- Secretion of the chief cell

Pepsin, the proteolytic enzyme of the stomach, is responsible for < 20% of the protein digestion
in the GIT. It is an endopeptidase that degrades proteins to peptides. It preferentially hydrolyses
peptide linkages where one of the amino acids is aromatic. It is formed from an inactive
precursor, pepsinogen, which is stored in granules and released by exocytosis. Two pepsinogens
are secreted by the stomach, I and II. Pepsinogen I, the major pepsin precursor, is secreted in the
oxyntic glandular area, and pepsinogen II by cells throughout the stomach as well as in
Brunner’s glands.

Pepsinogen is initially activated by H ions in the lumen. The activated enzyme then acts
autocatalytically increase the rate of formation of more pepsin. Stomach acidity also provides the
optimum pH for pepsin actions (~ pH 3.5).

4- Secretions of the mucous cell

Mucus is a viscous substance that contains glycoproteins known as mucins. Gastric mucus
lubricates the food. The epithelial cells secrete an opaque alkaline mucus which has a high
bicarbonate content. In addition, the mucus neck cells secrete a clear mucus. It is released from
cells by exocytosis or by desquamation of the epithelial cells.
Mucin form a dissolved gel that forms a layer on the surface of the mucosa. The alkaline mucus
forms a barrier that lines the stomach and protects it from damage by acid and pepsin.

Control of gastric secretion

The control of secretion of gastric juice involves extrinsic and intrinsic nerves, hormones and
paracrine mediators.

I- Hormonal control by Gastrin

It is secreted from the G cells of the gastric glands in the gastric antrum, although 20% are
present in the duodenal mucosa.
Two major forms of gastrin exist, gastrin-34 (G34, composed of 34 amino acids) and gastrin-17
(G17, composed of 17 amino acids). Over than 90% of the gastrin present in the antral mucosa is
the G17 form. Gastrin-17 has a short half-life in the circulation so, it is consistent with its main
influence on local receptors in the stomach.
G cells have receptors on the luminal membrane sense chemical substances in food, known
collectively as ‘secretogogues’, and regulate the release of gastrin. Gastrin is released into the
circulation in response to neural, endocrine or paracrine stimuli, and by local factors in the lumen
of the stomach.

Functions of gastrin Gastrin has a role in the preparation of the GIT for the digestion and
absorption of food.
- Gastrin stimulates acid secretion by two mechanisms: it stimulates the oxyntic cell
directly, by stimulating the expression of the gene for the proton pump, and indirectly
 through stimulation of the enterochromaffin-like cells (ECL cell), stimulates histamine
synthesis and release. Histamine in turn stimulates the oxyntic cell.
- Gastrin has trophic actions. It controls the growth and proliferation of a variety of cell
types in the gastric mucosa, including ECL cells and the precursors of oxyntic cells.
- Increases gastric secretion of pepsinogen
- Increases gastric motility and emptying
- Increases intestinal motility
- In large doses, it increases the tone of the lower esophageal sphincter

I- Neural control of gastric secretion

The functions of the stomach are controlled by intrinsic nerves and by extrinsic nerve. In general
activation of cholinergic fibres stimulates gastric secretion and motility. Activation of adrenergic
fibres generally inhibits secretion and motility.

It should also be noted that a number of sensory nerves leave the stomach and travel in the vagus
nerve and the sympathetic nerves. Sensory nerves in the stomach also provide afferent paths of
intrinsic reflex arcs. This provides some intrinsic control of smooth muscle contractions and
gastric juice secretion.

Acetylcholine released from cholinergic nerve fibres in local nerves can stimulate oxyntic cells
to release acid, or G cells to secrete gastrin.

Some fibres in the vagus contain gastrin-releasing peptide (GRP). GRP stimulates the G cells. It
probably also stimulates acid release by a gastrin-independent mechanism. This interaction of the
neural and gastrin control mechanisms facilitates a rapid response to food ingestion.

II- Inhibitory feedback control via acid

Gastric acid secretion is blocked if the contents of the stomach become too acid (pH 3.0, or
lower). This is a negative feedback mechanism that prevents the gastric and more importantly the
duodenal contents from becoming too acid.

The inhibition is indirect by inhibition of gastrin release. The acid stimulate the release of the
hormone somatostatin from D cells in the fundic and antral mucosa. Furthermore, gastrin itself
can stimulate somatostatin release.

Somatostatin is a potent inhibitor of gastrin and histamine. It acts primarily in a paracrine

manner, but it also acts systemically..

Somatostatin also acts upon the oxyntic cells to inhibit the release of acid directly.

III- Other inhibitory factors

a) The duodenal hormone cholecystokinin (CCK), which is secreted in response to fat, causes
inhibition of acid secretion in two ways:
● It competitively inhibits gastrin-mediated stimulation of acid release
● It is a potent antagonist of gastrin-stimulated acid secretion, by its action on D cells, to release
somatostatin.

b) The duodenal hormone secretin also produces a profound inhibition of gastrin release and
gastric acid secretion. It is released in response to the presence of food and acid in the
duodenum. Secretin inhibits the secretion of gastrin from G cells and the secretion of acid
from oxyntic cells.
c) Other peptides; gastric inhibitory peptide (GIP) released in response to fat in the duodenum or
ileum. Vasoactive intestinal peptide (VIP), which is released into the circulation from
nerve endings in the enteric nerves plexi. VIP and GIP act on the same receptors as
secretin on oxyntic cells and G cells to inhibit acid release.
d) Finally, prostaglandins synthesized in the gastric mucosa inhibit acid secretion. They function
to protect the deeper mucosal layers from damage by acid.

Control of pepsinogen secretion

1- H ions trigger the local cholinergic reflex that stimulates the chief cells. Ach secreted
from the vagus and local nerves is probably the most potent stimulus. It acts on
muscarinic receptors on the chief cell.
2- In addition H ions stimulate the release of secretin in the duodenum and secretin also
stimulates pepsinogen secretion. These effects of H may account in part for the
correlation between acid and pepsin secretion.
3- Gastrin stimulates pepsinogen secretion directly via CCK receptors, but the most potent
effect is its indirect action via acid secretion.
4- Pepsinogen secretion is decreased by somatostatin.

Protective mechanisms in the mucosa of the stomach and duodenum, The mucosal barrier:

● Secretion of alkaline fluid

● Secretion of mucus. Surface mucous cells secrete mucus in response to chemicals such as
alcohol, and in response to contact with roughage in the food. Mucus neck cells are also
stimulated by gastrin to secrete mucus
● Adequate blood flow
● The presence of growth factors which promote the replacement of damaged cells
● Prostaglandins, which maintain mucosal integrityand cause decreased acid secretion and
increased bicarbonate and mucin production and increased blood flow

Phases of the control of gastric secretion in relation to meal:

Acid is secreted at a low rate; 10% of the maximum rate, when the stomach is empty.

The basal rate is lowest in the morning and highest in the evening.
The control of gastric function during a meal can be conveniently divided into three main phases
depending on the location of the food:

1. The cephalic phase: occurs before the food reaches the stomach. It is a response to the
approach of food (i.e. smell, sight of food), or food in the mouth.
2. The gastric phase: occurs in response to food when it reaches the stomach.
3. The intestinal phase:due to food in the intestines, mainly the duodenum and upper
jejunum.

I. Cephalic phase (Nervous mechanism)

It is vagally mediated response. It accounts for less than 50% of the gastric secretion associated
with eating a meal. Pepsin is secreted in higher proportion.
Emotions were found to elicit increased or decreased acid secretion. Hostility and resentment
tended to increase gastric secretion whilst depression tended to reduce it.

The nervous mechanism is brought about via 2 types of reflex action,

a) Conditioned reflexes; become established early in life.

There is no food in the mouth cavity. They are brought about by:
 Stimulus: seeing, hearing, smelling of food.
 Receptors: lie in any special sense organs (e.g., eye, ear, nose, or in the cerebral cortex, or
the hypothalamus).
 Afferent: Any nerve of special sensation such as smell, sight, hearing.
 Centre: Cerebral cortex, which in turn sends impulses to the dorsal motor vagal nuclei in
the medulla oblongata.
 Efferent: Is along the vagi to the intrinsic nerve plexuses in stomach wall then
postganglionic vagal fibres to the gastric glands (effectors) leading to gastric secretion
(response). Stimulation of the nerves releases acid both directly from the oxyntic cell and
indirectly via the release of gastrin. 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 secre-
tion 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.

b) Unconditioned reflexes:
 Stimulus: The presence of food in the mouth, chewing and enjoying taste of food, even if
the swallowed food is not allowed to reach the stomach (by sham feeding).
 Receptors: Taste buds, touch receptors pharyngeal and esophageal receptors.
 Afferents: Impulses are carried from taste buds along the chorda tympani nerves, and
glossopharyngeal nerves to salivary centers and from there to vagal nuclei. Also, along
vagal nerves from pharyngeal and esophageal receptors.
 Centre: Dorsal motor vagal nuclei in the medulla oblongata.
  Efferent, effectors and response are the same as in the conditioned reflexes.
Secretion by this reflex is called appetite juice.

II. Gastric phase: this phase accounts for more than 50% of the acid secreted during a meal.
The amount of secretion depends on the chemical content of the food, and its volume, while
the food is in the stomach itself and in contact with gastric mucosa. The regulation of gastric
secretion in this phase is via coordinated neural, hormonal and paracrine mechanisms. The
neural signals are conducted in extrinsic nerves of the vagus nerve, and in intrinsic nerves of
the enteric nerve plexi.
Chemical substances in the food, or ‘secretogogues’, peptides and amino acids (in particular
tryptophan and phenylalanine), and caffeine (present in tea, coffee, coca cola), and alcohol,
stimulate gastric secretion, are sensed by APUD cells. The G cells sense peptides and amino
acids.
Distension, another stimulus that increases acid secretion, is detected by pressure receptors or
nerve endings in the mucosa. Distension is not as powerful a stimulant as the chemical
constituents of food. A low pH in the stomach causes inhibition of acid secretion, although
pepsinogen secretion is stimulated. The D cells sense H ions.

III- Intestinal phase

When the products of gastric digestion enter the duodenum, they stimulate secretion of
intestinal gastrin from the duodenal mucosa (the same as in the gastric phase).
Also other hormones are secreted to inhibit gastric secretion and emptying e.g. secretin,
Cholecystokinin, GIP, ...

Although food in the duodenum is largely inhibitory as far as gastric secretion is concerned,
there is an early stimulatory phase in response to slight distension of the duodenum, probably
due to the release of gastrin from APUD cells in the walls of the duodenum.

However, appropriate stimulation of the duodenum inhibits gastric secretion. Inhibitory stimuli
include distension of the duodenum, fats and peptides in the chyme, increased acidity, and
hypertonic solutions. All of these stimuli cause the release of hormones from APUD cells.

Acid in the duodenal chyme causes the release of secretin, and fat in the duodenal chyme causes
the release of CCK and GIP into the blood, and these hormones all inhibit secretion of gastric
juice. This is a feedback mechanism that prevents the duodenal contents becoming excessively
acid. It is important for several reasons:

● Digestive enzymes, which act in the small intestine require neutral or acid pH values for
optimum activity

● Micelle formation, which is necessary for fat digestion and absorption in the small intestine
will only take place at a neutral or slightly alkaline pH

● The duodenum is the most common site for ulcer formation in the digestive tract and acid is
the prime cause of ulceration in this region. The reduction of acid secretion begins when the pH
of the duodenal contents falls to 5.0, and it is complete at a pH value of approximately 2.5.
Control of the pH of GIT helps to maintain the pH of the blood within normal limits.