Gastrointestinal Physiology Flashcards
How is the gastrointestinal Blood flow called? What % of blood can be found in this circulation?
Splanchnic Circulation
- 25% of cardiac output feeds splanchnic circulation
- “Storage site” for blood
- When not needed (during fasting), blood is redirected to muscles during exertion, GIT circulation is shunted
Heart → Brain + Upper limbs or [rest of body → GIT or lower limbs
What are the glands of the human digestive system?
- 3x Salivary glands
- Liver
- Gall bladder
- Pancreas
What are functions of the Digestive System? How are these functions controlled?
- Move food through the alimentary tract (away from the mouth towards the anus)
- Secrete GI juices and digest food (make food digestible)
- Absorb digestive products, water & electrolytes (SI and colon)
- Circulate blood through the GI organs and carry away absorbed substances
**Controlled through local, enteric and autonomic reflexes residing in the gut wall
What volumes are inputed vs outputed in the GI tract?
Input through the mouth → 1200 mL of fluid + 800g food
Ouput through anus → 100 mL of fluid + 50 g solid
Fom glands:
- 1500 mL from salivary glands
- 500 mL from Liver
- 1500 mL from Pancreas
- 1500 mL intestinal secretions
**These fluids have to be absorbed for maintenance of homeostasis (total ~ 9L/days reabsorbed)
Small intestine → 8500 mL reabsorbed with food particles by osmosis
Large intestine → 350 mL reabsorbed with ions
What are the 3 main branches of Splanchnic circulation?
- Celiac Artery → Stomach & Spleen + Hepatic artery (stomach, proximal duodenum, liver, spleen, and pancreas)
- Superior Mesenteric Artery → Pancreas & Small Intestine (distal duodenum, jejunum, ileum, and the colon up to the splenic flexure)
- Inferior Mesenteric Artery → Large Intestine (distal colon (descending and sigmoid colon) and rectum)
**All blood leaving the GI tract (deoxygenated) travels through the portal vein to be filtered in the liver before integratingsystemic circulating and going back to the heart
Where does the Hepatic Artery takes its blood supply? and where does it bring the blood?
What % of the Splanchnic circulation goes through the Hepatic Artery vs the GI tract?
Celiac Artery → Hepatic artery → Liver (doesn’t pass by GI walls)
*Feeds oxygenated blood to hepatic cells
20% of blood flow → hepatic artery (brings oxygenated blood to the liver)
80% of blood flow → GIT → portal vein (deoxygenated) → liver for filtration
What are 3 subbranches of the Celiac Artery?
- Left Gastric Artery
- Splenic Artery
- Hepatic Artery
What are the 5 sub-branches of the Superior Mesenteric Artery (SMA)?
1 – Inferior Pancreaticoduodenal Artery → Feeds head of the pancreas and to the ascending and inferior parts of the duodenum
2 – Intestinal Arteries → branches to ileum, branches to jejunum
3 – Ileocolic Artery → 3 supplies last part of ileum, cecum, and
appendix
4 – Right Colic Artery → to ascending colon
5 – Middle Colic Artery → to the transverse colon
What are the 3 sub-branches of the Inferior Mesenteric Artery (IMA)?
1 – Left Colic Artery → descending colon
2 – Sigmoid Branches → the most superior being described as ‘the superior sigmoid artery’
3 – Superior Rectal Artery → the “terminal branch of the IMA” (the continuation of the IMA after all other branches)
What are features of the microvasculature of the villus?
Capillary loops at the level of the small intestine going up the villi
Artery → capillary bed up the villi → hepatic portal vein
- This allows enterocytes (absorptive cells) to be in close contact with the vasculature to send absorbed nutrients
What does Fick’s Law of Passive Diffusion describe?
It describes the rate of transport across membranes by passive transport
Depends on 3 factors:
- Permeability of the tissue
- Concentration of nutrients
- Total Surface Area of the tissue (for absorption)
How does the small intestine obey Fick’s Law for absorption of nutrients?
SI = main site of absorption → optimized for absorption
- Large surface area increased by villi
- Blood flow ensures «inside» concentration is low (high concentration gradient → driving force)
Concentrations: Lumen > Enterocytes > Capillary → blood stream
What are the different mechanisms of Transoirt allow for absorption in the small intestine (enterocytes) ?
- Passive Transport
- Diffusion based on concentration or electrical gradient
- No energy required
- Bidirectional - Active Transport
- Diffusion AGAINST gradient
- Requires ATP
- Used for cation transport - Facilitated Diffusion
- Diffusion along concentratoin gradient
- No energy required, but faster than passive transport
- Facilitated by ‘Carrier Protein’ or channels in membrane
- Ex: Glucose transporters (Glut1) - Pinocytosis
- Like phagocytosis
- Membrane surrounds and engulfs macromolecules
- Ex: low density lipoprotein (LDL)
How is Shistesoma pathological?
Blood Flow from the GIT → Hepatic portal vein → Liver
Shistesoma comes enters through skin via contaminated water → travels through blood stream → settles in the veins next to the GIT entry to the liver, has lots of nutrients to proliferate → lays eggs that get trapped in the liver via the hepatic portal vein → Strong immune response + Chronic inflammation → liver fibrosis
What are different factors that control blood flow? What are the 2 opposing states?
Vasodilation (increased blood flow) vs Vasoconstriction (decreased blood flow)
- Level of local activity → stretch promotes vasodilation
- O2 tension → hypoxia promotes vasodilation
- Hormone levels
- Autonomic nervous System
How do hormone levels affect GI blood flow ?
Cholecystokinin (CCK) → increase blood flow to pancreas/SI/LI
Gastrin → increase blood flow to the stomach
Kinins (bradykinin) secreted by gi glands, act as vasodilators
Which branch of the ANS leads to vasoconstriction vs vasodilation?
Parasympathetic activation → increased blood flow ot pancreas/SI
Sympathetic activation → decreased blood flow to stomach
What is motility in the GI tract monitored by? What are the 2 types of motility?
2 layers of smooth muscle:
- Outer Longitudinal
- Inner Circular
- Surrounded by Serosa → thick CT layer
Segmentation → Circular muscles → mixing of contents + bring them in close proximity with enterocytes for absorption
Peristalsis → Circular + Longitudinal muscles → forward movement of contents
What are the 2 types of smooth muscles fibers? (not circular vs longitudinal)
Phasic → Rapid contraction and relaxation (main bodies of GI tract)
- For mixing of the contents
Tonic → Slow and sustained contraction (spincter regions)
- Important for maintained contractions
How ar intestinal muscle fibers organized to allow for motility of the contents?
- Muscle fibers are organized in bundles of ~1000 parallel fibers → they extend longitudinally or circulary around the gut
- Muscle fibers connected by gap junctions → for coordinated activity
- Bundles are fused at many points → called syncytium
What is the basal electric rate of slow waves in the Stomach (pyloric/distal region) Duodenum vs Jujenum vs Ileum?
Slow waves = small undulating changes in the resting membrane potential
Amplitude = 5 - 15 mV
Frequencies:
Stomach → 3x/min
Duodenum → 12x/min
Jujenum → 8x/min
Ileum → 8x/min
Set by pacemaker cells → interstitial cells of Cajal
- Positioned between muscle cells → AP are transmitted throughout the muscle sheet (directional, does not cause APs in the muscles)
What are features of the pacemaker activity in the GI tract?
- Pacemaker cells in GI smooth muscle control contraction → interstitial cells of Cajal
- waves most abundant in longitudinal smooth muscle
- under nervous or hormonal influences
- continuous oscillation of resting membrane potential (BER) → does not cause spikes/contraction by itself
What are the main features of the Spike potentials of the GI muscles ?
Action Potentials:
- Threshold = -40 mV
- Resting Membrane Potential ~ -50 to -60 mV
Frequency: 1 - 10x/sec
- Depends on the increase on top of the slow wave potential (distension for ex, ACh)
Duration: Spikes last from 10-40 ms → 10-40x longer than in nerve fibers
Origin → Generated by Calcium-Sodium channels
- Much slower than skeletal muscle (only Na channels)
What factors can lead to changes in the baseline RMP (resting membrane potential) on top of the BER?
Depolarization promoted by:
- stretch of the muscle (myogenic reflex, mechanoreceptors)
- acetylcholine
- cholinergic parasympathetic fibers (leads to release of ACh → excitatory)
- GI hormones
Hyperpolarization promoted by:
- norepinephrine and epinephrine
- noradrenergic sympathetic fibers (leads to release of noradrenaline)
How does Calcium influx lead to muscle contraction? What is it related/not-related to?
Calcium influx → promotes calmodulin-dependent activation of myosin filaments
No Ca2+ influx during slow waves
Ca2+ influx accompagnies the spike potentials
How can heart failure / decreased cardiac output lead to an Ischemic gut?
Decreased cardiac output leads to:
- Decreased intestinal perfusion
- Increased blood viscosity (microthrombi)
- Generalized vasoconstriction
→ intestinal ischemia
What are physiological consequences of intestinal ischemia of the function of the small intestine?
Ischemia = inadequate blood supply, leads to:
- Decrease energy substrate supply + Hypoxia and anaerobic metabolism
↓ - Production of cytotoxic compounds (ROS)
↓ - Oxidization of cell membrane lipids
↓ - Irreversible changes in cell permeability + Disruption of active transport systems
↓ - Cell death, decreased absorption
diffusion of toxic substances to blood (shock) due to commensal microbiota infiltrating inside the systemic circulation (inflammatory storm)
What can be origins of the pain due to an ischemic gut?
Ischemia leads to:
Local inflammatory response
Inflammation of parietal peritoneum if it breaches to the tissues
What normal homeostatic mechanisms control blood flow in the gut?
- Level of local activity
- Hormone levels (CCK, gastrin)
- Kinins (bradykinin) secreted by GI glands for vasodilation
- Decreased O2 concentration increases blood flow
- Increase in adenosine causes vasodilation (hypoxanthine → superoxide & hydroxyl-free radicals)
- Autonomic Nervous System
How can a patient with an ischemic gut due to reduced cardiac output be treated?
- Maintain blood pressure, cardiac output and O2 supply
- Treat the infection
- Provide electrolytes and fluid replacement (for those the patients can’t absorb)
- Abdominal surgery to resect necrotic gut
What are the 2 major functions of the stomach?
- Motor functions:
- Storage of food
- Churning and mixing “Chyme”
- Regulating entry into duodenum - Secretory functions:
- Stomach = major secretory organ (2L/day)
- Exocrine – secretion of gastric juice into lumen H+, pepsinogen
- Paracrine – stimulates gastric juice secretion histamine
- Endocrine – acts locally and distally (Ex: Gastrin acts locally in the stomach, distally in SI, pancreas, liver)
What are the 2 main secretory regions of the stomach?
Proximal stomach (Fundus + Body):
EXOCRINE region → secretes mized gastric juices into the lumen of the stomach
- Storage, stretches/relaxes when receiving a meal
- Parietal/Oxyntic cells → secrete HCl and Intrinsic factor
- Chief cells → secrete pepsinogen
- Mucus neck/Goblet cells → secrete mucin & bicarbonate
Distal stomach (Antral + Pyloric regions):
ENDOCRINE region → secrete to circulation and proximal cells
- More motor activity for mixing of the chyme
- G cells → secrete Gastrin
- ECL cells (EnteroChromaffin-Like cells) → secrete Histamine
- D cells → secrete Somatostatin
What are 2 major reasons to perform partial gastrectomy?
- Weight loss → reduce the capacity of the stomach
- Stomach tumor
What are important functions of the proximal stomach?
- Storage of large quantities of food until it can be processed in the stomach and moved to the duodenum → muscles relax after a meal
- Mixing food with gastric secretions to form chyme
- Slow emptying of chyme from the stomach to the duodenum at a rate suitable for proper digestion and absorption in the small intestine
*Stomach Absorption: Aspirin, Alcohol (not much other absorption)
How would the composition of the gastric secretions
change after proximal gastrectomy?
Proximal Stomach Produces Mixed Gastric juice ~2 liters per day:
- Parietal juice:
- HCl → denature proteins
- Pepsinogen → break down proteins
- Intrinsic Factor → binds to Vit B12 for absorption in the Ileum - Alkaline juice (mucous-producing cells)
**Gastric juice is isotonic with plasma
What is refered to as the Oxyntic region?
Fundus + Body of the stomach, where we find oxyntic cells (parietal cells)
what is the importance of surface epithelial cells at the top of pits in the stomach?
- They protect cells in the gastric pit
- Secrete bicarbonate and mucin to protect tissue against the gastric mucosa
- They are connected by tight junctions → preent leakage of the gastric juice
What cells are responsible for secretion of gastroferrin? What is its importance?
Parietal/Oxyntic cells in the proximal stomach secrete gastroferrin
It is needed for absorption of Fe2+, binds to it and protects it to be later absorbed at the level of the Ileum
What are features of Parietal cells?
What mechanism allows secretion of its product?
- Found in proximal stomach
- Secret HCl, Intrinsic factor, Gastroferrin
- Lots of mitochondria to generate the energy required to pump H+ against the concentration gradient
- Canaliculi at the apical surface increase the surface area for secretion
Mechanism of secretion of HCl requires Active Transport:
1) Uptake of CO2 from blood
2) Carbonic Anhydrase generates Bicabonate + H+
3) Active transport of HCl into lumen coupled with Bicarbonate exchanged for Cl- in the blood
*Transport of H+ and Cl- into stomach lumen requires ATP (active exchange of K+)
*Net exchange of Cl- for HCO3- → increase blood pH
What are the main features of mucous cells?
Goblet cells in the proximal stomach
Secrete mucous and alkaline gastric juice to protect the epithelium from the acid gastric juice
What are the main features of Chief cells?
Peptic cells in the proximal stomach
Secrete pepsinogen → inactive
*Pepsinogen is hydrolyzed in the presence of H+ to pepsin (activated)
What is postprandial alkaline tide?
For every H+ moved into the lumen of the stomach (as HCl-), 1 HCO3- is moved into the bloodstream
For a patient with a partial gastrectomy in the proximal stomach, how can postprandial alkaline tide in the stomach lead to mild metabolic acidosis in the blood?
At the level of the Stomach, the blood becomes more basic as H+ is secreted into the lumen of the stomach
Later in the GI tract, Pancreatic, Liver & SI secretions into the lumen of the GI tract are more basic trying to neutralize the contents → inverse mechanism leads to H+ entering the blood
A patient that does not have bicaronate secretions in the blood at the level of the proximal stomach, only gets the H+ from later in the GI tract which leads to a net decrease in pH
How can a patient which had a partial gastrectomy in the proximal stomach suffer from anemia?
How can this be cured?
- No/Less secretion of instrinsic factor → no absorption of Vit B12 → Megaloblastic anemia (abnormally large blood cells)
- Because vitamin B12 is essential for DNA synthesis and cell division, particularly in the bone marrow
Cured by injections of B12, can’t be given orally as it can’t be absorbed
- No/Less secretion of gastroferrin → reduced absorption of Iron at the level of the Ileum → impaired RBC function (heme biosynthesis)
Food has Fe3+ → {HCl} → Fe2+ which is bound by Gastroferrin
Cured by Fe2+ supplements given orally as gastroferrin is not 100% required, but needs to be under Fe2+ form
What are features of G cells?
Part of the Antral and Pyloric regions (Endocrine)
- Has luminal membrane to sense gastric contents
- Secrete gastrin → promotes gastric juice secretion by parietal cells + promotes Histamine release by ECL cells
What are features of ECL cells?
Enterochromaffin-like cells
Part of the Antral and Pyloric regions (Endocrine)
- Secrete Histamine
- Binds to H2 receptor on parietal cells to release acid (gastric juice)
- Gastrin secreted by G cells binds to CCK-B receptors on ECL cells → promote histamine release
- No luminal membrane to sense gastric contents
What are features of D cells?
Part of the Antral and Pyloric regions (Endocrine)
- Has luminal surface in contact with gastric lumen/contents
- Has receptor for Gastrin
- Secrete Somatostatins → Inhibits Gastrin secretion (negative feedback loop)
- Stimulated by H+
- Somatostatins negatively regulate acid production
What is Gastrin?
What cells produce it?
What receptor does it bind to?
- Gastrin is a peptide hormone
- Produced by G cells (open APUD) in mucosa of gastric antrum and some in duodenal mucosa
Function activity resides in the terminal 4 AA
- Pentagastrin = terminal 4 AA + Alanine → can be used to stimulate Acid secretion in the stomach
Gastrin mainly binds to CCK-B receptors (on ECL and Parietal cells) and less to CCK-A receptors (on ‘D’ cells)
- Gastrin stimulate ECL and Parietal cells
- CCK (secreted from duodenum) competes for CCK-B R binding (doesn’t activate the cells, just blocks the receptor)
- CCK is inhibitory for gastric function (negative feedback)
What are open APUD cells?
APUD = amine precursor uptake and decarboxylation
Open = have luminal surface, can sense the gut contents
*They need amines to be able to form their secretions
What is the effect of CCK secretion?
Gastrin binds mainly to CCK-B receptors (ECL and Parietal Cells) and less to CCK-A receptors (‘D’ cells):
- Gastrin stimulates ECL and Parietal cells
- CCK (secreted from duodenum) competes for CCK-B R binding
- CCK is inhibitory for gastric function (negative feedback)
Ex: After a fatty meal, we don’t need to break down protein so we want to decrease H+ release
What factors stimulate secretion of gastrin by G cells?
- Food (peptides, AA)
- Neurotransmitters (ACh) → from mechanoreceptors sensing distention, from vagus nerve, vagal-vagal reflexes
- Gastrin release protein (GRP)
What negative feedback loop regulates gastrin secretion?
D cells secrete Somatostatin which negatively regulates acid production
D cells are stimulated by H+ in the lumen
- Express receptor for gastrin (negative feedback) → when high gastrin, then secrete somatostatin
Somatostatin secreted into the blood → binds to somatostatin receptors (ST-R) on ECL and G cells → slows down gastrin and acid secretion
What is the net effect of a partial gastrectomy of the proximal vs distal stomach?
Proximal stomach:
- Less H+ secretion
- Low Gastroferrin
- Low IF secretion
→ Matabolic acidosis + anemia
Distal stomach:
- Less H+ secretion
- Low Gastroferrin
- Low IF secretion
→ Matabolic acidosis + anemia
Same effects because of the tight feedback regulation between parietal/chief cells vs G/ECL/D cells
What are the 3 phases of gastric function?
- Cephalic phase:
- Before food (anticipatory)
- Stimulated by neurotransmitters (Vagus impulse)
- Unconditioned reflex
- Mediated by ACh signals → vagus nerve endings at secretory cells (G, ECL, Chief, Parietal cells)
- Motility reduced (no need for motility yet, no food in the stomach) - Gastric phase
- Stimulated by food in stomach (distention)
- Nervous, mechanical and doos-stimulated inputs
- Stimulated by secretagogues (peptides, AA)
- Stimulatory input from nervous system (vagal-vagal reflexes)
- Stomach empties at a rate proportional to the volume of chyme
- Myogenic reflex in pylorix region - Intestinal phase
- Stimulated by food in duodenum (stretch, fat, acid)
- Largely inhibitory (feedback to the stomach)
Stomahc motility is reduced by Secretin and CCK
