Secretions of GI Tract and Pancreas (Lopez) Flashcards
What are the functions of saliva?
- initial digestion of starches and lipids
- dilution and buffering of ingested foods
- lubrication of ingested food w/ mucus
What are the 3 major salivary glands and their function?
- parotid glands: composed of serous cells; secrete fluids composed of water, ions, and enzymes (rich in amylase); secrete 25% of daily output of saliva
- submaxillary and sublingual glands (mixed glands): composed of serous and mucus cells; secrete aqueous fluid and mucin glycoprotein for lubrication; secrete 75% of daily saliva output
What is the structure of salivary glands?
- acinus (blind end): acinar cells secrete initial saliva
- myoepithelial cells: have motile extensions, when stimulated by neural input they contract to eject saliva into mouth
- intercalated duct: saliva in ID is similar in ionic composition to plasma
- striated duct: lined by columnar epithelial cells (ductal cells); ductal cells modify the initial saliva to prod final saliva (hypotonic); ductal cells alter conc of various electrolytes
What is the composition of saliva?
- composed of H2O, electrolytes, α-amylase, lingual lipase, kallikrein, and mucus
- hypotonic compared to plasma: higher level of K+ and HCO3- conc; lower level of Na+ and Cl- conc
What is the mechanism of salivary secretion?
two main steps:
1) formation of isotonic plasma-like solution by acinar cells
2) modification of isotonic solution by ductal cells
How does saliva become hypotonic as it flows through the ducts?
- transport mechanisms results in combined action of absorption of Na+ and Cl- and secretion of K+ and HCO3-
- there is net absorption of solute (more NaCl is absorbed than KHCO3 secretion)
- ductal cells are H2O impermeable, meaning solutes can flow via transport mechanisms without osmosis occuring and changing the intended solute conc
What are the transport mechanisms on the lumen (apical side) and blood (basolateral side) of the salivary ductal cell?
- lumen (apical side): Na+/H+ exchange, Cl-/HCO3- exchange, H+/K+ exchange (HCO3- leaves the cell via cAMP-activated CFTR Cl- channel (not shown) or via the Cl-/HCO3- exchanger)
- blood (basolateral side): Na+/K+ ATPase, Cl- channels
What is the innervation to the salivary glands?
- parasympathetic: presynaptic nerves originate at facial and glossopharyngeal nerves, postsynaptic fibers in autonomic ganglia innervate individual glands
- sympathetic: preganglionic nerves originate at cervical ganglion, who postganglionic fibers extend to glands in the periarterial spaces
How is salivary secretion regulated and what factors influence regulation?
- regulation of salivary secretion is by the ANS
- (+) conditioning, food, nausea, smell
- (-) dehydration, fear, sleep
- parasympathetic: both activators and inhibitors of salivary secretion influence the parasympathetic NS (these effects dominate);
regulated via CN VII and CN IX > ACh released > atropine inhibits mAChR > mAChR activates IP3 which increases Ca2+ (within acinar or ductal cells) > saliva
- sympathetic: regulated by nerves from T1-3 > NE released > activates βAR > activates cAMP (within acinar or ductal cells) > saliva
- stimulation of salivary cells results in: increased saliva prod, increased HCO3- and enzyme secretions, and contraction of myoepithelial cells
What are the 2 unique features in regulation of salivary secretion?
- salivary regulation is exclusively under the control by ANS
- salivary secretion is increased by both parasympathetic and sympathetic stimulation: generally, PSNS and SNS have opposite actions (but not in this case)
What is the main composition of gastric juice (secreted by gastric mucosa)?
- HCl (H+): w/ pepsin, initiates protein digestion; necessary for conversion of pepsinogen to pepsin; kills large number of bacteria that enter stomach
- pepsinogen: inactive precursor
- mucus: lines the wall of the stomach and protects it from damage; lubricant; w/ HCO3-, neutralizes acid and maintains surface of mucosa at neutral pH
- intrinsic factor: required for absorption of vit B12 in ileum
- H2O: medium for action of HCl and enzymes; solubilizes much of ingested material
What are the divisions of gastric mucosa?
- oxyntic gland: located in proximal 80% of stomach (body and fundus), secretes acid
- pyloric gland: located in distal 20% of stomach (antrum), synthesizes and releases gastrin
Which cells of gastric mucosa secrete each component of gastric juice?
- parietal cells: intrinsic factor and HCl
- chief cells: pepsinogen
- G cells: gastrin (to circulation)
- mucus cells: mucus, HCO3-, pepsinogen
- major function of these cells is to secrete HCl
- the number of these cells determine the maximal secretory rate
- function of low gastric pH (1-2) is to convert pepsinogen to pepsin
- HCl is formed at the villus-like membranes of the canaliculi
parietal cells
What is the mechanism of HCl secretion by gastric parietal cells?
(on basolateral side):
- K+ brought into cell via Na+/K+ ATPase
- HCO3- exchanged for Cl- and absorbed into blood (“alkaline tide”)
(within parietal cell, reversible reaction):
- CO2 + H20 converted to H2CO3 by carbonic anhydrase
- H2CO3 converted to H+ and HCO3-
(on apical side):
- H+ exchanged for K+ and secreted (inhibited by Omeprazole)
- Cl- follows H+ and combines to form HCl
result:
- net secretion of HCl and net absorption of HCO3-
What is the two-component model of gastric secretion?
gastric juice can be seen as a mixture of 2 separate secretions:
- non-parietal: basal alkaline secretion of constant and low volume; primary constituents are Na+ and Cl-, K+ is present at same conc as plasma; HCO3- is secreted at conc of ~30 mEg/L
- parietal: slightly hyperosmotic; contains 150-160 mEq H+/L and 10-20 mEq K+/L; Cl- is the only anion present; as secretion rate increases, the conc of electrolytes begin to approach those of pure parietal cell secretion
What factors regulate H+ secretion by gastric parietal cells?
- vagus n. > ACh release (inhibited by Atropine) > M3 receptor > Gq > IP3/Ca2+ > (+) H+/K+ ATPase > (+) H+ secretion
- G cells (inhibited by somatostatin) > gastrin > CCKB receptor > Gq > IP3/Ca2+ > (+) H+/K+ ATPase > (+) H+ secretion
- ECL cells > histamine (inhibited by Cimetidine) > H2 receptor > Gs > activates cAMP > (+) H+/K+ ATPase > (+) H+ secretion
(ECL cells: activated by ACh and gastrin; inhibited by prostaglandins and somatostatin)
- D cells > somatostatin > ? receptor > Gi > inhibits cAMP > (-) H+ secretion
- prostaglandins > ? receptor > Gi > inhibits cAMP > (-) H+ secretion
- H+ secretion inhibted by Omeprazole
*there is a passive feedback mechanism regulating HCl secretion: as pH falls, gastrin release is inhibited which decrease HCl secretion*
Describe the role of the vagus n. in HCl secretion from parietal cells:
role of vagus n. is twofold:
1) direct pathway: vagus n. stimulates release of ACh (inhibited by Atropine) > ACh activates parietal cells to release HCl
2) indirect pathway: vagus n. stimulates release of GRP > activates G cells to produce gastrin > gastrin enters circulation > acts on parietal cells to release HCl
(atropine will not block vagal effects on gastrin secretion within indirect pathway bc the NT at the synapse on G cells is GRP)
Describe the regulation of gastrin release:
- somatostatin acts on G cells to inhibit gastrin release
- vagal activation stimulates gastrin release by releasing GRP and inhibiting release of somatostatin
- negative feedback by gastrin: gastrin itself increases somatostatin
- H+ in gastric lumen stimulates release of somatostatin (indirect inhibition)
What is the role of histamines, ACh, and gastrins in the secretion of HCl and what are pharmacological implications of this?
- potentiation: combined reponse to 2 stimulants exceeds sum of individual responses; requires the presence of separate receptors on target cell for each stimulant
- example: histamine potentiates actions of ACh and gastrin; ACh potentiates actions of histamine and gastrin
- pharmacological implications: antagonists of H2 receptors (e.g. Cimetidine) block direct action of histamine and also block potentiated effects of ACh and gastrin; antagonist of mAChRs (e.g. Atropine) block direct effects of ACh and ACh-potentiated effects of histamine and gastrin
- anatagonist of H2 receptors (histamine receptors)
- used to treat duodenal and gastric ulcers, and GERD
Cimetidine
What are the 3 phases of gastric HCl secretion?
- cephalic phase via vagus: parasympathetics excite pepsin and acid prod
- gastric phase: 1) local nervous secretory reflexes, 2) vagal reflexes, 3) gastrin-histamine stimulation; products enter circulation
- intestinal phase: 1) nervous mechanisms, 2) hormonal mechanisms
What are highlights of mechanism for stimulating HCl secretion per phase?
Describe the stimuli and mechanisms for gastric phase:
- accounts for ~60% of total HCl secretion in response to meal
- stimuli: distension of stomach; presence of breakdown of proteins, AA’s, and small peptides
- mechanisms (4):
- distension (activates mechnoreceptors in mucosa of oxyntic and pyloric glands): activates direct and indirect pathways of vagus n.
- distension of antrum: local reflexes > ACh > parietal cell and G cell
- amino acids and small peptides: gastrin > parietal cell
*coffee (caff and decaff) also stimulate gastric HCl secretion*
When is pepsinogen secreted?
- pepsinogen is secreted only when gastric pH is acidic enough to convert it to pepsin
- secreted by chief cells and mucus cells in oxyntic glands (req H+ secretion from parietal cells to lower pH of gastric contents, pH < 5)
- vagus n. stim is most important stim for pepsinogen secretion
- H+ triggers local cholinergic reflexes that also stim chief cells to secrete pepsinogen
What is the role of pepsin in the GI tract?
- degrades food proteins into peptides
- also converts more pepsinogen to pepsin
- it is a proteolytic enzyme (splits interior peptide linkages)
- optimal pH is between 1.8-3.5
- reversibly inactivated at > pH 3.5-5.0
- irreversibly inactivated > pH 7-8
What is the role of intrinsic factor (IF) in the GI tract?
- required for absorption of vit B12 in the ileum
- IF is a mucoprotein secreted by parietal cells and binds to vit B12
- only secretion by the stomach that is required (essential)
- failure to secrete IF is a/w achlorhydria and absence of parietal cells
- condition where stomach does not prod/secrete enough IF, which decreases vit B12 absorption
- development of this condition is not completely understood, it is difficult to study bc liver stores enough vit B12 to last for several years
- common causes: atrophic gastritis (chronic inflammation of stomach mucosa that leads to loss of parietal cells); autoimmune metaplastic atrophic gastritis (immune system attacks IF protein or gastric parietal cells)
pernicious anemia
What surgical procedures involving the stomach could disrupt the absorption of vitamin B12?
- gastrectomy: loss of parietal cells (source of IF)
- gastric bypass: exclusion of the stomach, duodenum, and proximal jejunum alters absorption of vit B12
How is the gastric mucosa protected from HCl and pepsin, and what factors specifically protect and damage it?
- gastric epithelium secretes HCO3- and mucus to form gel-like mucosal barrier (mucous cells secrete mucus and surface epithelial cells secrete HCO3-)
- mucosal barrier protects gastric mucosal epithelium from HCl and pepsin
- protection: HCO3-/mucus, prostaglandins (e.g. Misoprostol), mucosal blood flow, gastrin, and growth factors
- damage: acid, pepsin, NSAIDs (e.g. aspirin), Helicobacter pylori, bile, alcohol, smoking, and stress
What is the secretin stimulation test and what does it test?
- secretin is used in dx of gastrin-secreting tumors
- under nml conditions, secretin administration inhibits gastrin release
- in gastrinomas, injection of secretin causes paradoxical increase in gastrin release (basis for secretin stimulation test)
What is the underlying etiology of pathogenesis of H. pylori?
- H. pylori is major acquired factor in origin of both gastric and duodenal ulcers
- releases cytotoxins that breakdown mucosal barrier and underlying cells
- enzyme urease allows bacteria to colonize gastric mucosa
- urease converts urea to ammonia (NH3), which alkalinizes local environment
- resulting prod of ammonium (NH4+) believed to be major cause of cytotoxicity, damages epithelial cells and breaks mucosal barrier
- diagnostic test is based on urease activity
Summary of disorders of gastric H+ secretion:
What is the composition and function of pancreatic secretions?
- contains HCO3- for neutralization of H+ from stomach
- contains enzyme secretions to digest carbs, proteins, and lipids into absorbable molecules
What is the organization of the pancreas?
organized like salivary glands
- acinus: acinar cells synthesize and secrete major enzymes for digestion
- ducts: lined by ductal epithelial cells; extend to the region in the acinus containing centroacinar cells; ductal and centroacinar cells secrete aqueous solution containing HCO3-
Describe the specifics of the 2 components of pancreatic secretions:
- enzymatic secretion by acinar cells: pancreatic amylases and lipases are secreted as active enzymes; proteases are secreted in inactive forms and converted to active forms in lumen of duodenum
- aqueous secretion by centroacinar and ductal cells: secrete HCO3- rich fluid that alkalinizes/hydrates protein-rich primary secretions of acinar cell; initial secretion is modified by transport processes in ductal epithelial cells (net result is secretion of HCO3- into pancreatic ductal juice and net absorption of H+)
What is the role of the pancreas in cystic fibrosis?
- mutations in the cystic fibrosis transmembrane conductance regulator (CFTR: regulated Cl- channel in the apical surface of the duct cell)
- in CF, pancreas is one of the 1st organs to fail
- some CFTR mutations seem to be a/w loss of HCO3- secretion (ability to flush active enzymes out of duct may be lost, may lead to recurrent acute and chronic pancreatitis)
What is the regulation of pancreatic secretions?
- CCK induces release of pancreatic enzymes into duodenal lumen
- secretin induces secretion of HCO3- from pancreatic cells into duodenum
What is the regulation of pancreatic secretions during the intestinal phase?
- phenylalanine, methionine, tryptophan, small peptides, and fatty acids stimulate I cells to produce CCK
- ACh potentiates acinar cells production of IP3, Ca2+
- the above increase prod of enzymes
- H+ stimulates S cells to produce secretin
- ACh, CCK potentiate ductal cell production of cAMP
- the above increase aqueous secretion (Na+, HCO3-)
