1. PANCREAS Dr. Zainab H.H. Dept. of physiology College of medicine Al-Nahrain University

2. Learning objectives Learning objectives Describe the pancreatic secretion Describe the pancreatic secretion Describe the function of cystic fibrosis transmembrane conductance regulator (CFTR) Describe the function of cystic fibrosis transmembrane conductance regulator (CFTR) Describe the regulatory mechanisms of pancreatic secretion Describe the regulatory mechanisms of pancreatic secretion List the enzymatic components of pancreatic secretion List the enzymatic components of pancreatic secretion

4. PANCREAS -is present outside GI but connected to it by a duct. -has two components –Exocrine 90%: produces several digestive enzymes –ducts will secret an electrolyte solution that contain large amounts of water & bicarbonate ions –Endocrine 2%: produces hormones such as insulin

5. Composition of the pancreatic juice: –The volume is 1-1.5 liter per day. –PH is 8 –It contains water and different electrolyte - CATIONS (Na ⁺, K ⁺, Ca ⁺⁺, Mg ⁺⁺ ) - ANIONS (HCO3 ⁻, Cl ⁻, SO4 ⁼, HPO4 ⁼ ) - ANIONS (HCO3 ⁻, Cl ⁻, SO4 ⁼, HPO4 ⁼ ) –neutralizing acid chyme emptied by stomach –organic constituents: different digestive enzymes for digestion of protein, fat and CHO.

7. Acinar cells …….produce:  hydrolytic enzymes aid in digestion of fats, proteins, carbohydrates, and nucleic acids  secretagogues, -In apical region of acinar cells -is secretory granules -stimulate pancreatic enzyme secretion. - -causing an increase in cytosolic Ca2+Concentration. - they are : A-acetylcholine, secreted from vagal efferents, B-cholecystokinin;

9. PANCREATIC DUCT…. Secretion: Centroacinar and ductal cells produce the initial aqueous secretion, which is isotonic and contains Na, K, Cl, and HCO3 Centroacinar and ductal cells produce the initial aqueous secretion, which is isotonic and contains Na, K, Cl, and HCO3 This initial secretion is then modified by transport processes in the ductal epithelial cells as follows: This initial secretion is then modified by transport processes in the ductal epithelial cells as follows: The apical membrane of ductal cells contains a Cl –HCO3 exchanger, and the basolateral membrane contains Na –K ATPase and an Na –H exchanger. The apical membrane of ductal cells contains a Cl –HCO3 exchanger, and the basolateral membrane contains Na –K ATPase and an Na –H exchanger. In the presence of carbonic anhydrase, CO2 and H2O combine in the cells to form H2CO3. H2CO3 dissociates into H and HCO3. In the presence of carbonic anhydrase, CO2 and H2O combine in the cells to form H2CO3. H2CO3 dissociates into H and HCO3. The HCO3 is secreted into pancreatic juice by the Cl-HCO3 exchanger in the apical membrane. The HCO3 is secreted into pancreatic juice by the Cl-HCO3 exchanger in the apical membrane. The H is transported into the blood by the Na –H exchanger in the basolateral membrane. The H is transported into the blood by the Na –H exchanger in the basolateral membrane.

10. The net result, or sum, of these transport processes is net secretion of HCO3 into pancreatic ductal juice and net absorption of H ; absorption of H causes acidification of pancreatic venous blood The net result, or sum, of these transport processes is net secretion of HCO3 into pancreatic ductal juice and net absorption of H ; absorption of H causes acidification of pancreatic venous blood The Na and K concentrations are the same as their concentrations in plasma, but the Cl and HCO3 concentrations vary with pancreatic flow rate. The Na and K concentrations are the same as their concentrations in plasma, but the Cl and HCO3 concentrations vary with pancreatic flow rate. Cl− is recycled by Cl− channel from cell to lumen via: cystic fibrosis transmembrane conductance regulator (CFTR) Cl− is recycled by Cl− channel from cell to lumen via: cystic fibrosis transmembrane conductance regulator (CFTR) ■ Na+ secretion : is secreted into duct lumen following HCO3 − secretion;  water :  follows by osmosis  produce fluid secretion.

13. Which of the following is true about the secretion from the exocrine pancreas? Which of the following is true about the secretion from the exocrine pancreas? (A) It has a higher Cl– concentration than does plasma (B) It is stimulated by the presence of HCO3 – in the duodenum (C) Pancreatic HCO3– secretion is increased by gastrin (D) Pancreatic enzyme secretion is increased by cholecystokinin (CCK) (E) It is hypotonic

14. Effect of Flow Rate on Composition of Pancreatic Juice At the highest pancreatic flow rates (more than 30 mL/min), the HCO3 concentration of pancreatic juice is highest (and much higher than plasma HCO3), and the Cl concentration is lowest. At the highest pancreatic flow rates (more than 30 mL/min), the HCO3 concentration of pancreatic juice is highest (and much higher than plasma HCO3), and the Cl concentration is lowest. At the lowest flow rates, HCO3 is lowest and Cl At the lowest flow rates, HCO3 is lowest and Cl is highest The Na and K concentrations in pancreatic juice remain constant. The Na and K concentrations in pancreatic juice remain constant.

15. Regulation of Pancreatic Secretion Pancreatic secretion has two functions: Pancreatic secretion has two functions: (1) to secrete the enzymes necessary for digestion of carbohydrates, proteins, and lipids; the enzymatic portion of pancreatic secretion performs these digestive functions; (2) to neutralize H in the chyme delivered to the duodenum from the stomach

16. The enzymatic and aqueous portions are regulated separately: The enzymatic and aqueous portions are regulated separately: The aqueous secretion is stimulated by the arrival of H in the duodenum, The aqueous secretion is stimulated by the arrival of H in the duodenum, The enzymatic secretion is stimulated by products of digestion (small peptides, amino acids, and fatty acids). The enzymatic secretion is stimulated by products of digestion (small peptides, amino acids, and fatty acids).

17. REGULATION OF PANCREATIC SECRETION: 1.Nervous by vagus. 2.Hormonal a- Cholecystokinin-pancreozymin CCK. b- Secretin. PHASES OF PANCREATIC SECRETION: 1.Cephalic and Gastric phase: -acetylcholine released by vagal nerve. -secretion is rich in enzymes and poor in water & bicarbonate. -accounts for 20% of total secretion of pancreatic enzymes after a meal. 2. The intestinal phase is the most important phase and accounts for approximately 80% of the pancreatic secretion

18. Acinar cells (enzymatic secretion) have : Acinar cells (enzymatic secretion) have : 1. receptors for CCK (CCK-A receptors) 2. muscarinic receptors for ACh. During the intestinal phase, CCK is the most important stimulant for the enzymatic secretion. During the intestinal phase, CCK is the most important stimulant for the enzymatic secretion. The I cells of intestinal mucosa are stimulated to secrete CCK by the presence of amino acids, small peptides, and fatty acids in the intestinal lumen. The I cells of intestinal mucosa are stimulated to secrete CCK by the presence of amino acids, small peptides, and fatty acids in the intestinal lumen. ACh stimulates enzyme secretion and potentiates the action of CCK by vagovagal reflexes ACh stimulates enzyme secretion and potentiates the action of CCK by vagovagal reflexes

19. Ductal cells (aqueous secretion of Na+, HCO3-, and H2O). Ductal cells (aqueous secretion of Na+, HCO3-, and H2O). have receptors for: have receptors for: CCK, ACh, and secretin. Secretin, which is secreted by the S cells of the duodenum, is the major stimulant of the aqueous HCO3 -rich secretion. Secretin, which is secreted by the S cells of the duodenum, is the major stimulant of the aqueous HCO3 -rich secretion. Secretin is secreted in response to H in the lumen of the intestine, which signals the arrival of acidic chyme from the stomach. Secretin is secreted in response to H in the lumen of the intestine, which signals the arrival of acidic chyme from the stomach. To ensure that pancreatic lipases will be active (since they are inactivated at low pH), the acidic chyme requires rapid neutralization by the HCO3 -containing pancreatic juice. To ensure that pancreatic lipases will be active (since they are inactivated at low pH), the acidic chyme requires rapid neutralization by the HCO3 -containing pancreatic juice. The effects of secretin are potentiated by both CCK and ACh The effects of secretin are potentiated by both CCK and ACh

21. Secretion of which of the following substances is inhibited by low pH? Secretion of which of the following substances is inhibited by low pH? (A) Secretin (B) Gastrin (C) Cholecystokinin (CCK) (D) Vasoactive intestinal peptide (VIP) (E) Gastric inhibitory peptide (GIP)

22. Enzymatic component of pancreatic secretion (acinar cells). Enzymatic component of pancreatic secretion (acinar cells). Protein digesting enzymes: 1. Trypsin. 2. Chymotrypsin. 3. Elastase. 4. Carboxypeptidase. are secreted from pancreas in an inactive form: 1.trypsinogen, 2.chymotrypsinogen, 3.proelastase, & 4.Procarboxypeptidase. –activated after secreted into intestinal tract (not in pancreas).

23. Trypsinogen :  is activated by an enzyme called enterokinase or enteropeptidase  secreted by intestinal mucosa when chyme comes in contact with mucosa..  Enterokinase :convert inactive trypsinogen into Trypsin.  trypsin can activate: trypsinogen …into ………trypsin.  once trypsin is formed : it cause autocatalytic chain reaction by which more trypsinogen is activated into ……..trypsin. also activate:  chymotrypsinogen ……into ……..chymotrypsin,  procarboxypeptidase..into ….carboxypeptidase,  proelastase …………….. into ………elastase.

24. Trypsin and chymotrypsin will digest whole or partially digested protein into peptide level. Carboxypeptidase : will digest peptides into amino acids. Enzymes for the digestion of nucleic acids: 1.Ribonuclease: which acts on RNA. 2.Deoxyribonuclease: which acts on DNA. Enzymes for digestion of carbohydrates: α-amylase: similar to that of salivary secretion. It splits starches and glycogen into disaccharides such as maltose and isomaltose.

26. Fat splitting enzymes

27. Fat splitting enzymes: 1.Lipase. 2.Procolipase (colipase): secreted as procolipse (inactive form) activated into active form by trypsin. Colipase  is a protein that binds to surface of fat droplet  displacing emulsifying agents and anchoring lipase to droplet,. lipase :  not act on fat droplets covered by emulsifying agents without colipase.

28. 3-Phospholipase A2 –secreted as inactive form (prophospholipase A2) & activated by trypsin into phospholipase A2, –phospholipase A2 acts on lecithin In acute pancreatitis prophospholipase A2 is activated inside pancreas and cause partial digestion of lecithin into lysolecithin and a fatty acid. Lysolecithin causes damage of pancreatic tissue. 4-Trypsin inhibitor: is secreted by cells that secrete proteolytic enzymes It surrounds the enzyme granules and prevents its activation both inside acini or the ducts of pancreas.

29. Why Pancreas does not digest itself 1- enzymes are secreted in an inactive form. 2- Trypsin inhibitor. 3- Flow (no stagnation). amount of enzyme secreted will flow.

30. DEFICIENCY OF PANCREATIC ENZYMES: Caused by chronic pancreatitis or damage to pancreas. –fat digestion: It affects mainly –Protein digestion Will be affected protein loss will be significant. –carbohydrates digestion is little affected. deficiency of lipase : result in deficiency in digestion of fat lead to steatorrhoea. result in deficiency in digestion of fat lead to steatorrhoea. (stool bulky, pale, greasy and of bad odour and floats on water).

31. SECRETIN: -is secreted by the S cells of the duodenum -it ’ s secreted when chyme enters intestine. -important factor that causes release of secretin is: ACID → hydrochloric acid → causes release of secretin → absorbed by blood → to pancreas. - The secretion is a watery, alkaline juice poor in enzymes and chloride.

32. Importance of secretin mechanism: 1.neutralize the acid in the duodenum. 2. bicarbonate ions will provide a suitable PH for the action of the pancreatic enzymes. 3. provide the fluid medium to wash out enzymes that are secreted into acini.

33. CHOLECYSTOKININ-PANCREOZYMIN (CCK): -released from mucosa of upper s. intestine (I cells) in response to fat and partial byproducts of protein digestion. –CCK when released will be absorbed by the blood and then will go to pancreas to cause secretion of pancreatic juice -rich in enzymes but poor in water and bicarbonate. -similar to vagal stimulation but not blocked by atropine. -accounts for about 70-80% of total secretion of pancreatic digestive enzymes after a meal.

34. Cholecystokinin (CCK) inhibits Cholecystokinin (CCK) inhibits (A) gastric emptying (B) pancreatic HCO3– secretion (C) pancreatic enzyme secretion (D) contraction of the gallbladder (E) relaxation of the sphincter of Oddi