Chapter 41

Gastric Function
I. Functional anatomy of the stomach
a. The mucosa is composed of surface epithelial cells and glands
i. Three major segments
1. cardia
a. devoid of parietal cells
2. corpus
a. largest portion of the stomach
b. most proximal region called fundus
3. antrum
a. distal portion
ii. gastric glands
1. increase surface area
2. consist of a pit, neck, and a base
iii. cells
1. mucous
2. parietal
a. not in cardia portion
b. secrete acid and intrinsic factor
3. chief
a. secrete pepsinogen pepsin
4. surface epithelial cells
a. secrete HCO3- and mucus
5. endocrine cells
a. found only in the antrum
b. With increasing rates of secretion of gastric juice, the H+ concentration rises and the Na+
concentration Falls
i. Glands of the stomach secrete 2L/day (isotonic with plasma)
ii. At high rates of gastric secretion, [H] is high and [Na] is low
iii. At low rates of gastric secretion , [H] is low and [Na] is high
c. Proximal portion of the stomach secretes acid, pepsinogen, intrinsic factor, bicarbonate, and
mucus, whereas the distal part releases gastrin and somatostatin
i. Corpus (acid, pepsinogen, and intrinsic factor)
1. Parietal cells
a. Secrete acid
i. Activates pepsinogen and prevents colonization by bacteria
b. Secrete intrinsic factor a glycoprotein that is required for vitamin B12
absorption
2. Chief cells
a. Secrete pepsinogen
i. At pH values that are less than 3, pepsinogens are rapidly activated
to pepsins
3. Mucus-secreting cells
4. Enterochromaffin-like (ECL) cells (endocrine cell)
a. release histamine
ii. Antrum (NO parietal cells so NO acid or intrinsic factor released)
1. Chief cells
2. Endocrine cells (paracrine and endocrine)
a. G cells gastrin
i. Stimulates gastric-acid secretion
ii. Trophic or growth factor for GI epithelial cells

b. D cells somatostatin
i. Inhibits both gastrin release and parietal-cell acid secretion
iii. All over we have superficial epithelial cells that cover the gastric pits which secrete
HCO3d. The stomach accommodates food, mixes it with gastric secretions, grinds it, and empties the
chyme into the duodenum
i. Proximal and distal portions of the stomach behave as separate but coordinated entities
ii. Four events in gastric filling and emptying
1. receiving and providing temporary storage of dietary food and liquids
2. mixing of food and water with gastric secretory products (pepsin and acid)
3. grinding of food so that particle size is reduced to enhance digestion ad permit
passage through the pylorus
4. regulating the exit of retained material from the stomach into the duodenum in
response to various stimuli
iii. Empyting of liquids is primarily a function of the smooth muscle of the proximal part of
the stomach, while emptying of solids is regulated by antral smooth muscle
II. Acid secretion
a. The parietal cell has a specialized tubulovesicular structure that increases apical membrane area
when the cell is stimulated to secrete acid
i. When stimulated, tubulovesicular membranes containing the H-K pump fuse into the
apical membrane
1. surface area
2. appearance of microvilli
3. fusion is accompanied by insertion of the H-K pumps and K+ and Cl- channels in
membrane
ii. An H-K pump is responsible for gastric acid secretion by parietal cells
1. the H-K pump requires the and subunits for full activity
a. subunit is the pump
b. subunit required for targeting to apical membrane
2. inhibitors of H-K pump
a. substituted benzimidazoles (omeprazole) (potent inhibitor)
i. binds covalently to cysteines on the extracytoplasmic surface
b. substances that act as competitive inhibitors of the K+ binding site
3. H2O + CO2 go into the cell carbonic anhydrase HCO3- + H+
a. the H+ is pumped out via the H-K pump in exchange for a K+ (K+ leaks
back into lumen by K+ leak channels)
b. Cl- leaks out driven by electrochemical gradient
c. the HCO3- gets pumped out by Cl-HCO3 exchanger on basolateral side (so
the extra Cl that comes in then goes out the apical side
d. basolateral Na-H exchanger participates in intracellular pH regulation in
the basal state
e. Na-K pump provides the ATP for H-K pump
iii. Three secretagogues (ACh, gastrin, and histamine) directly and indirectly induce acid
secretion by parietal cells
1. ACh, gastrin, and histamine bind directly to their respective membrane receptors
on the parietal cell and synergistically stimulate and potentiate acid secretion
a. ACh from vagus nerve
b. Gastrin from D cells
c. Histamine from histidine in ECL cell
2. ACh and gastrin indirectly induce acid secretion as a result of their stimulation of
histamine release from ECL cells (maybe from mast cells as well)

iv.

v.

vi.
vii.

3. H2 blockers (histamine receptor antagonists on parietal cells) used to control acid

secretion
Three acid secretagogues act through either Ca2+/diacyglycerol or cAMP
1. all three secretagogues bind to G-protein coupled receptors on the parietal-cell
membrane
2. ACh
a. Binds to M3 muscarinic receptor on parietal cell basolateral membrane
b. Gq activates PLC get IP3 [Ca] rises acts on calmodulindependent protein kinase; DAG activates PKC; M3 also activates Ca
channel
3. Gastrin
a. Binds to the gastrin-cholecystokinin B receptor (CCKB)
i. CCKB has equal affinity for both gastrin and CCK
ii. CCKA receptor has 3x higher affinity for CCK
b. Gq activated (same as ACh pathway)
4. Histamine
a. H2 receptor coupled to Gs GTP-binding protein
b. Gs activated adenyly cyclase cAMP PKA phosphorylation of
proteins and H-K pump
Gastrin is released by both antral and duodenal G cells
1. what gastrin does
a. stimulation of acid secretion by parietal cells
b. release of histamine by ECL cells
c. regulation of mucosal growth in the corpus of the stomach and small and
large intestines
2. 2 forms: G-17 (antral) and G-34 (duodenal) (not dimmer of G-17) from single
gene
a. tyrosine residue may be either sulfated (gastrin II) or nonsulfated (gastrin
I)
b. present in equal amounts
3. CCK has identical C-terminal tetrapeptide sequence that posses all the biological
activities of gastrin and CCK
4. both forms found in blood (dependent of degradation rate)
5. Antral G cells release gastrin in response to luminal peptides and amino acids and
gastrin-releasing peptide (GRP) from vegal nerve endings
6. Inhibited by somatostatin from adjacent D cells
Histamine is released by ECL cells in the corpus
Somatostatin, released by gastric D cells, is the central mechanism of inhibition of acid
secretion
1. D cells are in antrum and corpus
2. direct inhibition pathway
a. somatostatin binds to basolateral Gi coupled receptor on the parietal cell
and inhibits adenylyl cyclase
b. source of somatostatin can be either paracrine (from D cells in corpus) or
endocrine (D cells in the antrum) (there are NO parietal cells in the
antrum)
c. neural and hormonal mechanisms stimulate D cells in the corpus (cant
sense pH of lumen), whereas low intraluminal pH stimulates D cells in the
antrum
3. indirect inhibition pathway
a. inhibits the release of histamine from ECL in the corpus
b. inhibits the release of gastrin from G cells in the antrum

c. gastrin stimulates somatostatin release whereas cholinergic agonists inhibit

somatostatin release
viii. Several enteric hormones and prostaglandins inhibit gastric acid secretion
1. Fat (most potent), acid, and hyperosmolar solutions in the duodenum are potent
inhibitors of gastric acid secretion
2. CCK, secretin, VIP, GIP, Neurotensin, peptide YY, somatostatin inhibit gastric H+
secretion
3. Secretin release by duodenal S cells
a. Inhibit gastric acid secretion after the entry of fat and acid into the
duodenum
b. Mechanisms:
i. Inhibition of Antral gastrin release
ii. Stimulation of somatostatin release
iii. Direct downregulation of the parietal-cell H+ secretory process
4. CCK and GIP release by K cells in duodenum and jejunum in response to luminal
fatty acids
a. GIP reduces acid secretion directly by inhibiting parietal-cell acid
secretion and indirectly by inhibiting the antral release of gastrin
b. GIP also stimulates release of insulin
c. CCK directly by reducing parietal-cell acid secretion
5. Prostaglandin E2 (PGE2) inhibits parietal-cell acid secretion by inhibiting
histamines activation of parietal-cell function
a. PGE2 binds to EP3 receptor and inhibits adenylyl cyclase
b. Also reduces histamine release from ECL cells and gastrin release from
antral G cells
ix. There are four phases of acid secretion: A basal phase and three phases associated with
eating
1. Basal state
a. Acid secretion is lowest in the morning before awakening and highest in
the evening
b. Men have higher rates of basal acid secretion
c. Acid secretion enhanced by eating
d. Intragastric pH depends on acid secretion and buffering power of food and
rate of emptying into duodenum
2. Cephalic phase
a. Smell, sight, taste, thought, and swallowing of food initiate the cephalic
phase mediated by the vagus nerve
b. Stimulates the dorsal motor nucleus of the vagus nerve in the medulla
c. This activates parasympathetic efferent nerves
d. Insulin induced hypoglycemia also stimulates vagus nerve and leads to
acid secretion
e. Stimulation of the vagus leads to (by way of ACh):
i. Stimulate parietal cells to release H+
ii. Histamine released from ECL cells in response to ACh H+
secretion
iii. In the antrum, peptidergic postganglionic parasympathetic vagal
neurons, as well as other enteric nervous system neurons release
GRP (gastrin releasing peptide) induces gastrin release from
antral G cells gastrin acts on parietal cell directly and on ECL
cells which release histamine that stimulates parietal cells H+
release

iv. In antrum and corpus, vagus inhibits D cells somatostatin not

released background inhibition eliminated
f. 30% of total acid secretion occurring before any food gets into stomach
g. Vagotomy cutting the vagus nerve to inhibit gastric-acid secretion
i. Side effects are delay in gastric emptying and diarrhea
3. Gastric phase
a. Distension of the gastric wall
i. Activates vagovagal reflex
1. vagal afferent pathway vagal efferent response from the
dorsal nucleus of the vagus nerve H+ secretion in
response to ACh
ii. Activates local ENS pathway
1. ACh release H+ secretion
b. Partially digested proteins (peptones) or amino acids directly stimulate G
cells
i. Low pH enhances pepsinogen to pepsin peptones stimulate G
cells lowers pH (loop)
ii. Wine, beer, and coffee stimulate acid secretion stimulate G cells
c. Feedback inhibition
i. Low intragastric pH stimulates antral D cells to release
somatostatin decreased gastrin release
ii. Peptones fail to stimulate gastrin release when the intraluminal pH
of the antrum is maintained at 1.0 or when somatostatin is infused
d. 60% of total gastric secretion
4. Intestinal phase
a. Peptones stimulate duodenal G cells to secrete gastrin
b. Peptones stimulate an unknown endocrine cell to release an additional
humoral signal
c. Amino acids absorbed by proximal small intestine stimulate acid secretion
d. Live normal eliminates these signals before reaching its target (corpus of
stomach)
e. 10% of total gastric acid secretion
III. Pepsinogen secretion
a. Chief cells, triggered by both cAMP and Ca2+ pathways, secrete multiple pepsinogens that initiate
protein digestion
i. Pepsinogen cleavage of an N terminal peptide pepsin
ii. Group I pepsinogen secreted from chief cells in corpus of stomach
iii. Group II pepsinogen secreted from chief cells AND mucous neck cells in cardiac, corpus,
and antral regions
iv. Secretion of pepsinogen is by compound exocytosis (secretory granules fuse with both
the plasma membrane and to other secretory granules)
v. Two groups of agonists stimulate chief cells
1. Via cAMP
a. Receptors for secretin/VIP, 2-adrenergic receptors, and EP2 receptors (for
PGE2)
b. Stimulate adenylyl cyclase cAMP
2. Via Ca2+
a. M3 (ACh) and CCKA (gastrin/CCK) receptors
b. Increased intracellular Ca2+
vi. Gastric acid produces additional pepsinogen secretion via:
1. fall in pH elicits a local reflex that results in ACh being released on chief cells

2. in duodenum, acids triggers the release of secretin from S cell

b. Low pH (<3.0) is required for both pepsinogen activation and pepsin activity
i. Pepsin optimal at 1.8 and 3.5
ii. Endopeptidase
iii. Peptones stimulate CCK release from duodenal I cells
iv. no gastric secretion of enzymes that hydrolyze starch or other saccharides
v. lingual lipases and gastric lipases for fat
IV. Protection of the gastric surface epithelium and neutralization of acid in the duodenum
a. Gastric diffusion barrier
i. Relative impermeability to acid of the apical membrane and epithelial cell tight junctions
in the gastric glands
ii. A mucous-gel layer overlying the surface epithelial cells
iii. An HCO3- containing microclimate adjacent to the surface of the epithelial cells that
maintains a relatively high local pH
b. Vagal stimulation and irritation stimulate gastric mucous cells to secrete mucin, a glycoprotein
that is part of the mucosal barrier
i. Mucus secretion by: surface mucous cells, mucous neck cells, glandular mucous cells
c. Gastric surface cells secrete HCO3-, stimulated by ACh (neural), acids, and prostaglandins
(PGE2)
i. HCO3 secretion at lower rate than acid, but important in protective mechanism
ii. Maintains a local pH of 7.0
iii. Na/HCO3 cotransporter on basolateral side gets HCO3 into the cell and HCO3 then
comes out on apical side through a channel
d. Mucus protects the gastric surface epithelium by trapping an HCO3- rich fluid near the apical
border of these cells
i. Secreted mucus forms a mucous-gel layer that is relatively impermeable to diffusion of
H+ from gastric lumen to surface of cells
ii. Beneath is a microclimate that contains fluid with a high pH and high HCO3 that
neutralizes H+
iii. PGE2 stimulates HCO3 secretion
iv. Viscous fingering to explain H+ movement past the mucus layer
1. H+ tunnels through the mucous layer covering the opening of the gastric glands
onto the surface of the stomach and does not get neutralized because does not
spread laterally
2. alkalinity of mucus inactivates pepsin
e. Entry of acid into the duodenum induces the release of secretin from S cells, thus triggering the
secretion of HCO3- by the pancreas and duodenum which in turn neutralizes the gastric acid
i. Secretin inhibits gastric-acid secretion and promotes pepsinogen secretion by chief cells
V. Filling and emptying of the stomach
a. Gastric motor activity plays a role in filling churning, and emptying
i. Gastric motor activity functions:
1. Reservoir function as smooth muscle relaxes in the proximal portion of the
stomach
2. Material is churned and thus altered to facilitate normal jejunal digestion and
absorption
3. Pyloric antrum, pylorus, and proximal part of the duodenum function as a single
unit for emptying to duodenum
ii. During fasting we have migrating myoelectric complex (MMC)
iii. Replaced by fed pattern when eating
iv. Proximal part of stomach is for storage and antrum more for churning the solids, etc.
b. Filling of the stomach is facilitated by both receptive relaxation and gastric accommodation
i. Receptive relaxation

1. relaxation of the fundus of the stomach mediated by vagovagal reflex

2. if vagal innervation to the stomach is interrupted, gastric pressure rises more
rapidly as food goes in
ii. Gastric accommodation
1. active dilation of the fundus that keeps intraluminal pressure from increasing as
food enters
2. enteric nervous system is the primary regulator permitting the storage of solids
and liquids without major increases in intragastric pressure
a. vagus nerve is mostly for modulation
c. The stomach turns its contents until the particles re small enough to be gradually emptied into the
duodenum
i. <2 mm can leave
ii. propulsion movement of particles towards the antrum
iii. grinding churning to reduce size
iv. retropulsion returning of particles to corpus
v. MMCs begin 2 hours after eating to get rid of anything left behind
vi. Sensors in small intestine sense low pH, high content of calories, lipid, a.a. and decrease
emptying by vagus nerve, secretin, CCK, and GIP release from duodenal mucosa
VI. Clinical
a. Gastric pH and Pneumonia
i. Prophylactic antiulcer treatments that raise stomach pH gram negative bacterial
colonization of stomach if aspirated in the airway, pneumonia can occur
b. Breakdown of Gastric Barrier
i. Salicylates, bile acids, and ethanol all impair the mucosal diffusion barrier and result in
H+ backdiffusion and increased intraluminal [Na], a fall in PD, and mucosal damage
damage to mast cells release of histamine and other factors ischemia tissue
injury
ii. Prostaglandins maintain mucosal integrity
1. inhibit acid secretion
2. stimulate both HCO3- and mucus secretion
3. increase mucosal blood flow
c. Helicobacter Pylori
i. Most ulcers are caused by H. pylori
ii. Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for approximately 20%
of ulcers
iii. H pylori induces inflammation of antrum inhibits the release of somatostatin no
inhibition of gastrin release by G cells increased acid secretion