Gastrointestinal System Lectures

PHPY 303.3
Lecture #5,
included in Midterm next week March 28

Instructor: Dr. Francisco Cayabyab

Department of Surgery

Office: Rm. GD30.5 D-Wing,

Health Science Building

Tel: 966-8191

Email: frank.cayabyab@usask.ca
Regulation of Pancreatic
Functions
Structure of Exocrine Pancreas
(Wirsungs duct)

Acinar cells
characterized by
numerous ER and
zymogen granules
(stores enzymes)
ACh, CCK
Duct cells
characterized by
abundant
mitochondria and
microvilli projecting
from apical
membrane
Secretin, ACh
 Pancreatic
Enzymes
Secretory
Products
Bicarbonate, water

Na+, Cl-, H2O, HCO3-

 Three Phases of Pancreatic Secretion
Pancreatic secretion regulated primarily by Cephalic: Vagal efferents to
SECRETIN, CCK, and VAGO-VAGAL REFLEXES pancreas stimulate both
ductules and acinar cells to
secrete
Mediated by ACh, greater
effect on enzymatic than
aqueous component
Cephalic
Gastric: Distension initiates
vagovagal reflexes to pancreas
Gastrin released by protein
digestion products and
Gastric
distension, both play little or
no role in stimulation of human
Intestinal pancreas
Intestinal: Presence of digestion
products and H+ accounts for 50-
80% of pancreatic secretion
Secretin and CCK mediate all
hormonal stimulation of
pancreatic secretion
Vagotomy reduces pancreatic
secretory response
 Factors Causing CCK Release
During Intestinal Phase
CCK-RP from
duodenal cells
and monitor
peptide from
pancreas control
CCK release
from the
duodenal cells
Active trypsin
inactivates CCK-
RP and monitor
peptide, thus
inhibiting CCK
release
Ingestion of
trypsin inhibitors
CCK-RP, CCK releasing peptide, GRP, gastrin-releasing peptide
stimulates
release of CCK
 Secretin and CCK Regulation of
Pancreatic Secretion During Intestinal
Phase (Rodents)

(ACh)
Pancreatic Secretion During Intestinal Phase in Humans

pH <4.5 release of secretin

(release up to pH=3)
But pH of duodenum rarely
drops below 4 to 3.5 (means
FAs, fatty acids low level of secretin release)
AAs, amino acids Secretin effects potentiated by
ACh
Protein and lipid breakdown
products release CCK, which
activates vagovagal reflexes
and ACh release causing
acinar secretion
In humans, small amounts of
secretin released by duodenal
acidification, potentiates
vagovagal reflexes activated by
Dashed lines indicate potentiative interactions. CCK
NB: Human acinar cells lack CCK and gastrin
receptors.
 Cellular Basis of Acinar Secretion
Actin-rich web
A acinar secretion)
No CCK-A or CCK-B receptors in
adult human acinar cells
Acinar cells do not respond to CCK
agonists (Ji B. et al.,
Gastroenterology 2001, 121:1380-
90)
Various species, but
not human, express
CCK-A, CCK-B or both
receptors
Ca2+, the major second
messenger for
secretion of digestive
enzymes by acinar cells
(Muscarinic m3
receptors play most
significant role for
Secretin + ACh (or
secretin + CCK, in other
species) potentiate
each others effect
Cellular Basis of Secretion: Ductular Cells
Na+
H2O
In contrast to acinar cells
that undergo granule
exocytosis, ductular cells
use membrane transport
proteins located in apical
and basolateral poles
ACh See also
Fig. 42-6
textbook,
for details.
Secretin
Membrane transport events
underlying ductular secretion
driven by cAMP, with Ca2+
playing a subsidiary role
In contrast to acinar secretion
(Ca2+ a major player, cAMP
has modulatory role)
Ion Transport Pathways in Pancreatic Duct Cells
Primary stimulus secretin, binds to basolateral GPCR
linked to adenylate cyclase)
cAMP elevation and PKA leads to CFTR phosphorylation
(allows efflux of Cl-)
Apical Cl-/HCO3- provides movement of HCO3- into duct
lumen
H2O and Na+ follow paracellularly in response to
electrochemical gradient
There is some evidence that CFTR is also permeable to
HCO3-

HCO3- from two sources:

intracellularly (carbonic anhydrase, generates H+ and HCO3- (H+
recycled via Na+-H+ exchanger, likely NHE-1)
from bloodstream (from alkaline tide from gastric secretion) via
basolateral Na+-HCO3- cotransporter (NBC), uses low intracellular
Na+ concentration established by the sodium-potassium ATPase
CFTR channel opening, which depolarizes cell, will
secondarily drive HCO3- uptake via NBC
Significance of Pancreatic Secretion
Pancreatic enzymes can provide digestion of all
nutrients (carbohydrates, protein, and fat)
In contrast to gastric and salivary enzymes,
pancreatic enzymes are necessary for adequate
digestion and absorption
Production of pancreatic enzymes cannot fall
<10% of normal level
Otherwise, inadequate nutrition (as seen when
outflow of pancreatic juice into intestine is obstructed)
Clinical Correlation of Abnormal Pancreatic
Secretion: Cystic Fibrosis
CF characterized by
decreased Cl-
secretion and
inability of cAMP to
regulate Cl-
conductance
Abnormal CFTR
channels leads to
severe decrease in
ductal secretion
Results in acinar
secretions
becoming
concentrated and
precipitated within
duct lumengland
destruction
 Pancreatic Pathophysiology
Cystic Fibrosis
Both volume and enzyme content of pancreatic juice are
decreased in CF patients

Pancreatitis
Chronic- patients have decreased volume and bicarbonate
output
Acute- patients have normal secretion,
have high levels of amylase in plasma

Pancreatic Tumours
Decreased volume of secretion

Kwashiorkor (protein-energy malnutrition)

Ductular and acinar secretions depressed, but amylase
secretion continues after trypsin, chymotrypsin, and lipase
activities are no longer seen; inadequate protein intake
 Biliary Tract and
Gallbladder Function

Objectives
Describe the anatomy of biliary system
and major constituents of bile secretions
 Anatomical Arrangement of the
Liver, Gallbladder, and Biliary Tract
The liver, the largest
internal organ, has
diverse functions
Metabolic functions
(carbohydrate, fat and
protein metabolism)
Hepatic ducts carry bile
secretions from liver
Pancreas secretes fluids
and proteinaceous
enzymes
Gallbladder stores bile
Functions of Liver
(1)Production of bile
(2)Metabolic processing of Anterior view
absorbed nutrients
(3)Detoxification (drugs, hormones,
foreign compounds)
Right lobe
Left lobe
(4)Synthesis of plasma proteins
(5)Storage (glycogen, fats, Fe, Cu,
vitamins)
(6)Activation of vitamin D (along
Gallbladder
with the kidney)
(7)Removal of worn-out red cells
(resident macrophages, Kupffer
cells)
(8) Urea production
 Blood Supply of Liver
Portal
Bile salts Hepatic Oxygen
Nutrients Vein (75%)
Artery Nutrients
Drugs (25%)
Bilirubin
Pro-hormones
Hormones
Foreign
substances Drugs

Bile salts Glucose

Bilirubin Plasma proteins
Hepatic
water, ions Bile Urea
Vein
cholesterol Vit. D, Hormones
Metabolites for
Intestine excretion
Microscopic Structure of the Liver
Intrahepatic bile system
composed of hepatocytes separated by large
capillary spaces, called sinusoids
Sinusoids contain phagocytic Kupffer cells
Structural features of liver allow efficient
modification of blood passing through it
Sinusoids have big pores, called fenestrae;
analogous to glomerular capillaries in kidney

Blood supply to liver

75% portal vein;
25% hepatic artery
Blood enters via
vessels in portal triad,
passes through hepatic
sinusoids, leaves via a
central vein, exits liver
via hepatic vein
Interrelationships of Major Cell
Types in Liver
Hepatocytes joined
by tight junctions and
apical membranes
form bile canaliculi
Blood-filled sinusoids
lined by fenestrated
endothelial cells
On loose connective
tissue called space of
Disse
Kupffer cells reside in
sinusoidal lumen,
while stellate cells
(stores lipids, e.g.,vit.
A) found in space of
Disse
Neurohumoral Control of Gallbladder Motility
Nutrients in duodenum
cause CCK release
CCK, via endocrine
and paracrine routes,
activate gallbladder
contraction and relax
sphincter of Oddi
Direct and indirect
effect of CCK on
gallbladder contraction
Secondary
neurotransmitters
released by enteric
nerves due to vago-
vagal reflexes are
ACh, VIP, and NO
Motility Response of Fasting Gallbladder
(NO, VIP)
Between meals, gallbladder
filling promoted by:
liver secretion pressure
high pressure of Sphincter of
Oddi
and receptive relaxation of
gallbladder smooth muscle
Postprandial gallbladder
contraction coincides with
gastric emptying
In between meals, phasic
contractions of sphincter
prevent backflow of
duodenal content into biliary
tree
But occasionally sphincter
muscles relax periodically
with MMC, which serves to
limit stasis of bile secretion
in the common bile duct
In cholesterol gallstone
disease, normal ratio of
cholesterol to biliary lipids
disrupted (gallstones form)
avoid prolonged fasting
or skipping meals
 Gallstones

Two types:
Ca bilirubinates
Cholesterol stones (85%)

Factors promoting formation:

Bile stasis
Cholesterol supersaturation in
bile
Nucleation factors
 Midterm #2 March 28
Material up to and including Motility of
Gallbladder and Gallstones slides