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Transcript
Gastrointestinal Physiology
Most images courtesy Joe Haeberle, UVM
Splanchnic Circulation
• Vasoconstrictors- Ang II, endothelin, NE
(a2-agonists), PGF2a, Vasopressin
• Vasodilators- Ach, Adenosine, Bradykinin,
CGRP, histamine, NO, VIP, b2-agonists
Vasorelaxation
cGMP
GPCR
dilator
Gs
cAMP
Decreased
free Ca++
AC
Vascular Smooth Muscle Cell
Splanchnic Circulation (cont’d)
• Myogenic Control- resistance vessels can close
themselves off in times of high MAP
– a mechanism for autoregulation
• Postprandial Hyperemia- increases in blood flow
to organs in response to a meal
– mediated through intrinsic VIP release
• Villar countercurrent mechanisms- make villi
susceptible to ischemic necrosis
– oxygen is shunted between arteriole and venule
Intrinsic Nervous System
(gut brain)
• Nerves that interconnect within GI organs and
plexuses, independent of the autonomic system.
– Auerbach’s, Meissner’s plexus contribute!
• Receptor neurons are sensory (detect stretch,
damage), effector neurons are motor (cause SM
contraction)
• Excitatory NT’s- Ach, Subst. P
• Inhibitory NT’s- VIP, NO
– what causes contraction/relaxation of smooth
muscle?
Gastrointestinal Smooth Muscle
• Single-unit (gap junctions, coordinated
contraction)
• Activated/inhibited by many
neurotransmitters, hormones
• Contraction can be tonic or phasic
depending on location/purpose of muscle
cells
– GI Wall vs. Sphincter
Smooth Muscle
Excitation/Contraction Coupling
• Slow Waves cause
“Spike Potentials”
during Ach stimulation
• Spike Potentials lead
to increased [Ca++]
• [Ca], hormones
–
–
activate MLCK
phosphorylates MLC
Slow Waves and SM Contraction
Questions:
1. Where are the slow
waves the most frequent
Orad
in the GI system?
2. Which cells initiate slow
Interstitial Cells of
wave activity?
• Slow Waves are regular
changes in SM VM.
• They do not cause SM
contraction unless they reach a
threshold and cause action
potentials.
• They are propagated along the
GI tract.
• Parasympathetic Stimulation
and other inputs increase the
probability that VM will reach
threshold.
Cajal
Slow Waves vs. MMC’s
• In fasting individuals, slow waves persist, but
contractions diminish, until an MMC.
• MMC (migrating motor complex) is a set of
strong contractions that lasts a few minutes in
one section of the digestive tract, then moves
aborally.
• These complexes last 90 minutes and will restart in the stomach approximately every 90
minutes as long as you’re fasting.
• Their roles
– to flush remaining food and bacteria into the large
intestine.
– to tell you that you’re hungry!
GI Smooth Muscle (cont’d)
• Less-obvious differences between Skeletal/Cardiac and
Smooth muscle:
– 1. Primary site of activation is thick filament (myosin light chain)
instead of thin (TnC)
– 2. Smooth muscle undergoes pharmacomechanical coupling
(hormones can contract SM without changing VM.)
• e.g. agents that induce MLC phosphorylation directly
• Similarities:
– 1. Both have actin/myosin and use cross-bridging to contract
• SM has 15:1 ratio of thin:thick filaments
– 2. Both are activated by intracellular [Ca++]
• Smooth Muscle Activators and Inhibitors:
– Activators: Ach, Histamine
– Inhibitors: NO, VIP
Saliva!
• Salivary Amylase
(ptyalin)
• Lingual Lipase
• Mucins (glyco-proteins)
• Fluid
– Hypotonic
– High [K+]
• With increased salivary
flow, [HCO3-]and
osmolarity increase
• Secretion is inhibited
by sleep
Saliva Secretion Control
Esophageal Peristalsis
• 1o Peristalsis:
– Initiated by swallowing
(not after vagotomy)
• 2o Peristalsis:
– Caused by residual food
in esophagus
• Vagal nuclei run the
show (ambiguus, DMN)
• SM Peristalsis persists
after vagotomy (enteric
NS takes over)
Diseases of the Esophagus
• Achalasia:
– Stenosis of LES, dilation of
body of esophagus
• “bird-beak” appearance on
barium study
• Hiatal Hernia
– LES protrudes into thoracic
cavity
• LES tends to be patent due to
negative pressure in thoracic
cavity
• LES Tone:
– Increased by Ach, Gastrin
– Decreased by
Sympathetics, PGE1
Acid Regulation in the Stomach
More Acid Regulation
Gastric Emptying
• Contraction in the
stomach
– Orad <<<< Caudad
(3/minute)
– Primarily peristaltic
• Solid food is usually
forced back into
stomach for mixing
• Duodenum contracts
much more often but
is phasic
(pseudosphincter)
Regulation of Gastric Emptying
• Chyme entering the duodenum
activates intestinal receptors.
• This leads to increased
contraction of the duodenum
and decreased contraction of
the stomach (Delayed Gastric
Emptying)
• Secretin, CCK, and GIP
(enterogastrone) are released
by the duodenum and feed
back on the stomach to slow
down.
Stomach Pathophysiology
• Dumping Syndrome
– Uncontrolled gastric emptying due to lack of feedback
inhibition by duodenum
• post-surgical
• neurological deficit
– Un-digested food makes it to the colon
– Patient barely makes it to the bathroom
• Pyloric Stenosis
– Projectile vomiting
– Pediatric disease
• failure to thrive
• projectile vomiting after breast feeding (wall’s sign)
• caused by atresia, improper formation of duodenum
Gastric and Duodenal UlcersH. pylori
• Gastric-stomach. Duodenal-obvious.
• Peptic- hydrochloric acid/pepsin present
• 80% of gastric, 90% of duodenal ulcers are
due to H. pylori infection
– weakens mucus barrier
– causes acid production (decreased
Bicarb)
• NSAIDs can also contribute (COX-1)
• Gastrin Carcinomas- secrete gastrin
– cause excessive acid secretion
• Treatment?
– triple therapy (2 antibiotics, one antacid or
bismuth)
– vagotomy
Pancreatic and Bile Secretions
• Acid in Duodenum activates
Secretion of Secretin to initiate
HCO3- secretion
• AA, Lipids stimulate Gastrin
(quick response) and CCK
(prolonged response) to initiate
pancreatic enzyme secretion.
• CCK also causes GB contraction,
Sphincter of Oddi relaxation, and
increased Bile Salt excretion by
the liver.
Components of Bile
• 50% Bile Acids (Cholic,
chenodeoxycholic, deoxycholic, and
lithocholic acid
– Product of Cholesterol + 7aHydroxylase, most is recycled from
distal ileum
– Form micelles- amphipathic
– pK= approx. 7 if unconjugated
– conjugated to taurine or glycine- pK
goes down, allows them to be soluble
in the intestine 
• Phospholipids (lecithin)
– solubilized by bile salts
• Cholesterol
• Bile pigments
– bilirubin glucuronide
Bilirubin Metabolism
senescent
RBC
heme
BilirubinAlbumin
Adduct
Macrophages
(spleen)
Bilirubin (indirect)
Urine Systemic Circulation
(urobilin)
Feces
(stercobilin)
Bilirubin Glucuronide
Portal Circ.
Urobilinogen
Bile Duct
Intestinal Flora
Hepatocyte
Enterohepatic Circulation
•
•
•
•
•
Most ile acids are taken up by
distal ileum epithelial cells by 2o
active transport when they are no
longer needed for digestion.
They travel to the liver via the
portal vein and are taken up by
hepatocytes through the NTCP
channel for recycling.
They re-enter the bile canaliculus
through the BSEP (bile salt
exchange pump)
Other pumps exist for bilirubin
glucuronide (MDR2), cations
(MDR1) and phospholipids
(MDR3).
Bile acid-dependent bile secretion
involves osmotic gradients created
by the transport of bile acids.
Liver Pathophysiology- Cholestasis
• Cholestasis is the absence of bile flow
– 2 Main Causes:
• Failure to secrete bile acids and salts (no osmotic
gradient)
• Obstruction of the biliary tree (cholelithiasis,
cholangitis, tumor)
– Cholestasis leads to jaundice (yellow
skin/sclera) due to bilirubin backup in plasma
• Indirect Bilirubin- unconjugated
• Direct Bilirubin- conjugated
Intestinal Reflexes
• Vagovagal - Vagal sensory nerves relay stretch
information to the brainstem, releasing vagal efferents to
(e.g.) parietal and G cells in the stomach.
• Intestinointestinal- distention of one portion of the
intestine leads to decreased contractions caudad of the
bolus.
• Gastroileal, gastrocolic - Stomach activity leads to
ileocecal relaxation and increased mass movements in
the colon
– These reflexes are mediated through both long and short
nervous pathways (extrinsic and intrinsic) and hormones (CCK,
gastrin)
Absorption of Sugars
• Polysaccharides are broken down in the
mouth, stomach, and small intestine
• Disaccharidases (e.g. sucrase) further
digest them into monosaccharides, which
are taken up by special transporters:
2’ AT
fac. diffusion
fac. diffusion
Absorption of Water/ Lytes
• Most water is absorbed in the small
intestine (approx. 7-9 L/ 24 hours!),
another 600 mL/day is absorbed in the
colon.
• Small intestine- water follows nutrients
• Large intestine- water follows electrolytes!
– Na+ enters via its concentration gradient,
pumped out the basolateral side by ATPase
– Cl- is exchanged for HCO3-, which is excreted.
Absorption of Proteins/ Lipids
SCFA’s
• Good bacteria in the colon produce Short
Chain Fatty Acids from carbohydrates.
• These acids have been shown to kill
harmful bacteria and nourish colon
epithelial cells.
• The End