Exocrine Pancreatic Secretions Flashcards
What does pancreatic juice consist of?
Pancreatic juice consists consists of hydrolases as well as sodium bicarbonate
What is hydrolase
Hydrolase is a pancreatic digestive enzyme which is secreted from the exocrine acini
Where is the aqueous alkaline solution secreted from
It is secreted from the epithelial cells lining the small ductules and larger ducts which lead from the acini
When is pancreatic juice juice secreted?
Pancreatic juice is secreted most abundantly in response to the presence of chyme in the upper portions of the small intestine.
What are the aqueous components of the pancreatic juice
It can be divided into acinar cell secretion as well as ductule cell secretion/output.
Discuss acinar cell secretion
80% of pancreas comprise of acinar cells which secrete small volume of isotonic fluid containing pancreatic digestive enzymes
The acinar fluid resembles plasma in its conc. of soduim,chloride, bicarbonate and potassium
It constitutes the basal exocrine secretion, but is equal to only about 2% of the maximal secretory rate of pancreatic juice
Discuss the ductule cell secretion/output
Comprise about 4% of the pancreas.
Large volumes of water and Sodium-Bicarbonate to neutralize the acidic chyme is emptied into the stomach into the duodenum is primarily secreted by the ductule cells
Discuss what happens at various rates of secretion
At all rates of secretion, pancreatic juice is essentially isotonic with plasma.
At low rates of secretion, the ionic composition remains to be a solution of Na+ and Cl-
As the rate of secretion increases in response to stimulation, Na+ and HCO3- predominate.
The ductule cells, including the centroacinar cells, and even some of the epithelial cells lining the intralobular ducts, are responsible for the high bicarbonate content.
Secretion of Bicarbonate
The ductule cells possess of a
mechanism to secrete HCO3 - against both its chemical and electrical gradient into the ductule lumen
- Stimulated ductule cells activates aCl-/HCO3-antiporter in the apical membrane.
This exchange process is based on a mechanism
known as secondary active
countertransport. (Why?)
Secretion of HCO3- depends on high
luminal Cl-, which is possible when
the Cl channels (2)are activated by cAMP in response to stimulation by secretin.
The secretin-stimulated secretion can have a HCO3-concentration as high as 145 mmol/L in the ductule lumen.
This provides a large quantity of alkali in the pancreatic juice.
The increased cAMP also let H+-pumps (3) move to fuse with the basolateral membrane. These Na+/H+ antiporters represents a secondary active transport mechanism.
The role of Na+,K+-ATPase on the basolateral membrane is that of primary active transport (4), creating an electrochemical gradient for Na+ to move into the cell on the H+ -pump (3), in exchange for H+,which leaves the cell.
CO2 now diffuses readily into the cell (5), combining with OH- of water to form HCO3-.
The formation of HCO3-is catalysed by carbonic anhydrase (CA). The continued movement of H+
across the basolateral membrane drives this reaction and leads to a build-up of HCO3-, resulting
in the movement of HCO3-across the apical membrane in exchange for Cl-
(1).
Much of the luminal Na+ diffuses through paracellular space (6).
Most of the Na+and HCO3-in pancreatic juice is derived from plasma.
The movement of these ions into the duct lumen also creates an osmotic gradient that causes osmosis of water
What is the role of bicarbonate in the pancreatic juice
It flows through the duct system,esp the larger intralobular ducts and even extralobular ducts, the HCO3 - moves down its concentration gradient, leaving the ducts in exchange for Cl-
This Cl-, HCO3 - exchange mechanism is not effective when the secretory rate begins to increase, and pancreatic juice will contain primarily HCO3-at concentrations of 115 up to 145 mmol/L.
But at low secretory rates, there is enough time for the
exchange to occur and Cl- becomes the predominant anion
How does the secretion of pancreatic digestive enzymes occur
They are secreted by acini though the stimulation of Cholecystokinin(Duodenal hormone) and Acetylcholine(Parasympathetic neurotransmitter)
They contain proteolytic enzymes.
Name the proteolytic Enzymes
Trypsin
Chymotrypsin
Carboxypolipeptidase
Pancreatic alpha-amylase
Pancreatic lipase
Cholesterol esterase
Phospholipase
Trypsin .
is an endopeptidase, splitting peptide bonds on
the C-terminal side of Lys and Arg
Chymotrypsin
An Endopeptidase, hydrolyses the peptide bond on C-terminal side of aromatic amino acids (Phe, Tyr, and Trp).
These two enzymes thus split whole
and partially digested proteins into peptides of various sizes but do not cause release of individual amino acids.
Pancreatic alpha-amylase
Hydrolyses polysaccharides such as starches and glycogen to form
disaccharides and a few trisaccharides.
The main enzymes for fat digestion:
Pancreatic Lipase
Cholesterol Esterase
Phospholipase
Pancreatic lipase
Which is capable of hydrolysing
triacylglycerols into free fatty acids and 2-monoacylglycerols.
Cholesterol esterase
Hydrolyses cholesterol esters
Phospholipase
Splits fatty acids from phospholipids
Prevention of autodigestion of the pancreatic tissue
Proteolytic enzymes are released into the pancreatic ducts in their inactive forms
trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.
They only become activated when entering the duodenal and jejunal lumen.
The reason is the localisation of the enzyme called enterokinase (enteropeptidase), which is expressed on the surface of enterocytes of the upper intestinal mucosa under influence of CCK stimulation.
Enterokinase hydrolyses trypsinogen present in chyme into trypsin plus a short peptide. Active trypsin can then also convert other trypsinogen molecules, as well as chymotrypsinogen and procarboxypolypeptidase into their active peptides.
Thus, once a small amount of trypsin is
formed, a catalytic chain reaction of activating all protease precursors within the lumen of the
duodenum and jejunum occurs.
Pancreatic acini secrete a peptide called trypsin inhibitor (or Kazal inhibitor) that
complexes with any small amount of trypsin which may find its way into the pancreatic
ductal system.
Therefore, any activation of the proteolytic enzymes while they are still
in the pancreatic ducts is inhibited, preventing digestion of the pancreas itself. With
inflammation or severe injury of the pancreas or when a duct becomes blocked, large
quantities of pancreatic juice may accumulate in the damaged area and the effect of
trypsin inhibitor overwhelmed, in which case activated trypsin can initiate autoproteolysis of the entire pancreas within a few hours.
The condition is called acute
pancreatitis. In 5% of cases the condition is extremely serious and even lethal because
of accompanying circulatory shock when the enzymes leak into the abdominal cavity,
resulting in the digestion of blood vessels, formation of a haematoma, and generalised
peritonitis.
Acute pancreatitis in any case leads to a lifetime of pancreatic insufficiency.
The presence of high concentrations of alpha-amylase in the blood can confirm the diagnosis
of acute pancreatitis.
Prevention of autodigestion of the pancreatic tissue
Proteolytic enzymes are released into the pancreatic ducts in their inactive forms
trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.
They only become activated when entering the duodenal and jejunal lumen.
The reason is the localisation of the enzyme called enterokinase (enteropeptidase), which is expressed on the surface of enterocytes of the upper intestinal mucosa under influence of CCK stimulation.
Enterokinase hydrolyses trypsinogen present in chyme into trypsin plus a short peptide. Active trypsin can then also convert other trypsinogen molecules, as well as chymotrypsinogen and procarboxypolypeptidase into their active peptides.
Thus, once a small amount of trypsin is
formed, a catalytic chain reaction of activating all protease precursors within the lumen of the
duodenum and jejunum occurs.
Pancreatic acini secrete a peptide called trypsin inhibitor (or Kazal inhibitor) that
complexes with any small amount of trypsin which may find its way into the pancreatic
ductal system.
Therefore, any activation of the proteolytic enzymes while they are still
in the pancreatic ducts is inhibited, preventing digestion of the pancreas itself. With
inflammation or severe injury of the pancreas or when a duct becomes blocked, large
quantities of pancreatic juice may accumulate in the damaged area and the effect of
trypsin inhibitor overwhelmed, in which case activated trypsin can initiate autoproteolysis of the entire pancreas within a few hours.
The condition is called acute
pancreatitis. In 5% of cases the condition is extremely serious and even lethal because
of accompanying circulatory shock when the enzymes leak into the abdominal cavity,
resulting in the digestion of blood vessels, formation of a haematoma, and generalised
peritonitis.
Acute pancreatitis in any case leads to a lifetime of pancreatic insufficiency.
The presence of high concentrations of alpha-amylase in the blood can confirm the diagnosis
of acute pancreatitis.
Regulation of the pancreatic secretion-Acetylcholine
Released when parasympathetic vagus nerve fibres carry impulses to the pancreas which binds to the muscarinic receptors on the basolateral surface of acinar cells.
Intracellular Ca2+ levels rise intiating phosphorylation of structural and regulatory protiens
Acetylcholine
Released when parasympathetic vagus nerve fibres carry impulses to the pancreas which binds to the muscarinic receptors on the basolateral surface of acinar cells.
Intracellular Ca2+ levels rise, initiating
phosphorylation of structural and regulatory proteins involved in the fusion
of secretory granules with the apical membrane and subsequent discharge of
the enzymes.
Although activation of gastro-pancreatic vagovagal reflexes has been described as a mechanism responsible for cholinergic impulses,
most acetylcholine is released as part of the cephalic phase of pancreatic
control.
Cholecystokinin (CCK)
a polypeptide containing 33 amino acids, is secreted by the I-cells of the
duodenal and upper jejunal mucosa when chyme enters the small intestine.
The I-cells release CCK into the interstitial space in response to smaller peptides and amino acids (products of partial protein digestion) present in the intestinal lumen, and also by the presence of long-chain fatty acids (products of partial fat digestion).
Circulating CCK has a half-life of 5 minutes. Its main functions are:
Increased pancreatic acinar fluid rich in enzymes when CCK binds to CCK-A receptors on
acinar cells, increasing the intracellular Ca2+ levels.
Rhythmical contractions of the wall of the gallbladder (with simultaneous relaxation of the
sphincter of Oddi).
Competitive inhibition of gastrin’s effect on gastric emptying and secretion.
Stimulating the expression of enterokinase on the brush border of small intestinal enterocytes
CKK main functions are:
- Increased pancreatic acinar fluid rich in enzymes when CCK binds to CCK-A receptors on
acinar cells, increasing the intracellular Ca2+ levels. - Rhythmical contractions of the wall of the gallbladder (with simultaneous relaxation of the
sphincter of Oddi). - Competitive inhibition of gastrin’s effect on gastric emptying and secretion.
- Stimulating the expression of enterokinase on the brush border of small intestinal enterocytes
Causes of Acute Pancreatitis
G.E.T.S.M.A.S.H.E.D
G-all stones
E-thanol
T-rauma
S-teroids
M-umps
A-utoimmune
S-corpion venom
H-Hypothermia/Hyperlipidemia
E-RCP
D-rugs
Secretin
Secretin is a polypeptide, containing 27 amino acids, that is present in an inactive form,
prosecretin, in so-called S-cells of the duodenal and jejunal mucosa.
Secretion occurs mainly in
response to acidic chyme in the lumen (pH of 4.5 or below), but also by peptides and amino acids
(products of protein digestion) present in the intestinal lumen.
It has a half-life of 5 minutes
Functions of Secretin
- Secretion of a bicarbonate solution by the ductule
cells of the pancreas and thus an alkaline watery juice. - Inhibits gastric secretion.
- The secretin-dependent bicarbonate-rich pancreatic juice serves to:
3.1 Neutralise the acidic chyme
emptied into the duodenum from the stomach which blocks further
peptic activity by the gastric juices in the duodenum, an essential protective mechanism to
prevent development of duodenal mucosal damage.
3.2 Secretin-dependent bicarbonate
secretion also provides an appropriate pH for action of the pancreatic enzymes, which function
optimally in a slightly alkaline or neutral medium, at a pH of 7.0 to 8.0.
- Phases of pancreatic secretion
Pancreatic secretion also occurs in three phases, the same as for gastric
secretion-cephalic
phase, the gastric phase, and intestinal phase
- Phases of pancreatic secretion
Acidic chyme enters the duodenum casing enteroendocrine cells of the duodenal wall to release secretin, whereas fatty protein-rich chyme induces release of Cholecystokinin
CKK and Secretin enter the bloodstream
Upon reaching the pancreas,CKK induces the realeae of enzyme-rich pancreatic juice.
Secretin causes copious secretion of bicarbonate richpancreatic juice
Secretion of Bile by the liver
Bile secretion is the principal digestive function of the liver. Bile
production is about 600 to 1000 ml/day. The liver cells secrete bile
continually, but most of it is normally stored in the gallbladder until needed
in the duodenum.
Functions of Bile:
- By far the most abundant substances secreted into the bile are the bile salts, responsible for the role that bile plays in lipid digestion and absorption.-
Bile salts:
(i) help to emulsify the large lipid droplets, enabling pancreatic lipase to act on the fat,
and
(ii) they aid in absorption of the digested fat end products
by the intestinal epithelial cells (enterocytes). - Bile serves as a means for excretion of several important waste
products from the blood, including bilirubin and cholesterol.
What are the main components of Bile
Bile Salts
Bile Pigment
Cholesterol
Alkaline electrolyte solution
Storage and concentration of bile in the gallbladder
The capacity of the gallbladder is about 30-60ml
Storage over a 12 hour period can result in bile being stored in about 450ml
This occurs because of active transport of Na+
through the gallbladder epithelium, followed by secondary absorption of Cl- and
water, concentrating the remaining bile constituents.
Composition of bile
Water
Bile salts
Bilirubin
Cholesterol
Bile secretion and release
Secretin via bloodstream stimulate liver ductal secretion
Vagal stimulation causes weak contractions of the gallbladder
CKK causes gallbladder contraction as well as relaxation of the sphincter of oddi
Bile Salts/Acids
The liver synthesises about 0.2-0.6 grams of bile salts daily.
Cholesterol is the precursor which is converted to either cholic acid or chenodeoxycholic acid in about equal quantities.
These two
molecules retain the steroid ring structure, but contain more OH-groups than cholesterol as well
as a 5-carbon side chain (with a polar carboxyl group).
The next step is conjugation of the bile
acids. They combine principally with glycine and to a lesser extent with taurine to form the
amides glyco- and tauro-conjugated bile acids.
Conjugation of bile salts lowers the pK of the bile salts, making them more ionised at the pH
environment of chyme in the intestinal lumen, which means that they act as better detergents.
Also, being ionised, the bile acids are present mainly as sodium salts. Therefore, the term
“bile salts”. (Both bile acids and bile salts are used interchangeably).
Differentiate and list the primary and secondary bile acids
Primary bile acids:
- conjugated cholic acid
- conjugated chenodeoxycholic acid
- crucial in fat digestion and absorption
Secondary bile acids: -deconjugated, dehydroxylated - bacterial action in colon
- Cholic acid>Deoxycholic acid
- Chenodeoxycholic acid>lithocolic acid
Secretion of bile:
Hepatocytes-initial secretion of bile acids, cholesterol and organic constituents
Through biliary system to gallbladder-concentration of bile
Bile salts:
Bile salts are amphipathic( contains hydrophobic
& hydrophilic domains can mix with fat &
water) structures
→ -OH groups on α side of rings
→ formation of water soluble molecular aggregates called micelles which form ‘groups’ that ‘stick
together
Enterohepatic recirculation of bile salts:
The secondary active transport absorbs
primarily conjugated bile salts and occurs in the terminal ileum.
The mechanism is a Na+-bile salt cotransport system powered by basolateral
Na+,K+-ATPases.
Secondary bile salts are absorbed
passively throughout the small intestine
Overall, more than 95% of the bile salts are reabsorbed into the portal blood. In the liver they are all reconjugated, but often not
rehydroxylated.
These bile salts, together with some newly synthesised primary bile acids, are again secreted by the liver.
The Steroid nucleus cannot be degraded in the
body and therefore is is excreted in faeces as:
− bile acids
− free cholesterol
Higher (more often) enterohepatic recirculation> higher quantities of bile secreted less absorption of bile salts> increased liver production
Excessive excretion>
diarrhoea without loss of fat
Cholesterol:
• Cholesterol almost completely insoluble in bile/chyme
– association with bile salts and lecithin micelles
– micelles carry hydrophobic bile substances to GIT for excretion
Normal:
1–2g cholesterol/day secreted into bile – excreted in faeces
= major route for removal of steroid nucleus from body:
free cholesterol
bile salts
What are substances which increase the rate of bile production
Choleretics
Causes of gallstones:
- Too much absorption of water from bile.
- Too much absorption of bile salts from bile.
- Too much secretion of cholesterol in the bile.
- Inflammation of epithelium-Cholesterol begins to precipitate, usually forming
many small crystals of cholesterol on the surface of the inflamed mucosa.