Detailed Physiology on human gastric acid secretion.

1. Deurali-Janta
Pharmaceuticals Pvt. Ltd.
Presented by:
Asad Kamran
Technical Consultant, MPD
Deurali-Janta Pharmaceuticals Pvt. Ltd.
Gastric Acid Secretion
Physiology

2. INTRODUCTION
• An intricate balance of chemotransmitters
delivered to the gastric mucosa by several
pathways.
• Stimulatory and inhibitory mechanisms.
• Remarkable ability of normal gastro-duodenal
mucosa to defend itself against injury –
Several mechanisms.
• Neural, endocrine, paracrine, and autocrine
control pathways.

3. INTRODUCTION
• There is limited understanding of the actual
physiologic and pathophysiologic importance
of most of these pathways and
chemotransmitters.
• Gastric acid is not essential for life.
• The benefits of gastric acid are to facilitate
digestion of proteins and the absorption of
calcium, iron, and vitamin B12.

4. INTRODUCTION
• Gastric acid suppresses growth of bacteria,
which can help prevent enteric infections and
small intestinal bacterial overgrowth.

5. Phases of Gastric Secretion

6. Phases Of Gastric Secretion
• Three interrelated phases: cephalic, gastric,
and intestinal.
• Cephalic phase is activated by the thought,
taste, smell and sight of food, and swallowing,
mediated mostly by cholinergic/vagal
mechanisms.
• Gastric phase is due to the chemical effects of
food and distension of the stomach.

7. Phases Of Gastric Secretion
• Gastrin appears to be the major mediator
since the response to food is largely inhibited
by blocking gastrin action at its receptors.
• Intestinal phase accounts for only a small
proportion of the acid secretory response to a
meal; its mediators remain controversial.

8. Phases Of Gastric Secretion

9. Secretion Of Acid & Pepsin

10. Secretion Of Acid & Pepsin
• Gastric acid secretion from parietal cells is
regulated by redundant, overlapping
pathways:
– endocrine (gastrin),
– paracrine (locally delivered histamine and
somatostatin),
– neural (acetylcholine),
– and probably autocrine (transforming growth
factor-alpha) factors.

11. Mechanism Of Acid Secretion

12. Mechanism Of Acid Secretion
• The hydrogen ion concentration in parietal cell
secretions is roughly 3 million fold higher than
in blood.
• Chloride is secreted against both a
concentration and electric gradient.
• Ability of the parietal cell to secrete acid is
dependent on active transport.
• The key player in acid secretion is an H+/K+
ATPase or "proton pump" located in the
cannalicular membrane.

13. Mechanism Of Acid Secretion
• Hydrogen ions are generated within the
parietal cell from dissociation of water.
• The hydroxyl ions formed in this process
rapidly combine with carbon dioxide to form
bicarbonate ion, a reaction catalyzed
by carbonic anhydrase.
• Bicarbonate is transported out of the
basolateral membrane in exchange for
chloride.

14. Mechanism Of Acid Secretion
• The outflow of bicarbonate into blood results
in a slight elevation of blood pH known as the
"alkaline tide".
• This process serves to maintain intracellular
pH in the parietal cell.
• Chloride and potassium ions are transported
into the lumen of the cannaliculus by
conductance channels, and such is necessary
for secretion of acid.

15. Mechanism Of Acid Secretion
• Hydrogen ion is pumped out of the cell, into
the lumen, in exchange for potassium through
the action of the proton pump; potassium is
thus effectively recycled.
• Accumulation of osmotically-active hydrogen
ion in the cannaliculus generates an osmotic
gradient across the membrane that results in
outward diffusion of water.

16. Mechanism Of Acid Secretion
• The resulting gastric juice is 155 mM HCl and
15 mM KCl with a small amount of NaCl.

17. Mechanism Of Acid Secretion

18. Control Of Acid Secretion

19. Control Of Acid Secretion
• Parietal cells bear receptors for three
stimulators of acid secretion.
– Acetylcholine (muscarinic type receptor)
– Gastrin
– Histamine (H2 type receptor)
• When low levels of each i.e. Acetylcholine,
Gastrin & Histamine are present, acid
secretion is strongly forced.

20. Control Of Acid Secretion
• Additionally, pharmacologic antagonists of
each of these molecules can block acid
secretion.
• Histamine's effect on the parietal cell is to
activate adenylate cyclase, leading to
elevation of intracellular cyclic AMP
concentrations and activation of protein
kinase A (PKA).

21. Control Of Acid Secretion
• One effect of PKA activation is
phosphorylation of cytoskeletal proteins
involved in transport of the H+/K+ ATPase
from cytoplasm to plasma membrane.
• Binding of acetylcholine and gastrin both
result in elevation of intracellular calcium
concentrations.

22. Control Of Acid Secretion

23. The Parietal Cell

24. The Parietal Cell
• In the resting state, parietal cells are filled
with secretory vesicles that coalesce with
stimulation to form channels (canaliculi) that
drain to the apical lumen.
• The secretory membrane lining these
structures contains the hydrogen-potassium-
ATPase acid-secreting pump.

25. The Parietal Cell
• This pump is always active, but exists in a
short-circuited state in resting vesicles
because the pathway necessary for
transporting potassium to the apical surface
for exchange with hydrogen is not present or
active.
• With stimulation, this pathway for potassium-
chloride cotransport becomes active, allowing
hydrogen-potassium exchange to occur.

26. The Parietal Cell
• Parietal cell activation involves an increase in
cytoplasmic calcium or generation of cyclic
AMP, followed by activation of a cAMP-
dependent protein kinase cascade that
triggers translocation of proton pump
containing membranes to the apical surface.
• The cessation of acid secretion is associated
with the re-internalization of the hydrogen-
potassium-ATPase pump.

27. The Parietal Cell

28. Gastrin

29. Gastrin
• Gastrin is the major endocrine regulator of the
secretory response to a protein meal.
• It is released from gastrin-expressing cells (G
cells) localized to the antrum.
• Gastrin enhances gastric acid secretion from
parietal cells primarily by stimulating the
synthesis and release of histamine from
oxyntic mucosal enterochromaffin-like (ECL)
cells.

30. Gastrin
• However, gastrin also has direct actions on
parietal cells.
• Acid secretion is tightly controlled by a second
hormone, somatostatin, which is a potent
inhibitor of both gastrin and histamine
synthesis and release, and, therefore, of
gastric acid secretion.
• Gastrin is the best identified trophic regulator
of parietal cell mass in humans.

31. Gastrin Receptors
• Gastrin acts via activation of the
cholecystokinin CCK2 receptor (also known as
the CCK-B or gastrin receptor), which has
equal affinity for cholecystokinin (CCK) and
gastrin.
• These receptors have been localized to
parietal and ECL cells, but it is likely that the
ECL cell gastrin receptor is of greater
importance in regulating acid secretion.

32. Gastrin Receptors
• Gastrin "receptors" have also been found on
somatostatin-secreting D cells.
• However, this receptor is a CCK1 or CCK-A
receptor that has much greater affinity for CCK
than for gastrin.
• This difference in receptor affinity may explain
why gastrin is so much more effective as a
stimulant of acid secretion, while CCK induces
greater release of the inhibitor somatostatin.

33. Gastrin Receptors
• CCK1 receptors exert inhibitory effects on acid
secretion in vivo, mediated by release of
endogenous somatostatin.

34. Regulation Of Gastrin secretion
• Complex mechanisms control gastrin release
from the antral G cells.

35. Regulation Of Gastrin secretion
• Two meal-related factors stimulate gastrin
secretion: gastric distention and amino acids.
• Low grade distention activates vasoactive
intestinal peptide neurons which stimulate
somatostatin release and therefore inhibit
gastrin secretion.
• Higher grade distention causes cholinergic
activation which reverses the pattern to one
of increased gastrin and reduced somatostatin
secretion.

36. Regulation Of Gastrin secretion
• Amino acids induce gastrin release; direct
actions on the G cell have been demonstrated
but amino acids also activate both cholinergic
neurons and bombesin neurons.
• The release of bombesin (also called gastrin-
releasing peptide) from mucosal nerves
directly stimulates the G cell.
• Somatostatin is the major inhibitory paracrine
regulator of gastrin release.

37. Regulation Of Gastrin secretion
• Gastrin itself contributes to this process by
enhancing the secretion of somatostatin.
• Cholinergic activation after gastric distention
or in response to a meal promotes acid
secretion by shifting the balance of
stimulatory and inhibitory mechanisms
toward the stimulatory side, directly activating
the parietal cell and stimulating gastrin
release while suppressing somatostatin
release.

38. Gastrin Summary

39. Histamine

40. Histamine
• Histamine is the major paracrine stimulator of
acid secretion.
• It is localized both in mucosal mast cells and in
endocrine cells, the latter called
enterochromaffin-like (ECL) cells because of
the silver-staining properties of their granules.
• The ECL cells are localized to the acid-
secreting oxyntic or body mucosa, in direct
proximity to the parietal cell.

41. Histamine
• Gastrin is the primary stimulus to histamine
release from ECL cells.
• ECL cells are also directly stimulated by
pituitary adenylate cyclase-activating
polypeptide (PACAP) and vasoactive intestinal
peptide (VIP).
• Somatostatin is a major direct inhibitor of
histamine release; calcitonin gene-related
peptide (CGRP), peptide YY, prostaglandins,
and galanin also inhibit release.

42. Histamine
• Stimulated ECL cells promptly degranulate,
with release of histamine and pancreastatin
from the vesicles; this is followed by an
increase in histamine synthesis.
• Although gastric mast cells outnumber ECL
cells, gastrin has only been demonstrated to
release histamine from ECL cells.
• Several lines of evidence indicate that ECL cell
histamine is the major physiological mediator
of acid secretion.

43. Histamine
• Inhibitors of the histamine-forming enzyme,
histidine decarboxylase (HDC), block the acid
secretory response to gastrin, but not to
histamine.
• The effects of histamine are largely mediated
by the H2 receptors, which explain the efficacy
of H2 receptor blockers in the treatment of
acid-peptic disease.

44. Histamine
• These drugs inhibit acid secretion in response
to gastrin, meal, and neural stimulation,
clearly establishing that histamine plays a role
as a universal mediator or modulator of the
acid secretory response.
• Histamine may also act at H3 receptors to
increase acid secretion via inhibition of
somatostatin release.

45. Somatostatin

46. Somatostatin
• Somatostatin is a potent inhibitor of acid
secretion.
• It is released from D cells, which are present
throughout the gastric mucosa.
• Although somatostatin has some effects on
parietal cells, its major effects are exerted on
the inhibition of histamine release and to a
lesser extent on gastrin release.

47. Somatostatin
• The secretion of somatostatin is increased by
gastric acid and by gastrin itself, suggesting
that a major function of somatostatin is to
modulate the feedback inhibition of the acid
secretory response to gastrin.
• Somatostatin primarily acts by suppressing
gastrin-stimulated release of histamine from
ECL cells.

48. Somatostatin
• Somatostatin secretion is also affected by
neural inputs. It is suppressed by cholinergic
activation and increased by vasoactive
intestinal peptide activation.

49. Acetylcholine

50. Acetylcholine
• Neural input may serve as an important
integrator of secretory function.
• The mucosal nerves, containing acetylcholine,
bombesin, VIP, and PACAP mediate the
response to the cephalic phase of acid
secretion and to gastric distention and amino
acids.
• Acetylcholine is the major stimulatory
mediator.

51. Acetylcholine
• The major effects of muscarinic receptor
activation are to increase gastrin release,
stimulate parietal cells, and inhibit
somatostatin secretion.
• Vasoactive intestinal peptide release has a
dual effect: a weak transient increase in acid
secretion, possibly due to direct effects on ECL
cells; and a sustained reduction due to
enhanced release of somatostatin.

52. Acetylcholine
• Vasoactive intestinal peptide release has a
dual effect: a weak transient increase in acid
secretion, possibly due to direct effects on ECL
cells; and a sustained reduction due to
enhanced release of somatostatin.
• Orexin, nitric oxide, and galanin may also
contribute to the neural regulation of acid
secretion.

53. Components Explained

54. Prostaglandins

55. Prostaglandins
• Prostaglandins are autocrine factors that
inhibit acid secretion, histamine-stimulated
parietal cell function, and gastrin-stimulated
histamine release.
• The effect on gastrin release is less clear as
both inhibitory and stimulatory mechanisms
have been described.
• They are generated from cells in the
epithelium and lamina propria.

56. Prostaglandins
• Macrophages and capillary endothelial cells
appear to be the primary source.
• The mechanisms regulating their release in
vivo are not well-understood.

57. Other Secretory Regulators

58. Other Secretory Regulators
• Transforming growth factor-alpha (TGF-alpha)
is an autocrine factor that is present in
parietal cells and inhibits gastric acid
secretion.
• Peptide YY (PYY) is released postprandially
from cells in the ileum and colon and inhibits
the cephalic and gastric phases of acid
secretion via central and peripheral effects.
• PYY binds to receptors on ECL cells and
inhibits gastrin-stimulated histamine release.

59. Pepsin

60. Pepsin
• Acid plus pepsin is much more ulcerogenic
than acid alone, leaving little question that the
"peptic" label appropriately reflects the
critical role in ulcer formation of the
proteolytic activity in gastric juice.
• The potentiating effect of pepsin may be due
in part to its mucolytic activity.
• Peptic activity is closely linked to acid
secretion and gastric pH.

61. Pepsin
• This relation is partly due to peptic digests of
dietary protein (primarily amino acids), which
are potent stimulants of gastrin release and
acid secretion.
• In addition, pepsinogen is converted to the
active protease pepsin at low gastric pH; on
the other hand, pepsin is inactivated when the
pH is increased above 4.

62. Pepsin
• This pH dependence probably accounts for the
requirement for elevating the intraluminal pH
above 4 to heal refractory ulcers.
• Pepsinogen secretion is enhanced by
acetylcholine and peptides of the CCK/
gastrin family.
• In addition, agents that raise cyclic AMP, such
as secretin and vasoactive intestinal peptide,
increase pepsinogen secretion in vitro.

63. Acid Secretory Regulation
in Human

64. In Human
• Aspiration of gastric contents via a nasogastric
tube is the easiest method of measuring acid
secretion, if collections are complete.
• Basal acid secretion can also be reliably
measured through an endoscope during a 15-
minute collection period.
• Alternatively, intragastric titration allows the
actual level of acid secretion to be measured
by the quantity of base required to hold the
gastric pH at a predetermined level.

65. In Human
• Placement of a gastric pH probe allows
hydrogen ion concentration to be measured
over a 24-hour period, but measuring
hydrogen ion concentration provides only an
indirect indicator of the rate of acid secretion.
• Basal acid output (BAO) is the level of acid
secretion when the subject is unstimulated;
measurements are widely variable among
individuals.

66. In Human
• Physiologic factors enhancing secretion are
vagal activation, food (particularly amino
acids), and gastric distention.
• Histamine release from enterochromaffin-like
(ECL) cells plays a major role since the acid
secretory in response to food, gastrin, and
vagal stimulation is inhibited by H2 receptor
antagonists.
• In contrast, carbohydrates and fat inhibit acid
secretion.

67. In Human
• Intestinal exposure is required for the
carbohydrate effect, but the mechanisms are
uncertain.
• Fat stimulates the release of cholecystokinin
(CCK), which is a potent inhibitor of acid
secretion; fat also releases other potential
mediators and it activates neural responses.

68. Effect Of
Helicobacter Pylori Infection

69. H. Pylori
• Acute H. pylori infection induces a short
period of hypochlorhydria.
• In contrast, chronic infection can lead to
increases in basal and stimulated acid output,
particularly in patients who develop duodenal
ulcer.
• H. pylori eradication reduces basal and
stimulated acid output by 50 percent at one
month, and to normal levels by one year.

70. H. Pylori
• One mechanism by which H. pylori may
enhance gastric acid secretion is via increased
release of gastrin.
• Patients with H. pylori infection have elevated
basal and stimulated concentrations of serum
gastrin, and a decreased concentration of
somatostatin.

71. Gastric Acid Hypersecretion

72. Hypersecretion
• Gastric acid hypersecretion (characterized by a
basal acid output >15 mEq/hour) is observed
in approximately 30 percent of patients with
duodenal ulcers.
• H. pylori infection is a contributing factor, but
some patients have acid hypersecretion
independent of H. pylori.

73. Hypersecretion
• Other uncommon conditions associated with
acid hypersecretion include the Zollinger-
Ellison syndrome (due to a gastrinoma),
mastocytosis, and a retained antrum following
partial gastrectomy.

74. Phr. Asad Kamran
Technical Consultant, MPD
Deurali-Janta Pharmaceuticals Pvt. Ltd.