Ganong Ch 25, 26; GI Physiology and Ischemia-Reperfusion MDRs

Columnar Epithelial Cells of the GI Tract

• Immediately adjacent to the nutrients in the lumen

• Single layer

• Barrier that nutrients must traverse to enter the body

Lamina Propria of the GI Tract

• Loose connective tissue below the epithelium

• Contains many immune and inflammatory cells even in health

Where are the myenteric and submucosal nerve plexuses of the enteric nervous system located?

In the submucosa between the circular and longitudinal muscle layers

What innervates the epithelium and muscle layers of the GI tract?

Secretomotor nerves

Intestinal Villi and Crypts

• Villi maximize surface area throughout the small intestines

• Stem cells that give rise to crypt and villus epithelial cells reside toward the base of the crypts and are responsible for completely renewing the epithelium every few days or so

  • Daughter cells undergo several rounds of cell division in the crypts then migrate out onto the villi where they are eventually shed

• Microvilli on the apical membranes of the villus epithelial cells have a dense glycocalyx (brush border)

  • Protects the cells to some extent from the digestive enzymes

  • Brush border hydrolases also present and perform the final steps of digestion for specific nutrients

What are the paired salivary glands that produce saliva?

Parotid

Submandibular

Sublingual

Functions of Saliva

• Initiates digestion, particularly of starch, mediated by amylase

• Protects the oral cavity from bacteria (immunoglobulin A and lysozyme)

• Lubricates food bolus (aided by mucins)

Tonicity and Acidity of Saliva

• Hypotonic compared to plasma

• Alkaline to neutralize any gastric secretions that reflux into the esophagus

Production and Modification of Saliva

• Salivary glands consist of blind end pieces (acini) that produce the primary secretion containing the organic constituents dissolved in a fluid that is essentially identical in its composition to plasma

  • Composition of saliva is modified as if flows from the acini out into ducts that deliver saliva into the mouth

    • Na+ and Cl- are extracted and K+ and bicarbonate are added

    • Ducts are impermeable to water so loss of NaCl makes the saliva hypotonic

What controls salivary secretion?

• Salivary secretion controlled almost entirely by neural influences

  • Parasympathetic branch of the autonomic nervous system plays the most prominent role

  • Sympathetic input increases the proteinaceous content of saliva but has little influence on volume

What triggers salivary secretion?

• Secretion is triggered by reflexes that are stimulated by the physical act of chewing

  • Initiated before the meal is taken into the mouth as a result of central triggers that are prompted by thinking about, seeing, or smelling food

  • Salivary secretion also prompted by nausea

What inhibits salivary secretion?

Fear

Fatigue

Sleep

What do glands in the cardia and pyloric region of the stomach secrete?

Mucus

What is the parasympathetic nerve supply of the stomach?

Vagus

What is the sympathetic nerve supply of the stomach?

Celiac plexus

What are the phases of gastric secretion?

Cephalic phase - stomach readies itself to receive a meal before its taken in

Gastric phase

Intestinal phase - once the meal has left the stomach

Contents of Normal Gastric Juice (Fasting State)

• Cations: Na+, K+, Mg2+, H+ (pH approximately 3.0)

• Anions: Cl-, HPO2-, SO42-

• Pepsins

• Lipase

• Mucus

• Intrinsic factor

What do surface mucous cells secrete?

Mucus

Trefoil peptide

Bicarbonate

What do parietal cells secrete?

HCl

Intrinsic factor

What do enterochromaffin like cells secrete?

Histamine

What do chief cells secrete?

Pepsinogen

Gastric lipase

Trefoil Peptides

Stabilize the mucus-bicarbonate layer

Intrinsic Factor

Important for later absorption of Vitamin B12 or cobalamin

Pepsinogen

Precursor of pepsin which initiates protein digestion

Lipase

Digests dietary fats

What are the 3 primary stimuli of gastric secretion?

Gastrin

Histamine

Acetylcholine

Stimulus of Gastric Secretion - Gastrin

• Released by G cells in the antrum of the stomach

• Released in response to gastrin-releasing peptide (GRP) and the presence of oligopeptides in the gastric lumen

• Binds to receptors on parietal (and likely chief) cells to activate secretion

• Binds to enterochromaffin-like cells (ECL cells) to release histamine

Stimulus of Gastric Secretion - Histamine

• Trigger for parietal cell secretion via binding to H2 receptors

Stimulus for Gastric Secretion - Acetylcholine

• Stimulates parietal and chief cells

• Released from enteric nerve endings in the fundus

Gastric Secretion During the Cephalic Phase

• Activated predominantly by vagal input

  • Originates from the dorsal vagal complex

• Vagal outflow to the stomach releases GRP and acetylcholine, initiating secretory function

Gastric Secretion During the Gastric Phase

• The meal triggers substantial release of gastric secretion

• Physical presence of the meal distends the stomach and activates stretch receptors, which provoke a "vago-vagal" as well as local reflexes that further amplify secretion

• Presence of the meal buffers gastric acidity

  • Otherwise acidity would serve as a feedback inhibitory signal to shut off secretion secondary to the release of somatostatin

Somatostatin

Inhibits G and ECL cells and secretion by parietal cells themselves

Secretion by the Parietal Cells

• Have many mitochondria that supply energy to drive the apical H+,K+ ATPase, or proton pump, that moves H+ ions out of the parietal cell against a large concentration gradient

• At rest, the proton pumps are sequestered in the parietal cell in tubulovesicles

• When the parietal cells begin to secrete, these vesicles fuse with invaginations of the apical membrane area (canaliculi), amplifying the apical membrane area and positioning the proton pumps to begin acid secretion

• Apical membrane also contains K+ channels which supply the K+ ions to be exchanged for H+ and Cl- channels that supply the counterion for HCl secretion

• Secretion of protons is accompanied by the release of equivalent numbers of bicarbonate ions into the bloodstream

How do gastrin and acetylcholine promote secretion from the parietal cell?

By elevating cytosolic free calcium concentrations

How does histamine stimulate increased secretion from the parietal cell?

By increasing intracellular cAMP

Synergistic Effect of Activation of the Parietal Cell

• Pathways for activation are synergistic with a greater additive effect when histamine plus gastrin or acetylcholine are present, or all three

  • High rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli

  • Therapeutically significant because secretion can be markedly inhibited by blocking the action of only one of the triggers (commonly histamine via H2-antagonists)

What enzyme does the salivary glands produce?

Salivary a-amylase

What activates salivary a-amylase?

Cl-

What is the substrate for salivary a-amylase?

Starch

Catalytic Function or Products of Salivary a-Amylase

Hydrolyzes 1:4a linkages, producing a-limit dextrins, maltotriose, and maltose

What are the enzymes produced by the stomach?

Pepsins (pepsinogens)

Gastric lipase

What activates pepsinogens?

HCl

What is the substrate for pepsin?

Proteins and polypeptides

Catalytic Function or Products of Pepsin

Cleave peptide bonds adjacent to aromatic amino acids

Substrate of Gastric Lipase

Triglycerides

Catalytic Function or Products of Gastric Lipase

Fatty acids and glycerol

Enzymes Produced by the Exocrine Pancreas

Trypsin (trypsinogen)

Chymotripsins (chymotripsinogens)

Elastase (proelastase)

Carboxypeptidase A (procarboxypeptidase A)

Carboxypeptidase B (procarboxypeptidase B)

Colipase (procolipase)

Pancreatic lipase

Cholesteryl ester hyrolase

Pancreatic a-amylase

Ribonuclease

Deoxyribonuclease

Phospholiapse A2 (prophospholiapse A2)

Trypsinogen Activator

Enteropeptidase

Chymotrypsinogen Activator

Trypsin

Proelastase Activator

Trypsin

Procarboxypeptidase A Activator

Trypsin

Activator of Procarboxypeptidase B

Trypsin

Activator of Pancreatic a-Amylase

Cl-

Activator of Prophospholipase A2

Trypsin

Substrate of Trypsin

Proteins and polypeptides

Substrate of Chymotrypsins

Proteins and polypeptides

Substrate of Elastase

Elastin, some other proteins

Substrate of Carboxypeptidase A

Proteins and polypeptides

Substrate of Carboxypeptidase B

Proteins and polypeptides

Substrate of Colipase

Fat droplets

Substrate of Pancreatic Lipase

Triglycerides

Substrate of Cholesteryl Ester Hydrolase

Cholesteryl esters

Substrate of Pancreatic a-Amylase

Starch

Substrate of Ribonulcease

RNA

Substrate of Deoxyribonuclease

DNA

Substrate of Phospholipase A2

Phospholipids

Catalytic Functions or Products of Trypsin

Cleave peptide bonds on carboxyl side of basic amino acids (arginine or lysine)

Catalytic Functions or Products of Chymotrypsins

Cleave peptide bonds on carboxyl side of aromatic amino acids

Catalytic Functions or Products of Elastase

Cleaves bonds on carboxyl side of aliphatic amino acids

Catalytic Functions or Products of Carboxypeptidase A

Cleave carboxyl terminal amino acids that have aromatic or branched aliphatic side chains

Catalytic Functions or Products of Carboxypeptidase B

Cleave carboxyl terminal amino acids that have basic side chains

Catalytic Functions or Products of Colipase

Binds pancreatic lipase to oil droplet in the presence of bile acids

Catalytic Functions or Products of Pancreatic Lipase

Monoglycerides and fatty acids

Catalytic Functions or Products of Cholesteryl Ester Hydrolase

Cholesterol

Catalytic Functions or Products of Pancreatic a- Amylase

Hydrolyzes 1:4a linkages, producing a-limit dextrins, maltotriose, and maltose

Catalytic Functions or Products of Ribonuclease

Nucleotides

Catalytic Functions or Products of Deoxyribonuclease

Nucleotides

Catalytic Functions or Products of Phospholipase A2

Fatty acids, lysophospholipids

Enzymes Produced by Intestinal Mucosa

Enteropeptidase

Aminopeptidases

Carboxypeptidases

Endopeptidases

Dipeptidases

Maltase

Lactase

Sucrase

Isomaltase

Nuclease and related enzymes

Substrate of Enteropeptidase

Trypsinogen

Substrate of Aminopeptidases

Polypeptides

Substrate of Carboxypeptidases

Polypeptides

Substrate of Endopeptidases

Polypeptides

Substrate of Dipeptidases

Dipeptides

Substrate of Maltase

Maltose, maltotriose

Substate of Lactase

Lactose

Substrate of Sucrase

Sucrose; also maltotriose and maltose

Substrate of Isomaltase

a-limit dextrins, maltose

Maltotriose

Substrate of Nuclease and Related Enzymes

Nucleic acids

Catalytic Functions or Products of Enteropeptidase

Trypsin

Catalytic Functions or Products of Aminopeptidases

Cleave amino terminal amino acids from peptide

Catalytic Functions or Products of Carboxypeptidases

Cleave carboxyl terminal amino acid from peptide

Catalytic Functions or Products of Endopeptidases

Cleave between residues in midportion of peptide

Catalytic Functions or Products of Dipeptidases

Two amino acids

Catalytic Functions or Products of Maltase

Glucose

Catalytic Functions or Products of Lactase

Galactose and glucose

Catalytic Functions or Products of Sucrase

Fructose and glucose

Catalytic Functions or Products of Isomaltase

Glucose

Catalytic Functions or Products of Nuclease and Related Enzymes

Pentoses and purine and pyrimidine bases

What is pancreatic secretion controlled by?

• In part by a reflex mechanism

• In part by the GI hormones secretin and cholecystokinin (CCK)