Gastric secretion is regulated by neural, hormonal, and paracrine pathways. The three major stimulants of acid secretion are gastrin from G-cells, acetylcholine as a neuromediator, and histamine from ECL cells. Somatostatin from D-cells is the main inhibitor. Parietal cells secrete hydrochloric acid and intrinsic factor, chief cells secrete pepsinogen, and surface mucous cells secrete mucus and bicarbonate to protect the gastric mucosa.

1. Gastric secretion
PRESENTER : BIDYARANI LOUKRAKPAM
MODERATOR : PROF. KSH. GOMTI DEVI
DATE : 08/11/2018
TIME : 1.00 PM

2. History
• 1825: William Beaumont, an army surgeon, described gastric
juice and many of its functions.
• 1983: Feldman: gastrin secretion , a major mechanism by
which chemical agents stimulate gastric acid secretion.
• 1886: Langley and Edkins: secretion of pepsinogen by gastric
mucosa occurs in response to food ingestion.

3. Contd. history
• 1920: Popielski, a Polish physiologist, discovered that
histamine stimulated gastric acid secretion. It was believed by
many that gastrin was actually histamine.
• 1938 : Kamarov demonstrated that histamine and gastrin were
two separate secretagogues in the gastric mucosa. MacIntosh
then suggested that histamine was the final common mediator
of acid secretion.
• 1924: Castle – first postulated the existence of intrinsic
factor(IF)

4. Contd. history
• 1983 : Feldman : Gastrin secretion is the major mechanism by
which chemical agents stimulate gastric acid secretion.
• 1987: Soil and Berglindh: Stimulation of parietal cell function
is linked to either calcium dependent or cyclic AMP-
dependent mechanisms.

5. Introduction
• The stomach is a complex organ capable of secreting a great variety
of products into the gastric lumen, vasculature and interstitium.
• Serves as temporary reservior following ingestion of meal.
• Gastric mucosal cell secretes important substances :
– Hydrochloric acid.
– Intrinsic factor
– Pepsinogen
– Mucus and bicarbonate
– Prostaglandins, regulatory peptides and other chemical
mesengers.

6. Contd.
• HCl secretion is the main secretory function of stomach.
• It facilitates digestion of protein as well as absorption of iron,
calcium , vitamin B12.
• Gastric acid secretion is tightly regulated by highly
coordinated dynamic interaction among neural, hormonal,
and paracrine pathways .
• Gastric muosal barrier protects stomach from acid and pepsin
digestion.

7. Functional gastric anatomy
• Anatomically, stomach
consists of 3 regions:
– Fundus
– Corpus (body)
– Antrum
• Functionally, 2 glandular
regions:
– Oxyntic gland mucosa
(hallmark: oxyntic/parietal
cell)
– Pyloric gland mucosa
(hallmark: G or gastrin
cell)

8. Gastric gland anatomy

9. Contd.
Structure of a gastric gland from the fundus or body of the stomach

10. Functional Neural Anatomy

11. Gastric acid(HCl) secretion
• Parietal cells secrete hydrochloric acid at a concentration of
approximately 160 mM or pH 0.8.
• Acid is thought to gain access to the lumen via channels in the
mucus layer created by the relatively high intraglandular
hydrostatic pressures generated during secretion, about 17 mm
Hg
• gastric glands secrete about 2.5 L of HCl in a day.

12. Contd. Gastric acid…
• Functions
– the digestion of protein
– absorption of iron, calcium, and vitamin B12
– prevents growth of pathogenic bacteria
– Provides optimal pH for action of pepsin

13. Parietal cell
Parietal cell receptors and schematic representation of the morphological changes

14. Mechanism of HCl secretion
Acid secretion requires:
1. functional H+,K+-ATPase
2. apical K+ and Cl−channels
3. basolateral transporters/
channels for K+, Cl−, and
HCO3−.

15. Regulation of gastric acid secretion
Neural, hormonal, and paracrine pathways directly regulating parietal cell acid (H+)
secretion

16. Factors affecting HCl secretion
Stimulating factors:
•Ach released from postganglionic enteric neurons (neurocrine),
• Gastrin released from antral G cells (hormonal),
• Histamine released from oxyntic ECL cells (paracrine)
Inhibiting factors:
•Somatostatin released from oxyntic and antral D cells (paracrine)
•Low pH in stomach (< 3)
• Prostaglandins

17. Acetylcholine
• Released from postganglionic neurons whose cell bodies are
located primarily in the submucosal (Meissner’s)plexus
• Stimulates the parietal cell directly : M3 receptor coupled to
activation of phospholipase C with generation of inositol
trisphosphate and release of intracellular calcium
• Stimulates acid secretion indirectly by activating M2 and M4
receptors on D cells coupled to inhibition of somatostatin
secretion.

18. Gastrin
• main stimulant of acid secretion during meal ingestion.
• produced in G cells of the gastric antrum and lesser amount
from proximal small intestine, colon, and pancreas.
• released in response to dietary protien , amino acid, amines and
gastric distension.
• Gastrin secretion is inhibited by
– antral acidification below a pH of 2.5
– Somatostatin
– prostaglandin

19. Contd. Gastrin
• 2 classical gastrin:
– G17 (amidated gastrin 17)
– G34 (amidated gastrin 34)
• 2 main classes of gastrin /CCK receptors :
1. CCK1 /CCK-A: specific for CCK
2. CCK-2 /CCKB : equal affinity for both CCK and gastrin
• directly stimulates the parietal cell via CCK-2 receptors that
activate phospholipase C to induce release of intracellular calcium
• indirectly by releasing histamine from ECL cells.

20. Contd. Gastrin
• Regulates the secretion and synthesis of histamine in a
biphasic manner.
1st phase : release of stored histamine.
2nd phase :replenishment of histamine stores
• Also functions as a trophic hormone to stimulate mucosal
proliferation

21. Histamine
• Produced in ECL cells by decarboxylation of L-histidine by
histidine decarboxylase (HDC)
• Stimulates acid secretion directly :
binding to H2 receptors
↓
activation of adenylate cyclase and generation of cAMP
• Stimulates acid secretion indirectly :
binding to H3 receptors
↓
inhibition of somatostatin release from oxyntic D cells
↓
stimulation of histamine release and acid secretion

22. Somatostatin
• Polypeptide hormone made by D-cells in the antrum and
corpus of the stomach
• Main inhibitor of acid secretion
• 2 types
– SST-14 predominantly found in stomach
– SST 24
• SSTR2:
– predominant receptor regulating acid secretion
– Present on ECL & parietal cell
– Receptor coupled to reduction of intracellular cAMP, thus
reducing acid secretion

23. Contd. Somatostatin
• In the stomach, somatostatin cells are closely coupled to their target
cells (gastrin cells in the antrum, or parietal and ECL cells in the
fundus/body) either directly via cytoplasmic processes or indirectly
via the local circulation.
• Exert tonic restraint on acid secretion from the parietal cell,
histamine secretion from ECL cell and gastrin secretion from G cell.
• Removing this restraint (i.e., disinhibition), by activation of
cholinergic neurons, is an important physiologic mechanism for
stimulating acid secretion

24. Inhibitory actions of somatostatin

25. Enteric hormones that inhibit gastric H+ secretion

26. The direct and indirect actions of the three acid
secretagogues: ACh, gastrin, and histamine

27. Receptors and signal transduction pathways
in the parietal cell.

29. Model illustrating the neural, paracrine and
hormonal regulation of gastric acid secretion

30. PEPSINOGEN SECRETION
• Inactive precursor (proenzyme) of pepsin
• Mainly secreted by chief cells of the main gastric glands -
pepsinogen I
• Also secreted in less amount by mucous cell of pyloric glands
- pepsinogen II
• Synthesized and stored as zymogen granules in the apical
region of the chief cells
• Pepsinogen is converted to pepsin (the active form) by the
action of HCl or preformed pepsin

31. Contd. Pepsinogen…
Pepsinogen secretion stimulation
Calcium signaling pathway Adenyl cyclase pathway
• Acetylcholine*
• CCK
• Gastrin
• GRP
• Secretin
• VIP
• Histamine
• Isoproterenol
 Inhibitor of pepsinogen secretion: somatostatin, neuropeptide Y

32. Contd. Pepsinogen…
• Function :
– Pepsin, the active form of pepsinogen, is a proteolytic
enzyme that begins the process of protein digestion.
– It splits protein into proteoses, peptones and polypeptides.
 It is important to note that the optimum pH for the action of
pepsin is 2.0,therefore, acid secretion by the stomach is as
essential as pepsinogen secretion for the digestion of proteins.

33. INTRINSIC FACTOR (IF) SECRETION
• Glycoprotein secreted by the parietal cells of gastric mucosa,
chiefly by those in the fundus
• Essential for absorption of Vitamin B12 ( form a complex with
B12 which is carried to terminal ileum where vitamin is absorbed)
• Secretion of IF by parietal is linked to action of histamine through
cAMP mechanism
 Secretion of IF far exceeds the amount necessary for cobalamin
absorption. Thus, in most patients with hypochlorhydria, continued
IF secretion in low amounts is sufficient to prevent cobalamin
deficiency.

34. MUCUS SECRETION
• Mucus is of 2 types: insoluble and soluble.
• Soluble mucus:
– Secreted from mucous neck cells
– Consists of mucoprotiens and mixes with gastric chyme
lubricatig it.
– Vagus nerve stimulation and Ach increases the secretion

35. Contd. Mucus secretion
• Insoluble mucus:
– Secreted by the surface mucous cells lining the entire
gastric mucosa which also secrete HCO3-
– Secreted in response to chemical /physical stimulants and
friction with roughage in diet
– Secreted as gel that entraps alkaline components, thus
protecting mucosa with an alkaline layer of lubricant
– Sheded mucus containing surface cells trapped in mucus
layer
– Neutralizes certain amount of acid and prevents pepsin
from coming into contact with mucosa

36. Gastric mucosal barrier

37. Phases of gastric secretion
3 phases in response to meal:
1. Cephalic phase
2. Gastric phase
3. Intestinal phase
• Basal secretion / Interdigestive secretion:
– Occurs in absence of environmental and gastrointestinal
stimulation
– Probably contributed by parasympathethic stimulation and
small of circulating gastrin

39. Experimental demonstration of regulation of
gastric secretion
• Sham feeding: an experiment to demonstrate cephalic phase
of gastric secretion.
• Pavlov’s pouch experiment : to demonstrate that vagus is
secretomotor nerve to stomach
• Heidenhain’s pouch experiment :to demonstrate existence
of some blood-borne mechanism regulating gastric secretion

40. Sham feeding experiment to demonstrate initiation
of cephalic phase of gastric secretion

41. Pavlov’s pouch experiment
A. showing the site of incision
B. Pavlov’s pouch opening outside through anterior abdominal wall

42. Applied aspect
Peptic ulcer :
• Excavation of mucosa of duodenum or pyloric part of
stomach caused by digestive action of gastric juice.
• Caused by either of 2 ways:
Diminished activity of
gastroduodenal-mucosal barrier
• NSAID
• H. pylori infection
• factors like ethyl alcohol, vinegar,
bile salts
Excessive gastric acid secretion
•Zollinger- Ellison syndrome

43. Contd. Applied…
Helicobacter pylori infection
• Urea NH3 + H+ (neutralize gastric acid allowing
bacteria to withstand in acid
environment)
NH4+
• directly damage epithelial cell
• increases permeability of mucosa
• Autoimmune gastritis
– a/w anti parietal cell autoantibodies and cytotoxic cells
directed against H+/K+ ATPase
– triggered by molecular mimicry between HP
lipopolysaccharide and H+/K+ ATPase.
urease

44. Contd.
Helicobacter pylori–induced perturbations in acid
secretion
• Acute infection with HP results in hypochlorhydria
• Chronic infection results in either hypo or
hyperchlorhydria

45. Contd. Applied…
Zollinger- Ellison syndrome (ZES):
• Acid hypersecretory condition cause by gastric producing
tumor, i.e gastrinoma.
• Gastrin synthesized by tumor →blood stream
↓
bind to CCK2 receptors on
parietal and histamine containing ECL cell
↓
induced HCl secretion & proliferation
• Serum gastrin: 500pg/ml (normal-35 pg/ml).

46. Contd. Applied…
Proton pump inhibitor:
• PPIs are weak bases (pKa 4-5)
• accumulate and activate in acidic environment of apical
canaliculus
• binds covalently with certain cysteine residues within α-subunit
of inserted H+/K+-ATPase
• Produces irreversible inhibition of H+ /K+ -ATPase
↓
prolonged suppression of gastric acid secretion
• Omeprazole, pentaprazole, lansoprazole.

47. Summary
• The function of gastric juice are attributed to acid, pepsin,
intrinsic factor and mucus.
• Acid is secreted by parietal cells, which contain the enzyme
H+,K+ ATPase on their apical secretory membranes and is
secreted at a concentration of approximately 160 mM or pH
0.8.
• Acid converts inactive pepsinogen to active enzyme pepsin,
kill bacteria, and solubilizes protien.
• acid secretion is regulated by neural, hormonal and paracrine
pathways .

48. Contd. Summary
• 3 major stimulant of acid secretion are
– gastrin from G-cell
– acetylcholine , cholinergic neuromediator
– Histamine from ECL cell in response to gastrin and Ach
• main inhibitor : somastatin from D- cell.
• During cephalic phase of secretion, vagal activation stimulates
parietal cells directly via Ach and gastrin.
• During gastric phase of secretion , parietal cell is stimulated by
– distention of stomach wall
– Gastrin releases via both mucosal & vagovagal reflexes
– Protien digested product stimulating G-cells directly to
release gastrin

49. Contd. Summary
• When pH of luminal contents drops below 3, somatostatin is
released from D-cell in antrum & oxyntic gland area, where it
inhibits gastrin release and acid secretion.
• Acid secretion is inhibited further when chyme enters
duodenum and triggers release of inhibitory hormone.
• Pepsinogen secretion is stimulated by vagal activation and
Ach.
• Intrinsic factor, secreted by parietal cells, is required for
absorption of vit B12.
• Mucus and bicarbonate secreted by surface mucous cell are
main component for gastric mucosal barrier.

50. References
• Best & Taylor’s Physiological Basis of Medical Practise,13th
edition
• Physiology of Gastrointestinal Tract, Leonard R. Johnson,
Vol-1 , 5th Edition
• Ganong’s Review of Medical Physiology, 25th edition
• Boron & Boulpaep Medical Physiology.2nd Edition 2012
• Medical Physiology by Indu Khurana
• Guyton & Hall Textbook of Medical Physiology 12th Edition.
• Sleisenger and Fordtran’s Gastrointestinal and Liver Disease
9th edition