Role of hydrochloric acid?
1) Hastens breakdown of food via proteolysis
2) Inhibits bacterial proliferation
How does the proton pump work?
- Stored within intracellular tubulovesicles, and is the final common pathway for gastric acid secretion.
- Steps:
1) Parietal cell stimulation
2) Cytoskeletal rearrangement and fusion of tubulovesicles with apical membrane of secretory canaliculus
3) Heterodimer assembly of enzyme subunits into microvilli of secretory canaliculus
4) Acid secretion (H+ is released against a gradient, hence need for mitochondria)
5) K+ and Cl- are simultaneously secreted into apical canaliculi
When are proton pump inhibitor drugs best taken?
Before or during a meal, when the parietal cell is stimulated.
Substances that stimulate the parietal cell to secrete hydrochloric acid?
Stimulate phospholipase C via G-protein-linked mechanism, increase IP3, stimulate calcium release, activate protein kinases and proton pump:
1) Gastrin: Binds to type B cholecystokinin (CCK) receptors
2) Acetylcholine: Binds to M3 muscarinic receptors
Stimulates adenylatecyclase via G-protein linked mechanism, increases intracellular cAMP, activates protein kinases and proton pump:
3) Histamine: Binds to H2 receptor
What is the physiologic stimulus for acid secretion?
Food ingestion
Three phases of acid secretion?
1) Cephalic (vagal)
2) Gastric
3) Intestinal
Describe the cephalic phase.
- Begins with the thought, sight, smell of food.
- Cortical and hypothalamic sites are activated (tractus solitarius, dorsal motor nucleus, dorsal vagal complex).
- Signals are transmitted to the stomach via the vagal nerves.
- Acetylcholine is released.
- ECL and parietal cells are stimulated.
- Cephalic phase accounts for 30% of total acid secretion in response to a meal (shorter than the other two phases).
- SHAM feeding stimulates gastric acid secretion only by this phase.
Describe the gastric phase.
- Begins when food reaches the stomach.
- Accounts for 60% of acid secretion in response to a meal.
- Amino acids and small peptides directly stimulate antral G cells to secrete gastrin.
- Gastrin is carried in the bloodstream to parietal cells and stimulates acid secretion.
- Proximal gastric distention stimulates acid secretion via a vagovagal reflex arc.
- Antral distention stimulates antral gastric secretion.
- Acetylcholine stimulates gastrin release.
- Gastrin stimulates histamine release from ECL cells.
Describe the intestinal phase.
- Begins on gastric emptying of ingested food.
- Continues as long as nutrients remain in proximal small intestine.
- Mediated by hormone from proximal small bowel mucosa in response to luminal chyme.
- 10% of meal-induced acid secretion.
What happens in between meals?
- Interprandial basal acid secretion is 2-5 mEqs HCl per hour.
- 10% of maximal acid output.
- Greater at night.
- Probably contributes to lower bacterial counts in stomach.
- Basal acid secretion is reduced to 75-90% by vagotomy or H2 receptor blockade.
How is gastric acid secretion regulated?
- A large part of acid stimulatory effects of ACh and Gastrin are mediated by histamine from ECL cells.
- Somatostatin from the mucosal D cell inhibits histamine release from ECL cells, and Gastrin release from antral G cells.
How does H. Pylori infection cause hyperacidity?
The function of D cells is inhibited by H. Pylori infection, inhibiting somatostatin, and leading to an exaggerated acid secretory response.
How is pepsinogen secreted?
- Stimulated by food ingestion.
- Acetylcholine is the most important mediator.
- Inhibited by Somatostatin.
- Chief cells: produce pepsinogen I.
- Surface epithelial cells: produce pepsinogen II.
- Pepsinogen is cleaved to active enzyme pepsin in an acidic environment.
Activity of pepsin at varying pH levels?
Maximally active at pH 2.5 (catalyzes hydrolysis of proteins)
Inactive at pH>5 (denatured at alkaline pH)
How is intrinsic factor produced?
Activated parietal cells secrete intrinsic factor. This binds to luminal Vitamin B12, and is absorbed as a complex in the terminal ileum.
What are the components of mucosal defenses in the stomach?
1) Mucous barrier
2) Bicarbonate secretion
3) Epithelial barrier: Hydrophobic phospholipids, tight junctions, restitution
4) Microcirculation/mucosal blood flow
5) Afferent sensory neurons
What are the mediators of mucosal defenses in the stomach?
1) Prostaglandins
2) Nitric oxide
3) Epidermal growth factor
4) Calcitonin gene-related peptide
5) Hepatocyte growth factor
6) Histamine
7) Gastrin-releasing peptide
Physiology of Gastrin.
- Produced by: Antral G cells.
- Most common form: Little gastrin (G17)
- Stimulated by: Peptides and amino acids
- Inhibited by: Luminal acid (via Somatostatin from antral D cells)
- Mediated by: Histamine from ECL cells
- Function: Stimulates acid secretion during the gastric phase.
Physiology of Somatostatin.
Produced by: D cells
Most common form: Somatostatin 14
Stimulated by: Antral acidification
Inhibited by: Acetylcholine from vagal nerve fibers
Functions:
1) Inhibits acid secretion from parietal cells.
2) Inhibits Gastrin release from G cells.
3) Decreases histamine release from ECL cells.
Physiology of Gastrin-releasing peptide.
Functions:
1) Stimulates both Gastrin and somatostatin release by binding to receptors on G and D cells in the antrum.
2) Peripherally, stimulates acid secretion.
3) Centrally, inhibits acid secretion.
4) Mediates gastroprotective increased mucosal blood flow in response to luminal irritants.
Physiology of Leptin.
Synthesized in: Adipocytes & by Chief cells
Function: Decreases food intake via vagally-mediated pathways
Physiology of Ghrelin.
Produced in: Stomach
Function:
1) Secretagogue of pituitary growth hormone
2) Orexigenic regulator of appetite (stimulates appetite when elevated)
Excitatory neurotransmitters in the enteric nervous system.
Acetylcholine
Tachykinins
Substance P
Neurokinin A
Inhibitory neurotransmitters in the enteric nervous system.
Nitric oxide
Vasoactive intestinal peptide
