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LECTURE 2
GASTROINTESTINAL HORMONES
Gastrin
 The functions of gastrin are coordinated to promote
hydrogen ion (H+) secretion by the gastric parietal
cells.
 Gastrin, a 17-amino acid straight chain peptide, is
secreted by G (gastrin) cells in the antrum of the
stomach.
 The 17-amino acid form of gastrin, which is called G17
or "little" gastrin, is the form of gastrin secreted in
response to a meal.
 A 34-amino acid form of gastrin, which is called G34 or
"big" gastrin, is secreted during the interdigestive
period (between meals). It is secreted at low basal
levels.
 G34 is not a dimer of G17, nor is G17 formed from
G34. Rather, each form of gastrin has its own
biosynthetic
pathway,
beginning
with
its
own
precursor, a progastrin molecule.
 The minimum fragment necessary for biologic activity
of gastrin is the C-terminal tetrapeptide.
 Although the C-terminal tetrapeptide is the minimum
fragment necessary for activity, it still is only one-sixth
as active as the entire gastrin molecule.
Secretion of gastrin
In response to eating a meal, gastrin (G17) is secreted
from G cells located in the antrum of the stomach. The
physiologic stimuli that initiate gastrin secretion all are
related to ingestion of food. These stimuli include:

the products of protein digestion (Among the
products of protein digestion, the amino acids
phenylalanine and tryptophan are the most potent
stimuli for gastrin secretion).

distention of the stomach by food

vagal stimulation (Local vagal reflexes also stimulate
gastrin secretion. In these local reflexes, the
neurocrine released from vagal nerve endings onto
the G cells is gastrin-releasing peptide (GRP,
bombesin)).
In addition to these positive stimuli, gastrin secretion is
inhibited by a low pH of the gastric contents and by
somatostatin.
Actions of gastrin.
Gastrin has two major actions:
1. It stimulates H+ secretion by gastric parietal cells, and
2. It stimulates growth of the gastric mucosa, a trophic
effect.
The physiologic actions of gastrin are nicely illustrated in
conditions of gastrin excess or deficiency.
For example, in persons with gastrin-secreting tumors
(Zollinger-Ellison syndrome), H+ secretion is increased,
and the trophic effect of gastrin causes the gastric
mucosa to hypertrophy.
Conversely, in persons whose gastric antrum is resected
(which removes the source of gastrin, the G cells), H+
secretion is decreased, and the gastric mucosa
atrophies.
Zollinger-Ellison syndrome is caused by a gastrinsecreting tumor or gastrinoma, usually in the non-β-cell
pancreas.
The signs and symptoms of Zollinger-Ellison syndrome all are
attributable to high circulating levels of gastrin:

increased H+ secretion by parietal cells,

hypertrophy of the gastric mucosa, and

duodenal ulcers caused by the unrelenting secretion of H+.

Steatorrhea, the increased H+ secretion also results
in acidification of the intestinal lumen, which
inactivates pancreatic lipase, an enzyme necessary
for fat digestion. As a result, dietary fats are not
adequately digested or absorbed, and fat is excreted
in the stool (steatorrhea).
Treatment of Zollinger-Ellison syndrome includes:

administration of H2 receptor-blocking drugs (e.g.,
Cimetidine & Ranitidine);

protone pump inhibitors (e.g., Omeprazole);

removal of the tumor;

the last resort is gastric resection, which removes
gastrin's target tissue.
Cholecystokinin
The functions of cholecystokinin (CCK) are coordinated
to promote fat digestion and absorption.
CCK is a 33-amino acid peptide, which is structurally
related to gastrin. The C-terminal five amino acids (CCK5) are identical to those of gastrin and include the
tetrapeptide that is minimally necessary for gastrin
activity. Thus, CCK has some gastrin activity.
The minimum fragment of CCK necessary for its biologic
activity is the C-terminal heptapeptide [CCK-7].
CCK is secreted by the I cells of the duodenal and jejunal
mucosa in response to two types of physiologic stimuli:
(1)
monoglycerides
and
fatty
acids
(but
not
triglycerides), and
(2)
small peptides and amino acids.
These stimuli alert the I cells to the presence of a meal
containing fat and protein, which must be digested and
absorbed. CCK will then ensure that appropriate
pancreatic enzymes and bile salts are secreted to aid in
this digestion and absorption.
There are five major actions of CCK, and each
contributes to the overall process of fat, protein, and
carbohydrate digestion and absorption.
1. Contraction of the gallbladder with simultaneous
relaxation of the sphincter of Oddi ejects bile from
the gallbladder into the lumen of the small intestine.
Bile is needed for emulsification and solubilization of
dietary lipids.
2. Secretion of pancreatic enzymes.
Pancreatic lipases digest ingested lipids to fatty
acids, monoglycerides, and cholesterol, all of which
can be absorbed.
Pancreatic amylase digests carbohydrates,
pancreatic proteases digest protein
3. Secretion of bicarbonate (HCO3-) from the pancreas.
This is not a major effect of CCK, but it potentiates
the effects of secretin on HCO3- secretion.
4. Growth of the exocrine pancreas and gallbladder.
5. Inhibition of gastric emptying. CCK inhibits or slows
gastric emptying and increases gastric emptying
time. This action is critical for the processes of fat
digestion
and
absorption,
which
require
a
considerable amount of time.
Secretin
Secretin, a 27-amino acid peptide, is structurally
homologous to glucagon. Fourteen (14) of the 27 amino
acids of secretin are identical and in the same position
as those of glucagon. In contrast to gastrin and CCK,
which have active fragments, all 27 amino acids of
secretin are required for its biologic activity.
Secretin is secreted by the S cells (secretin cells) of the
duodenum in response to H+ and fatty acids in the
lumen of the small intestine. Thus, secretion of secretin
is initiated when the acidic gastric contents (pH < 4.5)
arrive in the small intestine.
The function of secretin is to promote the secretion of
pancreatic and biliary HCO3-, which then neutralizes H+
in the lumen of the small intestine. Neutralization of H+
is essential for fat digestion; pancreatic lipases have pH
optimums between 6 and 8, and they are inactivated or
denatured when the pH is less than 3.
Secretin also inhibits the effects of gastrin on the
parietal cells (H+ secretion and growth of gastric
mucosa).
Glucose-Dependent Insulinotropic Peptide.
(Gastric inhibitory peptide, GIP)
Glucose-dependent insulinotropic peptide (GIP), a 42amino-acid peptide. GIP has 9 amino acids in common
with secretin and 16 amino acids in common with
glucagon. Because of this homology, pharmacologic
levels of GIP produce most of the actions of secretin.
GIP is secreted by K cells of the duodenal and jejunal
mucosa. It is the only gastrointestinal hormone that is
secreted in response to all three types of nutrients:
glucose, amino acids, and fatty acids.
The major physiologic action of GIP is stimulation of
insulin secretion by the pancreatic β cells. This action
explains the observation that an oral glucose load is
utilized by cells more rapidly than an equivalent
intravenous glucose load. Oral glucose stimulates GIP
secretion, which stimulates insulin secretion (in addition
to the direct stimulatory action of absorbed glucose on
the β cells). Glucose given intravenously stimulates
insulin secretion only by the direct action on the β cells.
The other action of GIP is inhibition of gastric H+
secretion (secretin-like action).
Motilin, a 22-amino acid peptide. It is secreted from the
upper duodenum during fasting states. Motilin is
believed to increase gastrointestinal motility and,
specifically, to initiate the interdigestive myo-electric
complexes that occur at 90-minute intervals.
Pancreatic polypeptide is a 36-amino acid peptide
secreted by the pancreas in response to ingestion of
carbohydrates,
proteins,
or
lipids.
Pancreatic
polypeptide inhibits pancreatic secretion of HCO3- and
enzymes, although its physiologic role is uncertain.
Enteroglucagon is released from intestinal cells in
response to a decrease in blood glucose concentration.
It then directs the liver to increase glycogenolysis and
gluconeogenesis.
Somatostatin is secreted by D cells of the gastrointestinal mucosa in response to decreased luminal pH.
In turn, somatostatin inhibits secretion of the other
gastrointestinal hormones and inhibits gastric H+
secretion. In addition to these paracrine functions in the
gastrointestinal tract, somatostatin is secreted by the
hypothalamus and by the delta (δ) cells of the endocrine
pancreas.
Histamine is secreted by endocrine-type cells of the
gastrointestinal mucosa, particularly in the H+-secreting
region of the stomach. Histamine, along with gastrin
and ACh, stimulates H+ secretion by the gastric parietal
cells.
NEUROCRINES
Neurocrines
are
synthesized
in
cell
bodies
of
gastrointestinal neurons. An action potential in the
neuron causes release of the neurocrine, which diffuses
across the synapse and interacts with receptors on the
postsynaptic cell.
Substance
Source
Acetylcholine (ACh)
Cholinergic neurons
Norepinephrine (NE)
Adrenergic neurons
Actions
 Contraction of smooth
muscle in wall but
Relaxation of sphincters
 ↑ Salivary secretion
 ↑ Gastric secretion
 ↑ Pancreatic secretion
 Relaxation of smooth
muscle in wall but
Contraction of sphincters
 ↑ Salivary secretion
Vasoactive Intestinal Peptide
(VIP)
Neurons of mucosa and
Gastrin-Releasing Peptide
(GRP)
Neurons of gastric
mucosa
Enkephalins (opiates)
Neurons of mucosa and
smooth muscle
smooth muscle
Neuropeptide Y
Neurons of mucosa and
smooth muscle
Substance P
Co-secreted with ACh
 Relaxation of smooth
muscle
 ↑ Intestinal secretion
 ↑ Pancreatic secretion
 ↑ Gastrin secretion
 Contraction of smooth
muscle
 ↓ Intestinal secretion
 Relaxation of smooth
muscle
 ↓ Intestinal secretion
 Contraction of smooth
muscle
 ↑ Salivary secretion
The neurones are divided into:

Cholinergic neurons: parasympathetic neurones
and release Acetylcholine (Ach).

Adrenergic neurons: sympathetic neurones and
release norepinephrine.

Peptidergic neurons: parasympathetic neurons but
noncholinergic. They release the other neurocrines.
Effect of Gut Activity and Metabolic Factors on
Gastro-intestinal Blood Flow
Under normal conditions, the blood flow in each area of
the gastrointestinal tract, as well as in each layer of the
gut wall, is directly related to the level of local activity.
For instance, during active absorption of nutrients,
blood flow in the villi and adjacent regions of the
submucosa is increased as much as eightfold.
Likewise, blood flow in the muscle layers of the
intestinal wall increases with increased motor activity in
the gut. For instance, after a meal, the motor activity,
secretory activity, and absorptive activity all increase;
likewise, the blood flow increases greatly but then
decreases back to the resting level over another 2 to 4
hours.
Possible Causes of the Increased Blood Flow During
Gastrointestinal Activity.
Although the precise cause or causes of the increased
blood flow during increased gastrointestinal activity are
still unclear, some facts are known.
First, several vasodilator substances are released from
the mucosa of the intestinal tract during the digestive
process. Most of these are peptide hormones, including
cholecystokinin, vasoactive intestinal peptide, gastrin,
and secretin.
Second, some of the gastrointestinal glands also release
into the gut wall two kinins, kallidin and bradykinin, at
the same time that they secrete their secretions into the
lumen. These kinins are powerful vasodilators that are
believed to cause much of the increased mucosal
vasodilation that occurs along with secretion.
Third, decreased oxygen concentration in the gut wall
can increase intestinal blood flow at least 50 to 100 per
cent; The decrease in oxygen can also lead to as much
as a fourfold increase of adenosine, a well known
vasodilator that could be responsible for much of the
increased flow.
“Countercurrent” Blood Flow in the Villi.
The arterial flow into the villus and the venous flow out
of the villus are in directions opposite to each other, and
that the vessels lie in close apposition to each other.
Because of this vascular arrangement, much of the
blood oxygen diffuses out of the arterioles directly into
the adjacent venules without ever being carried in the
blood to the tips of the villi.
As much as 80 per cent of the oxygen may take this
short-circuit route and therefore not be available for
local metabolic functions of the villi.
Under normal conditions, this shunting of oxygen from
the arterioles to the venules is not harmful to the villi,
but in disease conditions in which blood flow to the gut
becomes greatly curtailed, such as in circulatory shock,
the oxygen deficit in the tips of the villi can become so
great that the villus tip or even the whole villus suffers
ischemic death and can disintegrate.
Therefore, for this reason and others, in many
gastrointestinal diseases the villi become seriously
blunted, leading to greatly diminished intestinal
absorptive capacity.
Nervous Control of Gastrointestinal Blood Flow
Parasympathetic stimulation of the nerves going to the
stomach and lower colon increases local blood flow at
the same time that it increases glandular secretion. This
increased flow probably results secondarily from the
increased glandular activity and not as a direct effect of
the nervous stimulation.
Sympathetic stimulation, by contrast, has a direct effect
on essentially all the gastrointestinal tract to cause
intense vasoconstriction of the arterioles with greatly
decreased blood flow.
After a few minutes of this vasoconstriction, the flow
often returns almost to normal by means of a
mechanism called “autoregulatory escape.” That is, the
local metabolic vasodilator mechanisms that are elicited
by ischemia become prepotent over the sympathetic
vasoconstriction and, therefore, redilate the arterioles,
thus causing return of necessary nutrient blood flow to
the gastrointestinal glands and muscle.
Importance of Nervous Depression of Gastro-intestinal
Blood Flow When Other Parts of the Body Need Extra
Blood Flow.
(1)
It allows shut-off of gastrointestinal and other
splanchnic blood flow for short periods of time during
heavy exercise, when increased flow is needed by the
skeletal muscle and heart.
(2)
Also, in circulatory shock, when all the body’s vital
tissues are in danger of cellular death for lack of blood
flow—especially the brain and the heart—sympathetic
stimulation can decrease splanchnic blood flow to very
little for many hours.
Sympathetic
stimulation
also
causes
strong
vasoconstriction of the large-volume intestinal and
mesenteric veins. This decreases the volume of these
veins, thereby displacing large amounts of blood into
other parts of the circulation.
In hemorrhagic shock or other states of low blood
volume, this mechanism can provide as much as 200 to
400 milliliters of extra blood to sustain the general
circulation.
GIT MOVEMENT
Propulsion and Mixing
Contractions of gastrointestinal smooth muscle can be
either phasic or tonic.
Two types of phasic movements occur in the
gastrointestinal tract:
(1) propulsive movements, which cause food to move
forward along the tract at an appropriate rate to
accommodate digestion and absorption, and
(2) mixing movements, which keep the intestinal
contents thoroughly mixed at all times.
Propulsive Movements—Peristalsis
A contractile ring appears around the gut and then
moves forward, any material in front of the contractile
ring is moved forward.
Peristalsis is an inherent property of many syncytial
smooth muscle tubes; stimulation at any point in the
gut can cause a contractile ring to appear in the circular
muscle, and this ring then spreads along the gut tube.
(Peristalsis also occurs in the bile ducts, glandular ducts,
ureters and many other smooth muscle tubes of the
body.)
Stimuli for Peristalsis:
(1) The usual stimulus for intestinal peristalsis is
distention of the gut. That is, if a large amount of food
collects at any point in the gut, the stretching of the gut
wall stimulates the enteric nervous system to contract
the gut wall 2 to 3 centimeters behind this point, and a
contractile ring appears that initiates a peristaltic
movement.
(2) Other stimuli that can initiate peristalsis include
chemical or physical irritation of the epithelial lining in
the gut.
(3) Parasympathetic nervous signals to the gut will elicit
strong peristalsis.
Role of the Myenteric Plexus in Peristalsis.
Effectual peristalsis requires an active myenteric plexus.

Peristalsis occurs only weakly or not at all in any
portion of the gastrointestinal tract that has
congenital absence of the myenteric plexus.

Also, it is greatly depressed or completely blocked
in the entire gut when a person is treated with
atropine to paralyze the cholinergic nerve endings
of the myenteric plexus.
Directional Movement of
Peristaltic Waves Toward the Anus.
Peristalsis, theoretically, can occur in either direction
from a stimulated point, but it normally dies out rapidly
in the orad direction while continuing for a considerable
distance toward the anus. The exact cause of this
directional transmission of peristalsis has never been
ascertained, although it probably results mainly from
the fact that the myenteric plexus itself is “polarized” in
the anal direction, which can be explained as follows.
Peristaltic Reflex and the “Law of the Gut.” When a
segment of the intestinal tract is excited by distention
and thereby initiates peristalsis, the contractile ring
causing the peristalsis normally begins on the orad side
of the distended segment and moves toward the
distended segment, pushing the intestinal contents in
the anal direction for 5 to 10 centimeters before dying
out. At the same time, the gut sometimes relaxes
several centimeters downstream toward the anus,
which is called “receptive relaxation,” thus allowing the
food to be propelled more easily anally than orad. This
complex pattern does not occur in the absence of the
myenteric plexus. Therefore, the complex is called the
myenteric reflex or the peristaltic reflex. The peristaltic
reflex plus the anal direction of movement of the
peristalsis is called the “law of the gut.”
Mixing Movements
Mixing movements differ in different parts of the
alimentary tract.
(1)
In some areas, the peristaltic contractions
themselves cause most of the mixing. This is
especially true when forward progression of the
intestinal contents is blocked by a sphincter, so
that a peristaltic wave can then only shake the
intestinal contents, rather than propelling them
forward.
(2)
At other times, local intermittent constrictive
contractions occur every few centimeters in the
gut wall. These constrictions usually last only 5 to
30 seconds; then new constrictions occur at other
points in the gut, thus “chopping” and “shearing”
the contents first here and then there.
SHEWING
Chewing has three functions:
1. It mixes food with saliva, lubricating it to facilitate
swallowing;
2. it reduces the size of food particles, which facilitates
swallowing (although the size of the swallowed
particles has no effect on the digestive process);
and
3. it mixes ingested carbohydrates with salivary
amylase to begin carbohydrate digestion.
Chewing
has
both
voluntary
and
involuntary
components. The involuntary component involves
reflexes initiated by food in the mouth. Sensory
information is relayed from mechanoreceptors in the
mouth to the brain stem, which orchestrates a reflex
oscillatory pattern of activity to the muscles involved in
chewing. Voluntary chewing can override involuntary or
reflex chewing at any time.
Swallowing
There are three phases involved in swallowing: oral,
pharyngeal, and esophageal. The oral phase is
voluntary, and the pharyngeal and esophageal phases
are controlled by reflexes.
Oral phase. The oral phase is initiated when the tongue
forces a bolus of food back toward the pharynx, which
contains a high density of somatosensory receptors.
Activation of these receptors initiates the involuntary
swallowing reflex in the medulla.
Pharyngeal phase. The purpose of the pharyngeal phase
is to propel the food bolus from the mouth through the
pharynx to the esophagus in the following steps:
1.
The soft palate is pulled upward, creating a
narrow passage for food to move into the
pharynx so food cannot reflux into the
nasopharynx.
2.
The epiglottis moves to cover the opening to
the larynx, and the larynx moves upward
against the epiglottis to prevent food from
entering the trachea.
3.
The upper esophageal sphincter relaxes,
allowing food to pass from the pharynx to the
esophagus.
4.
A peristaltic wave of contraction is initiated in
the pharynx and propels food through the
open sphincter. Breathing is inhibited during
the pharyngeal phase of swallowing.
Afferent nerves. the sensory portions of the
trigeminal and glossopharyngeal nerves.
Reflex centre: The deglutition or swallowing
center in the medulla and lower pons.
Efferent nerves. To pharynx and upper esophagus
by the 5th, 9th, 10th, and 12th cranial nerves and
even a few of the superior cervical nerves.
Effect of the Pharyngeal Stage of Swallowing on
Respiration.
The entire pharyngeal stage of swallowing usually
occurs in less than 6 seconds, thereby interrupting
respiration for only a fraction of a usual
respiratory
cycle.
The
swallowing
center
specifically inhibits the respiratory center of the
medulla during this time, halting respiration at
any point in its cycle to allow swallowing to
proceed. Yet, even while a person is talking,
swallowing interrupts respiration for such a short
time that it is hardly noticeable.