Exam 1 Flashcards
1
Q
What are the 3 arms of the autonomic nervous system?
A
Parasympathetic
Sympathetic
Enteric
2
Q
What are the receptors on skeletal muscle?
A
Ach (N)
3
Q
What is another name for parasympathetic autonomic NS and the transmitters?
A
Cranio-sacral
Nerve to medulla to vagus n to Ach (N) to gut smooth muscle (Ach - M)
4
Q
What is another name for sympathetic autonomic NS and the transmitters?
A
Thoraco-lumbar
Nerve to spinal cord to interneuron to prevertebral ganglion (Ach - N) to adrenergic (NE) -
5
Q
What are the 4 major sensory inputs?
A
- Mechanoreceptors
- Chemoreceptors
- Thermoreceptors
- Mediators released from enteroendocrine cells - osmolality, nutrients, drugs, bacterial products (cholecystokinin, secretin, somatostatin, serotonin, CRF, etc)
6
Q
What are the 2 main nerves for the parasymapthetic NS in GIT?
A
Vagus n (90% gut) Pelvic nerve (distal colon)
7
Q
What is the set up of the parasympathetic NS?
A
Long pregangloinic and short post-ganglonic nerve
Ganglion is within organ (Ach - N)
Post ganglionic (Ach-M) - other nonadrenergic/noncholnoergic (NANC) are also located here
8
Q
What is the role of the parasympathetic NS in the gut?
A
Contraction and stimulation
9
Q
What is the set up of sympathetic NS?
A
Short preganglionic (Ach - N), and long post ganglionic nerve (Adrenergic - NE) onto alpha or beta
Some are NANC here too
10
Q
What is the enteric NS?
A
Nerves within the submucosal and myenteric plexus
Secretes lots of different mediators (small molecules, peptides, gases)
Acted on sympathetic and parasympathetic NS
11
Q
What are other inhibitory NTs in enteric NS?
A
Vasoactive intestinal polypeptide (VIP) NO Enkephaline Somatostatin ATP Neuropeptide Y Carbon Monoxide
12
Q
What are other stimulatory NTs in enteric NS?
A
Ach
Serotonin (5-HT)
Substance P
Neurokinins
13
Q
Describe the peristaltic reflex?
A
Distension of isolated loop of dog intestine results in forward movement of contents = “Law of intestine”
Distension activates cholinergic pathways upstream from bolus and non-adrenergic/non-cholinergic pathways below bolus = Leading to contraction oral to bolus and relaxation in the aboral direction
14
Q
What is the extrinsic vs intrinsic innervation?
A
Extrinsic: Sympathethetic and Parasympathetic
Intrinsic: Enteric NS (hard wired and will continue without innervation)T
15
Q
What is the pacemaker in gut motility?
A
Activity of smooth muscle is modulated but NOT initiated by extrinsic autonomic nerves
Intrinsic pacemarker mechanism in smooth muscle coats sets pace for contraction
Exceptions: Ruminant forestomach
Avian Gizzard
Pacemarkers = Nerve-like cells (Interstitial cells of Cajal) - located btwn intestinal circular and longitudinal smooth muscle layers - Spontaneous rhythmic depolarization
16
Q
What is a slow wave?
A
Cyclic depolarizations of resting membrane potential arise from pacemarked cells and spread circumferentially and longitudinally down gut from smooth muscle cells to smooth muscle cell
Depolarizations are sub-threhold = NOT accompanied by contraction in gut wall
17
Q
What is a slow wave?
A
Cyclic depolarization of resting membrane potential arise from pacemarker cells and spread circumferentially and longitudinally down gut from smooth muscle cell to smooth muscle cell
Depolarization that are sub-threhold (NOT accompanied by contractions)
18
Q
What is contraction?
A
Results from neuroendocrine stimulation (vagus n) that depolarize slow wave threshold
19
Q
What determines the maximum rate of contraction?
A
Determined by slow wave frequency and number of waves that exceeding threshold (bear spikes)
20
Q
What inhibited contractions?
A
Inhibited by neuroendocrine input (sympathetic nerves) that hyperpolarize the slow waves away from threshold
21
Q
What drives the fasting motility pattern?
A
Driven by slow waves and directed (programmed) by enteric NS (does NOT require extrinsic innervation by vagus n)
22
Q
What is interdigestive motility pattern?
A
Consists of powerful contractions orginate in stomach and propagate along length of intestine to distal small bowel
Sweeping retained solids, pooled liquids and bacteria to colon
23
Q
What are the 3 phases of interdigestive motility?
A
Phase 1: No contractions (but slow waves are in the background)
Phase 2: Intermittent contractions
Phase 3: Every slow wave results in a contraction
24
Q
What is another name for interdigestive motility?
A
House keeping = Migrating Myoelectric Complex (MMC)
MMC orginate in stomach and LES and propagate through intestine
25
What happens to motility during feeding?
Digestive motility: feeding interrupts MMC cycling dt extrinsic nerve (Vagus) act upon ENS - Different pattern and freq of contractions that is intermittent (Phase 2-like) - To promote mixing and increased digestion/absoprtion
26
Which animal dose feeding not interrupt the MMC cycline?
Ruminants!
27
Is there a difference in slow wave frequency?
Faster slow wave freq in duodenum faster than in distal ileum - Acid is within it and it needs to spread out (start digestion)
28
T/F. Slow waves = motility.
False
Slow waves do not mean motility
Need actions of enteric NS or extrinsic NS to raise threshold to allow for contraction of GIT
29
What are the 2 types of digestion?
1. Digestive phase (extrinsic NS - vagus makes the spikes above threshold in the slow waves)
2. Interdigestive (enteric NS) makes spikes above threshold in slow waves
30
What cells are present in the cardiac mucosa?
Cardiac glands secrete mucus and bicarbonate
31
What cells are present in proper gastric mucosa?
Parietal cells - H+ (intrinsic factor)
- Chief cells (pepsinogen)
- Enterochromaffin-like cells: Histamine
D cells (somatostatin)
32
What cells are present in antral/pyloric mucosa?
G cells - Gastrin
D cells -Somatostatin
33
What are the functions of acid in the stomach?
1. Sterilization (pathogens)
| 2. Activate enzymes (B12, pepsinogen to pepsin)
34
What are the 3 mediators of gastric HCL secretion?
Gastrin (CCK receptor - Ca)
Histamine (H2 receptors - cAMP)
Acetylocholine (Muscarinic M3 receptors - Ca
35
What controls the fine tuning of acid secretion?
Somatostatin secreting cell (D cell)
36
What is the most important ligand for stimulation of parietal cell HCl Secretion?
Histamine
Both gastrin and Ach stimulate histamine release from ECL cells
cAMP synergized with either Ca second messenger to stimulate HCl secretion
37
What are the secondary messenger systems of acid secretion?
Histamine - cAMP
Ach - Ca
Gastrin - Ca
When you add cAMP + Ca pathway = Syngery!!
When you add Ca + Ca = Additive
38
What inhibits gastric acid secretion?
1. When the stimulus is not present (vagal n, gastric distension, or protein in stomach)
2. Low intragastric ph (high H=) - D cell secrete somatostatin which inhibits gastrin release from G cells and histamine release from ECL cells = Directly inhibits parietal cells
39
What effect does gastrin have on gastric mucosa?
Proliferative (trophic effects) - Proliferation of ECL cells
40
What is the rebound secretory response?
Concern that increase in gastrin from basic pH in the stomach - lead to proliferation of ECL cells - So when you stop PPI, there is a massive rebound secretory response
41
What are the differential effects of H. pylori?
Helicobacter stimulates inflammation and cytokines that also stimulate these cells
Within Antrum: Leads to acid secretion
• TNF alpha - Can inhibit D cells
• IFN-y - Stimulate G cells to make gastrin = Leads to increased acidity
○ Peptic ulcer formation
Within the body:
• TNF-alpha - Inhibits parietal cells, ECL cells, and D cells = Decreases acid
○ Bacterial overgrowth and even cancer formation
42
What are the 6 major ways to prevent back diffusion of H+ with the gastric mucosal barrier?
1. High resistance of epithelial cells membrane and tight junction to H+ movement
2. Thick, unstirred mucus (mucin) layer
3. Trapping of secreted bicarbonate in mucus gel
4. Restitution (migration of uninjured epithelial cells to cover denude basement membrane)
5. Mucosal blood flow
6. Endogenous prostaglandins and nitric oxide (stimulate mucsoal blood flow, inhibit cAMP by parietal cells (less acid secreted), stimulates mucus and bicarbonate secretion, cytoprotective)
43
What are the mechanisms of endogenous PGs and nitric oxide?
Endogenous prostaglandins and nitric oxide (stimulate mucsoal blood flow, inhibit cAMP by parietal cells (less acid secreted), stimulates mucus and bicarbonate secretion, cytoprotective)
44
What section in the stomach as no protective barrier?
Stratified Squamous epithelium!!! No mucus or bicarbonate in this region
Epithelium is at risk for acid exposure
45
How is the barrier maintained in the stratified squamous epithelium?
High electrical resistance to strong electrolytes (tight junctions, glycoconjugate secretions)
Proximal to distal pH, pepsin, SCFA, bile acid gradients
No restitution unknown role of prostaglandins
46
What are barrier breakers in the stomach?
1. Weak acids (high SCFA - pig and horses)
With HCl - diffuse into cells - Intracellular acidification = Cell swelling and death
Bile Salts: At low pH unionized and lipid soluble
Disruption of gastric stratification
(finely ground diet)
47
What results in the differences in absorption along the villus?
As cells move up from crypts they gain and lose transporters
48
What are the extramural vessels?
Celiac artery (stomach and prox duodenum)
Cranial mesenteric artery (80% of gut)
Caudal mesenteric artery (distal segment of colon)
Portal Vein
49
What are the intramural vessels?
Muscle capillaires
Submucosal vessels
Muscosal capillaries
50
What is a critical location for ischemic injury and why?
Mucosa is the most metabolically active and thus can lead to ischemic injury
51
What is the blood supply at the villus?
central arteriole and peripheral veins
Counter current exchange
52
What is the overall aspect of sympathetic stimulation during hemorrhagic shock?
Skeletal: Increase pressure and massive shunting of blood = Autotransfusion
Intestine: Decrease pressure and blood pooling - leading to mucosal injury and sloughing
53
Why does the villus slough from tip down during ischemia?
There is lower oxygen tension at the tip of the villus dt counter current exchange results in pathologic hypoxia and the tips will slough off into the lumen
54
What is the significance of the Gruenhagen's space?
Epithelium still have some transport function and there is extracellular fluid that ends up pooling in this region - Build up of fluid starts to peel off this epithelium and exacerbates the lesion of ischemia
55
What section of the villus is most resistance to hypoxia?
The crypt!! It has its own blood supply
56
Which neutrophils are important for reperfusion injury?
The resident (tissue) neutrophils
57
What is the model of reperfusion injury?
1. All phosphates are removed from ATP - Leading to hypoxanthine
2. Xanthine Dehydrogenase is converted to xanthine oxidase (by proteases)
3. Xanthine oxidase converts hypoxanthine in the presence of oxygen to superoxide
4. Superoxide leads to lipid membrane peroxidation - leading to leukotriene T4
5. LT4 is a chemoattract for neutrophils
6. Activated resident neutrophils then lead to formation of additional ROS (H2O2 and HOCl)
LOTS OF Oxidative Injury
58
What 2 mechanisms make intestinal mucosa extremely vulnerable to hypoxia?
1. High metabolic demand
2. Villous counter current exchange mechanism (short circuiting of oxygen from central vein to peripheral capillaries) - Pathologic tip hypoxia
59
What is responsible for the majority of ROS and mucosal injury during reperfusion?
Resident (mucosal) neutrophils
60
Differences btwn Villus and Crypt in:
Brush Border hydrolyases
Nutrient Transport
Net Water/Ion Transport
Permeability
Brush Border hydrolyases
V: Abundant
C: Sparse
Nutrient Transport
V: High
C: Low
Net Water/Ion Transport
V: Absorption
C: Secretion (mostly chloride)
Permeability
V: Low (increased tight junctions)
C: High (less tight
junctions)
61
What is the single transporter that drives most transport in cell?
Na-K- ATPase
3 Na out and 2 K into cell
Sets up electrochemical gradient (more electronegative in the cell)
62
What regulates the degree of Cl secretion?
CFTR - Cystic Fibrosis Transmembrane Conductance Regulator
63
What is the driving force for Chloride to exit the cell?
Electronegative center of the cell, drives chloride out
64
Describe the structure of the CFTR.
The R-domain will block the channel (closed)
When Protein kinase A is activated by cAMP - phosphorylates the R-domain heavily making it negatively charged and thus it is repelled and the channel opens to allow Cl out
65
What also opens K channels?
Ca can open basolateral K channels (released from ER - internal store of Ca)
K channel opened by Ca - Allows K out faster will allow for cell to be more electrically negative (synergetic effect!)
66
How is chloride secreted from apical membrane?
```
Multiple Cl- channels
Cl (ORCC)
CIC-2
Cl (CFTR) - cAMP/PKA
Cl (Ca stimulated)
```
67
When do you have maximal chloride secretion?
When there is cAMP and Ca (through IP - PKC) released here that stimulate the CFTR
68
How does CFTR impact Na absorption?
CFTR communicated with adjacent Na channels to shut them down
When Chloride is secreted from CFTR, it will shut down the NHE3 and this is down through NHERF
69
What are the methods of HCO3 secretion?
From the basolateral membrane: Absorbed into cell with Na
At apical membrane: AE-1 (HCO3 out and SCFA in)
DRA (HCO3 out and Cl into cell)
CFTR (HCO3 and Cl out of cell)
70
In rehydration solutions, what drives Na into the cells?
Adding glucose/sugars (But the transporters need to be in place for this to work)!!!
71
How is glucose transported into cells?
Glucose transporter (SGLT-1) on apical membrane in the SI (NOT within colon)
Using chemical component of the gradient
• 2 Na and glucose bind - Conformational change and it flips Na and glucose within the cell
• GLUT2 - Opens on basolateral membrane when glucose high within the cell and Glucose within the blood
72
When the Na/glucose transporter is overloaded, how can Na and glucose be absorbed?
Na and Glucose activated Myosin light chain kinase (MLCK)
• Once MLK phosphorylated the myosin will contract = Leading to opening of tight junctions - Influx of glucose, Na, and water at over the tight junction
• Used mannitol (same size as glucose and does not have a transporter)
○ After contraction of tight junction there was an increased in mannitol within the paracellular space (since there are no transporters)
• Thought that when Na/glucose transporter is overloaded that then it can contract the tight junction to open to allow
• Cytokines can also open the tight junctions and paracellular space
73
What accounts for 10% of glucose absorption?
Na and Glucose activated Myosin light chain kinase (MLCK)
• Once MLK phosphorylated the myosin will contract = Leading to opening of tight junctions - Influx of glucose, Na, and water at over the tight junction
• Used mannitol (same size as glucose and does not have a transporter)
○ After contraction of tight junction there was an increased in mannitol within the paracellular space (since there are no transporters)
• Thought that when Na/glucose transporter is overloaded that then it can contract the tight junction to open to allow
Na accumulates in the basolateral area and thus when the tight junction opens that water rushes in and this drags glucose with it
• Thought to accounts for 10% of glucose transport
74
How do bile acids and amino acids get into the cell?
Linked to Na, just like glucose
All have basolateral transporters to allow them to diffuse out
75
What happens with NHE3 not working?
When NHE3 not working - Na will remain in the lumen meaning that more water is present (overwhelming the colon's absorptive ability = leading to diarrhea)
• Simple colons: Mice, humans, and dogs (changes in SI result in overwhelming colon)
○ Different in pig and horse - Their colons are able to adapt and absorb a very large amount of Na and water to compensate.
76
How does NHERF work?
NHE is inhibited by PKA via interaction with NHERF (NHERF is attached to the cytoskeleton
• Unknown if this effects opening of the paracellular space
• Coordinated NHE3 with anion exchange and Protein kinase A (PKA) that phosphorylates then it blocks the NHE3 when there is lots of chloride within the lumen)
77
What is the net effect of cAMP secretion?
Secretion of Chloride in to the lumen
Stops absorption of Chloride from lumen (linked via NHERF)
78
What are the mechanisms of SCFA transport in the colon?
Short chain fatty acid CANNOT be easily transported (there is a SCFA cotransporter with bicarbonate - but some people to not believe this) - LOW RATE
MAJOR mechanism - Production of proton that are pumped out and interacts with SCFA to the protonated form and it is easier to get across the membrane into the cell - HIGH RATE (diffuse directly into the cell)
79
What happens with K transport in the colon?
Proximal colon: Goal is to get rid of K! K channel on luminal side!!!
Distal Colon: Can retrieve it (several transporters - K/H exchanger and HKC ATPase)
80
What are the main ways that Na is absorbed?
1. Nutrient dependent Na Absorption: Linked to Glucose (SGLT-1) and AA
2. Nutrient Independent Na Absorption:
Jenjunum: Electroneutral (NHE3)
Ileum: Linked NHE3 to Cl/HCO3 exchanger
Distal Colon: Electrogeneric Na (requires energy)
81
What is found in colonic cells as you ascend the crypt?
Reduced CFTR and increased NHE and anion exchangers
MORE CFTR within the crypt
82
What is the intestinal mucosa lined by?
Single layer of columnar epithelium - Responsible for secretion of fluid, absorption of water, electrolytes, and nutrients
83
What forms the barrier layer of the intestines?
Apical membrane together with interepithelial tight junctions - Continuous seal = BARRIER
84
What is the role of the Na/K ATPase transporter?
Found on basolateral surface, generates electrical potential across cell that provides energy to move other ions in and out of cell (allowing Na to enter the cell)
85
What are the divisions within crypt-villus axis?
Secretory epithelium = Crypt
Absorptive Epithelium = Villus
Migrate and mature up from the crypts (replaced every 5 days)
86
Which portion of the GIT is leaky?
Small intestine = Dt loose tight junctions btwn adjacent epithelial cells (move via paracellular route, leading to 95% permeability)
87
Which portion of the GIT is tightly apposed?
Within colon - This reduces the passive movement of solute and fluid across the paracellular space (50% permeability)
88
What is the role of fluid secretion in the GIT?
Flush mucus from crypts into the lumen
Provide fluid in lumen to aid in digestion
89
What is the principal ion secreted that results in fluid movement?
Chloride (numerous apical Cl channels)
90
Why are Na and water drawn across the paracellular space?
Dt secretion of chloride - in response to electrical and osmotic gradients
91
How does Cl enter the cell?
NKCC1 or Na-K-2Cl channel (basolateral) - Which is driven by electrochemical gradient of Na set up by Na/K ATPase
92
What drives secretion of chloride?
Intracellular environment is electronegative dt the N/K ATPase
K channels on basolateral to allow K back in - further increasing electronegative intracellular environment
93
Can other chloride channels such as CIC2 and Outwardly rectifying Cl channel compensate for defects in CFTR?
NO!!
94
Besides chloride, what also uses CFTR?
HCO3 - Important to bugger HCl in SI
95
What is the consequence of increasing cAMP?
increased activation of PKA which will phsophorylate regulatory domain (R domain) of the CFTR - leading to opening of the channel and then Chloride secretion
Examples: Pro-inflammatory prostanoids (PGE2) and chlorea toxin and E. coli heat labile (increased cGMP) enterotoxin = All increased cAMP levels
96
What is the classic mechanism by which Ca is elevated in intestinal cells?
It is the secondary messenger system for interaction with Acetylcholine and M3 receptors
Increased Ca results in enhanced basolateral K channels = Increasing electronegatively within cell - Leading to synergistic Cl secretion - Open additional apical chloride channels and drives up the electromotive force to drive chloride out of the cells
97
What is the principal ion involved in absorptive processes?
Na - takes advantage of electrochemical gradient of Na (from Na/K ATPase) to enter cell
Many linked to other nutrients (glucose, AA, vit B)
NHE
98
Why is the SGLT-1 transporter so important?
Most oral rehydration solutions stimulate Na and water absorption by supplying glucose to epithelium (4 fold increase)
99
What is the solute drag?
Debated but thought that Na-glucose transport enchanes absoprtion of Na and water, in which fluid and solutes drawn into the paracellular space based on the osmotic gradient generated by Na and glucose exiting cell
Also support that there are SGLT-1 induced alteration in cytoskeletal tone on myosin light chain kinases - opening tight junctions
100
What drives the NHE transporters?
Since they are electroneutral - driven by internal pH of cell, when pH drops in cell from metabolism - NHE2/3 open to expel protons in exchange for Na (linked to Cl/HCO3)
101
When you absorb NaCl what is it in exchange of?
H+ and HCO3
Can be driven by glutamine
102
How does RAAS affect the intestines?
Stimulated ENS to release NE which stimulates NaCL absorption
Aldosterone in stimulation of NaCl absorption too (pigs, horse, sheep)
103
How are SCFA transported?
Acetate, butyrate, and propionate - Formed in ionized molecule and transported unionized once linked to H+ (driven by NHE or carbonic anhydrase)
104
Explain how cholera results in secretory diarrhea?
Best example of secretory diarrhea
• Epithelial layer is intact but the organism attaches and results in intense secretion
• Receptor on epithelium (brush border - microvilli) -
• Toxin is translocated within the cell
• Toxin binds to adenylate cyclase (increased cAMP - continuously production uncontrolled)
• cAMP = Protein kinase A stimulated and major ion secretion is through the CFTR (releases chloride) - Pouring chloride into the lumen (secretory diarrhea)
○ Death dt dehydration
• Neutral NaCl (NHE) - Blocked (phosphorylation of NHE)
• Involvement of enteric nerves
105
How does inflammation result in diarrhea?
1. Stimulated secretion and inhibits absorption
2. Stimulation of enteric nerves = Propulsive contractions and stimulate secretion
3. Mucosal destruction and increased permeability - neutrophils squeeze through tight junctions (eventually blow them apart)
4. Nutrient maldigestion and malabsoprtion
106
What are the 2 general categories of diarrhea?
```
Toxin induced (secretory)
Damage and mucosal inflammation (crypto, salmonellosis)
```
107
How do you get secretion with mucosal inflammation?
Reduced absorption (loss of epithelium)
Increased ion secretion (via secondary messengers )
Enteric nerves exacerbate secondary messengers
Increased osmotic load in the lumen
108
What results in water absorption with oral rehydration solutions?
Osmotic gradient from Na and glucose being transported into cell = Draws Cl and water across tight junctions via paracellular space
