Johnson - Physiology Flashcards
What are the four functions of the GI tract?
- Motility: inner layer of circular muscle (contracted = lumen shrinks) + outer layer of longitudinal muscle (contracted = lumen expands)
- Secretion
- Digestion: chemical breakdown of food products
- Absorption: primarily in upper part of small intestine; almost all nutrients absorbed by the time contents leave the jejunum
What is the enteric nervous system?
- Local or intrinsic reflexes
- Info received from the local microenvironment, and can relay this up and down the gut
- Signal that NEVER leaves the GI tract
Why is the barrier function so important in the GI tract?
- Because the inside of the GI tract is essentially “outside” the body
What cell layer varies most in the GI tract?
Epithelium
Describe the integration of the PARA and SYM nervous systems in the GI tract.
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PARA: Vagus N covers mouth through transverse colon + Pelvic N in the remainder of the colon
1. 75% of fibers in Vagus N are afferent: vago-vagal reflex
2. Primarily stimulatory via Ach (nicotinic in myenteric and muscarinic in submucosa) -
SYM: innervates muscle, blood vessels, mucosal cells, and both the myenteric/submucosal plexuses
1. Mostly INH, i.e., constricting of blood vessels, INH gastric secretion - NOTE: enteric nervous system also critical
What are the 3 ways in which peptides are delivered to their targets in the GI tract?
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Hormones: released into interstitial space, blood, liver, heart, then distributed throughout the body; specificity determined by RECEPTORS
1. EX: gastrin, secretin, CCK, GIP, motilin -
Paracrine: specificity via receptors AND location
1. EX: somatostatin, histamine (NOT a peptide) - Neurocrine: ex. is Ach release into synaptic cleft in response to action potential
What is a physiologic effect?
- One that occurs with a dosed hormone that does not raise blood levels more than what occurs during a meal
How are gastrin and CCK related structurally?
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Gastrin: 17-AA peptide whose 4 terminal AA’s make up its active center (primary receptor: CCK-1)
1. Pyroglutamyl and NH2 on the C-terminals prevent deactivation in the liver
2. Most gastrin comes from antrum of the stomach during a meal, and is G17; in fasting, G34 is released from the duodenum - CCK: 33-AA peptide with same 5-AA C-terminus as gastrin -> must have sulfated tyrosyl at position 7 for CCK action (gastrin action if de-sulfated: CCK-1)
- Differences in activity depend on whether tyrosine is in 6th of 7th position from C-terminus + whether or not it is sulfated -> CCK-2 activity > CCK-1 only if 7th AA is a sulfated tyrosyl
How does desulfation affect strength of contraction of the gallbladder via CCK?
- Desulfated CCK does NOT cause gallbladder contraction, even at 4x physiologic level
- Will only cause small contraction, even at a pharmacologic concentration (40x physiologic)
Which peptides are related to secretin?
- VIP
- GIP
- Glucagon
- NOTE: secretin has NO minimal fragment activity; occurs as an alpha-helix, so all AA’s needed for tertiary, active form of the hormone
Where are hormones released from GI endocrine cells?
- From the BASOLATERAL MEMBRANE: hormone-containing granules at the basal surface of the cell in the attached image
1. Released into the INTERSTITIAL SPACE, not the lumen - Note the microvilli in contact with the lumen of the gut
How are the hormones distributed along the GI tract (image)? Why is this important?
- Not in discreet glands, but in cells scattered over various areas of the gut, allowing them to sample what is happening over a wide area, and respond
- Enclosed black areas: hormone there, but mostly NOT released there
1. Acid rapidly neutralized when it reaches the gut, so secretin is hardly ever released there, for example
What are the stimuli for release of each of the 5 GI hormones (table)?
- Gastrin: distention (vago-vagal and enteric), nerve, protein (INH by pH<3.5)
- CCK: fat, protein
- Secretin: acid (pH<4.5)
- GIP: protein, fat, carb (primarily carbs)
- Motilin: nerve
What are the important actions of the 5 GI hormones (image)?
- Gastrin: acid secretion, mucosal growth
- CCK: gallbladder contraction, panc enzyme secretion, potentiates panc bicarb release (by secretin), panc growth, INH gastric emptying
- Secretin: pancreatic and gallbladder bicarb release, panc growth, INH acid secretion
- GIP: insulin release, INH acid secretion
- Motilin: gastric + intestinal motility
Where are the 3 GI neurocrines released? What do they do?
- VIP: vasodilation of blood vessels via stimulation of NO synthesis (panc effect probably pharmacologic)
- GRP: vagal mediator for release of gastrin (NOT Ach); can’t INH Vagal gastrin release w/atropine
- Enkephalins (Met- and Leu-): stimulate opioid receptors, and do opposite of VIP -> probably interact with VIP physiologically to cause peristalsis (drug forms INH diarrhea)
What are the actions of the GI paracrines? Where and how are they released?
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Somatostatin: probably INH all peptide hormone release in the body
1. INH parietal secretion of acid (located close to parietal cells) and gastrin
2. May regulate interplay between insulin and glucagon (INH both) - REMEMBER: these substances are PARACRINE, so they need to be near the things they are affecting
What 2 endocrine cell tumors are caused by the over-production of GI peptides?
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Gastrinoma: tumor in pancreas OR duodenum, so NO CONTROL of release of gastrin -> normally, these tumors don’t grow rapidly, and they do fine
1. Steatorrhea: fat in the stool
2. Treated pharmacologically for the most part: INH of H-K ATPase (i.e., Omeprazole, a PPI); can prevent all acid secretion - Pancreatic cholera: VIP -> pancreatic and intestinal secretion; losing bicarb in the stool
Where is there smooth muscle in the GI tract? What are 2 unique features of this muscle?
- GI tract is all smooth muscle except upper 2/3rds of the esophagus and the external anal sphincter
- Very few cells actually innervated, so muscle can contract as a unit -> functionally coupled system via nexi
- Phasic contractions vs. tonic contractions: UES, and other sphincters -> myogenic property of the smooth mm themselves that they can remain contracted for long periods of time
Describe the chewing/swallowing reflex.
- Food in mouth INH muscles of mastication and jaw drops
- Mixes food with saliva so it is easily passed, and INC surface area, making it available for digestive enzymes
- Have to have at least something in there to begin swallowing reflex, i.e., saliva
Describe the resting and swallowing pressures in the esophagus. What are primary and secondary peristalsis?
- 2,3,4 at (-) pressure b/c they are in the thorax, which has a (-) pressure -> pressure DEC on inhalation, and INC on exhalation
- (+) pressure when you get past the diaphragm; INC in pressure when you breathe in, rather than the DEC seen above
- When bolus reaches diaphragm, the LES relaxes; LES important because it prevents acid reflux
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Primary peristalsis: initiated by a swallow
1. Secondary: if something becomes stuck in the esophagus, it will contract above and relax below, starting new peristaltic wave
What sphincter in the GI tract is anatomically identifiable?
Upper esophageal sphincter (UES)
How is the Vagal N involved in swallowing?
- Vagus N directly innervates skeletal muscle in the upper 1/3rd of the esophagus, but innervates NN in myenteric plexus in the lower parts of the esophagus
- Following a vagotomy, peristalsis is interrupted in the striated muscle, but it can continue in the smooth muscle
What is GERD? Tx? Causes?
- Acid reflux, heartburn
1. Normal for some amt of GER to occur, but it is cleared by 2o peristalsis - Treated by INH acid secretion -> PPI’s, i.e., Omeprazole (1 pill can last 24 hours)
- Casuses: hiatal hernia, pregnancy, failure of 2o peristalsis
What are the 2 areas of the stomach? What is unique about the muscle here? 1o function?
- Oxyntic (parietal cell) area and pyloric (G-cell) area
- Only part of the GI tract with an oblique layer (goes across both surfaces of the stomach); thicker muscle in pyloric gland area b/c stronger contractions here
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Primary function: storage
1. Also mixes up, contents
2. Gastric emptying is highly regulated
How does pressure in the stomach respond to swallowing? Why? Mediator?
- Swallow ends when orad part of stomach relaxes (accommodation) -> RECEPTIVE RELAXATION
- Can put in about 1.5L of food and only INC pressure 10mg Hg
- Vago-vagal reflex
Describe gastric motility.
- Slow waves (3-5cpm) via Interstitial Cells of Cajal (depolarize rhythmically), but most do NOT cause a contraction
- Contractions get stronger as you move in a caudad direction, and occur more rapidly after e/o
- As amplitude of depolarization INC, contraction occurs (see below: orad to caudad) -> spiking not necessary to produce contraction, but does result in stronger and longer contraction
- These are going on all the time, but will only cause contractions w/other involvement, i.e., Vagal activity (which will be higher with food in the stomach)
What feature of gastric emptying does this image highlight?
- Retro-pulse of food back into stomach -> continued churning until the food particles are small enough to enter the duodenum
- This process can take several hours
How do gastric slow waves vary from the fundus to the pylorus?
- No contractions in the fundus
- Frequency remains the same, but the amplitude changes from 3 (body) on
- Can never have more contractions than frequency of the slow waves
How does gastric emptying vary for liquids vs. solids?
- Liquids empties more rapidly than solids
- Solids plateau b/c have to be reduced in size before they can be emptied
What 4 things are responsible for control of contraction in the stomach?
- CONTROL:
1. Contraction/pressure in orad stomach
2. Peristalsis of stomach
3. Pylorus can contract and relax
4. Duodenal motility: as acid enters, it triggers intrinsic reflex to INH gastric peristalsis and emptying -> helps prevent duodenal damage (must have a low enough acid for pancreatic enzymes and bicarb to control it) - NOTE: hyper- and hypotonic solutions also empty more slowly than isotonic ones b/c duodenum is an osmotic control
How do high-fat meals affect gastric emptying?
- More fat = slower rate of gastric emptying
- CCK DEC contractions of the stomach
What are some things that can impair gastric emptying? Symptoms?
- Obstruction: ulcer, cancer
- Vagotomy
- Symptoms: fullness, loss of appetite, nausea
What might cause increased gastric emptying? Consequences?
- Inadequate regulation
- May lead to diarrhea, or duodenal ulcers
What do you see here? Why?
- Small intestine fed motor pattern: brief & irregular contractions + segmentation -> mixes material and exposes to wall of the GI tract
- Virtually all ABSORPTION happens in duodenum and jejunum (small intestine)
- Motility in small intestine regulated so material is mixed and exposed to surface of gut; moves at a relatively slow rate
- Can remove up to 60% of gut, and digestion and absorption will occur normally
What does this image show?
- Peristalsis: not the length of the gut, but partially down the gut
- Weak peristaltic response; all of the patterns occur in the fed individual
- Law of the intestine: a stimulus in the intestine (the presence of food) initiates a band of constriction on the proximal side and relaxation on the distal side, and results in a peristaltic wave
What is the migrating motor complex?
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Fasted individual: intense group of contractions about every 90 minutes
1. Occurs only during fasting to get rid of any remaining material in the gut, incl. bacterial overgrowth - This is triggered by MOTILIN: released by nervous stimulation
How are slow waves in the intestine triggered? Frequency?
- Contractions triggered by spiking, rather than amplitude -> amplitude does NOT vary; spikes are what matter
1. Frequency of spiking determined by digestive state of the individual - Freq of slow waves varies also: less frequency as you move distally
1. Interstitial cells of Cajal (ICC)
How is peristalsis regulated in the small intestine? Does slow wave frequency vary?
- Peristalsis regulated by VIPs (DEC), enkephalins (INC), and Vagal (INC)
- Slow waves are NOT propagated -> fewer contractions occurring in the distal gut
1. Slow waves set the maximal number of contractions
What is unique about the anatomy of the colon? Innervation? Functions?
- Incomplete longitudinal muscle: teniae colli and haustra (physiological more than anatomical) distinguish from small bowel
- External INNERVATION:
1. Vagus N: proximal through transverse
2. Pelvic N (from sacral region): sigmoid, rectum
3. SYM fibers (from hypogastric plexus): distal rectum and anal canal
4. Somatic Pudendal N: external anal sphincter (striated muscle) - FUNCTIONS: to remove final amt of water (1400 in, and about 100-150 out), also a storage organ
Describe the regulation of the ileocecal sphincter.
- Normally tonically contracted -> intrinsically regulated phenomenon: NN entirely contained in gut itself (myogenic resting tone)
1. When ileum stretched, relaxes so material can enter colon
2. If colon is distended, contracts to prevent retrograde mvmt - Gastro-ileal reflex from stomach to iliocecal sphincter —> CCK
How does mass movement happen in the colon?
- Organized segmental contraction (oral-to-aboral direction) during “mass movement” 1-2x/day
1. Segmental movement stops; haustrations disappear
2. Colon undergoes contraction -> aboral direction
2. After, haustrations and phasic contractions return - Moves material forward through the colon
Describe the rectosphinteric reflex.
- IAS relaxes when rectum distended
- External sphincter tonically contracted: spinal cord
- EAS striated muscle controlled voluntarily via the Pudendal N
1. Physical INC of pressure in the abdomen (Valsalva maneuver)
2. No teniae coli in rectum, but rather more continuous longitudinal and circular muscle - NOTE: tonic contraction state of EAS via reflex activation of dorsal roots in sacral segments; paraplegics lack tonic contraction -> incontinence
What is a salivon? Function? Blood supply? Innervation?
- Acinar cells: elaborate the original saliva
- Myoepithelial cells: contractile (may also be on intercalated ducts)
- Salivary production can be as high as 1mL/min/gm of tissue -> HIGH rate of secretion
- Tremendous BLOOD FLOW to these glands: 20x that to the muscle
- Innervated by 7th and 9th cranial NN (facial and glossopharyngeal)
- REMEMBER: copious salivary flow prior to vomit
How do electrolyte contents vary with the rate of saliva secretion?
- K+ always high
- Na+ and Cl- concentration INC with flow (i.e., a fast rate of secretion would result in a higher Na and Cl concentration in the saliva)
- Bicarb INC with time too, but curve very steep at the beginning, then plateaus
- HYPOTONIC at all rates of secretion, and only approaches isotonicity at very high rates of excretion
How are electrolytes absorbed/secreted as saliva travels through the salivon?
- Acinar cells elaborate a saliva that is essentially identical to plasma in terms of its electrolyte composition
- Na+ concentration DEC and K+ INC as you move down the ducts
1. Na+ is ACTIVELY TRANSPORTED by ducts
2. Cl- reabsorbed
3. K+ and bicarb (stimulated by flow rate) secreted (stimulated by secretagogues) - Much more Na+ and Cl- leave than K+ and bicarb enter, so saliva is hypotonic (almost impermeable to water)
How are the salivary glands innervated? Name 2 hormones that can affect saliva electrolyte content.
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PARA and SYM stimulate salivary flow:
1. SYM, vasoconstriction initially, but INC BF w/hyperemia toward end (dotted line curve) - Stimulation of salivation is ENTIRELY NEURAL
- Electrolyte content of saliva can be modified via:
1. Aldosterone: DEC Na+ in saliva and INC K+ by inserting carriers in the membrane that reabsorb and conserve Na+
2. ADH can do this too -> not a regulation, but a modification of the contents
What PARA nerves stimulate salivary secretion? Name some stimuli that INH or INC secretion.
- CN 9 (glossopharyngeal) and 7 (facial), NOT 10
- SYM: stimulation not as strong; elim of SYM does NOT cause salivary gland atrophy
- See attached image for (+) and (-) stimuli
What are the 2 secretory regions of the stomach, and their secretions?
- OXYNTIC: acid-secreting (HCl)
- PYLORIC: gastrin-secreting
Describe the orientation of cell types within the gastric glands.
- Neck cells: stem cells
- Chief cells: capable of division, but can also be derived from stem cells
- Parietal cells: 150-160mEq/L acid secretion -> concentration gradient of 3-4 million fold over pH of blood (<1 vs. blood pH of 7.4)
Describe the mechanism of acid secretion in the stomach.
- Bicarb exchanged for Cl- on the basolateral mem
1. APICAL: Cl- diffuses into the lumen, down its concentration gradient; H/K ATPase
2. BASOLATERAL: some Na+ leaks back in (N/H exchanger), creating more impetus for Cl- to move into the cell (Cl/bicarb exchanger)
a. Na/K ATPase
b. Mvmt of Cl − from blood to lumen against electrical and chemical gradients is the result of excess OH – in the cell after the H + has been pumped out (CA) - H/K ATPase is the target of PPI’s: concentrate in acid spaces, interact with ATPase sulfhydryl groups
How does parietal cell architecture change to allow secretion?
- TUBULOVESICLES contain H/K ATPase
- When secretion is stimulated, canaliculus gets much larger, taking up almost all of the inside of the cell, except the mito
- Lumen lined with MICROVILLI -> these are the tubulovesicles
- Takes about 10 minutes for secretion to begin, and acid never in the cytoplasm of the cell
How is the potential difference across the oxyntic gland mucosa maintained?
- Cl- accounts for most of the potential difference
1. Following stimulation of acid secretion, the potential difference decreases to −30 or −40 mV because the positively charged H+ moves in the same direction as Cl − - H+ ion secreted down its electrical gradient, but against its concentration gradient
What is used as an index of gastric mucosal barrier breaking? Name 2 things that can facilitate this “breakage.”
- Potential difference: goes towards 0 if the barrier is damaged
- Aspirin is a weak acid, so it moves into the cell, and H+ can accumulate w/in the cell
How do the ion concentrations of gastric secretion change based on flow rate?
- Always high K+
- H+ INC with INC rate of secretion (INC volume of oxyntic fluid)
- Hypokalemia and metabolic alkalosis if chronic vomiting -> this can be particularly problematic for young kids
What is the electrolyte composition of the oxyntic and non-oxyntic fluids?
- When parietal cells stimulated, only oxyntic fluid excreted
What is the 2-component hypothesis of gastric secretion?
- Non-oxyntic secretion is produced continuously at low rates, and is overwhelmed when secretion is stimulated from the parietal cells
1. When parietal cells stimulated, only oxyntic fluid excreted
How do the 3 mediators responsible for gastric acid secretion work together?
- Gastrin releases histamine from enterochromaffin-like cell (ECL cell)
- All 3 stimulants activate different receptors on the parietal cell
- Histamine POTENTIATES the effects of Ach + gastrin
How does Cimetidine work?
- Block the direct effects of histamine, and in so doing, blocks the potentiated effects of the 3 hormones
Describe basal gastric acid secretion.
- Acid diurnal variation is NOT due to changes in gastrin -> highest during the night
What is the peak acid secretion rate?
- 30 mEq/hr
- Note that this secretion INC at the beginning of the meal -> cephalic phase
What is the influence of sham feeding on human gastric acid secretion? Implications?
- CEPHALIC PHASE: stimuli present in the head
1. Amount of acid secretion depends on nature of the meal
2. This phase contributes 30-40% of the maximum secretion
Does the Vagus have a direct affect on acid secretion in the absence of gastrin?
- Yes!
- Get rid of gastrin, and stimulate Vagus, and you still get acid -> this means Vagus directly stimulates parietal cells
- Vagus also stimulates gastrin release
How is stimulation of acid secretion triggered by receptors in the head? What types of stimuli?
- STIMULI: smell, taste, chewing, swallowing, hypoglycemia
- Vagus stimulates:
1. G-cell gastrin secretion via GRP, and
2. Parietal cell acid secretion via Ach
When is most acid released? What foods elicit the highest acid response?
- Gastric phase is when most acid release occurs
- Protein in the food releases the hormone gastrin, which stimulates histamine and acid release
How is somatostatin involved in gastrin release?
- Somatostatin released when pH of stomach <3.0
1. INH ALL GASTRIN release, regardless of the stimulus -
Vagus INH somatostatin release (via Ach) and stimulates gastrin release (via GRP)
1. Pts with duodenal ulcers have defect here in regards to somatostatin release: may have pH limit of 1.5 or 2 instead of 3
Summarize all of the mechanisms affecting gastrin release (table).
What mechanisms INH acid secretion?
- Enterogastrone: something from small intestine that INH acid release in the stomach
- GIP: gastric inhibitory polypeptide
How do pH, volume, and gastric secretion vary over time in response to a meal (graph)?
- Vagal release of acid first, in cephalic phase
- Empty stomach pH <2, so gastrin is not released until you begin to eat, and food enters the stomach, neutralizing the acid, and allowing gastrin to be released
- Back to where you started in about 3-4 hours
Regulation of pepsinogen secretion
- Acid triggers a local cholinergic reflex that stimulates the chief cells to secrete
1. Strongest stimulant of pepsinogen secretion is Ach - Acid (H+) in pylorus stimulates secretin secretion, which then stimulates pepsinogen secretion
- GASTRIN also stimulates pepsinogen secretion (weak)
- Pepsinogen -> pepsin conversion instantaneous at pH around 4 (denatured around pH 5-6)
What is a pancreon (image)?
- Centroacinar cells: secrete water and electrolytes
- Pancreatic enzymes: low-volume secretion (from acinar cells)
What are these? Describe the cells and mediators.
- Acinar cells: highly developed reticular endothelium -> most active protein-synthesizing cells in the body (about 100g/d)
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Zymogen granules: all pancreatic enzymes secreted into lumen of the gut
1. Eventually digested, like o/proteins in diet
2. Granules secreted out into the lumen; remain intact until there is a secretory stimulus - Enzymatic component stimulated by Ach and CCK
What is the mechanism of pancreatic secretion?
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Na/K ATPase is major active process: moves Na+ out of cell -> diffuses down concentration gradient back into the cell, providing 2o transport of H+ out
1. Oubain INH this - Cl- comes in to maintain electroneutrality (and bicarb out); buildup of Cl- in cell allows luminal mvmt of Cl- via CFTR
1. Cystic fibrosis: problem w/CFTR (cylindrical) - Na+ diffuses paracellularly, and water moves osmotically (NEVER goes against concentration gradient) transcellularly (Aquaporin 1 channels)
- REMEMBER: alkaline tide in gastric venous blood when acid released (pH INC), but opposite (of parietal cells) with pancreatic secretion
How does the ion concentration of pancreatic juice vary according to rate of flow?
- Na+ here equivalent to Cl- in stomach
- Cl- here equivalent to Na+ in stomach
- Bicarb here equivalent to H+ in stomach
- NOTE: all rates of pancreatic and gastric secretion essentially isotonic -> only one that is hypotonic is salivary
Enzymes synthesized on RER; hydrophobic AA’s added first (leader sequence), allowing protein to cross inside RER —> membrane-bound until they are secreted. This is a mechanism to prevent pancreatic cells from digesting themselves (never get out into the cytoplasm).
Budded off, move into Golgi, get incorporated into condensing vacuoles, where they are concentrated, and then become zymogen granules that move to apical membrane and await secretory stimulus. Step 6 is the only one that requires a secretory stimulus; the others are ongoing. 2, 3, 4 require energy; must have supply of ATP.
Amylase: starch
Lipase: fat
Protease: protein
All occur in basically the same proportions, unless there is a major dietary change that lasts for some time. This occurs at the level of mRNA.
All proteases synthesized as inactive enzymes. TRYPSIN is responsible for activation of these enzymes, and is autocatalytic. Cell also contains an anti-trypsin.
Secretion lasts until all contents have been digested. Enzyme secretion can last 6-7 hours (until meal is fully digested).
Sham feeding cephalic phase INC in enzyme release (stimulation of acinar cells alone, with very little INC in pancreatic bicarb). Vagus does this! Ach has little effect on ductule cells (that produce water and bicarb).
There is a basal rate of pancreatic secretion; we’re not sure if there is a regulator of this (may be an inherent property of the gland). Not INH by atropine.
Major phase of pancreatic secretion is the intestinal phase (70-80% of max pancreatic response; cephalic phase only 15-20%).
pH for release of secretin <4.5. pH<3 does not change output, but greater area of exposure will because more cells are then capable of releasing secretin.
FA’s must be C8 or greater (C16, 18, most common in the diet, and most common releasers of CCK). Also released by AA and peptides. Most potent releasers in man are phenylalanine, tryptophan, etc (glycine ineffective).
CCK’s act via CCK-2 receptor, activating vago-vagal receptors Ach also potentiates effects of secretin on ductal cells (very important because it allows pancreas to secrete maximally).
Material entering the duodenum is neutralized very rapidly; just a small area is acidified sufficiently to induce secretin secretion and bicarb release from the pancreas.
Potentiation allows small amounts of secretin to result in max pancreatic secretion.
Different second messengers and different receptors.
CCK also potentiates this action of secretin.
VIP, glucagon also have the secretin affect here, so they cannot potentiate its activity.
