Physiology Exam 3-Gi

Front 1

What are the two primary types of secretion?

Back 1

1. digestive enzymes are secreted from the mouth to the terminal regions of the intestine
2. mucus is secreted throughout the GI tract by mucous glands to provide lubrication and protection

Front 2

What are the different types of glands associated with secretion?

Back 2

single cell mucous glands, crypts of Leiberkuhn, tubular glands, salivary glands, pancreas and liver

Front 3

Describe the single cell mucous glands.

Back 3

(mucous cells/goblet cells) Are located in the epithelium and are found in most parts of the GI tract and respond to local stimulation of the epithelium by extruding their mucus onto the epithelial surface to act as a lubricant and to protect the epithelial surface.

Front 4

Describe the crypts of Leiberkuhn.

Back 4

in the small intestine, invaginations of the epithelium into the submucosa are called Crypts of Leiberkuhn, these crypts are usually deep and contain specialized secretory cells

Front 5

Describe the tubular glands of the GI system.

Back 5

Located in the stomach and upper duodenum are large numbers of deep tubular glands which often secrete acid and pepsinogen.

Front 6

Describe the salivary glands, pancreas and liver.

Back 6

More complex glands with a primary function to provide secretions for digestion and emulsification of food. The salivary and pancreatic glands are compound acinous (containing many acinar cells) glands that lie outside the wall of the GI tract and are connected via ducts that empty into the GI tract itself.

Front 7

What are the three major salivary glands and what drains them?

Back 7

parotid, submandibular and buccal, drained by a single major excretory duct (monostomatic)

Front 8

Describe the minor salivary glands.

Back 8

consist of single many packages and are polystomatic

Front 9

In what glands is sexual dimorphosism found?

Back 9

mandibular glands, the type of secretions from the mandibular glands differs with sexes, males have serous secrfetions and females mucous

Front 10

What type of innervation does the myoepithelial cells associated with secretory endpieces get?

Back 10

receive both parasympathetic and sympathetic input to regulate secretion

Front 11

Describe the mechanical mechanism for stimulating GI glands.

Back 11

the presence of food in a particular segment of the GI tract causes glands to secrete digestive juices, this is in part due to a result of direct contact of the food with surface glandular cells and epithelial stimulation that activates the enteric system via tactile, chemical and distension mechanisms, the INC in neural activity causes mucus glands and deeper glands in the mucosa to INC secretion

Front 12

What is the rate of salivary secretion?

Back 12

normally low (approx. 30 mL/hr), submandibular gland contributes about 2/3 and the parotid ¼ of salivary secretions, neural stimulation (para and sympathetic) can INC it to about 400 mL/hr

Front 13

Describe the parasympathetic stimulation of salivary secretion.

Back 13

INC rate of glandular secretion, esp. the glands of the upper GI tract that are innervated by the vagus and other cranial para nerves (ex: salivary glands, esophageal glands, gastric glands, pancreas and Brunner’s glands, distal portion of large intestine)

Front 14

What stimulates the secretion of the remainder of the small and large intestines?

Back 14

it is stimulated in response to local neural and hormonal stimuli in each segement of the gut

Front 15

Describe the role of the sympathetic stimulation of salivary secretion.

Back 15

some cause a slight/moderate INC in secretion by the respsective glands, also leads to constriction of the blood vessels supplying the respective glands resulting in a dual effect, it INC if para nerve stimulation is low, if high then sympathetic will result in a reduction in secretion mainly by a reduction in blood supply to that organ

Front 16

Describe the role of hormonal regulation in secretion.

Back 16

in the stomach and intestine several different GI hormones (polypeptides and their derivatives) help regulate secretion in areas such as gastric, pancreatic and gallbladder secretion, secreted from the mucosa in response to the presence of food in the lumen, absorbed into circulatory system and carried to gland where they stimulate secretion

Front 17

What are the steps in secretion by glandular cells?

Back 17

1. transportation of the nutrient material needed for formation of the secretory material must diffuse into the base of the glandular cell from the capillary
2. synthesis of the secretory substance occurs in the ER and golgi
3. secretory substance is transported through ER, passing to the vesicles of the golgi
4. in the golgi, the substance is modified, added to, concentrated and eventually discharged into the cytoplasm in the form of a secretory vesicle
5. secretory vesicles are normally stored in the apical ends of the cell until neural or hormonal signals cause them to empty their contents through the cell’s surface
6. exocytosis of the secretory vesicle is calcium dependent, causes an INC in intracellular Ca2+, which leads to a fusion of the secretory vesicle with the apical membrane

Front 18

What else is a necessity for glandular secretion?

Back 18

sufficient water and electrolytes need to be secreted along with the organic substances

Front 19

How is water stimulated to pass through the glandular cells?

Back 19

1. nerve stimulation has a specific effect on the basal portion of the cell membrane, causing active transport of Cl- to the cell interior
2. causes INC in negativity inside the cell causing + charged ions to move into the cell
3. this causes excess of both ions inside the cell creating a hyperosmotic gradient and an osmotic force pulls water into the cell, INCing the hydrostatic pressure inside the cell and causing it to swell
4. INC in hydrostatic pressure causes minute rupturing of the secretory border, water is loss through the openings which results in the flushing of electrolytes and organic substances out of the secretory end of the cell and into the lumen of the gland

Front 20

What supports above process that defines how water is stimulated to pass through the glandular cells?

Back 20

1. neural endings on glandular cells are usually on the basal side of the cells
2. parasympathetic stimulation causes the membrane potential to become 10-20 mV more polarized (i.e. suggesting that a negative charge (Cl- ions) move into the cell

Front 21

What is the composition of mucus?

Back 21

composed of electrolytes, glycoproteins and water, does vary in the GI tract but is an excellent lubricant and protectant

Front 22

Describe some of the properties of mucus.

Back 22

1. adherent properties of mucus allow it to tightly bind to food and spread a thin film over the surface of particles
2. acts as a barrier to stop food coming into contact with the mucosa
3. DEC resistance for slippage of luminal contents along the GI tract
4. mucus allows fecal materal to bind together so that feces can be expelled in one mass
5. mucus is strongly resistant to digestion
6. the glycoproteins in mucus have amphoteric properties (act as a buffer), presence of bicarb allows for buffering of acids

Front 23

What does mucus do?

Back 23

mucus allows for the easy passage of food along the GI tract and also prevents abrasions or chemical damage to the epithelium

Front 24

What is the rate of salivary secretion?

Back 24

800-1500 mL/day of saliva is important to the hygiene and comfort of the teeth and mouth

Front 25

What is the function of saliva?

Back 25

lubricating ability is entirely dependent upon its content of mucus, facilitates the swallowing process and is necessary for speech

Front 26

What are the constituents of saliva?

Back 26

1. ptyalin (alpha-amylase)-the serous secretion, an enzyme for digesting starches, pH of saliva is 6-7.4 which is optimum for ptyalin
2. mucin-mucus secretion, for lubrication purposes
3. lactoferrin-chelates iron and inhibits the growth of organisms that require it for growth
4. lysozyme-proteolytic enzyme, attacks bacterial cell walls
5. thiocyanate ions-bacteriacidal
6. binding glycoprotein for IgA-forms secretory IgA that is immunologically active against viruses and bacteria

Front 27

Describe the salivary secretions of the different types of glands.

Back 27

1. parotid glands-mostly serous type of saliva
2. submandibular and sublingual-secrete both mucus and serous types
3. buccal glands-secrete predominantly mucus type

Front 28

What are the modifications made to saliva?

Back 28

1. Na+ ions are reabsorbed from all of the salivary ducts and K+ ions are secreted in exchange for Na+ but at a slower rate, results in a -70 mV potential in the ducts, results in passive reabsorption of Cl- causes [Cl] to fall
2. Ca2+ ions and bicarb are secreted by ductal epithelia due to exchange of bicarb for Cl-
3. this results in low Na+ and Cl- (10% of plasma), K+ higher (7 times), bicarb higher than K+ (2-3X)

Front 29

What happens to the modification made to saliva in the presence of excess aldosterone?

Back 29

aldosterone secretion causes Na+ and Cl- ion absorption and K+ ion secretion is greatly INC

Front 30

What delivers the parasympathetic stimulation of the salivary glands?

Back 30

by the facial and glossopharyngeal nerves from salivatory nuclei to autonomic ganglia from which postganglionic fibers pass to individual glands, salivatory nuclei are excited by taste and tactile stimuli from the tongue (sour taste elicits copious secretions of saliva (8-20 times basal rate))

Front 31

Describe the stimulation of salivation by higher CNS centers.

Back 31

salivation is also stimulated/inhibited by higher CNS center (smell) and can occur in response to reflexes originating in the stomach and upper intestines (when irritable foods are swallowed), saliva secretion is through to DEC the irritation by dilution or neturalization

Front 32

What happens when the myoepithelial cell contracts?

Back 32

enhances INC secretion, innervated by the parasympathetic system, INC cellular activity in response to parasympathetic stimulation causes a release of Kallikrein resulting in the production of bradykinin (vasodilator) and also growth of the salivary glands

Front 33

What are the mediators acting on the salivary glands?

Back 33

cholinergic from parasympathetic nerves and adrenergic from sympathetic acting on beta receptors

Front 34

What causes an INC and DEC in salivary gland activity?

Back 34

get INC glandular activity from chewing, consuming spicy or sour-tasting foods and smoking, inhibition can be caused by sleep fear, dehydration and fatigue

Front 35

What is the parasympathetic and sympathetic effect on saliva output, temporal response, composition and response to denervation?

Back 35

1. saliva output-para (copious), sympathetic (scant)
2. temporal response-para (sustained), sympathetic (transient)
3. composition-para (protein-poor, high K+ and HCO3-), sympathetic (protein-rich, low K+ and HCO3-)
4. response to denervation-para (DEC secretion, atrophy), sympathetic (DEC secretion)

Front 36

What is xerostomia?

Back 36

dry mouth, is associated with chronic ulceration’s of the buccal mucosa and with dental caries, saliva dissolves and washes out food particles from between teeth

Front 37

What is congenital xerostomia?

Back 37

absence of saliva

Front 38

What is Sjogren’s syndrome?

Back 38

atrophy of the glands and DEC saliva production, in CF, salivary Na+, Ca2+ and protein are elevated, digitalis drugs cause INC Ca2+ and K+ concentrations in saliva

Front 39

What is Addison’s disease?

Back 39

[Na+] are INC

Front 40

What is Cushing’s syndrome?

Back 40

[Na+] are DEC as they are in primary aldosteronism during pregnancy

Front 41

What are the pathophysiological conditions with saliva secretion due to tumors?

Back 41

excessive salivation is observed with tumors of the mouth or esophagus and with Parkinson’s disease

Front 42

What are the constituents and functions of gastric juice?

Back 42

1. intrinsic factor-required for the absorption of vita B12 by the ileal mucosa
2. hydrogen ions-acid is necessary for the conversion of pepsinogen to pepsin and kills bacteria (exception is H. Pylori)
3. pepsin-and acid begin the breakdown of protein
4. mucus-protects the mucosa lining of the stomach, lubricates and neutralizes a small amount of acid

Front 43

What are the different portions of the gastric mucosa?

Back 43

divided into the oxyntic gland area and the pyloric gland area

Front 44

What is the function of the oxyntic gland area?

Back 44

secretes acid and is located on the proximal 80% of the stomach, distal 20% (antrum) synthesizes and secretes the hormone gastrin, the gastric mucosa is composed of pits and glands (lined with mucous or surface epithelial cells), oxyntic glands contain the acid producing parietal cells and the peptic or chief cells (secrete pepsinogen), in the pyloric region pyloric glands replace the oxyntic glands and gastrin secreting glands replace parietal cells

Front 45

What are the mucous neck cells and where are they found?

Back 45

present wehre the glands open into the pits, these cells divide and the daughter cells migrate to the surface where they become mature mucous cells and down into the glands where they become parietal cells in the oxyntic gland area or G cells in the region of the pyloric gland mucosa, peptic cells are capable of mitosis but also arise from mucous neck cells during repair

Front 46

What is the structure of the parietal cells?

Back 46

they are dominated by numerous tubulovesicles in the resting state, also possesses an intracellular canaliculus that is continuous with the lumen of the oxynthic gland

Front 47

What is the anatomical mechanism of HCl secretion by parietal cells?

Back 47

1 billion parietal cells secrete HCl at a concentration of 150-160 mm/L, pH is 0.8-1 with an [H+] of 3 million times that of blood, requires over 1500 cal/L gastric juice, when stimulated to secrete acid the tubulovesicles of the parietal cells become microvilli and project into the canaliculus, which becomes greatly expanded to occupy much of the cell, carbonic anhydrase and ATPase enzyme activity INC during acid secretion

Front 48

What is the physiological mechanism for secretion of acid?

Back 48

on the luminal (apical) cell membrane there is an active H+/K+ ATPase that pumps H+ ions out of the cell in exchange for K+ ions, needs an adequate supply of K+ outside the apical side of the membrane, an INC in K+ conductance occurs with active acid secretion which ensures plenty of K+ is in the lumen

Front 49

Where do the H+ ions that are pumped out by the H+/K+ ATPase come from?

Back 49

thought to be derived from the dissociation of H2O, to replenish the dissociated water molecule, the OH- combines with H+ ions derived from the dissociation of carbonic acid, H2CO3 <-> H2O + CO2

Front 50

What role does the electroneutral CL/HCO3- exchanger play in acid secretion?

Back 50

found on the basolateral membrane, balances entry of CL- with HCO3- into the bloodstream (making it quite alkaline, due to alkaline tide), leak into the lumen through Cl- channels down an electrochemical gradient, HCL is secreted into the lumen, water is also drawn into the lumen maintaining isoosmolallity of acid secretion

Front 51

Describe the neural regulation of gastric secretion.

Back 51

vagal nerve stimulation is the neural pathway, ACh stimulates secretion of all the cells located in the mucosa of the stomach including pepsinogen, HCl, mucus and gastrin secreting

Front 52

Describe the hormonal regulation of gastric secretion.

Back 52

gastrin and histamine strongly stimulate the release of HCl by parietal cells, histamine works through H2 recetpros (cimentidine is a H2 receptor antagonist and is effective at blocking acid secretion), histamine is from mast cells in the lamina propria, additive with neural stimulation

Front 53

What are the 3 phases of acid secretion during a meal?

Back 53

cephalic phase, gastric phase, intestinal phase

Front 54

Describe the cephalic phase of the gastric secretion during a meal.

Back 54

often occurs before the food bolus enters the stomach and is initiated by smell, sight, taste, greater the appetite the more intense the stimulation, neurogenic stimulus comes from the cerebral cortex or in the appetite centers of the amygdala or hypothalamus which reach the stomach via the vagus and dorsal motor vagus, nerves also release gastrin releasing peptide which stimulates G cells to release gastrin which indirectly stimulates parietal cells, 30% of gastric secretion is associated with the cephalic phase

Front 55

Describe the gastric phase of the gastric secretion during a meal.

Back 55

gastric distension and partially digested proteins stimulate mechanoreceptors which stimulate the parietal cells through short local enteric reflexes and long vagovagal reflexes, vagovagal reflexes are those arising from afferent and efferent pathways in the vagus, digested proteins in the stomach stimulate acid secretion through a gastrin mechanism, 60% of gastric secretions is associated with this phase

Front 56

Describe the intestinal phase of the gastric secretion during a meal.

Back 56

the presenc of proteins in the upper intestine (duodenum) can cause the release of small amounts of gastric juice possibley through the release of gastrin, distension causes acid secretion through enterooxyntin from endocrine cells, several inhibitory factors released by the intestine can override the minor excitatory effects of gastrin, 10% of gastric secretion is associated with the intestinal phase

Front 57

What is the enterogastric reflex and what is its role in the inhibition of gastric secretion?

Back 57

this reflex is stimulated by the presence of food in the duodenum, transmitted through the ENS, results in inhibition

Front 58

What can lead to DEC in secretion?

Back 58

distension, acid in the upper intestine, protein breakdown products and irritation of the mucosa can result in a DEC in secretion

Front 59

What are enterogastrones?

Back 59

they are the hormones that are released from the duodenal mucosa by acid, fatty acids or hyperosmotic solutions, often inhibit gastric emptying as well as acid secretion

Front 60

What does secretin and cholecystokinin do and what causes their release?

Back 60

are intestinal hormones that are released by acid, fat protein breakdown products and hyper-hypo osmotic fluids, both inhibit gastric secretion, also important in pancreatic secretion, CCK is also important inhibiting gastric emptying and plays a role in emptying bile from gallbladder

Front 61

What do somatostatin, VIP and gastric inhibitory peptide (GIP) do?

Back 61

all inhibit secretion, usually associated with a reduction in gastric secretion by these peptides is an inhibition in gastric motility, when pH DEC below 3.0, endocrine cells (D cells) in the antrum secrete somatostatin that inhibits the release of gastrin and gastric secretion

Front 62

Describe the secretion and activation of pepsinogen.

Back 62

several different cell types secrete pepsinogen (mucous and chief cells) which is inactive when it is secreted, activated by HCl to pepsin (a proteolytic enzyme that is active at low pH (1.8-3.5)

Front 63

Describe the secretion of intrinsic factor and its purpose.

Back 63

is essential for absorption of vita B12 in the ileum, secreted by parietal cells along with HCl, failure to secrete vita B12 (as in chronic gastritis), can result in the development of pernicious anemia (failure of maturation of RBCs occurs in the absence of vita B12 stimulation of the bone marrow)

Front 64

Describe the secretion of mucous in the stomach.

Back 64

the pyloric glands are similar to the oxyntic glands but contain few parietal cells, they contain mostly mucous cells that secrete a thin mucous to protect the stomach wall from digestion by acid, the pyloric glands also secrete the hormone gastrin, between glands the entire surface of the stomach has mucous cells that secrete a thick viscous alkaline mucous which coats the wall and protects it from digestion

Front 65

Describe the secretion of gastrin.

Back 65

Vagal and local stimulation cause the release of gastrin from pyloric glands. Gastrin comes in two forms G-34 and G-17, both being important but the smaller more abundant. Gastrin is absorbed and carried in the blood stream and stimulates the release of HCl from parietal cells. HCl then causes further release of HCl and secretion of enzymes by peptic cells.

Front 66

Describe the secretion of histamine.

Back 66

Histamine stimulates HCl secretion via H2 receptors. Histamine has a synergistic effect with ACh and gastrin to greatly enhance acid secretion. Antihistaminic drugs cause a dramatic decrease in the secretion of HCl thus ACh and gastrin cause significant release on their own (cimetidine is a H2 receptor antagonist).

Front 67

Describe how pepsinogen secretion is regulated.

Back 67

Vagal nerve and ENS stimulation via release of ACh from nerve terminals stimulate pepsin cells and HCl stimulates peptic cells most probably indirectly via enteric reflexes.

Front 68

What are some other enzymes secreted in the stomach?

Back 68

Small quantities of other enzymes including lipases, amylases and gelatinases are secreted in the stomach.

Front 69

Describe the secretions of the pancreas.

Back 69

The pancreas is a large compound gland similar in structure to the salivary glands. Along with secreting insulin (Islets of Langerhans), the pancreas secrets enzymes for proteins, carbohydrates and fats. The proteolytic enzymes are trypsin, chymotrypsin and carboxypolypeptidase.

Front 70

Describe the carbohydrate enzymes.

Back 70

The carbohydrate enzyme is pancreatic amylase which hydrolyzes starches, glycogen and other carbohydrates (except cellulose) to form di- and tri-saccharides.

Front 71

Describe pancreatic lipase

Back 71

Pancreatic lipase hydrolyzes neutral fat to fatty acids and monoglycerides. Cholesterol esterase hydrolyzes cholesterol esterases and phospholipase which splits fatty acids from phospholipids.

Front 72

What form are the proteolytic enzymes when they are synthesized?

Back 72

When synthesized the protolytic enzymes are inactive in the forms of trypsinogen, chymotrypsinogen and procarboxypolypeptidase. They only become active when secreted into the intestine. Trypsinogen is activated by enterokinase (secreted by mucosa when chyme comes into contact with it) and by trypsin. Chymotrypsinogen forms chymotrypsin when activated by trypsin. Trypsin inhibitor stops the enzymes from degrading the pancreas. It is released from glandular cells and inhibits the activation of trypsin inside the secretory cells, in the acini and in the pancreatic ducts.

Front 73

WHat do the acini secrete?

Back 73

The enzymes of the pancreas are secreted by acini. Bicarbonate and water are secreted by the epithelial cells of the ducts from the acini (approx 1L/day). When the pancreas is stimulated to secrete pancreatic juices it also releases bicarbonate ions (approx. x5 that of the plasma). The Na+ and K+ concentrations in pancreatic secretion are approximately similar to that of plasma, but Cl- ion secretion is lower. The HCO3- ion secretion increases with secretion rate yielding a solution of pH 8.2 (see Figure 10).

Front 74

What are two mechanisms that have been proposed to explain secretion of a bicarb solution?

Back 74

(i). First mechanism: Some cells, probably the acinar cells, secrete a plasma-like fluid containing predominantly Na+ and Cl- ions, while other cells, probably duct cells secrete a bicarbonate rich solution. Depending upon the rates of secretion from these cells the concentration of ions in the secretion will vary.
(ii) Second mechanism: The primary secretion is rich in HCO3- ions. As the secretion moves down the ducts the primary secretion is modified, HCO3- ions are exchanged for Cl- ions when flow is fast little exchange takes place.

Front 75

What are the steps involved in the secretion of electrolytes by pancreatic ductal cells?

Back 75

(i) There is a Na/H exchanger located on the basolateral side of the cell membrane. The energy required to drive the exchanger is provided by the Na/K ATPase-generated sodium gradient.

(ii) CO2 diffuses into the interior of the cell from the blood stream and combines with water under influence of carbonic anhydrase to form carbonic acid. Carbonic acid dissociates into bicarbonate and hydrogen ions. The H+ is extruded by the Na/K exchanger and HCO3- ions are exchanged for Cl- ions from the lumen of the ducts via a HCO3-/Cl- exchanger (see Figure 11).

(iii) The H+ ions formed by the dissociation of carbonic acid are exchanged for Na+ ions across the blood barrier by an active transport mechanism. Na+ ions diffuse through or are actively transported through the luminal border providing electrical neutrality for the bicarbonate ions (through a paracellular path).
(iv) The movement of Na+ and bicarbonate ions create a hyperosmotic environment in the lumen of the ducts, causing water to diffuse passively out of the epithelial cells.

Front 76

What are the four basic stimuli that are important for the stimulus of pancreatic secretion?

Back 76

(i) ACh, released from parasympathetic vagus nerve terminals and other cholinergic nerves in the ENS.

(ii) Gastrin, released during the gastric phase of the stomach.

(iii) CCK, secreted by the duodenal mucosa when food enters the small intestine.

(iv) Secretin, is secreted when low pH products enter the small intestine.

Front 77

What effect do the above substances have on pancreatic secretion?

Back 77

The above substances have a synergistic effect on pancreatic secretion when acting together. ACh, Gastrin and CCK all stimulate the acinar cells of the pancreas producing large quantities of digestive enzymes, without much fluid, resulting in the build up of enzymes in the acani and ducts. Secretin, stimulates the secretion of large quantities of sodium bicarbonate solution by ductal epithelium, but little enzyme secretion.

Front 78

What is potentiation in terms of pancreatic secretion?

Back 78

Potentiation, as previously described for gastric secretion also exists in the pancreas. In the pancreas it is a result of agonists acting on different receptors and stimulating down stream events. Secretin stimulates adenylate cyclase which increases intracellular cAMP. ACh, CCK and Substance P trigger the release of Ca2+ from intracellular stores.

Front 79

What are the phases in pancreatic secretion?

Back 79

(i) Cephalic phase, (ii) Gastric phase (iii) Intestinal phase.

Front 80

Describe the cephalic and gastric phase of pancreatic secretion.

Back 80

(i) and (ii) ACh released at neural endings in the pancreas cause moderate amounts of enzymes to be secreted into the acini, however little flows out into the intestine because of the lack of water secretion.

Front 81

Describe the intestinal phase.

Back 81

(iii)When chyme enters the small intestine pancreatic secretion is increased considerably, mainly in response to the hormones secretin and CCK.

Front 82

What is secretin and describe its release?

Back 82

Secretin is released from S cells in the mucosa of the upper small intestine in an inactive form, prosecretin. The stimulus for release is gastric acid and long chain fatty acids. HCl is the most potent stimulant, with a threshold for secretin release being 4.5 with a linear increase to approx. pH 3.0. ACh and CCK shift the dose response curve to the left. After secretin is released it is absorbed into the blood, stimulating the pancreas to release large quantities of fluid and bicarbonate ions. Secretin does not stimulate the acinar cells. Following the release of bicarbonate ions, HCl reacts with NaHCO3 to produce NaCl and H2CO3. Carbonic acid dissociates into H2O and CO2. The carbon dioxide is absorbed into the blood and expired in the lungs. This is a protective mechanism to avoid the digestion of the intestinal mucosa by HCl. Bicarbonate secretion also increases the pH of luminal contents which is more optimal for pancreatic enzymes (pH 8.0).

Front 83

What is CCK and describe its release?

Back 83

CCK is released from I cells within the mucosa of the duodenum and upper jejunum. The stimulant that causes the release of CCK appears to be proteoses and peptones (products of partial protein and long chain fatty acid digestion). CCK is also absorbed into the blood stream and travels to the pancreas where it stimulates the release of large amounts of digestive enzymes, similar to the effects of vagal stimulation and gastrin.

Front 84

What is the function of bile?

Back 84

(i) Help to emulsify large fat particles into smaller particles where they can be attacked by lipases released from the pancreas. Bile salts also help in the transport of these fat particles through the mucosa of the small intestine.
(ii) Bile serves as a means for excretion of waste products from the blood, including bilirubin and excess cholesterol production by liver cells.

Front 85

Describe the secretion of bile.

Back 85

Bile acids are secreted continually (although rates vary considerably).
The rate of secretion is related to the amount of bile delivered to the liver by the hepatic
circulation. The bile that is secreted by the liver hepatocytes contains large amounts of
bile acids, cholesterol and other organic constituents, secreted into the small bile
canaliculi that lie between the hepatic cells and the hepatic plates. Bile then flows into
the terminal bile ducts and to the hepatic duct and common bile duct where it can be
diverted into the gallbladder by the cystic duct or empty directly into the duodenum.

Front 86

What is added to the bile when bile is in the bile duct?

Back 86

In the bile ducts sodium and bicarbonate ions are added to the bile, increasing the quantity by up to 100% This secondary secretion is stimulated by secretin. These secretions also supplement the bile neutralization of acid in the duodenum.

Front 87

What are the pathways involved in the absorption of bile salts?

Back 87

(i) Bile salts are absorbed through the entire small intestine by passive diffusion.

(ii) Absorbed in the terminal ileum by an active carrier process. This process is extremely efficient with less than 5% of bile escapes into the colon.

(iii)Bacteria in the colon deconjugate bile salts to bile acids which are more lipophilic and can be absorbed passively These pathways are termed the enterohepatic circulation (see Figure 13): The enterohepatic circulation works as a negative feedback mechanism (i.e. if bile salt concentrations are low in the enterohepatic circulation then bile acid synthesis is high and vice versa). There are approx. 1-2g of bile acid in the enterohepatic circulation, with approx. 0.5g being lost daily. Cholic and chenodeoxycholic acids are the only
bile salts produced by the liver (primary bile salts). Secondary bile acids are produced in the intestine by the actions of microorganisms on primary salts; e.g. deoxycholic and lithocholic acids).

Front 88

WHat happens to cholesterol and phospholipids secreted by hepatocytes as bile acid secretion INC?

Back 88

Cholestrol and phospholipids secreted by hepatocytes increases as bile acid secretion increases. Bilirubin (primary bile pigment) is derived from the metabolic breakdown of hemoglobin from aged RBC's. Hepatocytes can extract bilirubin from blood, conjugate it with glucuronic acid and secrete the conjugated product into the bile. In the intestine bacteria in the terminal ileum and colon reduce bilirubin to urobilinogen. A portion of the urobilinogen is excreted, but part is reabsorbed and returned to the liver. A portion of the urobilinogen is conjugated and returned to the intestine with bile, while some in the systemic circulation is excreted by the kidneys

Front 89

Describe the storage of bile.

Back 89

The bile secreted by the liver is normally stored in the gallbladder (between meals) until needed. In the gallbladder Na+ and Cl- ions and water are absorbed by the gallbladder mucosa (Ca2+ ions are not). This has a net effect of concentrating the bile products, including bile salts, cholesterol, bilirubin and lecithin (phospholipid). The concentration of bile is normally about 5 fold but can increase up to 20 fold that of primary liver secretions.

Front 90

What is the composition of bile?

Back 90

The concentrations initially secreted by the liver and those stored in the gallbladder differ considerably (see above). Bile salts represent approx. 50% of the solutes in bile.

Front 91

Describe the transport of bile.

Back 91

The flow of bile into the gallbladder appears to be a passive process. As secretions into the bile duct occurs, then pressure within these ducts rises forcing bile in one direction (since the hepatic end of the ducts are blind). Pressure can rise as high as 10-20 mm Hg in the ducts.
Whether bile flows into the duodenum or gallbladder depends upon a balance of the resistance met. Most of the time the gallbladder can readily expand and accept bile, while the sphincter of Oddi is often contracted to prevent bile from entering the duodenum. The human gallbladder can accommodate approx. 20-50 ml of fluid, while the amount of bile secreted by the liver is often much more. The ability of the gallbladder to concentrate the bile accounts for the discrepancy.

Front 92

Describe the absorption of water in the gallbladder.

Back 92

Absorption of water in the gallbladder is partially an active process. Na+ transport appears to be electroneutral depending upon the presence of Cl- or HCO3- ions. Water movement is a passive process following that of Na+ ions

Front 93

Describe the expulsion of bile.

Back 93

The majority of secretion occurs during meals. However some is excreted during the migratory motor complex in a fasting state. Shortly after eating the gallbladder musculature contacts regularly and empties bile into the bile duct. The stimulus for this process appears to be hormonal i.e. CCK that is released into the duodenum and carried via the blood to the gallbladder, where it appears to have a direct excitatory effect on the smooth muscle in the gallbladder wall. Bile expulsion is also influenced by contractions of the duodenum, with bile often entering in spurts during duodenal relaxation’s. CCK also relaxes the sphincter of Oddi, allowing for more bile to enter the duodenum

Front 94

What are Brunner's glands and what regulates their secretion?

Back 94

Brunner’s glands, found extensively in the duodenum between the pylorus and papilla of Vater, secrete mucus in response to
(i) tactile stimuli
(ii) irritating stimuli
(iii) (iii) vagal stimulation
(iv) GI hormones, in particular secretin.

Front 95

What inhibits the secretion of Brunner's gland?

Back 95

Secretion of Brunner’s glands is inhibited by sympathetic stimulation, which can lead to the duodenal bulb being unprotected. This is thought to be one of the factors leading to peptic ulcers in this region of the GI tract. The function of this mucus is to protect the intestinal wall from digestion by gastric juices.

Front 96

What are the Crypt's of Lieberkuhn?

Back 96

Crypt’s of Lieberkuhn, line the small intestine and secrete extracellular fluid (pH 7.5-8.0; 1800 ml/day), which is rapidly reabsorbed by the villi. This solution acts as a carrier for absorption of nutrients.

Front 97

What is the mechanism of secretion?

Back 97

The mechanism of this secretion is believed to involve two active processes. (i) Active secretion of chloride into the crypts (ii) Active secretion of bicarbonate ions. Na+ ions move down their electrochemical gradient and create an osmotic potential, which results in the movement of water into the crypt.

Front 98

Describe the secretions of the large intestine.

Back 98

Crypts of Lieberkuhn line the mucosa of the large intestine, villi are not present. Mucus, which contains large quantities of bicarbonate ions is secreted by mucous cells in the crypts of Lieberkuhn (see figure 17). Parasympathetic stimulation results in copious amounts of mucus secretion. Mucus in the large intestine protects the lining from acid that is formed deep in feces. It also provides a medium for the formation and binding of fecal material.

Front 99

Descirbe the specialized features of the intestinal mucosa that can amplify the mucosal surface area.

Back 99

To ensure maximal absorption of nutrients the gastrointestinal tract has a number of unique features. The small intestine undergoes segmentation (contractions of the muscle layers) which ensure proper mixing of the lumenal contents, exposure of the contents to digestive enzymes and maximal exposure of the digestion products to the intestinal mucosa. The rhythmic contractions have a gradient along the small intestine with the highest frequency in the duodenum and the lowest in the terminal ileum. This gradient ensures oral to aboral movement of the contents in the lumen of the intestine.
The architecture of the intestine is also unique. Circular concentric folds increases the surface area about 3 times. Villi further increase the surface area of the intestine about 30 times. Each enterocyte on the villi have microvilli increasing the surface area even further to about 600 times that of a cylinder

Front 100

How is the GI tract able to maximize digestion and absorption?

Back 100

To ensure maximal absorption the GI tract has several unique features. After a meal the small intestine undergoes rhythmic segmental contractions. This ensures proper mixing of the luminal contents, exposure of the contents to digestive enzymes and exposure of the contents to the mucosal surface.
The architecture of the intestine is also designed to increase its surface area. Circular muscle folds, villi and microvilli increase the surface area of the intestinal mucosa by 600 fold and as a consequence increase its absorption abilities.
The process of digestion allows for carbohydrates, proteins and fats to be absorbed across the mucosal lining of the GI tract. The chemistry of digestion is a process of hydrolysis, where enzymes return water, H and OH ions, to their appropriate substrates. All the digestive enzymes are proteins, their secretion was discussed earlier.
Most nutrients are absorbed in the duodenum and jejunum. However other substances are absorbed in the terminal ileum (e.g. bile salts).

Front 101

Describe the digestion and absorption of carbs.

Back 101

Three major sources of carbohydrates exist as a food source, they include the disaccharide’s, sucrose and lactose and the polysaccharides or starches. Other
carbohydrates that are usually ingested to a lesser degree include amylose, glycogen, alcohol, lactic acid etc. Cellulose, which is a carbohydrate, cannot be broken down for absorption in the gastrointestinal tract.

Front 102

Describe salivary digestion of starches.

Back 102

At the point of entry into the GI tract, food is chewed and mixed with saliva. Saliva contains the enzyme ptyalin (-amylase) secreted by the parotid glands. -amylase hydrolyzes starch (which consists of the two polysaccharides amylopectin and amylose) into the disaccharide maltose and other small polymers of glucose. Due to the short period of time in the mouth, probably 3-5% of starches becomes hydrolyzed in the mouth before the food is swallowed. In the stomach, hydrolysis continues for a period of up to 1 hour. The activity of the salivary amylase is blocked by the low pH (<4.0) of gastric secretions, by this time 30-40% of the starches will have been hydrolyzed to maltose.

Front 103

Describe the pancreatic digestion of starches.

Back 103

Pancreatic secretion contains a lot of -amylase, that is identical in function to that found in saliva, but is several times more powerful. Following neutralization of chyme that enters the proximal duodenum, by bicarbonate secretion. Pancreatic secretion of amylase continues the digestion of carbohydrates, producing maltose, maltoriose and -limited dextrins. The digestion products of starch and other disaccharide’s are further digested by enzymes located at the brush border membrane. These enzymes are located near the carrier of the membrane transports the liberated glucose or galactose into the enterocyte. Thus, preventing any feedback inhibition on the enzyme. The speed of these processes also reduces the possibility of osmotic diarrhea that would occur with a build up of these products in the lumen of the intestine. The disaccharide enzymes maltase and sucrase can be up-regulated due to diets that contain a lot of sucrose and fructose. These enzymes are also being continually synthesized because of the high activity of proteolytic enzymes.

Front 104

What enzymes are found in the epithelial cells lining the microvilli of mucosa of the small intestine?

Back 104

(i) Lactase Splits lactose into glucose and galactose
(ii) Sucrase Splits sucrose into glucose and fructose
(iii) Maltase Splits maltose into molecules of glucose
(iv) -dextrinase non-specific dextrin enzyme

Front 105

Describe the absorption of monosaccharides.

Back 105

Monosaccarides are absorbed by intestinal epithelial cells (enterocytes) either actively or by facilitated transport. Glucose and galactose are absorbed by a symporter, that transports one molecule of glucose with 2 Na+ ions.

Front 106

What is the mechanism of monosaccharide absorption?

Back 106

(i) The movement of Na+ down its concentration gradient effects the movement of glucose up its concentration gradient.
(ii) The intracellular Na+ concentration is maintained low by a basolateral Na+/K+ ATPase.
(iii) The osmotic effects of sugars increases the Na+/K+ ATPase activity and the K activity of the basolateral membrane.
(iv) Sugars accumulate at higher concentrations in the enterocyte than in the plasma.

Front 107

What is Vmax for absorption of glucose and galactose and why is there a Vmax?

Back 107

There is a Vmax to the rate of absorption of glucose and galactose suggesting an active transport mechanism. Both compete for the same carrier and the carrier must bind Na+ before transporting a molecule of either sugar. This process is termed the sodium-glucose co-transport mechanism. Upon binding of the glucose molecule to the transport protein a conformational change allows both Na+ and glucose to cross into the cell. The Na+ is then actively transported out of the enterocyte into the lateral intercellular space by an active Na+ pump.

Front 108

Describe the diffusion of sugars from the enterocyte.

Back 108

Diffusion of sugars from the enterocyte occur by Na+ independent facilitated transport or passive diffusion mechanisms. Following absorption, sugars are transported to the liver via the portal system where they are converted into glycogen.

Front 109

What is lactose intolerance?

Back 109

Pathophysiological states exist because of the lack of membrane bound enzymes resulting in the malabsorption of carbohydrates. Undigested lactose causes osmolality changes. Osmolality is further increased by the production of lactic acid by intestinal bacteria acting on the lactose. Osmolality increases in the intestinal lumen cause water to enter the lumen. Increases in luminal water cause distension and increased propulsion in the intestine producing a watery diarrhea (see Figure 4). The enzymatic deficiency can be both genetic or by factors such as viral infections which results in diarrhea, flatulence and distension.

Front 110

What is the epidemiology of lactase deficiency?

Back 110

10% - Gentile Caucasians
60 % - Jews, Arabs, American Indians
70-95% - Blacks, Orientals and Eskimos.
and is inherited as a dominant trait.

Front 111

What happens to fibers that are not absorbed?

Back 111

Dietary fibers that are not absorbed form an important addition to the bulkiness in stool. The bulkiness in feces greatly reduces transit time. It has been suggested that dietary fibers reduce the incidence of colonic cancer by shortening gastrointestinal transit which reduces the formation of carcinogenic bile acids (e.g. lithocholic acid). Lithocholic acid is formed by the decongugation of chendeoxycholic acid by bacteria in the lumen.

Front 112

Describe the digestion and absorption of protein. What are some sources of protein?

Back 112

Almost all proteins require digestion before absorption. One exception is the direct absorption of -globulins from milk by newborns. However, after absorption they are subsequently digested in the mucosal cells. Although this form of passive immunity occurs in lower animals, it does not appear to be the case for humans. They require their passive immunity to be derived across the placenta to the fetus. Ingested -globulins are not digested in the human neonate as the stomach contains milk buffers and the pH of gastric contents are not acidic enough to activate pepsinogen.
A second source of protein is derived from the intestinal mucosa that is continually sleuthed off into the lumen. This source can account for up to 50% of the dietary protein. A third source of protein are the many enzymes that are secreted into the GI tract. The enzymatic protein may often exceed the protein derived from the diet. Enzymatic proteins are probably digested by secreted or bacterial protease’s before absorption. Pancreatic enzymes may be absorbed intact by pinocytosis and recycled in the pancreas.

Front 113

What is celiac sprue?

Back 113

In the disease celiac sprue (gluten sensitive enteropathy), a specific fraction of wheat protein attacks the microvilli of the mucosa, denuding it of these cells. patients with celiac sprue are thought to lack certain peptidases and the consequent incomplete digestion of gluten results in the production of a toxic substance. In unaffected individuals, gluten hydroxylase breaks down the toxic wheat peptide.

Front 114

Describe the absorption of peptides and amino acids.

Back 114

Gastric pepsin and pancreatic peptidases digest proteins into di and tripeptides. Both of these along with amino acids are readily absorbed across the brush border of mucosal cells. Inside the cytosol of epithelial cells various peptidases break the remaining linkages. As amino acids, they pass to the opposite side of the mucosal cell into the blood. The absorption of amino acids is coupled to the transport of sodium similar to that described for the absorption of monosaccharide’s

Front 115

What are 4 classes of amino acid transport mechanisms?

Back 115

(i) Basic: actively absorbed at less 3 mM.
(ii) Neutral: requires concs. of 20 mM to be absorbed.
(iii) Acidic: are significantly metabolized prior to absorption.
(iv) Imino:

Front 116

Where are most of the proteins absorbed?

Back 116

Proteins are almost entirely absorbed in the jejunum, although the intestine has the capability for amino acid absorption.

Front 117

Describe the digestion and absorption of lipids.

Back 117

Because lipids are soluble in the lipid bilayer of the intestinal membrane they are passively absorbed into the mucosal cells. However it is necessary for these substances to dissolve in the watery chyme. This requires a certain amount of conjugated bile salts to emulsify the lipids and incorporate them within the lumen as micelles. Lipids are packaged into chylomicra within the cytoplasm of intestinal cells which serves the same function of dissolving lipids in an aqueous media. Lipase is secreted in excess and therefore it's activity is dependent upon the substrate concentration. The size of the fat globules is the limiting factor in absorption. Before emulsification by bile salts lipid globlules have an average diameter of 100 nm, and after bile emulsification have a diameter of 5 nm, increasing the surface area considerably.

Front 118

What is the charge of lipase B and bile salts?

Back 118

Lipase B is electrically negative, as are bile salts. Their mutual repulsion is prevented by a polypeptide cofactor found in pancreatic juice, colipase, which complexes lipase to bile salts. Colipase also lowers the pH optimum of lipase to pH 6.0-7.0.
Bile salts are not absorbed across the unstirred layer with micelles, but are recycled to the lumen, where they form new micelles. Ultimately, bile salts are actively reabsorbed into the enterohepatic circulation in the distal ileum

Front 119

Describe how enterocytes process absorbed lipids to form lipoproteins.

Back 119

After entering the enterocytes, fatty acids and monoglycerides migrate to the smooth endoplasmic reticulum. In the SER, monoglycerides and fatty acids are rapidly reconstituted to form triglycerides. Fatty acids are first activated to form acetyl-CoA, which is then used to esterify monoglyceride to form diglyceride, which is transformed to triglyceride. Cholesterol can be transported out of the enterocyte as free cholesterol or as esterified cholesterol.

Front 120

What do enterocytes secrete?

Back 120

chylomicrons and VLDL, The reassembeled triglycerides, cholesterol and cholesterol ester are packaged into lipoproteins and transported from the enterocyte. The intestine produces 2 major classes of lipoproteins chylomicrons and VLDL’s

Front 121

What are apoproteins?

Back 121

Apoproteins (apo- A-I, apo I-IV and apo B) are among the major proteins associated with the production of chylomicrons and VLDL’s. Apo B is essential for the formation of chylomicrons and VLDL’s. After the chylomicrons and VLDL’s enter the plasma apo-I is rapidly transferred from Chylomicrons and VLDL’s to high-density lipoproteins (HDL’s). Apo-IV is the major protein associated with plasma HDL’s. Chylomicra, approx. 2 nm in diameter maintain a low concentration of lipids within the cell.

Front 122

Describe the absorption of the fat soluble vitamin A.

Back 122

Vitamin A can be derived directly from animal sources or from -carotene. One molecule of -carotene produces two molecules of vitamin A. Vitamin A is rendered water soluble by micellar solubilization and is absorbed by the small intestine passively. It is converted in the enterocytes to an ester (retinyl ester), which is incorporated in chylomicrons and eventually taken up by the liver.

Front 123

Describe the absorption of the fat soluble vitamin D.

Back 123

Vitamin D3 is absorbed in a similar mechanism as vitamin A. It is transported in the small intestine in a free form in association with chylomicrons. Vitamin D3 is transferred to a vitamin D binding protein in the plasma and is stored in various organs.

Front 124

Describe the absorption of the fat soluble vitamin E.

Back 124

Vitamin E derived from vegetable oils is again absorbed by passive diffusion. In the circulation vitamin E is transported in the circulation associated with lipoproteins and erythrocytes. Vitamin K can be derived from green vegetables or gut flora. The phylloquinones derived from greens is taken up by an active process but menaquinones derived from gut flora are taken up passively.

Front 125

Describe the absorption of the water soluble vitamin C.

Back 125

Vitamin C is taken up by an active process in the ileum. Vitamin B1 at low concentrations is taken up by an active carrier mediated process. At higher concentrations it is absorbed by passive diffusion. Intestinal absorption of vitamin B12 is by a receptor mediated process

Front 126

Describe the absorption of the water soluble vitamin B.

Back 126

B2 Riboflavin is absorbed by specific, saturable, active transport system located in the proximal small intestine.
B6 Absorbed by simple diffusion.
Biotin Absorbed by a Na+-dependent active transport system. At high concentrations it is absorbed passively.

Front 127

Describe the absorption of the water soluble folic acid.

Back 127

Folic acid is usually found in the diet as polyglutamyl congugates (petropolyglutamates). An enzyme on the brush border degrades petropolyglutamates to yield monoglutamylfolate, which is taken up by the enterocyte by facilitated transport. Folic acid is important in the formation of nucleic acids, maturation of RBC’s and promotion of growth.

Front 128

Describe the absorption of water and electrolytes.

Back 128

The intestinal mucosa absorbs virtually all of the large volume of fluids that are secreted by all the glands, as well as the water and electrolyte that is ingested. It is achieved by the simple process of active Nab transport, which then passively draws along anions and water. 25-30 g of Na+ is ingested and must be absorbed each day, as little as 0.5% of the sodium is lost each day. From the duodenum to colon the Na+ and Cl- ions become progressively lower in the GI lumen than plasma concentrations. Na+ that is approx.140 mM in the duodenum decreases to 35-40 mM in the colon (see Figure 9).

There is an increased effectiveness in absorbing ions along the GI tract that is partially attributable to the decreased permeability to ions, preventing back diffusion in the terminal parts of the GI tract. Cl- ions are also extremely well conserved, and can be exchanges for HCO3- ions.

Front 129

What transport routes do ions take?

Back 129

Sodium ions flow into and out of the lumen via the lateral spaces, and are
regulated by the zonula occludens or tight junctions, which are twice as permeable to Na+ and K+ ions than Cl- ions.

Front 130

Describe the absorption of fluids.

Back 130

Occurs in response to the osmotic forces established with solute and ion transport and can be explained in terms of a 3-compartment model.
1st. Compartment : Is when solutes are moved from the lumen into and then out of the epithelial cell. 2nd Compartment: This creates a local osmotic gradient causing water to move into the intercellular space. 3rd. Compartment: The increase in hydrostatic pressure in the intercellular space, causing a flow of water through the basement membrane into capillaries.
In the non-absorbing intestine the imbalance of forces across the capillary wall, leads to filtration of fluid into the interstitium. However, the capillary filtration rate is balanced by lymphatic drainage

Front 131

Describe the absorption of Ca2+.

Back 131

Calcium absorption by enterocytes is an important component in the regulation of whole body Ca2+. The transepithelial movement of the cation occurs against an electrochemical potential gradient. The process of Ca2+ absorption appears to be localized in the proximal intestine and occurs in 4 major steps.
(i) Entry at the brush border membrane.
(ii) Regulation of intracellular Ca2+.
(iii) Vitamin D affects at least one of these steps.
(iv) Ca2+ exit must occur at the basolateral side of the membrane.

Front 132

How much Ca2+ is taken in and how much is absorbed?

Back 132

About 1g of calcium is taken orally, of which approximately 40% is absorbed. Fatty acids retard the absorption of calcium by creating a calcium soup.

Front 133

What is the mechanism for Ca2+ absorption?

Back 133

Calcium transport is initiated by 1,25-dihydroxyvitamin D3, which is derived from vitamin D3. Vitamin D3 is formed by the action of UV rays on 7-dehydrocholesterol in the skin. Vitamin D3 is transferred to the liver and converted to 25-OH-D3. The kidney converts 25-OH-D3 to 1,25-dihydroxyvitamin D3, a step regulated by parathyroid hormone. Enterocytes take up the 1-25-dihydroxyvitamin D3, where it reacts with a receptor molecule in the cytoplasm or nucleus (exact region not known). Transcription of specific DNA and protein synthesis are mandatory steps in the in the action of 1,25-dihydroxyvitamin D3 in calcium transport.

Front 134

What do the binding proteins in the brush border do in Ca2+ absorption?

Back 134

At least one binding protein is inserted into the brush border and allows for Ca2+ entry down a concentration gradient.
In the cytoplasm calcium concentrations are minimized by CaBP on the endoplasmic reticulum and Golgi.

Front 135

What are the 2 mechanisms involved in the exit of Ca2+ at the basolateral side agianst an electrochemical gradient?

Back 135

(i) The most important is a calcium -ATPase (may be 1,25-dihydroxyvitamin D3 sensitive).
(ii) A Na+-Ca2+-exchanger which functions when the calcium -ATPase is saturated.

As calcium absorption increases and plasma concentrations increase the rise in calcium concentration in the plasma inhibits the secretion of parathyroid hormone and the subsequent formation of 1,25-dihydroxyvitamin D3 leading to the waning of calcium absorption.

Front 136

Describe the absorption of iron.

Back 136

Absorption of iron is regulated by total body requirements and bioavailability. Dietary iron is acquired through transport processes in the proximal small intestine. However epithelial cells in the stomach, ileum and colon possess some capabilities to absorb iron. Because body iron is conserved the amount of iron absorbed is relatively low compared to the amount ingested.
Heme (derived from meat) is an important dietary source (although not the major source) and is thought to be absorbed by endocytosis where it is digested by lysosome enzymes to release free iron. In all other extents iron is absorbed only to the extent it can be released from food particles in an ionizable form.

Front 137

What are the different forms of iron?

Back 137

Iron in food is present in two states: ferric (Fe3+) and ferrous (Fe2+) iron. At neutral pH most iron is in the ferric (oxidized) state, which is virtually insoluble. In order to make it more soluble it is reduced to the ferrous state. Ferrous iron is absorbed easier because it crosses the mucous layer of the small intestine more readily to reach the absorptive cells. There, Fe2+ must have an electron removed to form Fe3+, before it enters the absorptive cells. Fe3+ binds to a receptor protein which finally transfers the iron inside the cell. Absorption is primarily influenced by the amount of current iron stores. Absorption is controlled because there is no physiological mechanism for excretion.

Front 138

What role does gastric acid play in iron absorption?

Back 138

Gastric acid is important in iron solublization and thus patients with poor gastric acid secretions often have poorer iron absorption. Organic acids (ascorbic and citric) also reduce Fe3+ to Fe2+ (Fe2+ is absorbed more efficiently).

Front 139

How is non-heme iron absorbed?

Back 139

Enterocytes of the proximal small intestine release an iron binding protein called transferrin which binds to irons to the lumen. The transferrin - iron complex is bound to
the brush border by specific receptors. The complex is absorbed and the receptor recycled and the transferrin - iron complex transported to the basolateral side of the membrane. Iron appears in blood bound to a plasma transferrin (a ß1-globulin) by a relatively unknown mechanism. Some iron can also become bound to an intracellular protein, apoferritin, to form a complex called ferritin.
A small amount of iron can be taken up slowly from ferritin, however much is thought to be lost when the enterocytes exfoliate.

Front 140

Describe the regulation of iron uptake.

Back 140

Regulation of iron uptake is thought to occur at the level of (i) the specific brush border receptors and (ii) the ratio of ferritin to transport protein. Formation of ferritin is greatest when body iron levels are high.

Front 141

What are the effector systems?

Back 141

The musculature, mucosal epithelium and blood vessels are all called effector systems. The overall behavior of any region of the GI tract at any given time reflects the integrative activity of the effector systems.

Front 142

What does the enteric nervous system do?

Back 142

In addition to stimulating or inhibiting the effector systems the enteric nervous system coordinates/regulates their activity. For example mucosal secretion and muscle contractions are coordinated in a timed sequence during propulsion of contents in the intestine. Secretion of water electrolytes and mucus occurs first followed by muscle contraction and propulsion. While this is happening, the nervous system acts to increase blood flow that supplies water and electrolytes in support of the secretory behaviour. The end result is that secretory activity flushes material from the mucosa and lubricates the luminal lining in preparation for muscular contraction and propulsion of material out of that segment of the bowel.

The nervous system of the digestive tract is like a minibrain that contains a library of programs for different programs of behavior.

Front 143

What innervates the GI tract?

Back 143

Sympathetic, parasympathetic and enteric divisions of the autonomic nervous system innervate the GI tract.

The GI tract is innervated by the autonomic nervous system and by sensory nerves from the spinal cord and brainstem. The sensory nerves are not components of the autonomic nervous system. Sympathetic and parasympathetic pathways transmit signals from the central nervous system to the GI tract. Neurons of the enteric nervous system make up the local control circuits.

Front 144

Describe the sympathetic nerveous system.

Back 144

Sympathetic pathways emerge from the thoracic and lumbar segments of the spinal cord.
The preganglionic neurons in these pathways are cholinergic and form nicotinic synapses on the cell bodies of sympathetic post ganglionic, noradrenergic neurons in the prevertebral ganglia. Noradrenergic nerves run from cell bodies of prevertebral autonomic ganglia to the blood vessels and intrinsic ganglia of the gastrointestinal tract.

Many fibers synapse with the ganglia in the myenteric plexus, whereas only a few fibers supply the muscle in non-sphincteric muscles directly.
The noradrenergic nerves that run to the myenteric ganglia are usually inactive at rest. Their discharge is evoked through reflex pathways that originate both within and outside the wall of the GI tract. Most sphincteric muscle is supplied by a plexus of noradrenergic nerves.
Stimulation of sympathetic nerves normally reduces gastrointestinal motility in non-sphincteric muscle, often by inhibiting the release of ACh from enteric excitatory cholinergic neurons.
In sphincteric muscle, noradrenaline has a direct excitatory effect on smooth muscle cells through -adrenoreceptors.
Sympathetic nerves also contain a large number of sensory axons. The afferent fibers will discharge during stretch of the abdominal viscera, initiating adrenergic reflexes. These reflexes will modify the activity of the sympathetic neurons by which they act as buffers to inhibit gastrointestinal motility.

Front 145

Describe the parasympathetic nervous system.

Back 145

Emerges from the cranial and sacral regions of the spinal cord. The parasympathetic nervous system innervating the GI tract is provided by the vagal and pelvic nerves. Where the vagal influence ends and the pelvic innervation begins often varies between species. In humans it is thought to occur at the level of the mid-transverse colon.
The vagal and pelvic nerves release acetylcholine both at the synapse with enteric neurons and at the neuromuscular junction.

Front 146

What are the two types of post-synpatic receptors of the PNS?

Back 146

(i) Nicotinic receptors on enteric neurons.
(ii) Muscarinic receptors on the smooth muscle membranes.

Enteric neurons activated by nicotinic receptors at cholinergic synapses include the cholinergic excitatory neurons and the non-adrenergic non-cholinergic inhibitory neurons both of which innervate the muscle coats.

Front 147

Describe the efferent fibers of the vagal nerve.

Back 147

Efferent fibers of the vagal nerve originate in the Dorsal Motor Nucleus of the vagus in the medulla. Only about 10% of the fibers are efferents. The remaining 90% of the fibers are afferent fibers whose cell bodies lie in the nodose ganglia (swelling at the base of the brain). Fibers from sympathetic ganglia, such as the superior cervical and stellate ganglia also run in the vagal nerves.
In the distal regions of the gut, parasympathetic nerves are supplied by pelvic nerves. in most species the two groups of fibers form a complex pelvic plexus and cannot be separated.

Front 148

What are the two types of afferent sensory fibers that run in the vagal nerves?

Back 148

(i) Mucosal endings that function as rapidly-adapting mechanoreceptors or slowly adapting chemoreceptors.
These endings are sensitive to light mechanical and chemical stimulation, and therefore function as contact receptors, detecting the presence of food particles etc.
(ii) Slowly-adapting mechanoreceptor found in the muscle coat. That responds to stretch of the receptive field and to contraction of the muscle coat. They may also function as volume detectors and are believed to mediate vago-vagal reflexes such as receptive relaxation of the stomach.

Front 149

Describe the enteric nervous system. Where is it located?

Back 149

Located within the walls of the GI tract, The enteric nervous system is organized like an independent intergrative system.
Like the brain and spinal cord, the enteric nervous system is an independent integrative system containing 3 functional categories of neurons:
(I) Sensory neurons
(ii) Interneurons
(iii) Motor neurons

Front 150

Describe the sensory neurons of the ENS.

Back 150

The cell bodies of sensory neurons are found in the nodose ganglia of the vagal nerves, dorsal root ganglia of the spinal cord and ganglia of the enteric nervous system. Sensory afferent fibers carry information from the GI tract to the central nervous system. Most of the fibers in the vagal nerves are actually sensory fibers. Sensory nerves of the enteric nervous system provide information to the local processing nervous circuits and send processes to the prevertebral ganglia and CNS

Front 151

What role do the mechanoreceptors have in the ENS and CNS?

Back 151

Mechanoreceptors supply the ENS and CNS with information on the amount of stretch in the wall of the GI tract and on the movement of the luminal contents as they brush the mucosal surface. Chemoreceptors generate information on the pH of luminal contents. Thermoreceptors supply the brain with information used to regulate body temperature.

Front 152

What do the interneurons do?

Back 152

Millions of synaptic connections between interneurons form the information-processing center of the ENS. These synapses occur between the axons and cell bodies, between axons and dendrites and from axon to axon. The interneuronal microcircuits account for the higher functions associated with the ENS.

Front 153

What do the motor neurons do?

Back 153

Both excitatory and inhibitory motor neurons innervate the effector systems. Excitatory transmitters stimulate effector cells and inhibitory motor neurons depress activity.

Front 154

Describe reflexes.

Back 154

Reflex responses are a behavior of the effector systems that are evoked by activation of the sensory nerves. In a reflex circuit sensory nerves are connected to interneurons and interneurons are connected to motor neurons. The pattern of behavior in a particular reflex is the same, a result of the interconnection of the neurons that make up the reflex circuit, e.g. distension of the gut is detected by stretch receptors that lead to contraction of the circular muscle coat above the site of distension and relaxation of the circular muscle below the site of distension. This pattern of behavior is the same each time the mechanosensors are activated by stretch of the intestine wall.

Front 155

Describe the motor programs.

Back 155

Connections between interneurons form circuits that are responsible for the pattern-generating circuitry that drive the motor neurons for control of cycling activity e.g after a meal certain cyclic activity occurs. Program circuits determine the sequence of events in stereotyped repetitions of motor output to the effector system. Programmed motor behavior unlike reflex behavior does not require sensory input to start the program. For programmed behaviors the complete motor program may be set in motion by a single neuron (a command neuron). Interneurons also work together to achieve co-ordination of the behavior of individual effector systems.

Front 156

How do vagal nerves send command signal from the brain to enteric integrative circuits?

Back 156

There are as many neurons in the ENS as in the spinal cord. If the command neurons that control motor activity in the GI tract were located in the CNS, this would greatly expand its size. Long transmission lines from the CNS to the gut would lead to other communication difficulties. Therefore, vertebrates have evolved with most neural circuits close to the effector systems. Local integrative circuits in the ENS perform many operations independent of the CNS input.
The vagal nerves are the main transmission lines from the brain to the ENS. Efferent vagal nerves control large blocks of integrated nerves in the ENS (not individual motor neurons). This explains the profound influence efferent vagal nerves have on the effector systems.

Front 157

Describe the structure of the ENS.

Back 157

The ENS may be defined as the system of nerve cell bodies and their associated supporting cells that are found within the wall of the GI tract, including neurons within the pancreas and the gallbladder. It consists of ganglia, primary interganglionic fiber tracts and secondary and tertiary fiber projections to effector systems

Front 158

In what plexues are the neurons in the ENS located?

Back 158

(i) Auerbach's or myenteric plexus: lies between the circular and longitudinal muscle planes.
(ii) Meissner's or submucosal plexus: located in the submucosa.
The submucosal plexus has also been reported to consist of two separate plexuses in some species. Schabadache's or Henle’s lies in the inner surface of the circular muscle layer and Meissner's is located closer to the lamina propria.

Front 159

Where are the ganglia and the nerve fibers that innervate?

Back 159

Within ganglia and in the nerve fibers that innervate the circular and longitudinal muscle layers and the mucosa, nerve axons contain vesicles that are presumed to be the stores of neurotransmitters. In muscle tissues the nerve process are often devoid of glial cells and come into close contact with smooth muscle cells or interstitial cells of Cajal, which are thought to be the pacemaker cells in the gastrointestinal tract.

Front 160

What are the enteric ganglia?

Back 160

Dogiel (1899) reported the first morphological classification of different types of neurons within the ENS. This classification was based on differences of cell body size and shape and the branching characteristics of their processes

Front 161

What are Dogiel type I neurons?

Back 161

These neurons have many short stublike processes and a long process that extends in the circumfrential and longitudinal planes of the GI wall. The short processes are thought to be dendrites and the long process an axon. Dogiel type I neurons are both interneurons (that travel through ganglia) and motor neurons. The longest projections of Dogiel type I neurons are 2-3 cm.

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What are Dogiel type II neurons?

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Have smooth surfaces with long and short processes arising in a variety of configurations. The projections are thought to extend in all directions (orally, aborally and circumfrentially) extending through interganglionic fiber tracts of several ganglia (long) or within the same ganglia (short).

Front 163

What are Dogiel type III neurons?

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Similar in appearance to Dogiel type II, but contain more shorter processes. Intermediate processes terminate in the same or adjacent ganglia.

The physiological role of Dogiel type III neurons is unknown.

Front 164

What are the neurotransmitters and connections for the different types of neurons?

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The ENS uses at least 20 different neurotransmitters for chemical signaling and transfer of information. Often these substances are co-localized in the same neurons. ACh for example may be co-localized with excitatory peptides such as substance-P

Front 165

What are the receptors for the Dogiel type I neurons?

Back 165

Sub-populations of Dogiel type I neurons contain 5-HT, VIP, enkephalin or nitric oxide. Neurons that possess 5-HT that have smooth appearances in interganglionic tracts but have bead like appearances (varicosities) in ganglia are thought to be interneurons. Dogiel type I neurons that contain 5-HT in the myenteric plexus also send their processes to the submucosal plexus.
Dogiel type I neurons (which contain VIP or NO) in the myenteric plexus also send projections in an aboral direction, traveling for only a few millimeters before entering the circular muscle layer. Dogiel type I neurons containing VIP are also found in the submucosal plexus innervate the intestinal crypts.
Note: Dogiel type I neurons in the myenteric plexus that innervate the circular muscle layer are inhibitory. Those in the submucosal plexus are excitatory motor neurons to the intestinal crypts and are called setretomotor neurons, they stimulate the crypts to secrete water, electrolytes and mucus.

A further sub-population of Dogiel type I neurons found in the myenteric plexus that possess ACh and sub-P are excitatory motor neurons. These neurons when activated cause the contraction of the muscle layers.

Front 166

What do the Dogiel type II neurons do?

Back 166

Sub-P is also found in multipolar neurons, these cells are throught to be sensory neurons.

Front 167

Describe the functional relationship of enteric neurons?

Back 167

Neuroeffector junctions are not like the neuromuscular junction of skeletal muscles. They are simpler structures than motor endplates. Most motor axons release transmitters from varicosities (swellings in the axon) during propagation of the action potential. The transmitter can then diffuse over relatively large distances to the effector cells.

The structural organization of the motor neurons of the enteric nervous system is an adaptation for the simultaneous application of a transmitter to a large number of effector cells from a small no. of motor neurons

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What are the excitatory motor neurons of the ENS?

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Transmitters from excitatory motor neurons may trigger muscle contraction. Two types of muscle contraction exist. Excitatory neurotransmitters may trigger muscle contraction by membrane depolarization (to threshold) or by direct release of calcium from intracellular stores. The neurally evoked depolarizations of membrane potential are called excitatory junction potentials (EJPs). Direct release of intracellular calcium by neurotransmitters is called pharmaco-mechanical coupling.

Front 169

What are the inhibitory motor neurons of the ENS?

Back 169

Inhibitory motor neurons produce IJPs and suppress contractile activity. This occurs as a result of opening of potassium channels that move the membrane in a negative direction away from threshold and thus reducing intracellular calcium.

Front 170

Describe electrical and synaptic behavior of enteric neurons.

Back 170

Like other neurons enteric neurons use propagated action potentials to transmit signals from one part of the neuron to the other. Transmission of signals in the ENS uses synaptic transmission.

Front 171

What are S/type I neurons?

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have a distinct electrical behavior: They fire action potentials throughout the duration of a long lasting depolarization current pulses. The frequency of the repetitive spike discharge increases in proportion to the amplitude of the injected current. Often S/type I physiology is found in cells with a Dogiel type I-like morphology. “Like” is used because a variant fall outside this class. They possess short thread-like dendrites and are referred to as a filamentous neuron

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What are AH/type II neurons?

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: Fire 1 or 2 spikes on the onset of current injection which is followed by a long-lasting hyperpolarizing after-potential. Increasing the amplitude of the injected current does not alter this response. These cells have a morphology typical of Dogiel type-II neurons

Front 173

What does Tetrodotoxin do?

Back 173

it is a fast Na+ channel blocker

Action potentials evoked by depolarizing pulses in S/type I neurons are blocked by the fast sodium channel blocker tetrodotoxin (TTX). Action potentials evoked by depolarizing currents in AH/type II neurons are not blocked by TTX but the rate of rise is considerably reduced, suggesting a partial involvement of sodium ions in this action potential.

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What does hyperpolarization do to AH/Type II neurons?

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The hyperpolarization after potential of the AH/type II neurons summate when 2 action potentials are fired in close sequence. During this period the excitability of the neuron is reduced, preventing the discharge of another action potential. Action potentials cannot be fired faster than the rate the membrane requires to return to it’s prestimulus resting potential. During the after hyperpolarization, the membrane potential of AH/type II neurons is close to the potassium equilibrium potential. The input resistance of the cells is low suggesting that there is an ionic conductance being activated. Injection of current in this state does not lead to an action potential.

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What is the mechanism for the AH/type II neurons for the after hyperpolarization?

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involve Ca2+ and K+ channels

(I) Voltage-sensitive calcium channels are opened when the cell is depolarized.
(ii) Ca2+-activated potassium channels are activated by free intracellular calcium.
(iii) Potassium moves down its electrochemical gradient out of the neuron.
(iv) This results in hyperpolarization of the neuron and associated decrease in input resistance.
(v) The after-hyperpolarization decays as the high concentration of intracellular calcium is reduced by sequestration into intracellular storage sites or is pumped out of the neuron. (at the negative potential of the after-hyperpolarization the calcium channels are not open).

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What are the sequence of events that occur at synapses?

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(i) Action potential in the axon arrives at the presynaptic terminal.
(ii) Action potential triggers the release of transmitter substances from presynaptic terminal. The trigger for release of the transmitter substance is depolarization of the terminal and the entry of extracellular calcium.
(iii) The transmitter is released into the synapse and binds to post-synaptic receptors.
(iv) The change in membrane conformation of the receptor opens ionic channels in the post synaptic membrane.
(v) These events lead to a post-synaptic potential in the postsynaptic neuron.

Within the enteric nervous system. Chemical transmission occurs at axo-somatic, axo-axonal and axo-dendritic synapses.

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Describe the fast EPSP's in AH type II neurons.

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Depolarizing potentials with durations of less than 50 ms. All of the fast EPSPs in AH/type II neurons are mediated ACh acting on nicotonic receptors.
They are encountered less in AH type II than in S/type I neurons and are usually smaller in amplitude. The small epsp’s recorded in AH/type II neurons result from synaptic sites on dendritic processes removed spatially from the recording site in the soma.

Front 178

WHat are the slow EPSP's in AH/type II neurons?

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Recognized by a slowly activating membrane depolarization that is sustained from several seconds to minutes. The depolarization is associated with a decrease in conductance and increase in excitability. Enhanced excitability is revealed as repetitive spike discharges during the experimental depolarization. AH/type II neurons that fire only one spike will fire repetitively in response to the same experimental pulse during the slow EPSP. Electrical behavior of AH/type II neurons during the slow EPSP are much like S/type I neurons. The afterhyperpolarization, typical of AH/type II neurons is blocked during a slow EPSP. It appears that certain neurotransmitters block this potassium channel

Front 179

How is the slow EPSP signal transduced in AH/type II neurons?

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Evidence suggests that transduction of slow EPSP signals involves stimulation of adenylate cyclase and elevation of intraneuronal cAMP, phosphorylation of protein kinases and/or channel proteins and ultimately to the dramatic changes in excitability of the cell.
Slow EPSP’s are a mechanism for long lasting activation/inhibition of neuronal synapses and neuroeffector junctions within the gastrointestinal tract.

Front 180

What is the functional significance of slow EPSPs/

Back 180

The functional significance of slow epsp’s is prolonged activation or inhibition of gastrointestinal effector cells. Slow epsp’s in excitatory motor neurons to the muscles or mucosal epithelium result in prolonged muscle contraction or increased secretion and vice versa in inhibitory neurons.

Front 181

What are the slow IPSPs in AH/type II neurons?

Back 181

Slowly activating hyperpolarizations of the membrane potential that persist for several seconds after termination of the stimulus. They are found in cell bodies of the myenteric and submucosal neurons of the small and large intestine and in the gastric antrum. The hyperpolarization is associated with an increase in membrane conductance and decreased excitability, due to the opening of potassium channels

Front 182

What is the funcitonal significance of the slow IPSPs?

Back 182

The effects of IPSPs are to decrease membrane excitability and the probability of action potential discharge. Thus the probability that the somal membrane will reach threshold during invasion by incoming spikes or excitatory synaptic input is decreased. Slow ipsp’s in the Meisner’s plexus lead to a decrease in secretion

Front 183

What are the fast EPSPs in S/type I neurons?

Back 183

Fast EPSP’s in S/type I neurons are nicotinic and are coupled directly to the activation of a non-selective cation channels and an increase in conductance. All S/type I neurons receive fast EPSP input (unlike all AH/type II)

Front 184

What are the slow IPSPs in S/type I neurons?

Back 184

Two types exist in the submucous plexus. A robust component that is blocked by 2-adrenoreceptor antagonists and a more slowly activating component that is revealed after blockade of the adrenergic input. Somatostatin is a likely candidate for this event.
Experimental procedures revelaed that a large proportion of the S/type I neurons in the submucous plexus are secretomotor neurons. These cells when activated release transmitters at neuroepithelial junctions that evoke the secretion of water, electrolytes and mucus. Synaptic inhibition of spike discharge supresses secretion in epithelial cells.

Front 185

What is presynaptic inhibition?

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Presynaptic inhibition is supression of neurotransmitter release from axons. In the ENS it involves both fast and slow EPSP’s and motor transmission at the neuroeffector junctions. Presynaptic inhibition is mediated by chemical messengers acting at receptors on the axon. The inhibition may involve axo-axonal transmission, where release of a transmitter on one axon acts on receptors on another to suppress release of transmitter from the second axon. Inhibition of transmitter release can also be brought about by substances released from endocrine or other non-neuronal cells. Presynaptic inhibition can also occur in the form of auto-inhibition, where the release of transmitter from an axon accumulates around the release site and acts on presynaptic receptors to reduce further release (effectively a negative feedback loop)

Front 186

What controls the spread of information?

Back 186

gating mechanisms, Neural regulation controls peristaltic propulsion of luminal contents. This neural control requires gating mechanisms to determine distance and direction of the propagation.

Front 187

Describe the slow synaptic gating mechanisms.

Back 187

Slow EPSP's underlie a gating mechanism that controls the spread of action potentials between the axons and dendrites arising from opposite ends of the cell body of a multi-polar neuron.
Recordings in AH/type 2 neurons have demonstrated that action potentials propagating toward a cell body in one of its processes usually do not fire an action potential in the cell body. An action potential in an AH neuron is followed by the characteristic after-hyperpolarization which prevents the cell body from firing by any additional incoming spikes. It is also improbable that an inbound spike in a process will produce an action potential in the cell body. During a slow EPSP when excitability is increased this probability is greatly increased.
In a state of low excitability the membrane of a multipolar neuron acts like a "closed-gate" to the transfer of signals between its dendrites and axons. A closed somal gate isolates the initial segments such that spike discharge in one initial segment does not influence others attached to the cell body.
Slow EPSP's can therefore open the somal gate resulting in transfer of signals across the cell body to axons at the other pole

Front 188

What is the presynaptic mechanism of gating?

Back 188

Enteric nerves do not travel very far along the intestinal wall before they synapse with another neuron. Therefore, neuronal signals for propagated behavior must cross many synapses for the event to be propagated. Virtually all of the synapses in the enteric neural circuits have presynaptic inhibitory receptors at the release sites of neurotransmitters. Presynaptic mechanisms can therefore gate the distance, as well as the direction of travel of neuronal signals within plexuses.

Front 189

Describe the organization of neural circutis for GI motility.

Back 189

The basic peristaltic circuit consists of sensory neurons, interneurons and motor neurons. Blocks of this basic circuit are connected in series along the length of the intestine and repeated in parallel around the circumference of the GI tract. Synaptic gates determine the distance and direction of propagation of the peristaltic wave.

Front 190

What are driver networks and how do they synchronize motor events?

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Driver networks encircles each segment and is repeated in each consecutive segment all along the intestine. The driver networks are organized to activate motor neurons simultaneously around the circumference of a segment. Synaptic gates regulate whether sequential networks are activated for continued propagation of peristalsis.

Front 191

What makes up the dirver networks?

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Multipolar neurons with interconnections for feedforward excitation make up the driver networks. Slow EPSP’s are thought to provide the mechanism for coordinated discharge of neurons in the driver networks.

The morphology, direction of the long axonal process of and chemical coding (5-HT) of a subpopulation of Dogiel type I neurons suggest that these cells transmit descending timing signals.
Note: Some books do not emphasize the importance of sensory neurons for enteric reflexes. Figure 17 illustrates the importance of these neurons, many of which are stretch sensitive.

Front 192

Describe the devlopment of the ENS.

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All of the neurons and glial cells of the ENS are the progeny of immigrants. These being immigrants that are precursor cells that depart during ontogeny from two regions of the neural crest. The majority of the enteric nervous system is derived from vagal neural crest cells (NCC), which migrate from somites 1-7 of the neural crest to the developing gut. In the gut they proliferate, form plexuses and differentiate into enteric neurons and supporting glial cells. Vagal NCC migrate ventrally within the embryo and accumulate in the caudal branchial arches before entering the pharyngeal region and colonizing the entire length of the gut in a proximo-distal direction. During migration, vagal crest cells seem to follow different pathways depending on the region of the gut being colonized. In the pre-umbilical intestine, NCC are evenly distributed throughout the splanchnopleural mesenchyme while, in the post-umbilical intestine, they occur adjacent to the serosal epithelium. Behind this migration front, NCC become organized into the presumptive Auerbach's and Meissner's plexuses situated on either side of the developing circular muscle layer.
Controversy has existed as to whether cells from the sacral region (Caudal to somite 28) of the neural crest also contribute to the enteric nervous system. It has recently been shown that Vagal cells colonized the entire bowel, but sacral derived cells are observed only in the post-umbilical gut. The sacral neural crest, also appear to contribute to the enteric neuronal and glial populations of both the myenteric and the submucosal plexuses, caudal to the level of the umbilicus.

Front 193

What are the crest-derived cells and what role do they play in the development of the ENS?

Back 193

It is thought that the crest-derived cells are not fully committed to becoming enteric neurons or glial cells before they migrate. Crest-derived cells that colonize the bowel quickly develop a 110 kDa laminin binding protein expression on their surface, which is not present prior to colonization. The presence of the laminin binding protein has importance when considering that in lethal spotted mutant mice (ls/ls) there is a region in the distal colon that is aganglionic (no enteric ganglia are present). These mice possess an excess of laminin in the terminal regions of the gut and it is thought that this excess of laminin inhibits further colonization by the crest derived immigrants (i.e. laminin causes the terminal differentiation of crest-derived cells). A similar mechanism may be present in patients with Hirschprung's disease.

Front 194

How is the intestine classified as a sensory organ?

Back 194

The lining of the gastrointestinal tract is the largest vulnerable surface that faces the external environment. Just as the other large external surface, the skin, is regarded as a sensory organ, so should the intestinal mucosa. In fact, the mucosa has three types of detectors: neurons, endocrine cells, and immune cells. The mucosa is in immediate contact with the intestinal contents so that nutrients can be efficiently absorbed, and, at the same time, it protects against the intrusion of harmful entities, such as toxins and bacteria, that may enter the digestive system with food. Signals are sent locally to control motility, secretion, tissue defense, and vascular perfusion; to other digestive organs, for example, to the stomach, gallbladder, and pancreas; and to the central nervous system, for example to influence feeding behavior. The three detecting systems in the intestine are more extensive than those of any other organ: the enteric nervous system contains on the order of 108 neurons, the gastroenteropancreatic endocrine system uses more than 20 identified hormones, and the gut immune system has 70- 80% of the body's immune cells. The gastrointestinal tract has an integrated response to changes in its luminal contents. When this response is maladjusted or is overwhelmed, the consequences can be severe, as in cholera intoxication, or debilitating, as in irritable bowel syndrome. Thus it is essential to obtain a full understanding of the sensory functions of the intestine, of how the body reacts to the information, and of how neural, hormonal, and immune signals interact.

Front 195

Where are the systems for detecting changes in tissues located?

Back 195

Three systems for detecting changes in tissues are located in the wall of the intestine: neural, endocrine, and immune detecting systems. Neural sensations are conveyed by extrinsic and intrinsic primary afferent neurons (IPANs) and intestinofugal neurons. Endocrine messages are in the form of hormones released from cells in the mucosal epithelium. The hormones enter the circulation and thus act at remote sites, but they also act locally, on nerve endings, epithelium, microvasculature, and cells of the immune system. Immune messages are conveyed by local activation of lymphocytes and augmented by circulating lymphocytes that are activated by antigens from the lumen.

Front 196

What neurons are responsible for detecting the state of tissues?

Back 196

The neurons that detect the states of tissues are primary afferent neurons, primary because they are the first neurons in reflex pathways and afferent because they run toward reflex control centers. Three broad classes of primary afferent neurons are associated with the gut:

Front 197

What are the three broad classes of primary afferent neurons that are associated with the gut?

Back 197

1) intrinsic primary afferent neurons (IPANs, also called intrinsic sensory neurons), with cell bodies and connections in the gut wall, 2) extrinsic primary afferent neurons, with cell bodies in vagal and dorsal root (spinal) ganglia, and 3) intestinofugal neurons, with cell bodies in the gut and projections to neurons outside the gut wall

Front 198

Describe the arrangement of primary afferent neurons of the intestine.

Back 198

Intestinal primary afferent neurons include IPANs, vagal and spinal primary afferent neurons, and intestinofugal neurons. IPANs are multipolar, and their terminals are confined within the wall of the intestine. Vagal and spinal primary afferent neurons are pseudounipolar and have collaterals that run to enteric ganglia (e.g., arrows). Subgroups of these that respond to specific modalities may have specific patterns of ending in the gut wall (not shown). Vagal primary afferent neurons have cell bodies in the nodose ganglia, and their outputs are via terminals in the nucleus tractus solitarius within the brain stem. Cell bodies of spinal primary afferent neurons are in dorsal root ganglia, their central processes end in the dorsal horns of the spinal cord, and their peripheral axons pass through sympathetic ganglia to innervate the intestine. In many cases, primary afferent neurons are excited by hormones released by gut endocrine cells. Intestinofugal neurons are part of the afferent limb of intestinointestinal reflexes that pass through sympathetic ganglia

Front 199

What are some structural features that are common to all smooth muscle cells?

Back 199

Smooth muscle is responsible for the contractility of hollow organs, such as blood vessels, the gastrointestinal tract, the bladder, or the uterus. Its structure differs greatly from that of skeletal muscle, although it can develop isometric force per cross-sectional area that is equal to that of skeletal muscle. However, the speed of smooth muscle contraction is only a small fraction of that of skeletal muscle.

Front 200

What are some common morphological features common to all smooth muscle cells?

Back 200

The most striking feature of smooth muscle is the lack of visible cross striations (hence the name smooth). Smooth muscle fibers are much smaller (3-6 µm in diameter) than skeletal muscle fibers (10-100 µm).

Front 201

What is the difference between single-unit and multi-unit smooth muscle?

Back 201

It is customary to classify smooth muscle as single-unit and multi-unit smooth muscle. The fibers are assembled in different ways. The muscle fibers making up the single-unit muscle are gathered into dense sheets or bands. Though the fibers run roughly parallel, they are densely and irregularly packed together, most often so that the narrower portion of one fiber lies against the wider portion of its neighbor. These fibers have connections, the plasma membranes of two neighboring cells form gap junctions that act as low resistance pathway for the rapid spread of electrical signals throughout the tissue. The multi-unit smooth muscle fibers have no interconnecting bridges.

Front 202

Describe multi-unit smooth muscle tissues.

Back 202

In multi-unit smooth muscle tissues each cell operates entirely independent of other cells and the cell does not communicate with other muscle cells through gap junctions. The discrete cells are separated by a thin basement membrane and often innervated by a single neuron, and their main control is through nerve signals. Thousands of smooth muscle cells belonging to the multi-unit type join by the common innervation in a functional syncytium. Multi-unit smooth muscle is found in the eye (the ciliary muscle and sphincters as the iris muscle of the eye), in large arteries, in the vas deferens, and in the piloerector muscles that cause erection of the hairs. These muscle cells are normally quiescent, insensitive to stretch and they are activated only through their autonomic nerves. Each muscle is composed of multiple motor units, hence the name: multi-unit smooth muscles. The nerve fiber branches on a bundle of smooth muscle fibers, and form junctions with varicosities filled with transmitters. These junctions are analogous to the neuromuscular junctions of striated muscles. The neurotransmitters are acetylcholine and noradrenaline. Multi-unit smooth muscles have developed a contact junction with shorter latency than the slowly operating diffuse junctions mainly found in the single-unit type.

Front 203

Describe single-unit smooth muscle cells.

Back 203

Single-unit smooth muscle cells are arranged in bundles such as the arrangement in a viscera eg. intestine, uterus and ureter. These smooth muscle cells communicate through gap junctions, separating the cell membranes by only 2-3 nm, and from pacemaker tissue of variable location, action potentials are generated initiating a contraction of the muscle. The action potentials generated in one cell can activate adjacent cells by ionic currents spreading rapidly over the whole organ and securing a co-ordinated contraction as though the tissue were a single unit or a syncytium. These cells are characterized by their spontaneous motility and by their sensitivity to stretch. The spontaneous activity is usually modified by the autonomic nervous system. Visceral smooth muscle undergoing peristalsis, generates propagating action potentials from cell to cell.

Front 204

What are some typical features of smooth muscle cells?

Back 204

(i) Uninucleate cells.
(ii) Does not have T-tubules but an abundance of caveolae.
(iii) Relies heavily on Ca2+ entering from the extracellular space (through channels) to raise cellular calcium levels and so support prolonged contraction.
(iv) Cells are electrically coupled by gap junctions proteins (connexins) allowing electrical activity to propagate through the tissue.
(v) Possess numerous cell-cell and cell stromal connections.

(vi) Has an internal Ca2+ store (sarcoplasmic reticulum) that can be released in response to some transmitter substances.
(vii) Can exhibit action potentials or slow wave electrical activity (which cause contraction) but smooth muscle can exist in a partially contracted state (tone) for long periods without any obvious electrical events.
(viii) Electrical activity may be initiated and coordinated by a specialised type of cell, the interstial cells of Cajal (ICC). These cells may serve as GI pacemakers and they have been found in arterial smooth muscle.
(ix) Does not have troponin complex (on actin filament of striated muscle). Instead calcium binds to Calmodulin (related structurally to troponin) which activates the enzyme myosin light chain kinase (MLCK). MLCK has to phosphorylate the light chains of myosin in order for actin and myosin to interact and begin to cycle.
(x) Smooth muscle can generate similar levels of stress (force per unit area) as skeletal muscle
(xi) Contraction, particularly maintained contraction (tone), is very energy efficient, using only 1% of the energy of striated muscle.

Front 205

Describe the size of smooth muscle cells.

Back 205

Smooth muscle cells are approximately 3-6 µm in diameter and 100-500 µm in length. The spindle shaped cell is dictated by the insertion of filaments over the entire extent of the cell surface and is essential for the mechanical properties of the cell. An important parameter of smooth muscle cells is the surface to volume ratio, which reaches a value of 1.5- 2.5 µm2 of cell surface to every µm3 of cell volume.

Front 206

Describe the cell membrane of smooth muscle cells.

Back 206

Surrounding the surface of the plasma membrane of smooth muscle cells are 2 domains. (I) Areas occupied by dense bodies and (II) areas occupied by caveolae. There are chemical differences in the areas occupied by the two domains. The presence of calcium pumps in the area occupied by caveolae and the presence of veniculin and other cytoskeletion associated proteins in the regions of dense bands.

Front 207

What are caveolae?

Back 207

In-pockets of plasma membranes which are flask shaped (70 nm x 120 nm). In smooth muscle caveolae are arranged in rows interposed between dense bands and occupy about 50% of the plasma membrane present at the cell surface. In some smooth muscle cells there are approximately 170,000 per cell which adds about 70% to the amount of plasma membrane to the cell surface. Caveloae are often positioned close to the cisternae and tubules of the sacroplasmic reticulum. The plasmalemmal Ca-pump ATPase, the enzyme that extrudes calcium from the sarcroplasm, and thus maintains homeostasis is localized within caveloae. In addition the role of caveloae in calcium transport and it has been suggested that they may play a role in cell volume, act as miniature stretch receptors, or serve the role of creating a specialized compartment of the extracellular space.

Front 208

What are smooth muscle cell junctions?

Back 208

Several junctions exist between smooth muscle cells, between smooth muscle cells and the extracellular matrix, between specialized cells and smooth muscle pacemaker cells- interstitial cells of Cajal; endothelial cells) and possibly between enteric nerves and smooth muscle cells.

Front 209

What is the purpose of smooth muscle cell junctions?

Back 209

The crucial role of junctions between cells is to allow for the assembly of cells to work in a coordinated fashion. Junctions allow for the excitation or relaxation conveyed by nerves or pacemaker cells to spread to all the muscle cells. By means of junctions the mechanical effects of smooth muscle cell shortening and the development of tension in individual cells are added together and transmitted to the stroma, a process that leads to the macroscopic events of muscle contraction or relaxation.
Because of the nature of junctions, single uninucleated smooth muscle cells work like a unitary structure or syncytium.

Front 210

What are the three main types of cell junctions?

Back 210

(i) Occluding junctions (tight junctions).
(ii) Anchoring junctions (A) Actin filament attachment sites. Cell adherens junctions. Cell matrix adhesion junctions (focal contacts).
(B) Intermediate filament attachment sites
Cell-cell (desmosomes)
Cell-matrix (hemidesmosomes)
(iii) Communicating junctions.-Gap junctions. Chemical synapses.

Front 211

What are tight junctions?

Back 211

Usually found between epithelial cells that allow for these cells to serve as selective permeability barriers separating fluids on each side that have a different chemical composition.

Front 212

What are anchoring junctions?

Back 212

Enable groups of cells to function as robust structural units by attaching the cytoskeletal proteins of a cell to another cell or to the extracellular matrix. Composed of two classes of proteins (i) Intercellular attachment proteins that form a distinct plaque on the cytoplasmic side of the membrane and connect the junctional complex to actin or intermediate filaments. (ii) Transmembrane linker proteins whose cytoplasmic domains binds to one or more intercellular attachment plaques. While the extracellular domains interact with the extracellular matrix or the transmembrane linker protein of another cell.

Front 213

What are gap junctions?

Back 213

Gap junctions are the morphological correlates of direct cell-cell communication and are formed of hexameric assemblies of gap junction proteins (connexins) into aqueous pores or hemichannels (or connexons) provided by each coupled cell. Gap junction channels formed by each of the connexin subtypes (of which there are as many as 20) display different properties, which have been attributed to differences in amino acid sequences of gating domains of the connexins. Recent studies additionally indicate that connexin proteins interact with other cellular components to form a protein complex termed the Nexus. Gap junctions consist of intercellular channels that connect the cytoplasm of adjacent cells directly and allow the exchange of small molecules. These channels are unique in that they span two plasma membranes--the more orthodox ion or ligand-gated channels span only one. Each cell contributes half of the intercellular channel, and each half is known as a connexon or hemichannel. Recent studies indicate that connexons are also active in single plasma membranes and that they might be essential in intercellular signaling beyond their incorporation into gap junctions. Gap junctions can contain several hundred connexins that allow for the flow of inorganic ions and other water soluble molecules to pass from the cytoplasm of one cell to that of another. They therefore allow for electrical and chemical coupling between cells.

Front 214

What are connexins?

Back 214

Traditionally, gap junction proteins (connexins) have been considered as simple pore-forming proteins that exhibit little or no interaction with other cellular components. Thus, much of the work on gap junctions has focused on the structure and function of individual connexins. Evidence is now accumulating that this view of the gap junction has been too narrow and that connexins have rich interactions with a myriad of other proteins that may turn out to be important in multiple aspects of gap junction biology including function, regulation, and even structure.

Front 215

Describe the domains that make up the connexins.

Back 215

Connexins are four transmembrane domain (tetraspan) proteins with cytoplasmically localized amino terminus, cytoplasmic loop and carboxyl terminal domains (Fig. 4). It is these intracellular domains that are the most variable in amino acid sequence among the different connexins, with the cytoplasmic loop and carboxyl terminal domains conferring most of the diversity among connexin subtypes. The presence of these variable sequences, some of which contain known signaling domain motifs (for one example see fig. 5) implies that these regions may be important in differential connexin function. Studies now show that there are variations in the protein-protein interactions of these domains and it is these differing protein–protein interactions that may confer distinctive functional or regulatory pecificity to gap junctions formed of the individual connexins.

Front 216

What are dense bands?

Back 216

Structures associated with the cell membrane (30-50% of the cell profile) where contractile and cytoskeleton proteins are anchored to the cell surface. Dense bands are often coupled to other cells (adherens type) or coupled to the extracellular matrix. Dense bodies are dense bands found within the cytoplasm. Actin filaments are inserted into the dense bodies and are analagous to the z-lines of skeletal muscles.

Front 217

WEhat is the sarcoplasmic reticulum?

Back 217

Consisting of tubules and flattened sacs it is well developed in smooth muscle cells and interstitial cells of Cajal. These organelles play an important role of the release of intracellular calcium.

Front 218

What are myofibril proteins?

Back 218

In general, smooth muscle contains much less protein (~110 mg/g muscle) than skeletal muscle (~200 mg/g). Notable is the decreased myosin content, ~20 mg/g in smooth muscle versus ~80 mg/g in skeletal muscle. On the other hand, the amounts of actin and tropomyosin are the same in both types of muscle. Smooth muscle does not contain troponin, instead of it there are two other thin filament proteins, caldesmon and calponin.

Front 219

Describe the amino acid sequence of smooth muscle actin.

Back 219

The amino acid sequence of smooth muscle actin is very similar to that of its skeletal muscle counterpart, and it seems likely that their three-dimensional structures are also similar. Smooth muscle actin combines with either smooth or skeletal muscle myosin. However, there is a major difference in the activation of myosin ATPase by actin, smooth muscle myosin has to be phosphorylated for actin-activation to occur.

Front 220

Describe the size and shape of smooth muscle myosin.

Back 220

The size and shape of the smooth muscle myosin molecule is similar to that of the skeletal muscle myosin. There is a small difference in the light chain composition; out of the four light chains of the smooth muscle myosin two have molecular weight of 20,000 and two of 17,000. The 20,000 light chain is phosphorylatable. Upon phosphorylation of the light chain the actin-activated smooth muscle myosin ATPase increases about 50-fold, to about 0.16 mol ATP hydrolyzed per mole of myosin head per sec, at physiological ionic strength and temperature.

Front 221

What do caldesmon and calponin do?

Back 221

In vitro, both caldesmon and calponin are inhibiting the actin-activated ATPase activity of phosphorylated smooth muscle myosin. In case of calponin, this inhibitory activity is reversed by the binding of Ca2+-calmodulin or by phosphorylation. Calponin is a 34-kDa protein containing binding sites for actin, tropomyosin and Ca2+-calmodulin. Caldesmon is a long, flexible, 87-kDa protein containing binding sites for myosin, as well as actin, tropomyosin, and Ca2+-calmodulin. Electron microscopy and three-dimensional image reconstruction of isolated smooth muscle thin filaments revealed that calponin and caldesmon are located peripherally along the long-pitch actin helix (Hodgkinson et al., 1997; Lehman et al., 1997). The physiological role of caldesmon or calponin is not known.

Front 222

What initiates or stimulates contraction in smooth muscle?

Back 222

Contraction in smooth muscle can be initiated by mechanical, electrical, and chemical stimuli. Passive stretching of VSM can cause contraction that originates from the smooth muscle itself and is therefore termed a myogenic response. Electrical depolarization of the smooth muscle cell membrane will also elicit contraction, most likely by opening voltage dependent calcium channels (L-type calcium channels) and causing an increase in the intracellular concentration of calcium. Finally, a number of chemical stimuli such as acetylcholine, norepinephrine, angiotensin vasopressin etc. can elicit contraction. Each of these substances bind to specific receptors on the smooth muscle cell (or to receptors on the endothelium adjacent to the vascular smooth muscle) and can cause contraction of the VSM. The mechanism of contraction can involve different signal transduction pathways all of which converge to increase intracellular calcium.

Front 223

What is the mechanism that allows for an INC in intracellular Ca2+ to stimulate smooth muscle contraction?

Back 223

The mechanism by which an increase in intracellular calcium stimulates smooth muscle contraction is illustrated in Figure 7. An increase in free intracellular calcium can result from either increased flux of calcium into the cell through calcium channels or by release of calcium from internal stores (e.g., sarcoplasmic reticulum; SR). The free calcium binds to a special calcium binding protein called calmodulin. Calcium-calmodulin activates myosin light chain kinase (MLCK), an enzyme that is capable of phosphorylating myosin light chains (MLC) in the presence of ATP. Myosin light chains are 20-kD regulatory subunits found on the myosin heads. MLC phosphorylation leads to cross-bridge formation between the myosin heads and the actin filaments, and hence, smooth muscle contraction.

Front 224

How are Ca2+ levels maintained intracellularly?

Back 224

Intracellular calcium concentrations, therefore, are very important in regulating smooth muscle contraction. The concentration of intracellular calcium depends upon the balance between the calcium that enters the cells, the calcium that is released by intracellular storage sites (e.g., SR), and removal of calcium either back into storage sites or out of the cell. Calcium is re-sequestered by the SR by an ATP-dependent calcium pump. Calcium is removed from the cell to the external environment by either an ATP-dependent calcium pump or by the sodium calcium exchanger.

Front 225

Describe the interaction of contractile proteins.

Back 225

There is a remarkable heterogeneity in the time course of contractions among smooth muscles in the gastrointestinal tract. Phasic muscles such as those found in the small intestine contract and relax in seconds while tonic muscles such as the stomach contract and relax over periods of hours. As in skeletal muscle the contractility of smooth muscle is modified by intracellular calcium.

Front 226

What is the mechanism that leads to contraction?

Back 226

Interaction of myosin with actin with hydrolysis of ATP is the fundamental reaction where chemical energy is converted into mechanical energy in smooth muscle.
Essential in smooth muscle contraction is the phosphorylation of the 20 kd regulatory myosin light chain by myosin light chain kinase.
Steps leading to the activation of this kinase include:
(i) Increase in intracellular calcium via influx through voltage gated channels or release from intracellular stores.
(ii) Sequential binding of calcium to the four binding sites on the regulatory protein calmodulin.
(iii) The binding of calcium activated-calmodulin to MLC kinase to form the active complex Ca2+-calmodulin-MLC kinase.
Phosphorylation of MLC induces a conformational change in the myosin head that increases the ability of actin to activate myosin-Mg2+-ATPase and bring about the hydrolysis of ATP bound to the myosin head.

Front 227

Describe the cross-bridge cycle.

Back 227

At the start of the cross bridge cycle the myosin head with ATP bound to it (myosin.ATP) is either detached or weakly attached to an actin molecule in a thin filament. Hydrolysis of ATP by Myosin (Mg.ATPase) yields an intermediate with the products of hydrolysis still bound to it (myosin.ADP.Pi), which is either detached or weakly attached to the actin molecule.
Release of Pi from the myosin complex causes a change from a weak to a strong binding of myosin and actin and a change in the angle of the myosin head from 90 to 450. The strain imposed on the cross bridge imposed by the angle of the myosin is relieved when the actin molecule slides past the crossbridge. ADP is released slowly, the myosin head rebinds ATP and reverts to the 900 angle facing the next actin molecule.
The force generated by cross bridge cycling is dependent upon the number of cross bridges acting in parallel. Because the cross bridges do not act in unison the force that is generated by their action is both slow and continuous. Both the number and cycling of cross bridges are regulated in smooth muscle.

Front 228

What happens in sustained contraction of smooth muscles (tonic)?

Back 228

Sustained contraction of smooth muscles (tonic) produces a different king of cross bridge cycling. Upon stimulation there is a rapid increase in cytosolic Ca2+, MLC kinase activity, MLC phosphorylation and shortening velocity which is correlated with an increase in muscle tension. Within a few seconds there is a rapid decrease in cytoplasmic calcium, MLC phosphorylation and shortening velocity to low suprabasal levels. This is while muscle contraction reaches a peak and maintains a near steady state contraction (a condition termed the latch state). A state that reflects a transition from a population of rapidly cycling cross bridges to a population of attached, non-cycling or slowly cycling cross bridges. Force being maintained by “latch” bridges which becomes dephosphorylated while remaining attached and in this state have a slow detachment rate.

Front 229

What is an alternative hypothesis that explains contraction that does not involve phosphorylation of MLC?

Back 229

An alternative hypothesis that does not depend upon phosphorylation of MLC of cross bridge cycling for sustained tonic contractions depends upon the binding of a segment of the myosin core to caldesmon (150 kd protein associated with the actin filament). Cladesmon occupies the grooves between the actin double helix, its head piece in register with tropomyosin. In vitro, its presence increases greatly the affinity of actin filaments for heavy smooth muscle meromyosin. The tight binding of the actin helix to the myosin core involves the phosphorylation of caldesmon.

Front 230

Describe the mobilization of Ca2+.

Back 230

Ca2+ concentration in the cytosol is an essential determinant for the activity of the smooth muscle. Smooth muscle cells mobilize calcium in various ways to initiate, sustain and terminate contractions. Mechanisms differ depending upon the smooth muscle, i.e. blood vessels, GI smooth muscle or uterine smooth muscle. Differences in Ca2+ handling may reflect functional differences in different smooth muscle phenotypes.

Front 231

What are 3 possible ways that have been identified that allow Ca2+ to enter smooth muscle cells during contraction?

Back 231

(i) Interaction of a contractile agonist with a specific receptor on the plasma membrane generates a second messenger that causes the release of calcium from intracellular calcium stores.
(ii) Interaction of a contractile agonist with a specific receptor on the plasma membrane initiates the opening of voltage dependent Ca2+ channels on the plasma membrane directly via membrane depolarization (cation channel) or by way of release of second messengers.
(iii) Another cell type coupled to smooth muscle may regularly bring smooth muscle cells to threshold for activation of L-type calcium channels thus allowing for phasic contraction of smooth muscle cells.

Front 232

What is Ca2+ exchange and why is it useful?

Back 232

Intracellular calcium concentrations in smooth muscle cells ranges from 10-7 to 10-5 M. Extracellular concentration of calcium is about 2 x 10-3 M (2 mM). Therefore, there is a chemical gradient for calcium to diffuse into the cell. Because cells have a negative resting membrane potential (-40-80 mV) there is also an electrical force driving calcium into the cell. However, except during action potentials or slow waves when the cell membrane permeability to calcium increases, there is little leakage of calcium into the cell. The calcium that enters the cell during action potentials (e.g., during depolarization) must be removed from the cell otherwise an accumulation of calcium would lead to cellular dysfunction.

Front 233

What are two mechanisms by which Ca2+ is removed by cells?

Back 233

The first involves an ATP-dependent Ca++ pump that actively removes calcium from the cell. The second mechanism is the sodium-calcium exchanger. The exact mechanism by which this exchanger works is unclear. It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this exchanger. The direction of movement of these ions (either inward or outward) will depend upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration. One example of when this occurs is when the activity of the Na+/K+-ATPase pump is decreased. This energy requiring ATP-dependent pump transports sodium out of the cell and potassium into the cell. When the activity of this pump is reduced, for example, by cellular hypoxia (which causes ATP levels to fall) or by chemical inhibitors of this pump such as digitalis, then intracellular sodium concentrations increase. The Na+/Ca++ exchanger will then extrude the increased Na+ from the cell in exchange for Ca++ that will enter the cell. This leads to an accumulation of intracellular calcium. In the case of digitalis, this leads to increased ionotrpohy. Under hypoxic conditions, the enhanced calcium concentrations cannot increase inotropy because of the lack of ATP; however, the increased intracellular calcium (termed calcium overload) can damage mitochondria and effect other subcellular processes.

Front 234

What is the innervation to the smooth muscle?

Back 234

Smooth muscle is primarily under the control of autonomic nervous system, whereas skeletal muscle is under the control of the somatic nervous system. The single-unit smooth muscle has pacemaker regions where contractions are spontaneously and rhythmically generated. The fibers contract in unison, that is the single unit of smooth muscle is syncytial. The fibers of multi-unit smooth muscle are innervated by sympathetic and parasympathetic nerve fibers and respond independently from each other upon nerve stimulation.

Front 235

What does nerve stimulation in smooth muscle cause?

Back 235

Nerve stimulation in smooth muscle causes membrane depolarization that leads to excitation or hyperpolarization and relaxation. Excitation, the electrochemical event occurring at the membrane is followed by the mechanical event, contraction. In the case of smooth muscle, this excitation-contraction coupling is termed electromechanical coupling; the link for the coupling is Ca2+ that permeates from the extracellular space into smooth muscle. There is another excitation mechanism in smooth muscle, which is independent of the membrane potential change; it is based on receptor activation by drugs or hormones followed by muscle contraction. This is termed pharmacomechanical coupling. The link is Ca2+ that is released from an internal source, the sarcoplasmic reticulum.

Front 236

What is the role of mechanical events of smooth musle in the wall of hollow organs?

Back 236

1) Its tonic contraction maintains organ dimensions against imposed load. 2) Force development and muscle shortening, like in skeletal muscle.

Front 237

What are the different types of muscarinic receptors?

Back 237

Muscarinic receptors expressed on smooth muscle cells are primarily of the M(2) and M(3) subtypes. The M(3) subtype triggers contraction through an interaction with G(q) proteins to stimulate phosphoinositide hydrolysis and mobilize Ca(2+). In contrast, activation of M(2) receptors modulates contraction by preventing relaxation or by potentiating M(3) receptor-mediated contractions, which enhances heterologous desensitization. These effects can be explained by the coupling of M(2) receptors to G(i) proteins that mediate an inhibition of adenylyl cyclase and calcium-activated potassium channels.

Front 238

How is smooth muscle relaxed?

Back 238

Endothelial-derived relaxing factor (EDRF) is recently shown to be nitric oxide (NO). Activation of endothelial cells produces NO from arginine, and NO diffuses into the smooth muscle cells. NO stimulates directly the enzyme guanylate-cyclase, and by that intracellular [cGMP] elevates.

Front 239

What does NO do and where is it produced?

Back 239

Nitric oxide (NO) is produced by vascular endothelium and smooth muscle, cardiac muscle, and many other cell types. The substrate for NO is L-arginine that is transported into the cell. When acted upon by nitric oxide synthase (NOS), NO and citrulline are formed.

Front 240

What are the different forms of NOS?

Back 240

There are two general forms of NOS - constitutive and inducible. NO is continuously produced by constitutive NO synthase (cNOS). The cNOS found in endothelial cells is also referred as eNOS, ecNOS, or Type III NOS. The activity of cNOS is modulated by calcium that is released from subsarcolemmal storage sites in response to the binding of certain ligands to their receptors. Substances such as acetylcholine, bradykinin, histamine, insulin, and substance P stimulate NO production by this mechanism. Another important mechanism regulating the release of NO is shearing forces acting on the luminal surface of vascular endothelium. By this mechanism, increased flow velocity stimulates calcium release and increased cNOS activity. The inducible form of NOS (iNOS, or Type II NOS) is not calcium-dependent, but rather is stimulated by the actions of cytokines (e.g., tumor necrosis factor, interleukins) and bacterial endotoxins (e.g., lipopolysaccharide). Induction of this enzyme occurs over several hours and results in a production of NO that may be more than a 1,000-fold greater than that produced by cNOS. This is an important mechanism in the pathogenesis of inflammation.

Front 241

What is the mechanism behind NO activity?

Back 241

The mechanism of many of these actions of NO involves the formation of cGMP. When NO is formed by an endothelial cell, for example, it readily diffuses out of the cell and into adjacent smooth muscle cells where is binds to a heme moiety on guanylyl cyclase and activates this enzyme to produce cGMP from GTP. Increased cGMP activates a kinase that subsequently leads to the inhibition of calcium influx into the smooth muscle cell, and decreased calcium-calmodulin stimulation of myosin light chain kinase (MLCK). This in turn decreases the phosphorylation of myosin light chains, thereby decreasing smooth muscle tension development and causing vasodilation. There is also some evidence that increases in cGMP can also lead to myosin light chain de-phosphorylation by activating the phosphatase. The anti-platelet aggregatory effects of NO are also related to the increase in cGMP. Drugs that inhibit the breakdown of cGMP (inhibitors of cGMP-dependent phosphodiesterase such as sildenafil [Viagra]) potentiate the effects of NO-mediated actions on the target cell.

Front 242

What happens when NO production is impaired?

Back 242

When NO production is impaired as occurs when the vascular endothelium becomes damaged or dysfunctional, the following can result:
• Vasoconstriction (e.g., coronary vasospasm, elevated systemic vascular resistance, hypertension)
• Platelet aggregation and adhesion leading to thrombosis
• Upregulation of leukocyte and endothelial adhesion molecules leading to enhanced inflammation
• Vascular stenosis, or restenosis as occurs following balloon angioplasty and stent placement
• Increased inflammation and tissue damage mediated by reactive oxygen species such as superoxide anion and hydroxyl radical

Front 243

What diseases/conditions are associated with endothelial dysfunction and reduced NO production and/or bioavailability?

Back 243

There is considerable evidence that the following diseases/conditions are associated with endothelial dysfunction and reduced NO production and/or bioavailability:
• Hypertension
• Obesity
• Dyslipidemias (particularly hypercholesterolemia and hypertriglyceridemia)
• Diabetes (both type I and II)
• Heart failure
• Atherosclerosis, cigarette smoking, aging, and vascular injury

Front 244

Describe the gross morphology of smooth muscle layers.

Back 244

Longitudinal muscle fibers run along the gut whereas the circular muscle layer runs around the gastrointestinal tract. Isolated pieces of intestine spontaneously and rhythmically contract at a rate of 3-6 times per minute in the stomach, 4-14 times per minute in the small intestine and 6-20/min in the colon. These contractions are produced by rhythmic fluctuations in the membrane potential of the smooth muscle cell and are often referred to as slow waves in the GI tract (see figure 2).
Slow waves are not dependent upon neural activity since neural antagonists such as tetrodotoxin or hexamethonium do not block them.

Front 245

What are the interstitial cells of Cajal?

Back 245

Although smooth muscle cells respond to slow waves which leads to the rhythmic contractions of the gut, they do not appear to be the cell responsible for their origin. Slow waves appear to originate in a network of cells called interstitial cells of Cajal or ICC cells. These cells are believed to be analogous to the SA node of the heart providing a pacemaker function. Slow waves appear to originate in these cells and conduct electrically into smooth muscle cells. ICC and smooth muscle cells make electrical contact with each other via gap junctions

Front 246

What is the location of the ICCs?

Back 246

In the stomach and small intestine ICC are found between the circular muscle layer and longitudinal muscle layer where they form a thin (1-2 cells thick) but extensive layer of cells. They are often found surrounding ganglia and will appear on both sides (longitudinal and circular side). In the small intestine ICC are also found between the outer circular muscle layer and the inner circular muscle layer, at the level of the deep muscular plexus, where they probably provide a role in neural transduction to the circular muscle layer.
In the colon, where there is no inner circular muscle layer or deep muscular plexus. ICC form a thin monolayer at the submucosal surface of the of the circular muscle layer. Removing the ICC layer by dissection, adding chemicals that disrupts electrical communication or the addition of cytotoxic agents to mitochondria all inhibit electrical slow waves .

Front 247

What is the electrical mechanism underlying slow waves?

Back 247

Several ionic conductances are activated during a typical slow wave. The slow wave usually consists of a rapid upstroke, followed by a plateau phase of variable duration, which is followed by repolarization of the slow wave to the resting membrane potential. During the plateau phase of slow waves action potentials are often superimposed upon the slow wave, these action potentials appear to be derived from smooth muscle cells. The depolarization phase of slow waves is usually mediated by the flow of extracellular calcium ions since they are inhibited by low calcium or by calcium channel antagonists such as the dyhydropyridines nifedipide or nisoldipine. The repolarization phase of slow waves is due to the efflux of potassium ions. The plateau phase of slow waves is though to be a balance between influx of calcium and efflux of potassium ions. The depolarization of membrane potential can initiate a contraction of the smooth muscle cell (see below). It should be noted that not all gastrointestinal tissues produce slow waves, some tissues produce action potentials and others are tonic smooth muscle such as those found in sphincters.

Front 248

Describe the neural regulation of slow waves.

Back 248

Even though slow waves appear to originate in a special class of cells in the gut wall (ICC), they are influenced by neuotransmitters that are released from nerves. Excitatory agonists such as acetylcholine or substance P can increase the amplitude and duration of slow waves by modifying the conductances that are responsible for the slow wave. Increasing the amplitude or duration of slow waves will result in a larger and longer associated contraction of the smooth muscle cells. Excitatory agonists can also increase the frequency of slow waves.

Front 249

What are some examples of inhibitory substances and what do they do?

Back 249

Inhibitory substances released from neural endings such as nitric oxide, VIP, isoproternol and noraepinephrine decrease the amplitude and duration of slow waves as well as decreasing the frequency of these events. These effects are usually mediated at least in part by the activation of potassium conductances that usually terminate slow waves.

Front 250

What are the transit times through the GI tract?

Back 250

oropharyngeal phase-0.5-1s
esophageal phase-5-10 (10 in long)
stomach-2-3 hours (12 in long)
small intestine-2-4 hrs (6 m long)
large intestine-30 hrs-days

Front 251

What is the importance of the act of swallowing?

Back 251

The act of swallowing not only conveys food down the esophagus but also disposes of mucous loaded with dust and bacteria from the respiratory passages. During deglutination the Eustachian auditory tube is opened, thus equalizing the pressure on either side of the ear drum. Breathing is, however, stopped because the trachea is closed by the epiglottis.

Front 252

Describe the oral or voluntary phase of swallowing.

Back 252

The oral or voluntary phase of swallowing is initiated by separating a bolus of food from the mass in the mouth with the tip of the tongue. The bolus to be swallowed is moved upward and backward in the mouth by pressing first the tip of the tongue and later also the more posterior portions of the tongue as well against the hard palate. This forces the bolus into the pharynx, where it stimulates the tactile receptors that initiate the swallowing reflex.

Front 253

What are the following sequence of events in the pharyngeal stage?

Back 253

The Pharyngeal Stage of swallowing involves the following sequence of events, which occur in less than 1s:
a) The soft palate is pulled upward, and the palatopharyngeal folds move inward toward one another. This prevents reflux of food into the nasopharynx and provides a narrow passage through which the food moves into the pharynx.
b) The vocal cords are pulled together, and the epiglottis covers the opening of the larynx. The larynx is moved upwards against the epiglottis. These actions prevent food from entering the trachea.
c) The upper esophageal sphincter relaxes to receive the bolus of food. Then the superior constrictor muscles of the pharynx contract strongly to force the bolus deeply into the pharynx.
d) A peristaltic wave is initiated with contraction of the superior constrictor muscles of the pharynx, and it moves toward the esophagus. This forces the bolus of food through the relaxed upper esophageal sphincter (UES).
During the pharyngeal phase of swallowing, respiration is reflexly inhibited.

Front 254

Describe the esophageal phase of swallowing.

Back 254

it is also partially controlled by the swallowing center
1) After a bolus of food passes the upper esophageal sphincter, the sphincter reflexly constricts.
2) Primary peristalsis: A peristaltic wave then begins just below the upper esophageal sphincter and traverses the entire esophagus or reaches the stomach in about 5-10s moving at a velocity of 3 to 5cm/s. This initial wave of peristalsis is controlled by the swallowing center.
3) Secondary peristalsis: Should the primary peristalsis be insufficient to clear the esophagus of food, the distension of the esophagus would initiate another peristaltic wave that begins at the site of distension and moves downward. This latter type of peristalsis is called secondary peristalsis. It is partially mediated by the enteric nervous system, since it occurs (albeit weakly) in the extrinsically denervated (extrinsic nerves damaged or cut) esophagus. Input from esophageal sensory fibers to the central and enteric nervous system is involved in modulating esophageal peristalsis.

Front 255

What are the two ways that esophageal peristalsis is initiated?

Back 255

Esophageal peristalsis may be initiated by a swallow or by esophageal distension such as occurs spontaneously with gastroesophageal reflux or experimentally with distension of balloon in the esophagus. Years ago, peristalsis induced by a swallow was called "primary peristalsis". Peristalsis initiated by esophageal distension in the absence of a swallow, "secondary peristalsis“. Evidence today suggests both central and peripheral pathways are involved in primary and secondary peristalsis. The smooth muscle portion of the esophagus is capable, however, of generating a peristaltic wave in the absence of CNS connections. This response has been called tertiary or autonomous peristalsis. Conversely, a swallow in the absence of any bolus produces peristalsis in the smooth muscle portion of the esophagus indicating that the entire peristaltic complex can be executed through the central swallowing center without afferent input from the esophagus. This observation should not be taken to indicate that afferent impulses from the esophagus are not important in normal esophageal function. For example, afferents arising from the esophagus modify the peristaltic wave. Swallows of hot liquids increase the speed of the peristaltic wave; cold liquid swallows lead to failure of the stomach smooth muscle to respond to a swallow and acid swallows (pH1.5-2.0) delay esophageal peristalsis.

Front 256

Where are the swallowing centers located?

Back 256

The swallowing centers are located in the medulla. Each half of the center receives afferents from the ipsilateral side and its efferent output controls the muscles on the same side. This center orchestrates the complex sequence of relaxation and contraction of the many muscles involved in the swallowing complex.

Front 257

What is the nucleus ambiguous?

Back 257

motor to muscles of pharynx and striated muscles of esophagus

Front 258

What carries the major peripheral sensory inputs to the swallowing center?

Back 258

the maxillary branch of the trigeminal nerve (V2) [face, sinuses and teeth],
the glossopharyngeal nerve (IX) [Posterior 1/3 of tongue, tonsil, pharynx and middle ear]
and
3) the superior laryngeal branch of the vagus (X) [larynx, pharynx].

Front 259

What motor brancheas provide the motor ouptut of the swallowing center?

Back 259

trigeminal (V) [muscles of mastication], facial (VII) [muscles of face], glossopharyngeal (IX) [stylopharyngeous, upper pharyngeal muscles], vagus (X) [palate, pharynx, larynx, esophagus], and
hypoglossal (IX) [tongue mucles].

Front 260

What is oropharyngeal dysphagia?

Back 260

Oropharyngeal dysphagia (difficulty in swallowing) is the symptom of the failure of normal propulsion of the bolus from mouth to esophagus. Because the oropharyngeal phase of swallowing is coordinated with respiratory activity, respiratory symptoms often accompany oropharyngeal dysphagia. If the muscle disorder involves the muscles that close the glottis or those that move the larynx out of the path of the swallowed bolus, laryngeal penetration by the bolus and subsequent aspiration can occur. As swallowing is completed, respiration is resumed. If the pharynx has not been emptied by pharyngeal peristalsis, aspiration and choking are likely. Additionally, regurgitation into the nose will accompany swallowing if muscle weakness is the primary cause of dysphagia and the weakness involves the muscles of the soft palate and/or superior constrictors of the pharynx. Oropharyngeal dysphagia and associated respiratory symptoms are caused by:
1) a failure of the driving force
2) obstruction to flow
3) a combination of 1 and 2

Front 261

What defects are associated with oropharyngeal dysphagia?

Back 261

failure of propulsion (brain, CN, myoneural junction, muscle), obstructions to flow (mass effect, incomplete sphincter relaxation)

Front 262

What are some examples of oropharyngeal dysphagia?

Back 262

cerebral vascular accident, poliomyelitis, myasthenia gravis, dermatomyositis, tumor or abscess, cricopharyngeal achalasia

Front 263

What is Dermatomyositis?

Back 263

Dermatomyositis is one of a group of acquired muscle diseases called inflammatory myopathies. The disease, which has a somewhat severe onset, affects both children and adults. Females are more often affected than males. Dermatomyositis is characterized by a rash accompanying, or more often, preceding muscle weakness. The rash looks like patchy, bluish-purple discolorations on the face, neck, shoulders, upper chest, elbows, knees, knuckles, and back. Some people may also develop calcium deposits, which appear as hard bumps under the skin. The most common symptom is muscle weakness, usually affecting the muscles that are closest to the trunk of the body. Eventually, people have difficulty rising from a sitting position, climbing stairs, lifting objects, or reaching overhead. In some cases, muscles further away from the trunk of the body may be affected later in the course of the disease. Problems with swallowing (dysphagia) may occur. Occasionally, the muscles ache and are tender to the touch. Affected individuals may also feel fatigue and discomfort and experience weight loss or a low-grade fever.

Front 264

What happens if the driving force fails?

Back 264

Myasthenia gravis is a disorder of neuromuscular transmission involving striated muscle characterize by weakness and increased exhaustion. The transmission defect is due to a reduced number of acetylcholine receptors on the motor end plates. This deficiency of functional receptors is produced by an autoimmune mechanism in which antibodies directed against acetylcholine receptors reduce the number of functioning receptors available for synaptic transmission. Myasthenia commonly involves bulbar innervated muscles. Difficulty in swallowing may be due to weakness of tongue, palate, pharynx, or a combination of these factors. Anticholinesterase drugs which delay breakdown of acetylcholine improve synaptic transmissIon by increasing the concentration of acetylcholine at the end plates. Figure shows manometric tracing and barium swallow from a myasthenic patient before and after injection of the anticholinesterase drug, edrophonium (Tensilon).

Front 265

What is primary esophageal peristalsis?

Back 265

The primary peristaltic wave in the esophagus is a continuation of the peristaltic wave originating in the pharynx. First, there is relaxation of the esophagus, most clearly demonstrated in the sphincters. The peristaltic wave passes from the pharynx into the striated portion of the esophagus and then through the smooth muscle portion without any hesitation to suggest the transition from one type of neuromuscular arrangement to another. Lower esophageal sphincter (LES) relaxation is maintained until the peristaltic wave enters the sphincteric segment, after which sphincter pressure returns to or above the resting level. In the figure the esophagus is represented immediately after the initiation of the swallow. In panel A, the bolus is just entering the upper esophagus and the LES is still closed. Three pressure recording sites are at the levels 1, 2 and LES. On the right, the pressures recorded from levels 1,2 and LES are shown. (A) is immediately after swallow and the LES is closed. At (B) the swallowed bolus has passed into the esophagus and is flowing through the open sphincter (level LES) and the peristaltic wave has reached level 1. In (C) the bolus has moved into the distal esophagus and the peristaltic wave has reached level 2. In (D) the bolus has passed into the stomach and the LES has just closed as the peristaltic wave entered the sphincteric segment.

Front 266

What is ascending excitation?

Back 266

Temporal correlation between esophageal pressure and muscle thickness proximal to distension. Pressure and muscle thickness were recorded at 5 cm (distal; B) above LES. Each graph represents mean data from 5 observations in 5 subjects. Note a close temporal correlation between pressure and muscle wall thickness at proximal and distal esophageal sites. Onset of muscle thickness started ~0.5-1 s before pressure increase and lasted 2-3 s after pressure drop. Changes in circular and longitudinal muscle during contraction started at same time and during relaxation decrease in muscle thickness occurred at same time as well.

Front 267

What is descending inhibition?

Back 267

Temporal correlation between pressure and muscle thickness distal to distension. Proximal balloon was inflated with 8 ml of air. Note that there was either a small or no change in pressure distal to distension but longitudinal (lm) and circular muscle (cm) thickness was significantly decreased. Decrease in distal muscle thickness in response to esophageal distension represents descending inhibition in longitudinal and circular muscle layers.

Front 268

What is the efferent neural control of esophagus?

Back 268

Special visceral somatic fibers directly innervate skeletal muscle of both the longitudinal and circular muscle layers. Preganglionic fibers from the vagus nerve innervate the ganglion cells of the myenteric plexus. Fibers from the ganglion cells then innervate the smooth muscle cells of both layers. In addition, the ganglionic cells have neural connections with one another. The inhibitory motor neurons delay the onset of the contraction, which is generated by activation of excitatory motor neurons.

Front 269

What is LES relaxation?

Back 269

it is neurogenic

Relaxation of the LES after swallowing is mediated by the vagus nerve stimulating intrinsic enteric inhibitory neurons. These neurons release NO onto the cells in the LES and cause relaxation. After sectioning the vagus in the neck, stimulation of the peripheral end produces LES relaxation in both the cat and opossum (latter is considered a particularly good animal model for the human LES). The relaxation is not a vagus-mediated cholinergic response since muscarinic blockade fails to inhibit LES relaxation. Likewise, the neurotransmitter for sphincter relaxation is not adrenergic as adrenergic blockade also fails to inhibit relaxation. Tetrodotoxin (TTX) abolishes neurally-mediated responses but has no direct effect on smooth muscle. TTX inhibits the vagus-stimulated relaxation of the LES, indicating it is due to a neurogenic mechanism. Nitric oxide is the inhibitory neurotransmitter that mediates esophageal relaxation.

Front 270

What do anticholinergic drugs do to LES pressure?

Back 270

ANTICHOLINERGIC DRUGS DECREASE LES PRESSURE IN HUMANS
This means that part of the LES tone is produced by cholinergic excitatory neurons releasing ACh in the LES. There is little agreement as to the relative importance of neural activity in maintenance of normal resting sphincter tone. Much of the confusion stems from the reported effects of cervical vagotomy on resting LES pressure. In addition to interfering with sphincter relaxation, vagotomy has been observed to 1) increase LES pressure 2) decrease LES pressure and 3) have no influence on LES pressure (apparently some confusion in the literature). Observe anticholinergic effects on LES pressure in Fig. 20. Neurogenic, myogenic and hormonal factors play a role in determining resting LES pressure: 1) Neurogenic - cholinergic blockade decreases sphincter tone, 2) Myogenic - vagotomy or cholinergic blockade does not lead to total abolition of sphincter tone in any of the species studied hence it is reasonable to suggest a myogenic component; 3) Hormonal - the differing effects on LES pressure by fat and protein meals is best explained by hormonal action.

Front 271

What stimulates LES relaxation?

Back 271

LES relaxation is stimulated by a non-adrenergic and non-cholinergic vagal neurotransmitter

Neural control of the LES can be demonstrated by the following experimental techniques. First vagal nerve stimulation produces relaxation. Neither blockade of adrenergic nor cholinergic (muscarinic) receptors blocks this relaxation. Addition of tetrodotoxin (a blocker of the sodium channels in neurons) inhibits nerve impulses and inhibits the relaxation response.

Front 272

What does NO do?

Back 272

Nitric oxide is the major inhibitory neurotransmitter for esophageal relaxation

NO IS THE MAJOR NEUROTRANSMITTER FOR LES RELAXATION
Inhibition of nitric oxide synthase (NOS) blocks swallow (primary) or balloon (secondary) induced relaxations of the LES. This test shows that the predominant relaxation response in the LES is due to synthesis and release of NO.

Front 273

Describe the vagal control of LES relaxation.

Back 273

Muscle tone in the lower esophageal sphincter is partially maintained by firing in Vagal Excitatory Fibers (VEF), so called because they activate cholinergic motor neurons (release ACh) that lie within the myenteric plexus. During a swallow, the activity in VEF is reduced and activity in Vagal Inhibitory fibers (VIF) is increased. VIF fibers excite inhibitory motor neurons within the myenteric plexus that release Nitric Oxide (NO) to relax the smooth muscle of the LES.

Front 274

What are some factors that INC LES pressure?

Back 274

protein, INC intraabdominal pressure, gastric pH

Front 275

What are some factors that DEC LES pressure?

Back 275

fat, chocolate, peppermint, alcohol, smoking, gastric distensio (aerophagia)

Front 276

How does gastroesophageal reflux initiate a cycle of INCed esophageal acid exposure?

Back 276

The relationship between gastroesophageal reflux and altered pressures in the distal esophagus and lower esophageal sphincter is difficult to clarify. Do the abnormal pressures occur as a result of the chronic reflux or are they a primary event? A reasonable hypothesis at this point is that incompetence of the LES (probably initially produced by transient spontaneous relaxations) leads to reflux and prolonged esophageal mucosal acid contact causing esophagitis. The esophagitis results in chronic injury to the distal esophagus affecting the peristaltic function and causing frequent ineffective peristalsis which prolongs the acid contact secondary to reflux. The esophagitis may also cause chronic decreases in LES pressure, resulting in a damaging cycle of events that combine to perpetuate the reflux injury.

Front 277

What are the symptoms of esophageal dysfunction?

Back 277

dysphagia (failure of propulsive force, obstruction to flow, in-coordination of contraction and relaxation), esophageal pain (non-cardiac chest pain), gastroesophageal reflux symptoms

Front 278

What happens if there is a disorder of abnormal esophageal propulsion?

Back 278

Left series of traces shows normal manometric record of esophageal peristalsis following a swallow. The esophageal wave progresses down the esophagus and clears the swallowed material through the relaxed LES. In scleroderma the peristaltic contractions are weakened and this leads to a loss of propulsive force. The contractions in this case are normal in the skeletal portion of the esophagus, but weakened in the distal (smooth muscle) portion of the esophagus. Note also that the LES tone is abnormally low before the swallow.

Front 279

What is scerloderma?

Back 279

Scleroderma (sklere-o-DER-muh) is a rare, progressive disease that leads to hardening and tightening of the skin and connective tissues — the fibers that provide the framework and support for your body. It usually begins with a few dry patches of skin on the hands or face that begin getting thicker and harder. These patches then spread to other areas of the skin. In fact, scleroderma literally means "hard skin."
In some cases, scleroderma also affects the blood vessels and internal organs. Scleroderma is one of a group of arthritic conditions called connective tissue disorders. In these disorders, a person's antibodies are directed against his or her own tissues. Researchers haven't established a definitive cause for scleroderma. About 150,000 Americans have the disease. It's more common in women than in men and more common in adults than in children. Scleroderma can run in families, but in most cases it occurs without any known family tendency for the disease. It's not considered contagious or cancerous, but this chronic condition can greatly affect self-esteem and the ability to accomplish everyday tasks.

Front 280

What does diffuse esophageal spasm cause?

Back 280

the esophagus to contract in an uncoordinated way. As a result, what is swallowed is not pushed down into the stomach.

Front 281

What are the symptoms of diffuse esophageal spasm?

Back 281

Between 80 to 90 percent of the people with this condition have chest pain. The pain often starts or worsens when eating or drinking very hot foods or liquids, and it may feel similar to the pain of a heart attack.
Other symptoms include difficulty swallowing and more than half of patients with this condition experience the feeling of food getting stuck inside the center of the chest. Patients may also feel a burning sensation in the center of the chest (heartburn).

Front 282

What are the causes and risk factors of diffuse esophageal spasms?

Back 282

Diffuse esophageal spasms can be caused by disruptions or damage to the nerves that coordinate the muscles of the esophagus. In some cases, this condition can lead to achalasia.

Front 283

How is diffuse esophageal spasm diagnosed?

Back 283

This condition can be diagnosed using:
A barium swallow. X-rays taken of the esophagus while the patient swallows barium show an uncoordinated esophagus that sometimes looks like a corkscrew. Uncoordinated contractions may keep the barium from moving to the stomach.
Esophageal manometry. This test identifies when the muscles are tightening (contracting) without being coordinated.
Upper GI endoscopy is almost always performed if a patient describes food sticking in the esophagus after swallowing. This process involves putting a flexible tube with a tiny camera down the individual's throat so that the doctor can see inside the esophagus. This procedure can be help detect tumors, unusual masses or scars.

Front 284

What is the treatment for diffuse esophageal spasms?

Back 284

Treatment options include:
Botulinum toxin (BoTox®). Botulinum toxin is a poison produced by the bacteria that cause botulism. During upper GI endoscopy, a small amount of this substance can be injected into the muscle does not relax to block the function of nerves that make the muscle contract. This procedure may need to be repeated.
Drugs to relax the muscles. While medications can help some patients, they are not effective overall.
Peppermint oil. A small amount mixed in water makes the muscles of the esophagus contract normally again.
Surgery to cut the muscles along the lower esophagus. This procedure is usually performed only in serious cases that do not respond to other therapy.

Front 285

WHat is achalasia?

Back 285

Achalasia is a rare disease of the muscle of the esophagus (swallowing tube). The term achalasia means "failure to relax" and refers to the inability of the lower esophageal sphincter (a ring of muscle between the lower esophagus and the stomach) to open and let food pass into the stomach. As a result, patients with achalasia have difficulty swallowing food.

Front 286

Describe the manometric records from a case of achalasia.

Back 286

Normal records are shown on the right. In achalasia there are often multiple defects in esophageal motor function. Here there are weakened peristaltic contractions and loss of the normal proximal distal progression of the contractions. There is also heightened LES tone, and a poor relaxation response to swallowing. These symptoms would lead to retention of swallowed materials in the body of the esophagus.

Front 287

What are the three basic motor functions of the stomach?

Back 287

The three basic motor functions are:
1. a reservoir for ingested materials;
2. a preparatory chamber in which ingested materials are broken down to permit passage through the pylorus;
3. an emptying regulator responsive to feedback from the duodenum so as to control the rate at which calories, hydrogen ions and chemical particles ("osmoles") are delivered to the duodenum.

Front 288

In what parts of the stomach are the functions carried out?

Back 288

The first of these physiologic functions is carried out by the proximal (fundus, corpus) stomach, the second by the distal (antrum) stomach and the third by the pyloric antrum and sphincter.

Front 289

How does the stomach accomplish reservoir function?

Back 289

changes in gastric volume accomplish reservoir function

When food is ingested, proximal stomach actively relaxes to accommodate the meal (gastric accommodation). With rather dramatic changes in volume, there is little or no change in pressure due to active relaxation (increase in compliance). The active relaxation of the proximal stomach is accomplished by similar mechanisms as relaxation of the LES (vagal inhibitory fibers activate enteric inhibitory neurons and release NO). Recent studies have suggested that NO stimulates interstitial cells of Cajal which communicate electrically with smooth muscle cells to produce relaxation. As the volume of the stomach decreases with gastric emptying, the tone of the proximal stomach gradually increases by removal of inhibition and some active cholinergic tone.

Front 290

What does swallowing induce?

Back 290

SWALLOWING INDUCES RECEPTIVE RELAXATION IN THE PROXIMAL STOMACH AND LES
With each swallow the proximal stomach relaxes to receive the bolus. As shown, the swallow-induced relaxation appears to be mediated through the same mechanism as LES relaxation (vagal inhibitory fibers activating intrinsic enteric inhibitory neurons). The neurotransmitter for these enteric inhibitory nerves is nitric oxide.

Front 291

What happens to gastric compliance with a vagotomy?

Back 291

As the gastric volume increases, the proximal stomach relaxes (gastric accommodation). This is seen as an increase in compliance (as volume increases there is little change in pressure over a wide range). After vagotomy the stomach is stiffer without the active relaxation of gastric accommodation (i.e. compliance has decreased). In this condition small changes in volume cause significant changes in pressure. This would result in an inability to eat large meals.

Front 292

What does the dominant pacemaker in the corpus do to the motor behavior of the stomach?

Back 292

Tissues from the corpus to the pyloric sphincter are intrinsically active and generate pacemaker activity. But the dominant frequency pacemaker resides along the greater curvature of the upper corpus. This pacemaker generates electrical slow waves that propagate around the stomach and down the stomach to the pylorus. These events trigger gastric peristaltic contractions.

Front 293

Describe the electrical activity of isolated gastric muscles from various anatomical regions of the stomach.

Back 293

Excitation-contraction coupling occurs by different electrical mechanisms in the fundus and the peristaltic regions of the stomach. In the fundus membrane potential changes slowly and regulates the level of tonic contraction. This effectively regulates gastric volume. Excitatory stimulation causes depolarization and enhances tone, inhibitory stimulation hyperpolarizes and relaxes the fundus. In the corpus electrical slow waves are generated at the fastest (dominant) frequency. Each event is coupled to a small contraction. Similar coupling occurs in the antrum and pylorus, but the intrinsic frequency of the pacemakers in these regions is slower than in the corpus. Thus the corpus pacemaker dominates. This figure shows electrical activity from isolated regions of muscle. But in the intact stomach the frequency of the corpus dominates and “paces” the more distal regions of the antrum and pylorus.

Front 294

Where do the dominant pacemkaers reside?

Back 294

The dominant pacemaker resides in the upper corpus in the network of interstitial cells of Cajal that lies between the circular and longitudinal muscle layr. The site of the dominant pacemaker in the corpus s is the site where the fastest frequency slow waves are generated. Interstitial cells of Cajal in more distal regions have slower intrinsic frequencies, and therefore are ‘paced’ by the dominant pacemaker.

Front 295

Describe the propagation of slow waves from the dominant pacemaker around the stomach.

Back 295

Slow waves spread faster around the stomach than down the length. This naturally organizes the slow waves into a ring of excitation (and a ring of contraction). Slow waves do not spread into the fundus due to lack of interstitial cells of Cajal in this region that are capable of regenerating the slow waves.

Front 296

Describe the propagation of the slow waves to the pyloric sphincter.

Back 296

SLOW WAVES PROPAGATE AS A BAND TOWARD THE PYLORIC SPHINCTER
The ring of excitation spreads relatively slowly toward the pyloric sphincter and it takes several sec to spread the distance from the dominant pacemaker to the pyloric sphincter. A microelectrode can measure slow waves in each cell of the musculature as the ring spreads by. The band of excitation (slow waves) couples to contraction of the muscle and generates the gastric peristaltic contractions. Generally, the propagation velocity increases as the slow wave approaches the pylorus. This causes a larger area of contraction and leads to nearly simultaneous contraction of the terminal few cm of the antrum and pylorus. Thus, when the contraction is near the terminal end of the stomach and very forcefully pushing the contents toward the pylrous, the pyloric canal contracts and blocks entry of the contents into the duodenum. The only place the contents can go is to be forcefully repelled (retropulsion) back toward the body (corpus) of the stomach.

Front 297

Describe the propagation of the electrical slow waves in the stomach.

Back 297

Slow waves originate from the dominant pacemaker in the orad corpus and spread toward the pylorus. This figure shows a schematic of a stomach instrumented with 8 extracellular electrodes (1-8) placed at equal distances apart. Traces from these electrodes are shown (2-8) over 5 slow wave cycles. Lines show propagation of events from corpus to pylorus. Note that steepening of the line suggests increased velocity of propagation as slow wave reaches terminal region of the stomach. This causes the essentially simultaneous contraction of the terminal antrum and pylorus.

Front 298

What does slow wave depolarization do to Ca2+ channels?

Back 298

slow wave depolarizaiton INC open probability of Ca2+ channels

Front 299

Where do slow waves originate?

Back 299

Slow waves originate in ICC-MY and then propagate into the longitudinal muscle (LM) and circular muscle (CM) layers initiating contraction.

Front 300

What does local stimulatioon from enteric neurons do to the amplitude and duration of slow waves?

Back 300

Slow waves continue to be generated and spread from the corpus to the pylorus all of the time. But during times of rest, slow waves are of smaller amplitude and duration (like region in blue) and these events generate less forceful peristaltic contractions. After a meal, activation of hormone release (most importantly gastrin) and stimulation of excitatory enteric neurons (that release ACh) cause the ongoing slow waves to be amplified in amplitude and duration (as in region in red) and to couple to much greater peristaltic contractions. In this way the enteric nerves “condition” the response of the muscle cells to the slow waves and cause the response either to be weak contractions or very strong contractions

Front 301

Describe the interuption that occurs from slow waves that originate from an ectopic pacemaker in tachygastria.

Back 301

Normal slow wave rhythm is 3 per min. In tachygastria emergence of an ectopic pacemaker in the distal stomach can generate slow waves too fast for normal corpus pacemaker to drive. Thus, slow waves from the ectopic site can spread in the oral direction and “collide” with slow waves propagating in normal direction. This disrupts normal gastric peristalsis and can interfere with gastric emptying.

Front 302

What is the difference between tachygastria and bradygastria?

Back 302

Tachygastria is a gastric dysrhythmia characterized by abnormal fast frequencies of gastric slow waves. Clinically measured frequencies are measured between 4-9 CPM. Bradygastrias are abnormally slow frequencies ranging from 0-2.5 CPM. Both dysrhythmias can be associated with delayed gastric emptying.

Front 303

What are the 3 phases of coordinated motility of the gastric antrum and pylorus?

Back 303

Combined evidence from fluoroscopic observations of the movement of intragastric contrast material and simultaneous recordings of muscular contraction suggest that motility of the antral pump can be divided into three phases consisting of: Phase I. Propulsion; Phase II. Evacuation-retropulsion; Phase III. Retropulsion-grinding.

Front 304

What motion helps break apart (triturate) solid particles?

Back 304

With the terminal antral contraction and pyloric closure the antral contents are forcefully retropulsed back toward the body of the stomach. This jet-like stream of material slowly triturates solids and reduces their size. The pyloric canal “sieves” these particles, letting out particles of only about 1 mm during the digestive phase. Thus, the trituration process is extremely important to emptying of solid meals.

Front 305

How does the composition of a meal affect the onset and rate of gastric emptying?

Back 305

Liquids empty faster than solids when a mixed meal is in the stomach. If an experimental meal consisting of solid particles of various sizes suspended in water is instilled in the stomach, emptying of particles lags behind the emptying of liquids. With digestible particles, the lag phase reflects the period of time required for the grinding action of the antral pump to reduce particle size.

Front 306

In what type of solution is the rate of gastric emptying most rapid?

Back 306

The tonicity of liquids in the stomach influences the rate of gastric emptying. Hypotonic and hypertonic solutions empty more slowly than do isotonic liquids. Slow of emptying by hypertonic solutions is abolished by vagotomy suggesting that part of the control is via a central reflex (i.e. vaso-vagal reflex). The tonicity of the fluid being emptied is detected by afferent nerve receptors in the proximal duodenum, and these generate input to the vagus. Efferent nerves from the vagus reduce the force of antral contractions and tend to reduce the forces responsible for fluid emptying. Pyloric tone may increase to produce more resistance to flow. A sympathetic nervous reflex and local reflexes may also be involved in slowing the rate of gastric emptying.

Front 307

What is the rate of gastric emptying dependent on?

Back 307

RATE OF GASTRIC EMPTYING IS DEPENDENT UPON THE CALORIC CONTENT OF ISOTONIC MEALS

Gastric emptying of isotonic meals follows a single exponential curve (NaCl, 0.9%). The volume of inert liquids of this nature delivered into the duodenum per unit time is a constant fraction of the volume of liquid remaining in the stomach. For example, a 250 ml volume of saline will empty twice as fast as 125 ml. Emptying of inert liquids is rapid during the initial 30 min. The presence of nutrients in the liquid meal slows the rate of emptying due to feedback control from the duodenum. Sensors of calories in the duodenal mucosal signal the vagus nerve (i.e. vaso-vagal reflex) and generate local reflexes to slow gastric emptying. Rate of emptying is directly related to caloric content of the meal within a given range (e.g. 0-1 M glucose). This helps provide a constant rate of caloric delivery to the duodenum.

Front 308

What are some things that can alter gastric motility via a vagal reflex pathway?

Back 308

Vago-vagal reflexes are an important aspect of duodenal feedback control of gastric emptying. Sensory receptors for glucose, fatty acids, amino acids, osmolarity, and pH are present in the duodenal mucosa. The receptors activate vagal afferent fibers that form the sensory arm of the vaso-vagal reflex. Information on osmolarity, pH and nutrients is transmitted via frequency coding within vagal afferents to the dorsal vagal complex (nucleus tractus solitarius and dorsal motor nucleus of the vagus) where the information is integrated. Output from the vagal complex travels back to the gut via vagal efferent fibers (thus the vago-vagal nomenclature). Vagal efferents activate inhibitory or excitatory neurons within the gastric enteric nervous system to produce the desired effect. For example, activation of inhibitory neurons in the fundus (gastric reservoir) relaxes muscular tone and decreases the driving forces that push the contents of the reservoir toward the antral pump. Vagal efferent signals that result in activation of excitatory motor neurons to the antral musculature will increase the depth of the 3/min peristaltic contractions, increase gastric retropulsion and reduction of solids, and tend to increase gastric emptying.

Front 309

What do lipids in the distal small intestine do to gastric emptying?

Back 309

Even the content of luminal materials in the distal small intestine is important for regulating gastric emptying. This figure shows the consequences of lipids reaching the lumen of the ileum. The presence of lipids in this region activates a reflex that slows emptying of solids. Other nutrients have the same effect. This reflex is known as the “ileal” brake, and is mediated by hormonal pathways including the hormone Peptide YY (PYY). This is an example of enteroendocrine regulation.

Front 310

What is gastric motor dysfunction?

Back 310

The most apparent and frequently identified gastric motor dysfunction is failure of gastric emptying. Delayed gastric emptying or gastric retention may be caused by failure of sufficient driving force and/or increase resistance to flow through the pylorus. Less easily recognized is duodenal reflux due to pyloric incompetence. This may be an important factor in the pathogenesis of some gastric ulcers and gastroesophageal reflux. The major factors associated with rapid gastric emptying are decreased gastric compliance (most commonly caused by vagal denervation), loss of pyloric function (possibly due to surgical bypass, resection or destruction), and failure of negative feedback from the duodenum.

Front 311

What are some causes of DEC gastric emptying?

Back 311

abnormal slow waves (tachygastria), normal slow waves (DEC electromechanical coupling (vagotomy), muscle loss (scleroderma, carcinoma), damage to enteric nervous system (diabetic gastroparesis), loss of extrinsic innervation (vagotomy))

Front 312

What are some causes of INC gastric emptying (resistance disorders)?

Back 312

hypertrophic pyloric stenosis, diabetic pylorospasm, a reduction in NO-containing inhibitory motor neurons could lead to an elevated tonic state in the pylorus and thus delay gastric emptying

Front 313

IN what type of patients is gastric dysrhythmias found?

Back 313

bloating, feeling of fullness, antral hypomotility, nausea, pregnancy, ischemic gastroparesis, motion sickness, diabetic gastroparesis, anorexia nervosa, intra-abdominal malignancies

Front 314

What are the components of the intrinsic control of intestinal motility?

Back 314

1. pacemaker system-lies at the myenteric border, generates electrical slow waves that conduct into the longitudinal smooth muscle and circular smooth muscle layer
2. enteric reflexes-generate peristalsis and other forms of motility patterns

Front 315

What are the components of the extrinsic control of intestinal motility?

Back 315

1. sympathetic nerves-inhibit motility and secretion by reducing transmitter release from enteric neurons
2. parasympathetic nerves- (VAGUS) INC motility by enhancing activity in enteric neurons

Front 316

What is the modified trendelenburg preparation?

Back 316

Intestinal peristalsis initiated by mechanical luminal stimuli can be studied in isolated specimens of small intestine using a preparation originally developed by Trendelenburg (1917) which has since been widely modified. Briefly, a segment of small intestine (usually guinea-pig) is cannulated at both ends. Fluid (usually a physiological solution) is infused in a controlled way at the oral end and the gut empties via the aboral cannula against a fixed back pressure, via a non-return valve. During fluid infusion the gut increases its diameter. When the threshold for activation of sensory neurons in the reflex is reached a peristaltic wave is generated. This is observed as a contraction that propagates from the oral to anal ends of the segment.

Front 317

Describe the histology of the myenteric plexus.

Back 317

Using the histochemical reaction that reveals endogenous NADPH diaphorase activity, the enteric myenteric plexus is visible in an intact tube of guinea pig colon. The irregular meshwork of ganglia and internodal strands is clearly seen and at the bottom of the slide is the mesenteric membrane and blood vessels. NADPH diaphorase staining under these conditions reveals nitric oxide synthase activity - the enzyme that produces nitric oxide, a potent inhibitory transmitter to the smooth muscle of the gut wall.

Front 318

Describe the layout of the human small intestine.

Back 318

Schematic diagram showing the major layers of the gut wall, roughly based on the human small intestine. The mesenteric membranes with blood vessels and extrinsic (mesenteric) nerves are shown. The outer longitudinal smooth muscle layer lies next to the circular muscle layer, with the myenteric plexus interposed. Within the circular muscle layer is the non-ganglionated deep muscular plexus which contains the axons of motor neurones. The submucous plexus in large animals, including humans, is split into several layers (three layers distinguished in humans) and gives rise the to mucosal plexus on the back of the mucosa. There is also major branching of the blood vessels in the submucosa from which mucosal vessels arise.

Front 319

What are polarised (ascending and descending) enteric reflexes?

Back 319

The presence of enteric neurons with specific projections, particularly excitatory and inhibitory motor neurons and some interneurons, provide the basis for polarized (i.e oral or aboral) responses to local distension. Thus inflating a balloon in a region of the small intestine evokes oral excitation and anal inhibition, resulting respectively in oral contraction and anal relaxation of the circular muscle. Bayliss and Starling (1899) suggested that these nerve mediated reflex responses are involved in peristalsis. As the bolus advances, pushed by the oral contraction into a relaxed area, it activates similar new reflex pathways. The propulsion of the contents is thus the result of sequential activation of the polarised enteric reflex pathways.

Front 320

Describe the intracellular electrical recording of junction potentials from circular muscle evoked by stroking the mucosa.

Back 320

In the guinea-pig small intestine, stroking the mucosa elicits reflex responses in the circular muscle (CM). These responses are excitatory orally and inhibitory aborally. The intracellular recording reveals such responses as excitatory junction potentials (EJP) orally and inhibitory junction potentials (IJP) aborally. In order to immobilise the preparation by blocking action potentials, Nifedipine (10 µM) is in the bath.

Front 321

What happens during stimulation of sensory neurons?

Back 321

Stimulation of sensory neurons excites at least two distinct neural pathways: one running orally to activate excitatory motor neurons and the other running anally to activate inhibitory motor neurons.

Front 322

What happens with activation of motility reflexes?

Back 322

Under normal circumstances, activation of motility reflexes occurs when food enters a region of intestine. The contents distend the intestine and deform the villi, and may activate chemoreceptors in the mucosa.
We show below that in the guinea-pig small and large intestine, both distension and deformation of the mucosal villi trigger an ascending excitatory and descending inhibitory nervous pathways that can be recorded electrically from the circular muscle and the S motor neurons and S interneurons lying within the nervous pathways.
These reflexes appear to be initiated by different intrinsic sensory neurons.

Front 323

What are some facts about 5-HT in the gut?

Back 323

1. Over 90% of the bodies 5-HT is contained in the gut.
2. 5-HT is released from the mucosa during peristalsis.
3. most of this 5-HT is stored in enterochromaffin (ECC) cells in the mucosa
4. descending interneurons also contain 5-HT, which appears to be involved in neuro-neuronal transmission
5. release of 5-HT from ECC cells is beleived to stimulate 5-HT3 receptors on the endings of AH sensory neurons that project to the mucosa
6. several lines of evidence support the use of serotonin subtype 3 (5-HT3) receptor antagonists for the treatment of IBS

Front 324

Describe the expression of serotonin transporters in enteric serotonergic neurons.

Back 324

Serotonin Transporter (SERT) expression by enteric serotonergic neurons probably
accounts for the inactivation of 5-HT during synaptic transmission within the ENS; however, there are no serotonergic neurons in the mucosa. The mucosa,
which contains 5-HT in enterochromaffin (EC) cells
contains 95% of the body’s 5-HT,and the sudden release of its 5-HT content can be lethal, as it is in anaphylactic shock in mice. Moreover, EC cells store 5-HT in granules at their base and secrete from their basolateral surfaces into the wall of the bowel

Front 325

What are enterochromaffin cells?

Back 325

Enterochromaffin cells contain 90% of the body’s 5-HT. They respond to mechanical stimulation and luminal chemicals including bacterial toxins. The latter is an essential part of a toxin detection system. 5-HT released from these cells activates vagal afferents which trigger the emetic response, secretion and diarrhoea to expel potentially harmful substances from the body. The cells have an apical microvillus tuft that detects luminal stimuli while 5-HT is released across the basolateral membrane to stimulate cells in their immediate vicinity that express a variety of 5-HT receptors. Epithelial cells also contain a reuptake transporter (SERT) that effectively mops up 5-HT following its release. The density of EC cells has been shown to increase following inflammation which SERT expression is decreased resulting in increased bioavailibility of 5-HT. This is hypothesised to be a factor in IBS and would explain the efficacy of 5-HT receptor ligands in treating some of the symptoms of IBS

Front 326

How many enterochromaffin cells are found in IBS patients?

Back 326

There are INC EC numbers in IBS, some studies have shown EC cell numbers are INC in post-infectious IBS patients

Front 327

Describe the human intestinal slow waves that are generated spontaneously.

Back 327

Human intestinal muscles generate spontaneous slow waves which are small depolarizations in membrane potential. Slow waves occur all of the time regardless of whether the small intestine is in the fed or fasting state. In the excited small intestine, the amplitude of slow waves is great enough to generate Ca2+ action potentials. The figure shows a series of slow waves with action potentials superimposed at the peak of each slow wave. The second trace shows that the action potentials are due to entry of Ca2+ into the muscle cells (the action potentials are blocked by nifedipine, a Ca2+ channel inhibitor). When slow waves have Ca2+ action potentials superimposed they are associated with powerful contractions. Inhibition of the Ca2+ action potentials blocks most of the contractile response.

Front 328

What is the electrical basis for excitation contraction coupling in phasic GI muscles?

Back 328

Electrical slow waves (bottom traces in the figure) depolarize the membrane potentials of smooth muscle cells. Smooth muscle cells express L-type Ca2+ channels in their plasma membranes (these channels are blocked by dihydropyridines such as nifedipine). The depolarization of the slow wave activates L-type Ca2+ channels. Above a certain membrane potential (usually about -40 mV) the depolarization of the slow wave is great enough to activate enough L-type Ca2+ channels to produce ‘mechanically-productive’ entry of Ca2+. Thus a mechanical threshold exists: if the slow wave crosses this level of depolarization, contraction is initiated. In some areas of the GI tract crossing the mechanical threshold can produce activation of enough Ca2+ channels to cause Ca2+ action potentials. These large, fast events bring significant Ca2+ into the cells and initiate powerful contractions. A slow wave not crossing the mechanical threshold is usually in a state of “inhibition”, and a slow wave initiating Ca2+ action potentials are usually in a state of “excitation”. Thus, the intestine can regulate it response to slow wave activity by “conditioning” the response of the smooth muscle cells to the slow wave depolarization.

Front 329

What happens to the frequency of electrical slow waves when going from the duodenum to the ileum?

Back 329

This figures shows a stepwise decrease in the slow wave frequency in the duodenum and proximal jejunum (12/min) to the distal ileum (8/min). Although this gradient in slow waves exists, intestinal slow waves do not propagate from one end of the intestine to the other, or even over long distances. This is because at the rate of intestinal slow wave frequency, the propagation distance is not more than several cm before a given slow wave “collides” with another slow wave generated in a nearby region.

Front 330

What are the major functions of the small intestine and its motility requirements?

Back 330

Digest macromolecular nutrients (requires significant agitation)

Absorb digestion products (requires stirring to maximize contact between nutrient molecules and epithelial cell membranes)

Retain nutrients in the small bowel until maximal digestion and absorption can be accomplished (requires slow distal movement of chyme)

Front 331

What is segmentation and what does it do?

Back 331

SEGMENTATION IS AN EFFECTIVE MIXING PATTERN AND IS CHARACTERISTIC OF INTESTINAL MOVEMENTS IN THE FED STATE
Segmentation movements consist of propulsive and receiving segments where there are net excitatory neural inputs and inhibitory neural inputs, respectively. Segmentation movements appear fluoroscopically as non-propagating contractions because, unlike long propagating contractions, there is no net movement. The digestive pattern of motility consists of segmentation intermixed with short propulsive peristaltic contractions. Thus, there is net aboral movement with time.

Front 332

What are the classifications available for spike (myoelectrical) activity?

Back 332

PROPAGATED AND SEGMENTAL MYOELECTRICAL ACTIVITY
An approach to the analysis of small intestinal motility is to determine the length of the propagation of spike activity associated with each individual slow wave by recording myoelectrical activity from a series of closely spaced electrodes. This figure diagrammatically represents a series of electromyograms from 4 slow wave cycles passing six electrodes placed 3 cm apart on a dog jejunum. Slow waves with spikes cause powerful contractions that can move or mix luminal contents. There are two segmental spike activities (recorded at a single electrode, hence, not propagated or at least not more than 3 cm). The longest propagation in this record is 12 cm.

Front 333

How does nutrients induce spatial patterning of the human duodenal motor function?

Back 333

Intraluminal manometry from multiple recording sites along the human duodenum reveals various patterns of contractile activity. Some contractions propagate aborally but some propagate orally for short distances. It is currently not clear which patterns depend specifically on slow wave propagation, as in the MMC, and which depend on nutrients-stimulated activity in enteric neural circuits.

Front 334

What are the contractile patterns of the small intestine?

Back 334

1. Peristaltic waves in small intestine: non-caloric meal

2. Stationary or segmental contractions proximal small intestine: Nutrients, especially protein

3. Giant migrating contractions distal small intestine

4. Clustered contractions
a) stationary in proximal small intestine Nutrients, esp. fat
b) migrating-down total small intestine- Nutrients, esp. fat

5. Migrating Myoelectric (or motor) Complex (MMC, Phase I, II, III)-Phase III contractions migrate down total small intestine interdigestive (fasting)

Front 335

What are peristaltic waves?

Back 335

Peristaltic waves are circular constrictions propagating aborally. Due to reflexes initiated by the enteric nervous system they are associated with an oral excitation and an aboral relaxation (or inhibition) of the smooth muscle. After a non-caloric meal peristaltic waves are the dominant feature. The peristaltic waves produce an aboral transport of chyme. The propagation velocity of the peristaltic waves is determined by the proximal to distal propagation of the slow waves in the smooth muscle syncitium. In dogs the propagation velocities of the peristaltic waves are: in the duodenum 7-12 cm/s, in the jejunum 4,7 cm/s and in the ileum 0,7-0,8 cm/s.

Front 336

What are stationary contractions?

Back 336

Stationary contractions occur isolated at single sites without a strict spatiotemporal relation. They occlude the intestinal lumen pushing the chyme orally and aborally and separating it into segments. Therefore, these contractions are also called “segmenting contractions”. The stationary segmenting contractions cause mixing of the luminal contents.

Front 337

Describe the clusters of contractions.

Back 337

Clusters of contractions and the so called phase III represent two complex contractile patterns. Clustered contractions are characterized by several repetitive contractions. The contractions represent short peristaltic waves pushing the chyme a few centimetres aborally followed by a partial back-flow during the period of relaxation. Thereby the chyme is mixed. When the repetitive short peristaltic waves of the clustered contractions move over the same intestinal segment, the clustered contractions are stationary. In contrast, when each subsequent peristaltic wave starts and ends a few millimetres further aborally, the clustered contractions slowly migrate distally. Clustered contractions usually migrate over a short intestinal segment. Both stationary and migrating clusters of contractions frequently occur after a fat meal.

Front 338

What is interdigestive migraging myoelectric complex (MMC) of the stomach?

Back 338

The figure shows the fundamental features of this behaviour in the stomach and small intestine, in the fasted conscious dog. Its key features are that it is cyclic and it migrates (propagates) along the intestine. There is a quiescent phase, during which slow waves are present but with no associated action potentials (phase I; flat line in the schematic figure), followed by a phase of irregular activity, where only some of the slow waves are associated with action potential (phase II; grey areas in the figure). This is then followed by a period of intense regular activity, in which every slow wave is associated with a burst of action potentials (phase III; black areas in the figure). Finally there is some activity before returning to quiescence (sometimes called phase IV). Recording at multiple sites also reveals the migratory character of the cyclic activity. MMC also stands for migrating motor complex. Contributed by Marcello Costa. myoelectrical activity at multiple sites reveals the cyclic nature of activity with a quiescent phase (phaseI) followed by a phase of irregular activity where only some of the slow waves show APs (phase II), then a period of intense regular activity in which every slow wave is associated to a burst of Aps (phase III) and a return to quiescence with or without some activity (phase IV). Recording at multiple sites also reveals the migratory character of the cyclic activity. Thus the term Migratinc Myoelectric Complex (MMCx). Recording of motor activity during the MMCx confirmed that corresponding contractile activity mirror the myoelectrical activity.

Front 339

What role does an intact enteric nervous system have on MMC propagation?

Back 339

Although extrinsic neural input is not necessary for MMC development and cycling in the intestine, the enteric nervous system is also essential for its initiation and orderly progression. In the experiment depicted, 12 electrodes were placed over the length of the intestine and the MMC was measured (left panel). Then the intestine was transected at 4 evenly spaced sites and reanastomosed. Orderly progression of the MMC was lost and each segment generated its own cyclic activity independent of the other segments. Orderly progression was restored after approximately 60 days, presumably because the enteric nervous system re-established connections between segments (rightmost panel). We can conclude that whether the initiation of the MMC is hormonal, neural or a combination, connections between enteric neurons are essential for orderly propagation of the MMC.

Front 340

What does feeding do to the MMC cycle?

Back 340

Feeding interrupts the interdigestive pattern (MMC) and initiates the fed pattern. The fed pattern is more conducive to digestion and absorption. In the experiment represented, myoelectric activity was measured in conscious dogs with monopolar electrodes implanted on the serosal surface of the duodenum, jejunum, proximal ileum, and distal ileum. Progression of the MMC;s down the intestine was recorded and plasma motilin levels were measured (not shown). Feeding the dogs interrupted the cyclic elevations of plasma notilin and MMCs.

Front 341

What role does vagal input do for the normal fed pattern?

Back 341

CNS input is important in the normal conversion from the fasting to the fed pattern. Upon vagotomy: (1) the amount of food required to interrupt the MMC is increased; (2) the time between feeding and interruption of the MMC is increased; (3) the interruption of the MMC is often incomplete; and (4) blocking vagal outflow during the fed state is associated with a conversion of the motor pattern in the small intestine from fed to fasting. (shown in figure). In this study in dogs, vagal discharge was blocked by cooling the vagal nerve trunks that had been brought to the surface in skin loops in the neck. Vagal outflow was confirmed to be blocked by the rise in heart rate (not shown). Before the meal, the MMC was recorded. After feeding of a 750-calorie meal, the fed pattern was recorded. This pattern was interrupted when the vagus nerves were blocked, and MMCs reappear. Upon release of the vagal block, the fed pattern returned.

Front 342

Describe the central and peripheral control of contractile patterns,

Back 342

The contractile patterns of the small intestine are caused by the enteric nervous system in connection with the slow waves of the smooth muscle cells. The enteric nervous system produces an inhibitory effect (neural brake) on intestinal motility by releasing the inhibitory transmitters NO and VIP. Thereby the slow waves of the smooth muscle cells remain below the spike threshold and the voltage sensitive calcium channels remain closed. Contractions only occur, when the neural brake is released and as a consequence an intestinal segment becomes excitable. This excitation of the intestine by the enteric nervous system can occur
independently in space and time and thereby produce different contractile patterns. The peristaltic reflex - the basic circuit of the enteric nervous system –plays an important role. The circuits of the peristaltic reflex are connected with each other by interneurones like a string of pearls. During the excitation of an intestinal segment the circuits of the peristaltic reflex are activated resulting in disinhibition of inhibitory neurones and thus the neural brake is released. Voltage sensitive calcium channels are opened by the release of acetylcholine and the influx of calcium induces action potential discharge as well as the electro-mechanical coupling leading to contractions. In this way the stationary segmenting contractions, the peristaltic waves, the stationary and migrating clusters of contractions and the phase III depend on the slow waves of the smooth muscle cells. In contrast, the giant contractions are independent of the electrical slow waves. They are exclusively controlled by the enteric nervous system: during the occurrence of giant contractions the slow waves of the smooth muscle cells are suppressed and a burst of action potentials slowly moving in oral or aboral direction are produced. It is likely that the enteric nervous system contains hardwired programs that initiate different contractile patterns and that are triggered by mechanical or chemical stimulation. There are a variety of additional intermediary cells important to code and transmit the sensory stimulus. The enterochromaffine cell appears to play a key role for transmitting chemical or mechanical stimulation of the mucosa to nerves. In addition it seems crucial that muscle cells maintain a certain tone. Finally, a number of
paracrine and endocrine mechanisms are intimately involved in short and long term regulation of contractile patterns. CCK, for instance, stimulates the peristaltic activity whereas in dogs neurotensin mainly produces stationary segmenting contractions. Somatostatin generally has an inhibitory effect on the intestinal motility.

Front 343

Who is your lover?

Back 343

Trina

Front 344

Who is the man?

Back 344

Colson, duh!

Front 345

What are the pathophysiological contractile patterns of the small intestine?

Back 345

1. Antiperistaltic waves proximal small intestine distal gastrectomy-(Gastrectomy is the surgical removal of all or part of the stomach).

2. Giant contractions

a) aborally propagating down proximal small intestine-strong stimuli (acetic acid) distal gastrectomy

b) orally propagating up proximal small intestine-stimuli associated with vomiting

Front 346

What are the antiperistaltic waves of the small intestine?

Back 346

Antiperistaltic waves of the small intestine are a pathological contractile pattern occurring seldom. In dogs periods of alternating peristaltic and antiperistaltic waves were frequently observed after distal gastrectomy. The characteristic features of the different intestinal contractile patterns are most clearly recognised by videofluoroscopy.

Front 347

What are the giant (power) contractions?

Back 347

In comparison with the regular intestinal contractions, the giant contractions or power contractions are characterised by a large amplitude and a long duration. Under physiological conditions they were observed at the ileum during the interdigestive period in dogs, horses and humans. In pigs giant contractions regularly occur at the ileum even during the digestive period. The giant contractions completely occlude the intestinal lumen and propagate slowly in an aboral direction pushing the luminal contents distally and cleaning the intestine. In respect to this procedure they are also called “stripping wave”. The propagation velocity of the giant contractions is usually slower than that of the peristaltic waves; in the ileum of dogs it is 0.4 to 0.8 cm/s. Only the postprandial giant contractions of the ileum in pigs have a higher propagation velocity of 3.9 cm/s. In pigs, they produce a regular transport of chyme from the ileum into the large intestine at intervals of 10-12 minutes.

Front 348

What is the precursor of vomitting?

Back 348

Giant contractions are often the motor precursor of vomiting. These giant contractions propagate orally. The occurrence of oral or aboral giant contractions during the postprandial period represents - with exception of the pig - a pathological contractile pattern. Aboral giant contractions of the small intestine are the typical contractile pattern in diarrhoea. In dogs, they can be induced by infections with Cholera toxin or Trichinella spiralis, by radiation, by oral administration of acetic acid or by chemical drugs like Erythromycin, whereas orally propagating giant contractions may be elicited by dopamine or apomorphine.

Front 349

What are the properties of power propulsions?

Back 349

-Peristaltic propulsion
-Large amplitude contraction
-Spike-triggered contractions
-Unrelated to slow waves
-Rapid propagation
-Long distance propagation
-Programmed by the enteric nervous system

Front 350

What is the function of the power propulsion?

Back 350

-Defense
-Rapid clearance
-Clearance of long segments
-Complements secretory defense mechanisms

Front 351

How does power propulsion do for motility patterns?

Back 351

Power propulsions occur as a protective response to harmful agents. As a motility pattern it is consists of strong, long-lasting contractions along the small and large intestines. The giant migrating contractions are considerably stronger than the phasic contractions during the MMC or fed pattern. Giant migrating contractions last 18-20 secs and span several cycles of electrical slow waves. They are a component of a highly efficient propulsive mechanism that rapidly strips the lumen clean as it travels at about 1 cm/sec over long lengths of intestine.

Front 352

How do power propulsions act in a retrograde direction?

Back 352

Power propulsions can also occur in the retrograde direction during emesis in the small intestine and in the orthograde direction in both the small and large intestines in response to noxious stimulations of the mucosa. Abdominal cramping sensations and sometimes diarrhea are associated with this motor behavior. Application of irritants to the mucosa, the introduction of luminal parasites, enterotoxins from pathogenic bacteria, allergic reactions, and exposure to ionizing radiation all trigger power propulsions. This suggests that this motility pattern is a protective adaptation for rapid clearance of undesirable contents from the intestinal lumen. It may also accomplish mass movement of intraluminal material in normal states, especially in the large intestine.

Front 353

Describe vomitting.

Back 353

Nausea and vomiting though related should not be considered the same entity, as their underlying mechanisms may not be identical. Nausea is an unpleasant, painless sensation associated with a heightened awareness of the upper gut and a feeling that vomiting is imminent. The vomiting reflex involves a complex integration of signals involving both somatic and the autonomic nervous system. This integration occurs in an area of the medulla oblongata called the vomiting center. The vomiting center may be activated by afferent visceral vagal neurons or by input from the chemoreceptor trigger zone (CTZ) located in the area postrema, a vascular body that protrudes into the 4th ventrical.

Front 354

What is the area postrema and how is it triggered?

Back 354

The area postrema may be triggered by vagal or splanchnic afferent stimulation (visceral pain, GI mucosal irritants) and circulating endogenous emetic substances (which are produced in pregnancy and chronic renal failure) or exogenous emetic agents (apomorphine, L-dopa, digitalis, chemotherapeutic agents, radiation). The incomplete nature of the blood brain barrier in the region of the area postrema facilitates, which lies near the DMV, such activation of the CTZ by circulating agents. Ingested toxins, radiation, chemotherapeutic agents may stimulate the release and synthesis of neuroactive chemicals (5-HT, free radicals, prostanoids) from the gut. these substances may then stimulate afferent neurons in the gut which communicate with the CTZ and vomiting center.

Front 355

What is vomitting?

Back 355

Vomiting is defined as „the forceful expulsion of gastrointestinal contents through the mouth“. Vomiting represents a defence reaction to protect the body against the intake of dangerous agents. Toxins in the GI tract can be recognized either before absorption via visceral parasympathetic and sympathetic afferent fibers or after absorption into the blood via the chemoreceptor trigger zone (CTZ) located in the area postrema. The visceral afferent fibers have inputs to the nucleus tractus solitarii – a part of the vomiting center – and parallel inputs to the area postrema. Thus the chemoreceptor trigger zone (CTZ) integrates both the afferent signals from the gastroinestinal tract and the chemical signals from the blood.

Front 356

What precedes vomitting?

Back 356

Recent studies on gastrointestinal motility have shown that a retrograde giant contraction precedes vomiting. It originates in the proximal jejunum, propagates orally towards the stomach and moves up to the proximal antrum. The retrograde giant contraction forces the chyme of the proximal small intestine across the widely opened pylorus into the relaxed gastric body. Some minutes later retching and vomiting occurs.

Front 357

What produces negative oxcillations in intrathoracic pressure and what causes an INC in intrabdominal pressure?

Back 357

Rhythmic inspiratory movements against a closed glottis produce negative oscillations in intrathoracic pressure and concomitant contractions of the abdominal muscles and the diaphragm cause an increase in intra-abdominal pressure. The distal part of the esophagus containing smooth muscle cells relaxes whereas the proximal striated esophagus contracts resulting in a funnel-like opening of the cardia and the distal esophagus. These rhythmic events during retching cause a repetitive flow of gastric chyme into the esophagus followed by an immediate backflow. Finally, vomiting occurs. In contrast to the events of retching, it is associated with a contraction of the intercostal muscles and an increase in the intrathoracic
pressure so that the chyme is forced into the mouth and expelled. Thus during retching and vomiting ejection of gastric contents is not produced by contractions of the stomach but by contractions of skeletal muscles, i.e. by somatic events.

Front 358

What are the different times for the transit of material through the GI tract?

Back 358

Stomach 1-3hrs.
Esophagus takes ~1s,
Small intestine takes 2-4 hrs,,

In contrast, transit of fecal material through the human colon takes ≥ 30 hrs.


The mechanisms underlying colonic slow transit and storage have yet to be elucidated.

Front 359

Describe the anatomy of the colon.

Back 359

The large intestine of man. Features of both carnivores and herbivores are evident in that it is relatively short but has haustra. Haustra, or colonic sacculations, result from the anatomic arrangement of the longitudinal muscle which is concentrated in three bundles or tenia coli. The wall bulges out where the longitudinal muscle is thin and these bulging bands are segmented by circular muscle contractions. These sacculations creating haustra change shape and position as the location of circular muscle contractions changes. In the lower sigmoid colon and rectum, there are no haustra as the longitudinal muscle coat is continuous around the circumference of the colon. At the terminus of the rectum, the circular muscle coat thickens and becomes the internal anal sphincter. This thickened segment is surrounded by the striated muscle of the external anal sphincter which is part of the pelvic floor. The right side of the colon receives dual parasympathetic and sympathetic innervation. Cranial parasympathetic innervation via the vagus nerve serves the right colon, whereas the sacral parasympathetic innervation, via the pelvic nerves, supplies the entire colon. Sympathetic innervation is similarly divided with the splanchnic nerves serving the right colon and the lumbar colonic nerves serving the entire colon.

Front 360

Describe the neural innervation of the distal colon and anal canal.

Back 360

The lumbar sympathetic outflow inhibits the colon and stimulates the internal anal sphincter. The sacral parasympathetic outflow in the pelvic nerves stimulates the colon and inhibits the internal anal sphincter. Afferent fibers from the tissues surrounding the anal canal and from the wall of the colon run in the pelvic nerves. The pudendal nerves innervate the external anal sphincter. Afferent fibers from the circumanal skin, from tissues surrounding the anal canal, and from the external analsphincter run in the pudendal nerves.

Front 361

What are some possible reasons for Taenia coli?

Back 361

1) Causes outpouching/haustra

2) In the outpouches there is likely little movement compared to central lumen, allowing for fermentation and absorption of water and electrolytes.

3) Relaxation of the taenia allows for greater luminal diameters and lengthening of the colon for storage.

4) Contraction of the circular muscle causes larger luminal occlusion than if a continuous muscle coat was present.

Front 362

What are the funcitonal differences between the right and left colon?

Back 362

Whereas the transit through the stomach and small intestine is measured in hours and each meal proceeds through without mixing with previous or subsequent meals, there is extensive mixing in the colon and colon transit can be measured in days. The majority of mixing and a delay of transit through the colon occurs in the right colon. Unlike the remainder of the alimentary tract where slow waves generally move in an aborad direction, they move orad in the right colon. This tends to delay transit and facilitate the mixing required for efficient absorption of water and electrolytes.

Front 363

Describe the propagation of the slow waves through the right colon.

Back 363

In the normal proximal gastrointestinal tract, slow waves tend to propagate in the aborad direction. Slow wave propagation and direction is much more complex in the colon, where these events tend to move orad in contrast to the stomach and small intestine. Although at times, both orad and aborad propagation can be recorded. When the right colon is sectioned, each segment has a dominant pacemaker frequency and generates slow waves that move orad 2/3 of the time. During the remaining 1/3 of the time, 2-4 or more different pacemakers can be identified simultaneously. Slow waves at times move both orad and aborad from a given pacemaker. In the transverse and descending colon there is little or no slow wave frequency gradient and little tendency for slow waves to propagate long distances.

Front 364

What are the 3 major contractile patterns in the colon?

Back 364

Colonic motility has been studied by different techniques. Motor patterns described by these techniques can be grouped into three basic contractile patterns: (1) Mixing movements (shown alone in the left panel, and with other contraction patterns in the middle and right panels). Mixing movements are the most frequently observed contractions. These contractions segment the colon and its contents, displacing the contents in both orad and aborad directions. The mixing pattern occurs more frequently in the proximal than the distal colon; (2) haustral migrations move the contents for several cm. In the proximal (right) colon, the direction of these movements are generally in the orad direction. The general direction is in the aborad direction in the distal (left) colon; (3) mass movements are the least frequent motor pattern. These are most commonly seen after meals, and they move in the aborad direction. Mass movements are preceded by relaxations of haustra and they cause propulsion of colonic contents 35 cm or more. After the mass movement, haustra reappear. Mass movements can deposit feces into the rectum and initiate an urge to defecate.

Front 365

What 4 different contractile patterns cause mixing and transport of digesta?

Back 365

1. Peristaltic and antiperistaltic waves

2. Aborally migrating segmenting contractions

3. Haustral movements and

4. Aborally propagating giant contractions. Sudden Mass Movements

Front 366

What are the functions of the large intestine?

Back 366

The large intestine has two main functions: 1) they are fermenting chambers in which fibre and indigestible nutrients are hydrolysed by microbes, and 2) they produce faeces by absorption of water. To fulfil these functions the digesta have to be intensively mixed and slowly moved aborally.

Front 367

Describe the peristaltic and antiperistaltic waves in the caecum and proximal colon.

Back 367

Peristaltic and antiperistaltic waves are a characteristic motor pattern of the caecum and proximal colon. As a special feature of the large intestine the circular constrictions of the waves are shallow. Consequently the pro- and retropulsion is low and the flow of digesta across the central opening of the constriction causes an intensive mixing.

Front 368

Describe the migrating segmenting contractions.

Back 368

The long lasting and aborally migrating segmenting contractions represent an unique contractile pattern of the large intestine. They occur most frequently in species producing faecal boli, but they are also a dominant pattern in carnivores. In the literature, the segmenting contractions of the large intestine are designated by different terms. In dogs and horses they are called “colonic motor complex” (CMC). The segmenting contractions separate the digesta into boli. In contrast to the segmenting contractions of the small intestine which alternately occur at various intestinal sites and last only a few seconds, that of the large intestine represent long lasting circular constrictions occurring simultaneously at adjacent sites and slowly moving distally.

Front 369

What is slow transit constipation?

Back 369

Estimates of the prevalence of constipation, which is the second most commonly self reported gastrointestinal symptom in North America, range from 1.9% to 27.2%, with most estimates from 12% to 19%.

Slow-transit constipation (STC), or colonic inertia, is a slower than normal movement of contents from the proximal to the distal colon and into the rectum.

It has been suggested that the basis for STC may be dietary or even cultural.

In other people suffering from STC it probably has a true pathophysiologic basis.

Front 370

What does an INC and/or DEC in colonic activity do?

Back 370

Hyperactivity of colon:
A reduction in the number, amplitude and duration of propulsive high amplitude waves in the colon.
Increased amplitude of phasic contractions and increased slow wave activity
Hypoactivity: Low amplitude contractions.
Lack of coordination between contractions

STC has been associated with:
5. Colonic elongation (redundant colon or dolichocolon)
6. An increase in Nitric oxide (NOS positive) releasing myenteric neurons.

Front 371

What is Hirschsprung's disease and where does it occur?

Back 371

HD usually occurs in children. It causes constipation.
Some children with HD can't have bowel movements at all. The stool creates a blockage in the intestine. This can cause serious problems like infection, bursting of the colon, and even death.

Hirschsprung's disease, or congenital aganglionic megacolon, involves an enlargement of the colon, caused by bowel obstruction resulting from an aganglionic section of bowel (the normal enteric nerves are absent) that starts at the anus and progresses upwards. The length of bowel that is affected varies but seldom stretches for more than a foot or so. This disease is named for Harald Hirschsprung, the Danish physician who first described the disease in 1886, describing two infants who had died with swollen bellies. "The autopsies showed identical pictures with a pronounced dilatation and hypertrophy of the colon as the dominant features" (Madsen 17).
Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation (Worman and Ganiats 487). In some cases the child may have delayed toilet training. A barium enema is the mainstay of diagnosis of Hirschsprung’s, though a rectal biopsy showing the lack of ganglion cells is the only certain method of diagnosis.
The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells

Front 372

Describe the pull-through surgery for Hirschsprung's Disease.

Back 372

Pull-through Surgery for Hirschsprung's Disease (HD) is treated with surgery called a pull-through operation. There are three common ways to do a pull-through, and they are called the Swenson, the Soave, and the Duhamel procedures. Each is done a little differently, but all involve taking out the part of the intestine that doesn't work and connecting the healthy part that's left to the anus. After pull-through surgery, the child has a working intestine.

Front 373

Describe gastrocolic reflex.

Back 373

-Ingestion of a meal stimulates the motility of the large intestine. Hence, the familiar urge to defecate following a meal.

-This stimulation is called “gastrocolic reflex“.

-Such gastrointestinal reflexes are elicited by distension of the stomach and by nutrients entering the duodenum. Additionally gastrointestinal hormones like CCK and gastrin are also involved in the stimulation of the large intestinal motility. Arrival of digesta at the large intestine causes a further stimulation of motility. This usually occurs 1.5 to 2 hours after the meal.

Front 374

Describe the response of teh colon to feeding.

Back 374

Eating a meal increases action potentials (spike activity) in the smooth muscle layers, hence contractions, in the colon. Mass peristalsis is also more frequent after a meal, and if material is propelled into the rectum, the urge to defecate occurs. This increase in spike activity occurs within 10 minutes of ingesting a meal and may persist for 30-40 minutes. The intensity of the spike activity is related to the fat content of the meal as shown in the figure.

Front 375

Describe defecation.

Back 375

Defecation is a complex act involving the left colon, rectum, anal sphincters and the striated muscles of the pelvic floor, abdominal wall and diaphragm. The afferent limb of the defecation reflex is activated by mechano-receptors, sometimes called stretch receptors, in the rectosigmoid. When distension reaches a threshold, afferents to the cerebral cortex provide the opportunity to determine whether to allow the reflex to continue to completion or to inhibit passage of feces. These events can be simulated experimentally by distending a balloon in the rectum and measuring the responses of the internal and external anal sphincters.In the figure, the responses to brief and prolonged distension of the rectum are shown. With brief distension, the external sphincter contracts as the internal sphincter relaxes. As the internal sphincter recovers its resting tone, the striated muscle of the external sphincter relaxes and continence is maintained. It is believed that internal sphincter relaxation allows rectal contents to come in contact with the mucosa of the upper anal canal which is very rich sensory innervation. This provides information about whether the material distending the rectum is solid, liquid or gas. If the distending balloon remains inflated, defecation can be prevented by voluntary contraction of the external anal sphincter. As the rectum accommodates to the increased volume, the stimulus for internal anal sphincter relaxation fades, and the external anal sphincter can be relaxed without risk of incontinence.

Front 376

Describe the neural innervation of the distal colon and anal canal.

Back 376

The lumbar sympathetic outflow inhibits the colon and stimulates the internal anal sphincter. The sacral parasympathetic outflow in the pelvic nerves stimulates the colon and inhibits the internal anal sphincter. Afferent fibers from the tissues surrounding the anal canal and from the wall of the colon run in the pelvic nerves. The pudendal nerves innervate the external anal sphincter. Afferent fibers from the circumanal skin, from tissues surrounding the anal canal, and from the external analsphincter run in the pudendal nerves.