Physiology of Acid Secretion

· Storage – 80% of food is stored in the proximal stomach (the gut works slowly) · Mechanical disruption – grinds/churns food · Digestion – acid, pepsin · Bactericidal barrier · Exocrine, paracrine, & endocrine secretions

Answer: Intrinsic Factor (For vitamin B12)

In gastric pits. Fuse tubovesicles together to form intercellular canaliculi in active state to increase surace area for acid secretion (takes about 10 min to go from resting to active stage - major cell remodeling)

Low flow rates: High Na+, high Cl- (at night, for example) – secretion comes from surface epithelium cells Max flow rates: almost entirely HCl (surface epithelium doesn’t stop secreting Na+, but the parietal cells are secreting so much HCl that it dilutes out the Na+) At very high secretion rates, individuals may produce 6-40 ml/h of HCl at a conc. of 0.1-0.2 M. At these rates, gastric juice tends to become isotonic w/ plasma – aqueous component contains little or no HCO3 to buffer HCl so pH can be pushed to 0.8 –1

1:1 exchange of H & K (H/K ATPase – this is the pump that’s inhibited by drugs like Omeprazole & PPIs) – active transporter; move H against a gradient so need ATP. For it to work, need the following: - Must have a K channel to let K out of cell b/c you are exchanging a K in the ATPase (K cycles futilely b/t the pump & channel) - H can’t exist by itself, needs Chloride for electroneutrality: Cl channel – Cl- leaves cell down its gradient in lumen of stomach. How can cell do this? Cell stuffed full of carbonic anhydrase which gives you bicarbonate from CO2 & water). Bicarbonate gets thrown out and Cl- comes in (exchange bicarb for Cl- on basolateral membrane = “alkaline tide” right where the pump is working hard) - Always have a Na/K pump in the basolateral membrane & a K leak channel - Also, have a Na/H exchanger to “mop up” any leftover H+ that’s inside the cell & get it out of the cell

Gastrin (CCK-B) ACh (M3 muscarinic receptor)

Histamine (H2)

All three hormones (gastrin, ACh, histamine) work to initiate remodeling through the canaliculi (and release of H through getting the H/K ATPase up to the membrane) - Gastrin & ACh both coupled to PLC --> IP3 --> increase intracellular calcium (released from ER) - Histamine - released from from ECL (enterochromaffin-like) cells & binds to H2 receptor (Ranitadine blocks these) à activates Gs à activates AC (?) à increase in cAMP à increase in PKA phosphorylation

Somatostatin Prostaglandins

Food is like a "buffer". Eating increases volume in stomach (distention) - also proton conc. drops & pH increases --> triggers acid secretion At 1 hr post-eating, stomach begins to empy & amount of buffers decreases. Proton secretion continues to rise. 3 hrs. post-eating, stomach is really empyting; acid secretion statrs to decrease

Process: Input from Vagus à ACh à acts on postganglionic neuronàcauses release of GRP (gastrin-releasing peptide) à G cell releases gastrin (hormone) that goes into the blood & finds its targets. Small peptides & AAs can also trigger G-cells Negative Feeback: At the same time (all happening in the antrum) – vagus causes an inhibitory neuron to secrete ACh to keep the somatostatin-secreting cell quiet. When pH gets below 3 the SS cell is triggered to “go next-door” and stop G cell production of gastrin (PARACRINE RELATIONSHIP). D cells work in close contact w/ ECL cells to release somatostatin when pH gets too low and in response to gastrin

· Oxyntic gland (aka gastric glands) are stimulated by pH<3 to release somatostatin · Antrum stimulated by pH<3 to release somatostatin · Duodenum stimulated by acid & hyperosmotic solutions to release secretin · Duodenum & Jejunum stimulated by fatty acids to release GIP

Protects against auto-digestion

Loosely adherent layer (lower HCO3 conc. than the firmly adherent layer) & firmly adherent layer

The glycoproteins are important in trapping bicarbonate to prevent back-diffusing acid. Surface epithelial cells (visible) & mucous neck cells (soluble) secrete mucins & HCO3 (bicarb) that form a mucus layer coating the stomach – in response to vagal efferent nerves. This alkaline mucus layer acts as a protective barrier (keeps pH of mucosa at 7) to gastric acid & pepsin.