Mechanism of secretion of gastric juice
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Mechanism of Secretion of Gastric Juice
Overview of Gastric Juice Composition
Gastric juice has four major components secreted by specialized cells in the gastric mucosa:
| Component | Secreting Cell | Location |
|---|---|---|
| HCl | Parietal (oxyntic) cells | Fundus/body (oxyntic glands) |
| Pepsinogen | Chief (peptic) cells | Fundus/body (oxyntic glands) |
| Intrinsic factor | Parietal cells | Fundus/body |
| Mucus + HCO3- | Mucous neck cells, surface epithelium | Throughout stomach |
| Gastrin | G cells | Antrum (pyloric glands) |
In the fasting state, the pH of gastric juice is approximately 3.0, and it contains Na+, K+, Mg2+, H+, Cl-, and HPO4 2-. When maximally stimulated, the H+ concentration reaches ~160 mmol/L with a pH of ~0.8 - approximately 3 million times the H+ concentration of arterial blood.
- Costanzo Physiology 7th Edition, p. 365; Ganong's Review of Medical Physiology, 26th Edition, p. 460
Structure of the Gastric (Oxyntic) Gland
Gastric (oxyntic) gland - Guyton and Hall
The oxyntic glands occupy the fundus and body (proximal 80%). Each gland opens into a gastric pit and contains:
- Mucous neck cells - secrete mucus
- Parietal (oxyntic) cells - secrete HCl and intrinsic factor; contain large branching intracellular canaliculi
- Chief (peptic) cells - secrete pepsinogen
- ECL (enterochromaffin-like) cells - secrete histamine
1. Cellular Mechanism of HCl Secretion (Parietal Cells)
This is the most energy-intensive secretion in the body, requiring >1500 calories per liter of gastric juice.
Mechanism of HCl secretion - Costanzo Physiology 7th Edition, Fig. 8.17
The steps are:
Step 1 - CO2 hydration inside the cell:
CO2 (from cellular metabolism or blood) + H2O → H2CO3, catalyzed by carbonic anhydrase inside the parietal cell. H2CO3 immediately dissociates into H+ and HCO3-.
Step 2 - H+ secretion at the apical (luminal) membrane:
H+ is actively pumped into the lumen via H+-K+ ATPase (the proton pump), in exchange for K+. This is a primary active transport mechanism working against a massive electrochemical gradient. K+ that leaks into the lumen via this pump is recycled back into the cell by the same H+-K+ ATPase. Cl- follows H+ passively through Cl- channels in the apical membrane - together forming HCl in the lumen.
Step 3 - HCO3- removal at the basolateral membrane:
HCO3- generated inside the cell is transported out into the blood via a Cl-/HCO3- exchanger on the basolateral membrane. This is responsible for the "alkaline tide" - gastric venous blood has a higher pH than arterial blood after a meal. The Cl- taken up by this exchanger is recycled to the apical side for HCl secretion.
Step 4 - Basolateral Na+-K+ ATPase:
Maintains low intracellular Na+, which drives Na+ reabsorption from the canalicular lumen, leaving H+ and Cl- behind.
Step 5 - Water:
H2O follows by osmosis into the canaliculus.
Final secretion: ~150-160 mEq/L HCl, 15 mEq/L KCl, small amount of NaCl.
Postulated mechanism of HCl secretion - Guyton and Hall Medical Physiology, Fig. 65.6
Key drug target: H+-K+ ATPase is inhibited by omeprazole (proton pump inhibitors), used clinically to reduce acid secretion. Cimetidine blocks H2 receptors.
- Guyton and Hall Medical Physiology, p. 802; Costanzo Physiology 7th Edition, p. 366
2. Mechanism of Pepsinogen Secretion and Activation
Chief cells secrete pepsinogen (inactive zymogen, MW ~42,500) by exocytosis, stimulated by ACh and gastrin. When pepsinogen contacts HCl in the lumen, it undergoes autocatalytic cleavage to form pepsin (MW ~35,000) - an active protease that initiates protein digestion. Pepsin itself can also activate further pepsinogen (autocatalytic). Pepsin is active at pH 1.8-3.5 and is inactivated at pH >5.
- Guyton and Hall Medical Physiology, p. 802-803
3. Regulation of Gastric Secretion - Three Stimulants
Three principal substances stimulate H+ secretion from parietal cells, each via a distinct receptor and second messenger:
Agents stimulating and inhibiting gastric H+ secretion - Costanzo Physiology 7th Edition, Fig. 8.18
A. Histamine (Paracrine)
- Released by ECL cells in the gastric mucosa
- Binds H2 receptors on parietal cells
- Second messenger: cAMP (via Gs protein → adenylyl cyclase → cAMP → protein kinase A)
- Blocked by: cimetidine (H2 blocker)
B. Acetylcholine (Neurocrine)
- Released by vagus nerve endings in the gastric mucosa
- Binds muscarinic M3 receptors on parietal cells
- Second messenger: IP3/Ca2+ (via Gq → phospholipase C → IP3 → intracellular Ca2+ release)
- Also stimulates peptic cells (pepsinogen) and mucous cells (mucus)
- Blocked by: atropine
- ACh also indirectly stimulates HCl secretion by causing histamine release from ECL cells
C. Gastrin (Endocrine/Hormone)
- Released by G cells in the stomach antrum into the bloodstream (endocrine, not paracrine)
- Binds CCK-B receptors on parietal cells
- Second messenger: IP3/Ca2+ (same pathway as ACh)
- Stimuli for gastrin release: stomach distention, luminal oligopeptides/amino acids, vagal stimulation (via GRP - gastrin-releasing peptide)
- Gastrin also acts on ECL cells to release histamine (indirect H+ stimulation)
Potentiation: The three stimulants potentiate each other's effects - their combined response exceeds the sum of individual responses. This explains why H2 blockers (cimetidine) have a greater-than-expected effect by blocking both direct histamine action AND the indirect histamine-mediated potentiation of ACh and gastrin.
- Costanzo Physiology 7th Edition, pp. 366-368
4. Inhibitors of Gastric Secretion
| Inhibitor | Source | Mechanism |
|---|---|---|
| Somatostatin | D cells (antrum/fundus) | Binds Gi protein → inhibits adenylyl cyclase → lowers cAMP; also inhibits gastrin release from G cells and histamine from ECL cells |
| Prostaglandins (PGE2) | Gastric mucosa | Bind Gi protein on parietal cells → reduce cAMP |
| Low luminal pH (<3) | Feedback | Stimulates somatostatin release from D cells → inhibits G cells (negative feedback loop) |
| GIP, secretin | Duodenum | Inhibit gastrin release during intestinal phase |
- Costanzo Physiology 7th Edition, p. 368; Ganong's Review, p. 461
5. Phases of Gastric Secretion
Cephalic Phase (~30% of total)
- Triggered by sight, smell, taste, and thought of food
- Mediated entirely by vagus nerve (CN X)
- Vagal outflow releases ACh and GRP → stimulates parietal cells directly (via M3) and G cells (via GRP → gastrin release)
- Can be abolished by vagotomy or atropine
Gastric Phase (~60% of total) - quantitatively most important
- Triggered once food enters the stomach
- Stimuli: stomach distention (activates stretch receptors → vago-vagal and local myenteric reflexes) + luminal peptides/amino acids (directly stimulate G cells to release gastrin)
- Food buffers gastric acidity, removing the feedback inhibition and allowing more secretion
- Results in large-volume acid secretion
Intestinal Phase (~10% of total)
- Triggered as chyme enters the duodenum
- Initially brief stimulation by amino acids absorbed from duodenum
- Quickly dominated by inhibition: secretin (released by acid in duodenum), GIP, CCK, and the enterogastric reflex all suppress gastric secretion as acid enters the intestine
- Ganong's Review of Medical Physiology 26th Edition, pp. 460-461; Guyton and Hall, p. 803
6. Mucus-Bicarbonate Barrier (Cytoprotection)
Surface epithelial cells and mucous neck cells secrete an alkaline mucus gel containing HCO3-. This layer:
- Maintains a pH gradient from ~2.0 at the lumen surface to ~7.0 at the cell surface
- Prevents autodigestion of the mucosa
- Also contains trefoil peptides that stabilize the mucus-HCO3- layer
Damage to this barrier (by aspirin, alcohol, NSAIDs, H. pylori) allows acid backdiffusion into the mucosa, causing peptic ulcer disease.
- Guyton and Hall Medical Physiology, p. 803; Ganong's Review, p. 460
Summary Flowchart
Stimuli (cephalic/gastric/intestinal)
↓
Vagus (ACh) + G cells (Gastrin) + ECL cells (Histamine)
↓
Parietal cell receptors (M3, CCK-B, H2)
↓
Second messengers (IP3/Ca2+ or cAMP)
↓
H⁺-K⁺ ATPase activation (apical membrane)
↓
H⁺ secreted into lumen + Cl⁻ follows = HCl
↓
HCO₃⁻ exits into blood (alkaline tide)
Inhibition: Somatostatin, prostaglandins, low pH feedback → reduce H+-K+ ATPase activity.
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