Transcript stimulation g

Today lecture
Gastric and intestinal secretion
**Types
**Functions
**Mechanisms
**Regulation
 special consideration will be on gastric
secretion
Types of gastric glands and cells
• Gastric cells
1. mucous neck cells
(secrete mucus)
2. surface epithelial cells
(secrete mucus)
3. chief cells (secrete
pepsinogen)
4. G cells (secrete gastrin in antrum)
5. parietal (oxyntic) cells
(secrete HCl and intrinsic
factor)
6. enterochromaffin-likecells (ECL) secrete
histamine.
• Gastric glands
1. The oxyntic glands (80% of
gastric glands)-body and fundus
2. Pyloric glands (20% of gastric
glands)- antrum region
Structure of a gastric exocrine secretory gland
The oxyntic glands
GASTRIC SECRETION
• approx. 2 L gastric juice per day
• secretion is isotonic, pH 2-3 (in stomach lumen)
Functions of gastric secretion
1. Intrinsic Factor: - from parietal cells, for vitamin B12 uptake in
lower small intestine (ileum).
- It is indispensable substance in gastric juice. It’s absence leads to
pernicious anemia
2. Mucus: protects gastric epithelium. It adheres to gastric surface
and prevents H+ and pepsin eroding the mucosa; failure of this
process leads to gastric ulceration
GASTRIC SECRETION (cont.)
3. HCl - from parietal (oxyntic) cells
• Function of Gastric acid
-to kill micro-organisms
– but H. pylori survives by making ammonia (alkaline) from urea
using urease enzyme.
-to activate pepsinogen (cleaved to form pepsin)
- pepsin: initiates protein digestion
-breaks down connective tissue in food
-denatures protein
4. Pepsinogen
- from chief (peptic) cells
- conversion to pepsin (active enzyme) requires low pH
- pepsin initiates protein digestion; optimum pH 1-2
Mucosal Protection of gastric
epithelium
• mucus layer on gastric surface forms a mucosal
barrier against damage to gastric epithelium
–
–
–
–
a gel about 1 mm thick
secreted by neck cells, surface epithelium
release is stimulated by acetylcholine from nerve endings
also rich in bicarbonate
• HCO3- content creates a "micro-environment" around surface cells to
prevent acid damage
• HCO3- secretion is inhibited by adrenergic input (prominent in stress!)
• prostaglandins are protective agent (increase mucus
production and blood flow)
– inhibition of enzymes involved in prostaglandin production (cyclooxygenases =COX) by NSAIDs (non-steroidal anti-inflammatory drugs)
such as aspirin, ibuprofen, etc. results in gastric damage
Gastric Mucous layer
***The surface epithelial cells of
the stomach secrete thick
insoluble, unstirred mucus
that lines the surface of the
stomach.
•
•
•
This mucus contains
glycoproteins that form an almost
gelatinous coating which contains
relatively high concentrations of
bicarbonate ion.
This coating protects the stomach
epithelium from gastric acid and
pepsin.
Glycosylation of mucin makes it
relatively resistant to proteolysis
by pepsin.
Mucus layer lining the gastric mucosa is for
protection
A second type of mucus (soluble) is secreted along with the
gastric juice from the gastric pits to lubricate the food bolus
and facilitate mixing. Soluble mucus restricts the access of
gastric juice to the gastric pit epithelial cells.
Viscid mucus
Soluble mucus
Parietal cells secret HCl and intrinsic factor
Parietal cells and it’s receptors
HCl secretion
Three chemicals stimulate production of
HCl from parietal cells:
1.
Acetylecholine: released from
cholinergic nerve fibres
(parasympathetic)
- acts on muscarinic receptors (M3 )
2. Gastrin: released from G cells of
pyloric glands acts on G receptors
3. Histamine: released from
enterochromaffin-like-cells (ECL)
and mast cells. It acts on H2
receptors (activates adenyl cyclase
enzyme). inhibited by H2 receptor
antagonists (eg. cimetidine)
-ECL are stimulated by gastrin and
acetylcholine
** each
one of the three
stimulants potentiates
the effects of the others
EFFECT of parietal stimulation by
the three stimulants are:
**more H+/K+-ATPase
insertion in membrane
**more Cl- channels insertion
PARACRINE HORMONES AND HCl RELEASE
IN THE GASTRIC PHASE OF SECRETION
Histamine: Released from mast cells in mucosa by Ach
(from nerves) and gastrin (G-cells)
***Acts directly on parietal cells to stimulate HCl
production.
H2-receptor antagonists block action of histamine
Somatostatin: Released from D-cells in gastric
epithelium by direct action of H+ (at lumen pH < 2).
Reduces gastrin release → reduced HCl secretion
One inhibitory and
three stimulatory
signals that alter
acid secretion by
parietal cells
in the stomach.
Inhibitory effect of
somatostatin is indirect
(through inhibition of G
cells)
inhibition of acid secretion through somatostatin
Interaction between different factors that
Regulate HCl secretion
histamine
ECL cell
Gastrin
secretion is
stimulated by:
1. Peptides
2. Gastrinreleasing
peptides
released
from
intrinsic
nerve
Histamine
release is
stimulated by
1. Ach
2. 2. gastrin
Mechanism of HCl formation
1. H+ ions are formed inside parietal
cells from dissociation of carbonic
acid which is formed from
combination of CO2 and water
under the influence of carbonic
anhydrase enzyme (HCO3 conc.
Increases inside parietal cell).
2. Cl- is pumped inside parietal cell in
exchange of HCO3 (antiporter).
3. H+ ions are pumped into gastric
lumen by K+/H+ pump.
4. Cl- moves out (by diffusion) of
parietal cell into lumen through
electrical gradients.
****H+/K+-ATPase (i.e. proton pump),
located in the luminal membrane
of parietal cells
Another version (Guyton) for Hydrochloric acid formation :
Hydrogen ions are formed from the dissociation of water molecules.
The enzyme carbonic anhydrase facilitates the reaction of carbon dioxide and water
forming carbonic acid which dissociates into a bicarbonate ion (HCO3-) and a
hydrogen ion (H+).
The bicarbonate ion (HCO3-) diffuses out in exchange with chloride ion (Cl-) which
diffuses inside.
Potassium( K+ ions diffuse into the canaliculi.
Hydrogen ions are pumped out of the cell into the canaliculi in exchange for potassium
ions, via the H/+K +ATPase.
Extra points regarding HCL formation
• During active secretion of HCl after a meal, the pH of the blood
drained from the stomach is elevated (due to secretion of HCO3
ions). this increase in pH of the venous blood leaving the
stomach is referred to as the alkaline tide. It raises the
pH of systemic blood and make urine alkaline (postprandial alkaline
tide).
• * The K+/H+ pump is very powerful and requires appreciable
amount of energy because H+ is pumped against more than
1000000 concentration gradient (pH 7 to pH 1) )
- It can concentrate H+ 3 million times.
- Inhibition of this pump by drugs called proton pump inhibitor
(Omeprazole ) helps in reducing the amount of HCl secretion.
• The pH of parietal cell secretion into canaliculi is very low (about
0.8).
Regulation of pepsinogen
secretion
1. Stimulation of chief cells by acetylcholine
released from
a. Vagus nerve endings
b. Gastric enteric nervous plexus
2. Presence of acid in the stomach: through
eliciting enteric reflexes. Absence or less
acid secretion will cause less pepsinogen
formation
Phases of gastric secretion
Cephalic phase: Occurs before food
enters stomach
~30% of total secretion
Direct vagal stimulation + gastrin
release
Gastric phase: Occurs while food is in
stomach
>60% of total secretion
Involvement of: vagal and enteric
nerves
paracrine (local) hormones (histamine)
endocrine hormones (gastrin)
Gastrin secretion is inhibited at lumen
pH <2
Intestinal phase: Occurs after food
enters small intestine
Largely hormonal:
- stimulatory effects (gastrin)
- inhibitory effects (secretin, GIP,
cholycystokinin)
Cephalic Phase of gastric secretion
1. The taste or smell of food, tactile
sensations of food in the mouth, or
even thoughts of food stimulate the
medulla oblongata (green arrow) via
stimulation of appetite center of
hypothalamus and amygdala.
2. Parasympathetic action potentials
are carried by the vagus nerves to
the stomach (pink arrow).
Taste or smell of food
Tactile sensation in mouth
Medulla oblongata
1
5
3. Parasympathetic vagus nerve
fibers stimulate enteric plexus of the
stomach.
4. Postganglionic neurons stimulate
secretion by parietal and chief cells
and stimulate gastrin secretion by
endocrine cells.
Vagus nerves
2
3
Gastrin
4
Circulation
5. Gastrin is carried through the
circulation back to the stomach
(purple arrow), where it stimulates
secretion by parietal and chief cells.
Secretions
stimulated
Stomach
**Peptides in stomach cause
also secretion of gastrin
***Inhibition of HCl
secretion by low
luminal pH. A local
effect to prevent
gastric damage by
very acidic gastric
contents
Medulla
oblongata
Vagus nerves
(long vago-vagal
reflex
Gastric Phase
1. Distention of the stomach activates a
parasympathetic reflex. Action potentials
are carried by the vagus nerves to the
medulla oblongata (green arrow).
1
Secretions
stimulated
2
Distention
2. The medulla oblongata stimulates stomach
secretions (pink arrow).
3
3. Distention of the stomach also activates
local reflexes that increase stomach
secretions (purple arrow).
4. Peptides in stomach cause secretion of
gastrin
Stomach
Local reflexes
stimulated by
stomach
distention
Phases of gastric secretion
3. INTESTINAL phase
- occurs when chyme enters small
intestine
- largely hormonal:
1. Initial stimulatory effects on gastric
secretion (via enteric gastrin)
2. Feedback inhibitory effects (secretin,
gastric-inhibitory-polypeptide)
Inhibition of gastric secretion by intestinal factors
**Chyme in the duodenum with
a pH less than 2 or containing
fat digestion products (lipids)
inhibits gastric secretions by
three mechanisms.
Vagus
nerves
1. Sensory vagal action potentials
to the medulla oblongata
(green arrow) inhibit motor
action potentials from the
medulla oblongata (pink arrow).
2. Local reflexes inhibit gastric
secretion (orange arrows) this
called reverse entrogastric reflex .
3. Acid, fat, protein breakdown
products, hyperosmotic or
hypo-osmotic or any irritating
factor in duodenum and upper
small intestine cause secretion
of Secretin and gastric inhibitory
polypeptide produced by the
duodenum (brown arrows)
inhibit gastric secretions in the
stomach. Secretion has more
powerful inhibitory effect than
other factors
Medulla oblongata
Decreased
gastric
secretions
Vagus
nerves
2
Local
reflexes
1
pH<2
or lipids
3
4
Circulation
Secretion from other parts of GIT
Esophygeal secretion: entirely mucus and it’s function is;
to prevent mucosal excoriation by newly entering food.
To protect the lower esophagus from the effect of refluxed gastric juice.
Duodenal secretion: alkaline (containing large amount of HCO3 ions)
mucus secretion from compound mucous glands called Brunner’s glands
which are found in large no. in duodenal wall in area between pylorus and
papilla of Vater.
Brunner’s glands secretion (about 200 ml/day) is stimulated by:
1. Tactile or irritating stimuli on duodenal mucosa
2. Vagal stimulation
3. Secretin hormone
Their secretion is inhibited by sympathetic stimulation
Function of Brunner’s gland secretion is to protect duodenal mucosa against
the destructive effects of acidic chyme coming from the stomach.
Secretion from other parts of GIT (cont.)
Secretion of small intestine about 1.8 liter/day (pure small intestine secretion contains
no digestive enzymes).
Intestinal epithelium (crypts of Lieberkuhn) has two types of cells
a. Goblet cells- secrete mucus (mucin) for lubrication and protection and also bind
some bacteria and Immunoglobulins. Secretion of mucus is increased by
parasympathetic stimulation and by chemical and physical irritation.
b. Entrocytes- secrete alkaline (pH 7.5-8) watery fluid similar to extracellular fluid.
This helps in absorption of different substances by intestinal villi.
***The mechanism of intestinal watery secretion:
Cl- and HCO3- ions are actively secreted.
Sodium diffuse because of electrical gradient.
Water will follow ions by osmosis.
Regulation of intestinal secretion:
** mainly by local enteric nervous reflexes initiated
by tactile and irritative stimuli
** Hormonal : secretin and CCK
(endocrine cell
secrete
defensins(
Secretion from other parts of GIT (cont.)
• Secretion of the large intestine (200 ml/day)
***The epithelium of large intestine consists mainly mucous cells that
secret mucus
* this mucus contains HCO3- ions (CHO3- ions are secreted by
non-mucus secreting epithelial cells).
* mucus secretion is increased by:
- tactile stimulation of epithelium lining the intestine.
- Local nervous reflexes
- Stimulation of parasympathetic nerve fibers
Functions of Mucus
a. Protection
b. Neutralization of acids formed in large intestine