gastric acid secretion Flashcards
secretion of gastric juice
composition (1.5 litres/day)
- HCl (kills microbes, solubilisation)
- lipase
pepsin
- intrinsic factor (absorption of vitamin B12)
- mucus (protection, lubrication)
mucous cell
nearest stomach lumen
mucus
parietal cells
in between stomach lumen and muscularis mucosae
HCl, intrinsic factor
chief cells
nearest muscularis mucosae
pepsinogen
- which is activated by stomach acid to form pepsin
pH in the stomach lumen compared to pH in parietal cells
pH in stomach is 2
pH in parietal cells is about 7.2
- This means there are 100000 x more potons outside the cell than inside
Large gradient to overcome
HCl secretion
Carbon dioxide and water combine to form carbonic acid
- Carbonic anhydrase breaks that down to form protons and bicarbonate ions
- Those protons are then pumped out of the cell
○ The gradient for this is constructed by potassium ions leaking out of the cell
how does receptor activation change parietal cell structure
-Tubulo vesicles combine with the canalicular membrane and they cause invaginated surface - greatly increasing surface area and this stimulates the proton potassium atpase exchange pump
- also increases the number of pumps in the apical membrane by 6 to 10 fold.
- what that means is that protons can be pumped out into the caciculus, into the canicular fluid
- . And then this drains into the gastric glands.
- So you are greatly increases the surface area for secretion to occur.
phases of control in gastric secretion
3 phases in control
1. cephalic phase
2. gastric phase
3. intestinal phase
cephalic phase of control of gastric secretion
cephalic phase (stimulatory)
-The cephalic phase of gastric secretion is mediated entirely through the vagus nerve.
-sensory stimuli including the sight, smell, and taste of food elicits acid secretion in the stomach
- It exerts its effects through two separate pathways: direct stimulation by acetylcholine and indirect through gastrin.
cephalic phase - direct stimulation by Ach
Parietal cells possess M3 cholinergic receptors that turn on acid secretion.
Stimulation of the vagus excites postganglionic parasympathetic neurons in the stomach, which then release acetylcholine onto parietal cells to stimulate acid secretion.
cephalic phase indirect stimulation by Gastrin
Cephalic efferents in the vagus nerve release gastrin-releasing peptide (GRP) onto G-cells in the pyloric glands and these release gastrin
- stimulate acid secretion by parietal cells
gastric phase of control of gastric secretion
(stimulatory/ inhibitory)
The gastric phase begins once the food arrives in the stomach.
- The gastric phase is stimulated by (1) distension of the stomach, (2) a decrease in the pH of the gastric contents, and (3) the presence of undigested material.
this causes a cascade of events that leads to the release of hydrochloric acid by the parietal cells that lower the pH and break apart the food.
Gastric secretion is stimulated chiefly by three chemicals: acetylcholine (ACh), histamine, and gastrin.
chief cells
secrete pepsinogen
inhibition in gastric phase
local nerves/ vagus -> gastric -> increased protons and decreased pH
decreased pH inhibits gastrin secretion (via somatostatin)
intestinal phase
The intestinal phase occurs in the duodenum as a response to the arriving chyme, and it moderates gastric activity via hormones and nervous reflexes.
Stretching of the duodenum enhances gastric function via the vagal nerve, as the chyme causes the secretion of gastrin
The acid and semi-digested fats in the duodenum trigger the enterogastric reflex: the duodenum sends inhibitory signals to the stomach by way of the enteric nervous system.
The chyme also stimulates enteroendocrine cells of the intestine to release compounds that stimulate the pancreas and gall bladder, while also suppressing gastric secretion and motility to allow the duodenum to process the chyme before receiving more from the stomach.
cellular control - stimulation
- G cells
GRP stimulates gastric cells -> G cells produce gastrin -> gastrin acts on proton pumps on parietal cell
G-cell also stimulated ECL cell in stomach to produce histamine, which stimulates acid secretion
what are ECL cells in stomach
Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric mucosa that control acid secretion by releasing histamine as a paracrine stimulant.
cellular control - stimulation
- nerves of DVC
- ACh stimulates parietal cells
- also stimulate ECL cell in stomach to produce histamine, which stimulates acid secretion
distention of stomach
detected by stretch receptors and
causes vaso-vagal response that enhances H+ secretion
cellular control - inhibition
Acid secretion will act on the D cells
- To cause release of somatostain
○ This will have a direct negative effect on the G cells:
- it will have a negative effect on the ECL cells
- Also will directly inhibit the parietal cells
Secretin, CCK and GIP activate D cells
mucosal protection
- control of H+ secretion essential to protect stomach and duodenum
- When protection fails or there is too much H+ it causes peptic ulcers
mucosal protection by mucus
forms a layer of protection
mucosal protection by HCO3-
protects gastric mucosa from luminal acid by a process of surface neutralization.
stomach = surface epithelium
- duodenum = brunners glands
ulcer
acid/ enzyme damage to stomach or intestinal wall
- complications: GI bleeding, perforation
- perforation is erosion through mucosal layer and is life threatening
how can NSAIDS cause ulcers
Interfere with the prostaglandin production and therefore the protective mechanism
how can smoking cause ulcers
Causes free radicals which will damage the epithelium lining - directly stimulate an increase in acid production - reduce the production of prostaglandins - reduce mucosal blood flow (can cause ischemia in the stomach
how does Zollinger - Ellison syndrome (gastrin secreting tumour) cause ulcers
increase production of acid
helicobacter pylori
a gram-negative bacteria -> inflammation of the stomach lining (50% UK population)
- slow growing in culture so difficult to identify
- not everyone with the infection develops ulcers
- the bacteria is also associated with stomach carcinoma
helicobacter pylori infection
- bacteria able to tolerate low pH of the stomach
- metabolise area - increase local pH with ammonia released
- penetrates mucus and lives attached to epithelial cells - changes structure of mucus
-Ammonia reacts with protons forming ammonium ion which is very toxic - inflammation in the antrum impairs somatostatin release = increased gastrin -> increased acid secretion
treatment of ulcers
- vagotomy = decreased vagal stimulation
- histamine receptor antagonists - block histamine receptors and reduce stimulation of parietal cells
- H+/K+ ATPase (proton pump) inhibitors
- antibiotics to kill H.pylori
H2 antagonists
- identified by design, i.e compounds with structural motives similar to histamine
- Benefit of these drugs - some of them are capable of raising the stomach pH up to greater than 3 - huge benefit to protecting the stomach - protection can last up to 10 hours
- these work in humans because human histamine is the predominant modulator of acid secretion
example H2 antagonist drugs
- cimetidine
- ranitidine - longer acting
potential anti ulcer drug targets
- muscarin receptors = side effects
- gastric receptors = no success
- ion channels and transporters
proton pump inhibitors - omeprazole
- lipid soluble, weak base - enters and accumulates in acid spaces
- activated in acid - chemically altered by H+ to an active sulphenamide form
- IC50 = 50nM
- forms irreversible S-S bond with H+/k+ ATPase
mechanism of omeprazole
given in encoated formulation to avoid breakdown by stomach acid
- it is absorbed in the small intestine and travels to parietal cells in the blood
triple therapy - eradicate H.pylori
2 antibiotics
- proton pump inhibitor
- bismuth compounds
why PPI and bismuth for treatment
H. pylori tolerates acid pH but only grows quickly at pH 6-8
- antibiotics work best on dividing bacteria
- PPI raises ambient pH; Bi2+ slows further acidification of bacterial interior
- so PPI and Bi 2+ enhance antibiotic action
potassium competitive acid blockers
- new class of proton pump inhibitor
- superior performance to PPIs
- elevate ambient pH more rapidly and for longer periods
- may further enhance antibiotic action
- e.g. tegoprazan, vonoprazan
NSAIDs and Ulcers
- NSAIDs inhibit COX1 = decrease PGE2 in the mucose of stomach and duodenum
- normal actions of PGE2:
- stomach = decreased protons from parietal cells
- stomach and duodenum = increased mucosal protection
so NSAIDs = increase proton and decrease protection
