Gastrointestinal Flashcards
Explain the innervation of the GI tract.
• innervated by both an intrinsic and extrinsic autonomic nervous system (ANS).
What is the relationship between peptide hormones, the gut nervous system, and the gut itself?
- Peptide hormones, secreted into the blood by endocrine cells scattered along the GI tract, act both at the level of the digestive organs and the CNS.
- The secretion and actions of gut hormones are intimately associated with ANS innervation of the GI tract.
Summary review card: Explain the difference between para and sympathetic innervation (extrinsic innervation) of the gut…
What extrinsic nerve (or ganglion) serves to innervate the gut?
What neurotransmitter is released?
Which branch of the extrinsic N.S. activates vs inhibits the gut?
- Para: Mostly Vagus and some Pelvic nerve. Post-ganglionic fibers release ACh (cholinergic). Activates digestion.
- Symp: Cardiac Ganglion, Superior Mestenteric Ganglion, Inferior Mesenteric Ganglion. Post-ganglionic fibers release nor-epi (adrenergic). Sympa inhibits digestion
- Note: pre-ganglionic ganglion always release ACh.
What comprises the intrinsic nervous system of the gut?
- Auerbach’s plexus (myenteric) between the circular and longitudinal muscles
- Meissner’s plexus (submucosal) in the submucosa deep to the circular muscles
- Note: para and sympa can interact with these plexuses
Fact: Endocrine cells fall into the broad category of “clear cells” which produce amines and peptides.
Fact: Endocrine cells fall into the broad category of “clear cells” which produce amines and peptides.
What is the significance of the “open” configuration of endocrine cells in the gasteroenero-pancreatic (GEP) system?
- luminal and serosal face
- enables cells to be affected by luminal factors
- potential for exocrine, paracrine, and endocrine functions
Which endocrine cells of the GEP system do not have an open configuration?
• pancreas and oxyntic region of the stomach
What are the to general groups of GEP hormones?
- Secretin and Gastrin families
* Note: there are others that do not fit neatly into those two families
What are peptides that make up the secretin family?
- Vasoactive Intestinal Polypeptide (VIP)
- Gastric Inhibitory Polypeptide (GIP)
- Pancreatic glucagon
- Gut Glucacon-like Immunoreactivity (GLP-1)
- Bombesin aka Gastrin Releasing Peptide (GRP)
- Chymodenin (not always considered part of this group)
What is Bombesin?
• Bombesin (aka GRP) is a vagal transmitter ==> release of gastrin following vagal stimulation
What peptides make up the Gastrin family?
- Gastrin
- cholecystokinin (CCK)
- motilin
- enkephalin
- Cerulein (not found in mammals)
What are GEP peptides that do not fall into the Gastrin or Secretin families?
- pancreatic polypeptide (PP)
- somatostatin (SRIH)
- urogastrone
- chymodenin
- tachykinins (substance-P like peptides)
Note: Gastrin is unique in that different types of grastrin have huge size differences. CCK also has some size differences.
Note: Gastrin is unique in that different types of grastrin have huge size differences. CCK also has some size differences.
What are the four major forms of gastrin? What are their relative sizes? Which is the most active?
- Preprogastrin (largest)
- Big gastrin (34 aa) (maybe a Progastrin?)
- Unnamed 17 aa form (most active)
- Unnamed 14 aa form
What are sulfonated and unsulfonated forms of gastrin? What is a guestimate on how many types of gastrin are in circulation?
- Each type of gastrin seems to have both a sulfonated and unsulfonated form, thereby doubling the number of types
- 20 or more
What is the form of gastrin most often used clinically?
Pentagastrin
What is pentagastrin?
- a synthetic pentapeptide
- C-terminal: gastrin and beta-alanine
- N-terminal blocking agent: tertiary butyloxycarbonyl (tBOC).
There several sizes of CCK. What is the active component of different CCKs?
C-terminal octadecapeptide
Does CCK only affect the GI tract?
• The smallest form of CCK may be neuronal and act as a neurotransmitter.
With all different sizes of Gastrin and CCK, it seems like changes aren’t such a big deal. What are some changes to Gastrin and CCK that diminish their activity?
• deamidation of the C-terminal residue or removal of the sulfate groups considerably diminishes the activity of both gastrin and CCK.
Does secretin have different sizes?
- Only one size biologically active size
* 27 a.a. residues
What are the major physiological roles of the Gastrins?
- stimulation of H+ from oxyntic cells ==> which also releases pepsinogen from chief cells
- a trophic action on the mucosa of the stomach (possibly caused by luminal gastrin)
- stimulation of gastric motility
What two compounds does Gastrin work with synergistically?
- Acetylcholine Ach
* Histamine
What nerve causes release of ACh at the stomach?
What does ACh release at the stomach then cause?
• Vagal impules ==> Ach release ==> GRP (gastrin releasing peptide, bombesin) ==> Gastrin
What stomach receptors do histmine bind to?
• type 2 histamine receptors
What drugs block histamine release?
• Tagamet (cymetidine)
What happens to Gastrins effects if histamine or Ach are blocked?
• There is only minimal H+ release by gastrin
Why should anti-histamines not be used indiscriminately?
• histamine type 2 receptors in the brain
All together: Explain the synergism between Gastrins, Ach, and Histamine?
- Gastrin ==> H+ from oxyntic cells
- Vagal impules ==>Acetylcholine Ach ==> GRP (gastrin releasing peptide, bombesin)
- Histamine ==> type 2 histamine receptors
- Tagamet (cymetidine) blocks H2R (or if Ach is blocked) ==> only minimal H+ release by gastrin
What causes Gastrin release?
- Vagus ==> Ach ==>GRP
- Amino acids in Chyme, specifically Trp, Phe, Arg
- Ca++
What inhibits Gastrin release?
- Inhibited by pH below 3.5 ==> somastatin release inhibits gastrin release
- Secretin inhibits gastrin release
- CCK inhibits Gastrin action via competitive inhibition
Thought Question: What happens with Gastrin levels in patients with atrophic gastritis, or other conditions that involve chronic decrease in the output or function of oxyntic cells?
• high circulating levels of gastrin because this pH ==> somastatin feeback is missing.
What is Zollinger-Ellison Syndrome (ZE)?
- Gastrin hypersecretion ==> ↑ H+ release in stomach leading to ulceration and excessive overgrowth of gastric mucosa
- Caused by gastrin-secreting tumor from non–beta pancreatic islet cell
- or… a hyperplastic mucosal G cells
What is a diagnostic test for ZE?
- Administer Secretin
- secretin normally inhibits release of gastrin
- patient with ZE, it conversely causes increases in circulating gastrin levels.
What causes Gastrin release (gastric phase)? What inhibits Gastrin release?
- ↑ via ↑Vagus ==> Ach ==> GRP
- ↑ via ↑Amino acids in Chyme, specifically Trp, Phe, Arg
- ↑ via ↑Ca++
- ↓ via pH below 3.5 in the antrum of the stomach ==> somastatin release inhibits gastrin release
- ↓ via Secretin
- ↓ via CCK via competitive inhibition with gastrin receptor
Review: in the stomach…
G cells release:
Chief cells release:
Parietal cells release:
In the stomach…
Gastrin is released by what cells?
Pepsinogen is released by what cells?
H+ is released by what cells?
What stimulates pepsinogen release?
- Pepsinogen is released from chief cells by…
- Vagal stimulation (ACh)
- Gastrin from chief cells
- Secretin from duodenal secretin cells
What are the physiological effects of cholecystokinin?
- stimulation of pancreatic proenzyme release
- stimulation of bicarbonate release from pancreas into duodenum (synergistic with secretin)
- contraction of the gall bladder and relaxation of the sphincter of Oddi
- reduction of gastrin-induced acid secretion by competitive inhibition
What causes CCK release?
- Peptides
- certain amino acids
- fats
- acidity
Which are potent stimulators of CCK?
Which are mild stimulators of CCK?
- potent stimulators are tryptophan and phenylalanine
- mild stimulators are valine, leucine, methionine, fats, and acidity
- other amino acids are ineffective
Recap:
What causes CCK release?
Which are potent stimulators?
Which are mild stimulators?
- Peptides, certain amino acids, fats, and acidity
- potent stimulators are tryptophan and phenylalanine
- mild stimulators are valine, leucine, methionine, fats, and acidity
- other amino acids are ineffective
How does CCK act? Directly? Indirectly?
- Directly on the acinar cells of the pancreas
- Directly on the muscle of the gall bladder
- Indirectly on intestinal muscle through the release of acetylcholine
What is CCK used to diagnose?
- Pancreatic disease
- Gall bladder disease
- roentgenological (radiology) investigations of the intestine (CCK sitimulates intestine)
Does CCK have therapeutic value?
- Eliminate obstructions (concretements) from the bile duct
* Little value beyond that
What are the principal physiological roles of secretin?
- ==> pancreatic bicarbonate secretion into the duodenum. (synergistic with CCK)
- inhibits gastrin and therefore stomach H+
- synergistically with CCK ==> pancreatic enzymes, flow and composition of bile (↑H2O/HCO3-)
What causes secretin release?
• acid into the upper small intestine.
Does innervation play a role in secretin release or effect?
- Secretin release is not dependent on neuronal innervation
* but its actions on the pancreas are reduced by vagotomy.
What is Glucagon-Like Peptide (GLP-1)?
Where is it produced?
What does it inhibit?
How is it used therapeutically? (single questions follow)
- most potent stimulator of insulin release from the pancreas
- intake of glucose increases release of GLP-1 into portal blood system ==> insulin release before glucose blood levels rise appreciably.
- produced by intestinal L cells
- inhibits gastric secretion and emptying.
- GLP-1 is anorexogenic (loss of appetite) and used in Type 2 diabetes
Where is GLP-1 produced?
• produced by intestinal L cells
What does GLP-1 inhibit?
• inhibits gastric secretion and emptying.
How is GLP-1 used therapeutically?
• GLP-1 is anorexogenic (loss of appetite) and used in Type 2 diabetes
What is Ghrelin?
What stimulates Ghrelin release?
• Growth Hormone Releasing Peptide GHRP (as opposed to hypothalamic GHRH)
• Called a brain-gut peptide
Elevated during fasting and insulin induced hypoglycemia
What are Ghrelin’s actions?
- GHRP stimulates growth hormone release by increasing GHRH release
- Inhibits somatostatin release (somatostatin inhibits GH release)
- direct positive effect on somatotrophs in the pituitary.
What are Leptin and Adiponectin?
What are their actions?
- anorexogenic peptide hormones produced by adipose tissue
- fat cells ==> leptin and adiponectin ==> inhibit appetite centers in brain
- Adiponectin also increases insulin responsiveness in T2DM
Where is Vasoactive Intestinal Peptide (VIP) found?
- Found in colon, ileum, jejunum, pancreas and in many nerve rich areas of the body.
- May be a neurotransmitter in addition to a gastrointestinal hormone
What causes Vasoactive Intestinal Peptide (VIP) release ?
• dilute HCl or fat in the duodenum.
What does VIP do?
- VIP acts with NO in producing sphincter relaxation.
- stimulate water and electrolyte secretion from mucosal surfaces of the intestine and pancreas
- (also inhibits gastric acid secretion and motility, inhibit gall bladder contraction, but this was not bolded in the notes)
What are the effects of tumors which secrete VIP in large amounts (VIPomas)?
• watery-diarrhea and electrolyte secretion
Summary of VIP… Found where? Released by what? Does what?
• Found in intestines • Released by acid and fat in duodenum • Acts with NO to relax intestinal sphincter • Stimulates water and electrolyte secretion At extreme (as in with a tumor) can cause clinical diarrhea
What are the minor functions of Gastric Inhibitory Peptide?
- inhibits gastric acid secretion
- Inhibits pepsin secretion
- Inhibits gastric motor activity.
What is the major function on Gastric Inhibitory Peptide?
What effects does blood glucose have on GIP?
- Increases insulin secretion (although it is not as potent in this regard as GLP-1).
- GIP is not insulinotropic in the presence of basal plasma glucose levels
- GIP is insulinotropic in the presence of raised glucose levels
What causes GIP release?
- Increased plasma glucose increases GIP (Main one. The rest are minor)
- Gastrin and CCK plus amino acids in the duodenum stimulate GIP
- Duodenal acidification does not appear affect GIP
Where is Somatostatin produced?
- growth hormone release-inhibiting hormones of the HHP system
- also a product of the D-cells of pancreatic islets and the gastric mucosa
- (is also an effective neurotransmitter in CNS and PNS)
What does Somatostatin do?
- inhibits release of all of the following
- both insulin and glucagon (counterintuitive)
- gastrin (and gastric H+)
- secretin
- CCK
- GIP
- VIP
- motilin.
What is Urogastrone?
Where is it found?
What does it do?
- A peptide epidermal growth factor that is also a potent inhibitor of stomach acid
- Skin, submaxillary glands, and Brunner’s glands of the duodenum.
- potent inhibitor of stomach acid secretion (may be therapeutic).
- Increases during pregnancy
What are Enkephalins?
Where are they found?
How do they effect the GI tract?
• Endogenous opioids
• GI tract
Inhibit pain and motility
What is Peptide YY?
What causes its release?
What does it do?
- Peptide with tyrosine residues (hence its name)
- Released in response to eating (fat)
- PYY ==> neuropeptide Y (NPY) receptors ==> vagus nerve
- inhibits gastric motility thereby increasing nutrient absorption
- increases water and electrolyte absorption in the colon.
What is Bombesin?
• gastrin-releasing hormone (GRP). It completely accounts for vagally stimulated gastrin release.
Text Not Highlighted by professor:
Peptides of Amphibian Skin. This group includes the bombesin-like peptides, cerulein, and the tachykinins. Bombesin-like peptides are contained in stomach and upper small intestine of mammals. They have biological activities identical to the bombesin peptides of amphibian skin. These include stimulation of gastric acid, pepsin, gastrin, pancreatic enzymes, and pancreatic peptide and inhibition of gastric and duodenal motility.
Text Not Highlighted by professor:
Peptides of Amphibian Skin. This group includes the bombesin-like peptides, cerulein, and the tachykinins. Bombesin-like peptides are contained in stomach and upper small intestine of mammals. They have biological activities identical to the bombesin peptides of amphibian skin. These include stimulation of gastric acid, pepsin, gastrin, pancreatic enzymes, and pancreatic peptide and inhibition of gastric and duodenal motility.
Text Not Highlighted by professor: Tachykinins and cerulein have been used extensively to study the dynamics of gut motility and secretion. The tachykinins, of which there are several, resemble substance P of mammals both in structure and activity. They stimulate GI motility and exocrine secretions of the pancreas. Cerulein bears a close resemblance, with regard to chemical structure, to the members of the gastrin family. It stimulates gastric motility, exocrine secretions of the stomach and pancreas, and release of insulin, glucagon, calcitonin, and pancreatic polypeptide.
Text Not Highlighted by professor: Tachykinins and cerulein have been used extensively to study the dynamics of gut motility and secretion. The tachykinins, of which there are several, resemble substance P of mammals both in structure and activity. They stimulate GI motility and exocrine secretions of the pancreas. Cerulein bears a close resemblance, with regard to chemical structure, to the members of the gastrin family. It stimulates gastric motility, exocrine secretions of the stomach and pancreas, and release of insulin, glucagon, calcitonin, and pancreatic polypeptide.
