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Homework 1 Innervation of the stomach Sympathetic nerve?

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1 Homework 1 Innervation of the stomach Sympathetic nerve?

2 A, Parasympathetic. Dashed lines indicate the cholinergic innervation of striated muscle in the esophagus and external anal sphincter. Solid lines indicate the afferent and preganglionic efferent innervation of the rest of the gastrointestinal tract. B, Sympathetic. Solid lines denote the afferent and preganglionic efferent connections between the spinal cord and the prevertebral ganglia. Dashed lines indicate the afferent and postganglionic efferent innervation. CG, celiac ganglion; IMG, inferior mesenteric ganglion; SMG, superior mesenteric ganglion. Gastrointestinal Physiology, Seventh Edition. LEONARD R. JOHNSON. 2007, Mosby, Inc.

3 Homework 2 Ionic mechanism of spike potential (Action potential):
Depolarization: Ca2+ influx? L-type Ca2+ current L-type Ca2+ channels provide the Ca2+ influx that initiates contraction. Blockade of Ca2+ channels reduces the duration and amplitude of electrical slow waves in many muscles and blocks generation of action potentials. Horowitz B, Ward SM, Sanders KM. Annu Rev Physiol. 1999;61:19-43.

4 Gastrointestinal Physiology (Part 2)
Xia Qiang, PhD Department of Physiology Zhejiang University School of Medicine

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6 PANCREATIC SECRETION

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8 Pancreatic juice pH 7.8~8.4 ~1500 ml/day Isosmotic Components:
Pancreatic digestive enzymes: secreted by pancreatic acini Sodium bicarbonate: secreted by small ductules and larger ducts

9 At low magnification At higher magnification

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11 Secretion of bicarbonate ions
Secreted by the epithelial cells of the ductules and ducts that lead from acini Up to 145mmol/L in pancreatic juice (5 times that in the plasma) Neutralizing acid entering the duodenum from the stomach

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13 Pancreatic acinar cell secretory products
Zymogens Function Trypsinogens Digestion Chymotrypsinogen Proelastase Proprotease E Procarboxypeptidase A Procarboxypeptidase B ACTIVE ENZYMES α-Amylase Carboxyl ester lipase Lipase RNAase DNAase Colipase

14 OTHERS Trypsin inhibitor Blockade of trypsin activity Lithostathine
Possible prevention of stone formation; constituent of protein plugs GP2 Endocytosis?; formation of protein plugs Pancreatitis-associated protein Bacteriostasis? Na , Cl , H2O Hydration of secretions Ca ?

15 Secretion of pancreatic digestive enzymes
Carbohydrates -- Pancreatic amylase Pancreatic lipase Fat Cholesterol esterase Phospholipase Trypsinogen Proteins Chymotrypsinogen Procarboxypolypeptidase Proelastase

16 Starches Pancreatic amylase Maltose and 3 to 9 glucose polymers

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19 Trypsin Inhibitor Inhibits the activity of trypsin and thus guards against the possible activation of trypsin and the subsequent autodigestion of the pancreas

20 Regulation of pancreatic secretion
Basic stimuli that cause pancreatic secretion Ach Cholecystokinin: Secreted by I cells Stimulates the acinar cells to secrete large amounts of enzymes Secretin: Released by S cells Acts primarily on the duct cells to stimulate the secretion of a large volume of solution with a high HCO3- concentration

21 Stimulation of protein secretion from the pancreatic acinar cell
Stimulation of protein secretion from the pancreatic acinar cell. A, The pancreatic acinar cell has at least two pathways for stimulating the insertion of zymogen granules and thus releasing digestive enzymes. ACh and CCK both activate Gα , which stimulates PLC, which ultimately leads to the activation of PKC and the release of Ca . Elevated [Ca ] also activates calmodulin (CaM), which can activate protein kinases (PK) and phosphatases (PP). Finally, VIP and secretin both activate Gα , which stimulates adenylyl cyclase (AC), leading to the production of cAMP and the activation of PKA. B, Applying a physiological dose of CCK (i.e., 10 pM) triggers a series of [Ca ] oscillations, as measured by a fluorescent dye. However, applying a supraphysiological concentration of CCK (1 nM) elicits a single large [Ca ] spike and halts the oscillations. Recall that high levels of CCK also are less effective in causing amylase secretion.

22 In addition to protein, acinar cells in the pancreas secrete an isotonic, plasma-like fluid.
Stimulation of isotonic NaCl secretion by the pancreatic acinar cell. Both ACh and CCK stimulate NaCl secretion, probably through phosphorylation of basolateral and apical ion channels. The rise in [Cl ] produced by basolateral Cl uptake drives the secretion of Cl down its electrochemical gradient through channels in the apical membrane. As the transepithelial voltage becomes more lumen negative, Na moves through the cation-selective paracellular pathway (i.e., tight junctions) to join the Cl secreted into the lumen. Water also moves through this paracellular pathway, as well as through aquaporin water channels on the apical and basolateral membranes. Therefore, the net effect of these acinar cell transport processes is the production of an isotonic, NaCl-rich fluid that accounts for ∼25% of total pancreatic fluid secretion.

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27 Regulation of pancreatic secretion
Phases of pancreatic secretion: A meal triggers cephalic, gastric, and intestinal phases of pancreatic secretion Cephalic Phase Gastric Phase Intestinal Phase

28 The three phases of pancreatic secretion
Stimulant Regulatory Pathway Percentage of Maximum Enzyme Secretion Cephalic Sight Smell Taste Mastication Vagal pathways 25% Gastric Distention Gastrin? Vagal-cholinergic 10%-20% Intestinal Amino acids Fatty acids H+ Cholecystokinin Secretin Enteropancreatic reflexes 50%-80%

29 Three phases of pancreatic secretion
Three phases of pancreatic secretion. A, During the cephalic phase, the sight, taste, or smell of food stimulates pancreatic acinar cells, through the vagus nerve and muscarinic cholinergic receptors, to release digestive enzymes and, to a lesser extent, stimulates duct cells to secrete HCO and fluid. The release of gastrin from G cells is not important during this phase. During the gastric phase, the presence of food in the stomach stimulates pancreatic secretions'primarily from the acinar cells'through two routes. First, distention of the stomach activates a vagovagal reflex. Second, protein digestion products (peptones) stimulate G cells in the antrum of the stomach to release gastrin, which is a poor agonist of the CCK receptors on acinar cells. B, The arrival of gastric acid in the duodenum stimulates S cells to release secretin, which stimulates duct cells to secrete HCO and fluid. Protein and lipid breakdown products have two effects. First, they stimulate I cells to release CCK, which causes acinar cells to release digestive enzymes. Second, they stimulate afferent pathways that initiate a vagovagal reflex that primarily stimulates the acinar cells through M cholinergic receptors.

30 Mechanisms that protect the acinar cell from autodigestion
Protective Factor Mechanism Packaging of many digestive proteins as zymogens Precursor proteins lack enzymatic activity Selective sorting of secretory proteins and storage in zymogen granules Restricts the interaction of secretory proteins with other cellular compartments Protease inhibitors in the zymogen granule Block the action of prematurely activated enzymes Condensation of secretory proteins at low pH Limits the activity of active enzymes Nondigestive proteases Degrade active enzymes

31 Acute pancreatitis

32 Acute pancreatitis Acute pancreatitis is sudden swelling and inflammation of the pancreas The symptomatology and complications of acute pancreatitis are caused by autodigestion (resulting from the leakage of pancreatic enzymes) of the pancreas and surrounding tissue It is commonly due to biliary tract disease, complications of heavy alcohol use, or idiopathic causes Mortality rates range from below 10% to more than 50%, depending on severity

33 BILE SECRETION

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35 Bile is stored and concentrated in the gall bladder during the interdigestive period

36 Synthesis of bile acids

37 Composition of bile HCO3- Bile salts Phospholipids Cholesterol
Bile pigments (include: bilirubin)

38 Excretion of bilirubin

39 Jaundice Jaundice is the most visible manifestation of an underlying hepatic and/or biliary tract disease. This is a yellow discoloration of the skin, sclerae, and mucous membranes that occurs secondary to elevated serum bilirubin in adults. Jaundice is usually not clinically apparent until the serum bilirubin concentration is >2.5mg/dL.

40 Functions of bile Emulsifying or detergent function of bile salts
Bile salts help in the absorption of: Fatty acid Monoglycerides Cholesterol Other lipids

41 Emulsifying large fat particles to facilitate its digestion

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43 Bile salts interact with cholesterol to form micelles to facilitate the absorption of insoluble fat products

44 Increasing bile synthesis & secretion

45 Enterohepatic circulation of bile acids

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47 Regulation of bile secretion
Substances increasing bile production Bile salts (Enterohepatic circulation of the bile) Secretin: stimulating H2O and HCO3- secretion from the duct cells Substance inhibiting bile production Somatostatin

48 Contraction of the gall bladder
Substances causing gall bladder contraction ACh CCK Gastrin

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51 Secretin and cholecystokinin are produced and secreted by cells in the lining of the alimentary tract. Which of the following statements about these 2 secretions is true? A They are produced by enteroendocrine cells in the lining of the stomach B They are digestive enzymes present within the lumen of the duodenum C They are produced by Paneth cells D They are hormones whose target cells are primarily in the pancreas and biliary tract E They are produced by Brunner’s glands and released into the lumina of the crypts of Lieberkühn

52 Liver bile flow is increased by:
A Gastrin. B Pancreatic secretion. C Vagal stimulation. D Sympathetic nerve stimulation

53 SMALL INTESTINE

54 Small intestinal juices
Secreted by: Brunners glands Crypts of Lieberkuhn 1~3 L/day pH 7.6 Isosmotic Components H2O Electrolytes (Na+, K+, Ca2+, Cl-) Mucus IgA Enterokinase

55 Small intestinal juices
Function: Completing the digestion of peptides, carbohydrates & fat Secretion by intestinal glands is mainly due to the local effects of chyme in the intestine and is regulated by both neural and hormonal factors

56 Movement of small intestine during digestion
Tonic contraction: maintaining a basal state of intestinal smooth muscle contraction Segmentation: consisting of the alternate contraction and relaxation of adjacent bands of circular smooth muscle Peristalsis: a ring of muscle contraction appears on the oral side of a bolus of ingesta and moves toward the anus, propelling the contents of the lumen in that direction; as the ring moves, the muscle on the other side of the distended area relaxes, facilitating smooth passage of the bolus

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58 Migrating motor complex (MMC)
Local areas of peristaltic contraction Present in the interdigestive period and disappear when feeding begins Sweeping material (undigested food residues, dead mucosal cells, bacteria) into the colon and keeping the small intestine clean Regulated by autonomic nerves and by the release of motilin

59 Contractions at three loci in the small bowel
Contractions at three loci in the small bowel. Note that at each locus, phases of no or intermittent contractions are followed by a phase of continuous contractions that ends abruptly. Also note that the phase of continuous contractions appears to migrate aborally along the bowel. Such a pattern is called the migrating motor complex (MMC). min, minute; mm Hg, millimeters of mercury

60 Regulation of intestinal motility
Autoregulation: Regulated by BER Neural Reflexes: mainly by ‘short’ reflexes in the intrinsic plexuses which are responsible for peristalsis and segmentation also by extrinsic nerves (sympathetic & vagal nerves) which mediate ‘long’ reflexes Hormonal control: Gastrin, CCK, motilin, 5-HT (+) Secretin, VIP, glucagon (-)

61 LARGE INTESTINE

62 Function of large intestine
The principle functions of the colon: Absorption of water and electrolytes from the chyme to form solid feces Storage of fecal matter until it can be expelled Digestion in large intestine: very limited Bacteria: vitamin B, K

63 Motility of the colon Haustration: mixing movement
Mass movement: propulsive movement Segmentation

64 A normal colon, with the typical haustration

65 Two mass movements. A, Appearance of the colon before the entry of barium sulfate. B, As the barium enters from the ileum, it is acted on by haustral contractions. C, As more barium enters, a portion is swept into and through an area of the colon that has lost its haustral markings. D, The barium is acted on by the returning haustral contractions. E, A second mass movement propels the barium into and through areas of the transverse and descending colon. F, Haustrations again return. This type of contraction accomplishes most of the movement of feces through the colon

66 ABSORPTION

67 General mechanisms of digestion and absorption

68 Sites of nutrient absorption

69 Major gastrointestinal diseases and nutritional deficiencies
Organ Site of Predominant Disease Defects in Nutrient Digestion/Absorption Celiac sprue Duodenum and jejunum Fat absorption, lactose hydrolysis Chronic pancreatitis Exocrine pancreas Fat digestion Surgical resection of ileum; Crohn disease of ileum Ileum Cobalamin and bile acid absorption Primary lactase deficiency Small intestine Lactose hydrolysis

70 Carbohydrates The three monosaccharide products of carbohydrate digestion— glucose, galactose, and fructose—are absorbed by the small intestine in a two-step process involving their uptake across the apical membrane into the epithelial cell and their coordinated exit across the basolateral membrane. The Na/glucose transporter 1 (SGLT1) is the membrane protein responsible for glucose and galactose uptake at the apical membrane. The exit of all three monosaccharides across the basolateral membrane uses a facilitated sugar transporter (GLUT2).

71 Proteins Action of luminal, brush border, and cytosolic peptidases. Pepsin from the stomach and the five pancreatic proteases hydrolyze proteins—both dietary and endogenous—to single amino acids, AA, or to oligopeptides, (AA) . These reactions occur in the lumen of the stomach or small intestine. Various peptidases at the brush borders of enterocytes then progressively hydrolyze oligopeptides to amino acids. The amino acids are directly taken up by any of several transporters. The enterocyte directly absorbs some of the small oligopeptides through the action of the H /oligopeptide cotransporter (PepT1). These small peptides are digested to amino acids by peptidases in the cytoplasm of the enterocyte. Several Na -independent amino acid transporters move amino acids out of the cell across the basolateral membrane

72 Absorption of whole proteins
Absorption of whole proteins. Both enterocytes and specialized M cells can take up intact proteins. The more abundant enterocytes can endocytose far more total protein than can the M cells. However, the lysosomal proteases in the enterocytes degrade ∼90% of this endocytosed protein. The less abundant M cells take up relatively little intact protein, but approximately half of this emerges intact at the basolateral membrane. There, immunocompetent cells process the target antigens and then transfer them to lymphocytes, thus initiating an immune response

73 Lipids The breakdown of emulsion droplets to mixed micelles

74 Micellar transport of lipid breakdown products to the surface of the enterocyte. Mixed micelles carry lipids through the acidic unstirred layer to the surface of the enterocyte. 2-MAG, fatty acids, lysophospholipids, and cholesterol leave the mixed micelle and enter an acidic microenvironment created by an apical Na-H exchanger. The acidity favors the protonation of the fatty acids. The lipids enter the enterocyte by (1) nonionic diffusion, (2) incorporation into the enterocyte membrane (collision), or (3) carrier-mediated transport.

75 Re-esterification of digested lipids by the enterocyte and the formation and secretion of chylomicrons. The enterocyte takes up short- and medium-chain fatty acids and glycerol and passes them unchanged into the blood capillaries. The enterocyte also takes up long-chain fatty acids and 2-MAG and resynthesizes them into TAG in the SER. The enterocyte also processes cholesterol into cholesteryl esters and lysolecithin into lecithin. The fate of these substances, and the formation of chylomicrons, is illustrated by steps 1 to 8.

76 Calcium Active Ca uptake in the duodenum. The small intestine absorbs Ca by two mechanisms. The passive, paracellular absorption of Ca occurs throughout the small intestine. This pathway predominates, but it is not under the control of vitamin D. The second mechanism—the active, transcellular absorption of Ca —occurs only in the duodenum. Ca enters the cell across the apical membrane through a channel. Inside the cell, the Ca is buffered by binding proteins, such as calbindin, and is also taken up into intracellular organelles, such as the endoplasmic reticulum

77 Iron Absorption of nonheme and heme iron in the duodenum. The absorption of nonheme iron occurs almost exclusively as Fe , which crosses the duodenal apical membrane through DMT1, driven by a H gradient, which is maintained by Na-H exchange. Heme enters the enterocyte by an unknown mechanism. Inside the cell, heme oxygenase releases Fe , which is then reduced to Fe . Cytoplasmic Fe then binds to mobilferrin for transit across the cell to the basolateral membrane. Fe probably exits the enterocyte through basolateral ferroportin. The ferroxidase activity of hephaestin converts Fe to Fe for carriage in the blood plasma bound to transferrin.

78 Summary General properties of GI Stomach Pancrea
Small and large intestine Absorption

79 End.


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