Twelve

Question 1

What are some functions that GI motility facilitates? What cells are involved?

Answer 1

The motor activity of the gastrointestinal tract is one of the integrated physiologic

functions essential for the normal assimilation of food. Gastrointestinal motility facilitates the

transport of nutrients, brings together digestive enzymes and their substrate for optimal

absorption, temporarily stores contents, and, finally, excretes nondigestible residue by defecation

in a well-coordinated function under voluntary control. These actions involve the coordinated

actions of multiple tissues and types of cells. The cells involved include the muscle, nerve,

interstitial cells and mucosal cells.

Question 2

What kind of muscles cells are found in the GI tract? What are the two branches of the nervous system involved int he GI nervous system? What are the different patterns of GI motility? What kind of input does the enteric nervous system receive?

Answer 2

The musculature of the digestive tract includes both skeletal and smooth muscle. A

third cell type, the interstitial cells are specialized pacemaker cells called interstitial cells of

Cajal. The nervous system includes the intrinsic nervous system (AKA enteric nervous system)

and the extrinsic nervous system, predominantly the autonomic nervous system. The enteric

nervous system organizes the motor activity of the gut smooth muscle into different patterns of

wall motions: mixing, propulsion, retropulsion. The enteric nervous system receives input and is

influenced by the extrinsic nervous system (autonomic nervous system), chemical signals

(peptides, hormones) – including those released from enterochromaffin cells, enteroendocrine

cells and cells from the immune system (e.g. mast cells and granulocytes), thus allowing the

digestive system to constantly adapt to a changing environment.

Question 3

What are some results of disorders of motility? What are some causes?

Answer 3

The ability of individuals to eat and enjoy food and to eliminate at socially appropriate

times has as near as much importance for social interactions as it does to providing the necessary

fuel for survival. Disordered motility results in significant distress for the individual and can be

socially isolating whether due to disordered swallowing or unpredictable bowel movements.

Disorders of motility are extremely common, are encountered in all clinical specialties and result

in a wide spectrum of symptoms including abdominal bloating, pain, nausea, vomiting, diarrhea,

constipation and bowel incontinence. In general, these symptoms may be the result of

abnormally accelerated transit, delayed transit or non peristaltic contractions. These symptoms

may also result from abnormal sensory patterns, such as an increased perception of normal

physiological stimuli (i.e. normal motor activity is perceived as discomfort), a mechanism

thought to be important in the pathophysiology of irritable bowel syndrome and other functional

gastrointestinal disorders.

Question 4

Where is smooth muscle found in the GI tract? How does it differ in the different parts? What are phasic contractions? Tonic contractions?

Answer 4

The contractile tissue of the gastrointestinal tract is made up almost entirely of smooth

muscle cells. Exceptions include the pharynx, the proximal one third of the esophagus and the

external anal sphincter which are skeletal muscle. The smooth muscle of the gastrointestinal

tract extends as a continuous structure from the middle of the esophagus to the anus. The

structure of the smooth muscle is similar throughout the gut, but with regional differences in

function. Phasic contractions promote the efficient mixing and transit of chyme and tonic

contractions generally serve to limit flow or to provide a reservoir function (e.g. sphincters).

Question 5

Describe various properties common to all smooth muscle and how they affect function. How do they compare to skeletal muscle?

Answer 5

Certain basic properties are common to all smooth muscle cells. Smooth muscle cells are

smaller compared to skeletal muscle. They also have micro-pits on their surface, called caveolae

that allow for an increased surface area on the smooth muscle. The caveolae also play a role in

transmembrane calcium flux during muscle cell stimulation. Another important structural

feature of the smooth muscle is the gap junction. Gap junctions are areas of close apposition for

intercellular communication through ion channels. These junctions functionally couple the

individual cells to each other, such that the stimulation of one cell results in the activation of a

number of cells. In this way, the smooth muscle cells perform as a syncytium such that a large

number of individual cells become activated and contract as though one unit. Inside the smooth

muscle cell, the contractile elements are not arranged in the orderly sarcomeres that are seen in

skeletal muscle. Instead, the contractile proteins, actin and myosin, are present in myofilaments.

The thin and thick filaments run through roughly parallel to the long axis of the smooth muscle

with greater thin than thick filaments. Shortening of the myofilament shortens the muscle along

its long axis. Smooth muscle also has the property of plasticity, which is the ability to stretch to

a greater length and compress to a shorter length than skeletal muscle. Smooth muscle

contractions are slow and sustained contractions as compared to the more rapid contractions seen

in skeletal muscle.

Question 6

What is gut smooth muscle like compared to other types of smooth muscle? What is it like electrically?

Answer 6

As noted above, the smooth muscle of the gut is functionally coupled to contract as one

unit. Thus, the classification of smooth muscle found in the gut is called unitary smooth muscle

(compared to multi-unit smooth muscle seen in ciliary muscle and ductus deferens). The unitary

smooth muscle has sparse innervation compared to multi-unit muscle. Thus, neurotransmitters

cause stimulation or inhibition of only a few of the muscle cells and the stimulation is then

spread directly from one cell to another through the gap junctions.

Gut smooth muscle shows spontaneous (basal) electrical activity even in the absence of

innervation. It has a high basal resting potential (-57 mV -vs- -80 mV) as compared to skeletal
muscle. Smooth muscle is more permeable to Na+ which accounts for this spontaneous

electrical activity. Gut smooth muscle has electromechanical channels that transduce electrical

activity, in one form or another, to the mechanical activity of actin and myosin. These include:

slow-leaking Ca+2-channels , ligand-gated channels, and voltage-gated Na+-channels.

Question 7

Describe the slow wave activity that exists in the gut? How is this modulated/brought about? What does it modulate? HOw does it differ at different places in the GI tract?

Answer 7

Smooth muscle cells in most of the stomach and most of the intestine distally exhibit

continuous rhythmic changes in membrane potential that are called slow waves or pacesetter

potentials. Each slow wave consists of a partial depolarization and repolarization. Slow waves

are the basic electrical rhythm of the smooth muscle. No contractions occur with slow waves.

The slow waves are also called the basal electrical rhythm of the gut. The magnitude of change

is 5 - 15 mV and results from Na+ fluxes in the cell. No calcium flux is associated with these

waves (and thus the reason no contraction occurs with them).

The slow waves in the gut differ in frequency by region from 3 waves per minute in the

stomach to 12 waves per minute in the small intestine. Recall that these slow waves are only

electrical, not mechanical. Key point: they determine the maximum frequency of contraction but

are not sufficient to cause contraction themselves. The activity of the extrinsic nervous system and hormones modulate this slow wave activity. While the maximum frequency is unaffected by

this neural or hormonal input, the strength of contraction is affected, influencing a greater or

lesser strength of muscular contraction. The origin of the slow wave rhythmicity comes from

cells known as the interstitial cells of Cajal.

Question 8

Describe how phasic smooth muscle contractions are produced and carried out? What determines the frequency of the contractions? What determines the strength of the contractions? What effect does acetylcholine have? NE?

Answer 8

Phasic smooth muscle contractions are produced by action potentials (rapid membrane

depolarizations, also called spike potentials) that are superimposed on the partial depolarization

that characterizes the slow wave. The amplitude of the slow wave must be sufficient to

depolarize the membrane to its threshold potential. Unlike the heart, the smooth muscle of the

gastrointestinal tract does not respond with contractions in a one to one basis to its pacemaker.

Greater depolarization and longer slow wave plateaus produce more action potentials and greater

contractions. The frequency of the slow wave remains constant for the particular region of the

GI tract. It is the amplitude and duration of the slow wave that can be influenced by neural or

hormonal factors resulting in greater or lesser contraction strength. More action potentials result

in greater muscle contraction strength. For example, acetylcholine increases the amplitude and

duration of the slow wave plateau, increasing the frequency of the action potential and thus

increasing contraction strength. Conversely, norepinephrine release results in the opposite

action.

Question 9

Describe the biochemical process by which ACh leads to smooth muscle contraction including the various steps/enzymes/second messengers/etc. What is the regulatory step?

Answer 9

Smooth muscle contraction is regulated through intracellular calcium levels in the muscle

cell. When a stimulatory neurotransmitter, such as acetylcholine, binds to the receptor on the

smooth muscle fiber it causes the membrane to depolarize. This opens a voltage gated calcium

channel in the cell membrane allowing extracellular calcium to move down its electro-chemical

gradient and enter the cytoplasm. It also activates membrane phospholipase C, which hydrolyzes

phosphatidyl inositol 4,5 biphosphate to produce inositol 1,4,5 triphosphate (IP3) and 1,2

diacylglycerol (DAG). These are second messengers for acetylcholine. IP3 mobilizes

intracellular calcium from sarcoplasmic reticulum stores. DAG activates protein kinase C, which

phosphorylates cytoplasmic proteins, activating enzymes and membrane receptors. As

intracellular calcium rises, it is bound by calmodulin. The calcium – calmodulin complex

activates the enzyme myosin light-chain kinase which then phosphorylates myosin. The

phosphorylated myosin interacts with actin forming cross bridges and producing a contraction.

This excitation-contraction coupling is called electromechanical coupling. Contractions cease

when cytoplasmic calcium is pumped out by the calcium pump or is taken up by the

sarcoplasmic reticulum. Calcium can also enter the cell through ligand binding of membrane

receptors. This is called pharmacomechanical coupling.

** Regulatory step is binding of Ca++ with Calmodulin.

Question 10

What happens when one gut smooth muscle is depolarized? Describe phasic contractions. Describe two different types. Describe tonic contractions.

Answer 10

Depolarization of gut smooth muscles results in the rapid transmission of the depolarization around the gut. In circular muscle, this forms a ring of smooth muscle contraction. In longitudinal muscle there is length shortening. In the GI tract depolarization results in two

types of smooth muscle contractions: phasic or tonic. A phasic contraction has a relatively short

duration of contraction followed by relaxation. Phasic contractions include segmentation and

peristalsis. Segmentation is prominent in the small and large intestines. During segmentation, a

section (segment) of muscle contracts with muscle on either side relaxing. This results in a to

and fro action that helps mix intestinal contents. Segmentation may also move chyme along the

intestine. Peristalsis is propulsive activity involving both circular and longitudinal muscle layers.

It occurs in the presence of a bolus distension. There is contraction proximal to the bolus and

relaxation below (see peristaltic reflex). Tonic contractions are characteristic of certain regions

of the GI tract that serve as sphincters (e.g. lower esophageal sphincter, pyloric sphincter).

Sphincters divide the GI tract into functional segments. Sphincters maintain tone (constant

contraction) at baseline and relax to allow luminal contents to pass.

Question 11

What is the ENS? How is it connected with the CNS? What are its functions? What cells are involved? Where/what are its plexuses? What do they connect with? What are its contractions like?

Answer 11

The enteric nervous system (ENS) was originally thought to be part of the autonomic

component of the peripheral nervous system. The ENS is often referred to as a minibrain that is

placed in close proximity to the effector system (the gut) it controls. It contains 100 million

neurons, approximately the number also seen in the spinal cord. The ENS is an independent and

integrative system with structural and functional properties similar to the central nervous system.

The ENS maintains its connection to the central nervous system through afferent and efferent

fibers of the sympathetic and parasympathetic neurons. The predominant functions of the ENS

are peristalsis (propulsion of intraluminal boluses), secretion and maintenance of the

interdigestive migrating motor complex (MMC, more about this later). The enteric neurons

comprise sensory neurons, interneurons and motor neurons. They have an almost exclusive role

in supplying the smooth muscle and mucosa of the gastrointestinal tract. Intimately related to the

ENS are plexuses deep within the circular muscle layer (Cajal’s plexus) that have pacemaking

functions.

The enteric nervous system is located within (between) the walls of the digestive tract. It

consists of a series of ganglionated plexuses with ganglia, primary interganglionic fiber tracts

and secondary and tertiary fiber projections to the effector systems (i.e. muscle, glands, blood

vessels). The two ganglionated plexuses are the myenteric plexus (Auerbach’s plexus) located

between the longitudinal and circular muscle layers of the digestive tract; and the submucosal

plexus (Meissner’s plexus) located in the submucosal region between the circular muscle and

mucosa. The ENS provides excitatory and inhibitory control of gut smooth muscle. The gut

smooth muscle is tonically contracted with superimposed, rhythmic, phasic contractions.

Individual smooth muscle cells are electrically coupled, enabling pacemaker cells to effect

sequential activation of neighboring cells in both the circular and longitudinal axes.

The intrinsic nervous system of the gut also includes nerve cell bodies, terminal bundles

of nerve fibers and glial cells. Glial cells outnumber enteric neurons and are speculated to play a

role in modulating inflammatory responses in the intestine.

Question 12

What NTs are involved in the ENS? Which ones are inhibitory and which are excitatory?

Answer 12

More than twenty candidate neurotransmitters have been identified in the ENS. Most

individual neurons contain several neurotransmitters. A wide variety of neurons performing different functions may use the same neurotransmitter. The two major populations of enteric

neurons contain: a) VIP and nitric oxide synthase (inhibitory) and b) Acetylcholine, tachykinins,

substance P and substance K (excitatory). In sphincteric muscle, the inhibitory neurons are

normally switched off and only activated as part of the coordinated event such as the relaxation

of the anal sphincter during defecation. In non sphincteric muscle, inhibitory neurons control the

extent of progression of myogenic excitation.

Question 13

What are the 3 types of ENS neurons? Describe how they are interrelated? Where do they synapse? Where do they project? What NTs do they use?

Answer 13

The neurons of the ENS are classified as: intrinsic afferent neurons, interneurons, and

motor neurons. The intrinsic afferent neurons form the sensory limb of the myenteric and

submucosal plexuses. Interneurons are interposed between the primary afferent neurons and the

motor or secretomotor neurons. Interneurons form multisynaptic pathways along the length of

the gastrointestinal tract and control the distances along the intestine for which peristaltic waves

are propagated. Motor neurons are either excitatory or inhibitory. Excitatory motor neurons

project locally or orally. Inhibitory motor neurons project caudally. Excitatory motor neurons

contain predominantly acetylcholine and substance P. Inhibitory motor neurons contain

predominantly vasoactive intestinal polypeptide and nitric oxide.

Question 14

Where do the GI tract parasympathetic and sympathetic nerves originate? What are the two parasymp pathways and what parts of the tract do they innervate? What is the result of these pathways?

Answer 14

The extrinsic innervation of the gastrointestinal tract consists of parasympathetic vagal

and sacral nerves (S-2,3,4) and sympathetic outflow from the interomediolateral column of the

spinal cord between the levels of the fifth thoracic and third lumbar segments.

Parasympathetic motor pathways consist of the vagus nerve (controls the motor and

secretomotor functions of mostly the upper gastrointestinal tract: esophagus, stomach and

proximal small intestine with some extension as far as the proximal colon) and the sacral nerves

(pelvic nerve) that regulate the functions of the distal colon and rectum. Interactions between the

CNS and ENS are regulated by parasympathetic modulations resulting from activities such as

stress, eating and other behaviors. The extrinsic fibers from sacral roots 2, 3, 4 and the pelvic

plexus supply parasympathetic fibers to the anorectum and left hemicolon. The external anal

sphincter is supplied by sacral nerves 2, 3, 4 and the pudendal nerve. This parasympathetic input

consists of predominantly cholinergic fibers (thus the mediator is generally acetylcholine) that synapse with ganglion cells within the enteric nervous system. The result of parasympathetic

stimulation includes motor and secretory effects and release of hormones.

Question 15

Where are the ganglions for the sympathetic fibers that innervate the GI tract? What are the targets for postganglionic nerve fibers? What are the postganglionic nerves? What do sympathetic fibers facilitate?

Answer 15

Sympathetic fibers are adrenergic, postganglionic fibers with cell bodies located in the

prevertebral ganglia. Thus, the preganglionic fibers synapse outside the GI tract in the

prevertebral ganglia. Targets include secretomotor neurons, presynaptic cholingergic nerve

endings, submucosal blood vessels and gastrointestinal sphincters. The sympathetic nerves from

the thoracolumbar spinal cord synapse in the celiac, superior mesenteric, and inferior mesenteric

ganglia. Postganglionic fibers travel through the hypogastric, splanchnic and lumbar colonic
nerves. The territories of neural supply in the gastrointestinal tract generally follow the vascular

supply of the respective arterial trunks. Sympathetic nerves facilitate contraction ( fibers) or

relaxation ( fibers) of sphincteric muscle and inhibit non-sphincteric muscle (e.g. 2 fibers).

The sympathetic nerves convey nociceptive (pain) information (approximately 50% of the

sympathetic fibers are afferent).

Question 16

Where are primary afferent neurons carried? What are they sensitive to? How does this work? What do extrinsic nerves modulate? In which parts of the tract do they exert more control? What happens in parasyp impairment? Symp impairment?

Answer 16

Nerves that carry sensory information to the CNS are called primary afferent neurons.

They are carried in the vagal and splanchnic nerves. Eighty percent of the vagal fibers are

afferent. These neurons are sensitive to mechanical distension of the gut, luminal concentrations

of glucose, amino acids, or long chain fatty acids, and other chemical mechanical stimuli.

Chemical transmitters released by mucosal endocrine cells (e.g. 5HT) are involved in

transducing the actions of some stimuli on the vagal afferent neurons.

The extrinsic nerves are involved in the modulation of the intrinsic neural circuits and

integrative activity of widely separated regions of the gastrointestinal tract. The extrinsic nerves

are more important in control of certain parts of the gastrointestinal tract such as the stomach and

distal colon than in others such as the small bowel. Disruption of the parasympathetic nerves

results in a greater effect on phasic than on tonic contractile activity. Sympathetic nerve

impairment results in excessive and incoordinated motor and secretory activity. In general, the

smooth muscle portion of the gastrointestinal tract can function fairly normally without the

extrinsic nerves. The cranial (vagal) afferents mediate brain-gut visceral reflexes and the spinal

afferents mediate viscerovisceral reflexes and nociception.

Question 17

Describe the process of peristalsis including the different stimuli, NT, and neuroconnections involved.

Answer 17

Peristalsis is the propulsion of material in the aboral (away from the mouth) direction.

Peristalsis results from a series of local reflexes, each consisting of a contraction of intestinal

muscle above an intraluminal stimulus and a relaxation of muscle below the stimulus. The

release of serotonin (5HT) by mucosal stimulation or mechanical distension of the gut lumen

triggers activity in the intrinsic afferent neurons. The process of peristalsis involves the

interaction of many neurotransmitters. The distension necessary to stimulate this reflex could be

a bolus of food, gas or a foreign body. Relaxation of the muscle below the bolus allows the food

to go forward. This relaxation is mediated by vasoactive intestinal peptide (VIP) and nitric oxide

(NO). Contractions occur predominantly through cholinergic stimulation. Contraction can also

occur through inhibition of inhibitory mediators.

Question 18

Describe the pattern of endocrine cells in the GI tract. Describe the actual endocrine cells. What happens when the hormones reach their target cell? What are the 4 ways in which the hormone can travel?

Answer 18

The GI tract is the largest and most complex (in terms of number of mediators and their

regulation) endocrine organ. Unlike “classical” endocrine cells which are organized into

homogenous organs, GI endocrine cells are dispersed as single cells throughout the epithelial

lining the gastric glands, intestinal crypts, and villi. Some GI peptides are located in nerves.

The endocrine cell is polarized epithelia with an apical membrane domain with

specialized villus projections into the intestinal lumen for interacting with luminal contents and a

specialized basolateral membrane domain which is in close proximity to capillaries and the

interstitial space for delivery of secretory granules which house the regulatory peptide(s).

To date, all GI regulatory “hormones” have been peptides. The specificity of the

response to the released peptide is mediated by the presence of specific plasma membrane-bound

receptors for the peptide on the target cell. Binding of the peptide to its receptor results in the

generation of intracellular second messengers (i.e. cAMP or increased intracellular calcium)

which results in the desired event (e.g. stimulation of secretion).

There are four mechanisms by which regulatory peptides released from the GI tract cells

are delivered to their target organs:

Endocrine:Classical hormone release into circulation for delivery to a distant target

Paracrine: Release of regulatory substances into the interstitium for interaction with adjacent

targets over a short distance by diffusion

Neurocrine/Neuroendocrine: Neurotransmitters may be released locally or into the

circulation

Autocrine: Some cells (particularly malignant) may release a substance (eg. growth factor)

which interacts with a receptor on the same cell.

Question 19

What is the function of gastrin? What are the two forms? Where do the two forms reside mainly? What cells secrete it? Where are these cells located? What causes gastrin to be released? What inhibits gastrin release?

Answer 19

The main physiologic effects of gastrin are the stimulation of gastric acid secretion and

its trophic effect. Gastrin circulates in two forms, “little” gastrin G-17, a heptadecapeptide and

G-34 “big” gastrin. Little gastrin accounts for 90% of the gastrin found in antral mucosa.

However, the gastrin measured in serum is predominantly big gastrin. Although it might seem

logical that little gastrin comes from splitting of big gastrin, this is not the case. Both pro G-17

and pro G-34 are produced. During meals gastrin levels increase 50 – 100%.

The C terminus of the gastrin peptide is required for biological activity. In fact, all the

biologic activity of gastrin is contained in the four c-terminal amino acids. Gastrin is released

predominantly from G cells of the antral mucosa, typically in response to a meal. Some release

also occurs from duodenal mucosa. Stimulants of gastrin release include products of protein

digestion, small peptides and amino acids. Phenylalanine and tryptophan have the greatest

gastrin releasing activity. Gastrin is also released during gastric distension. This can be induced

by a meal but could also result from gastric outlet obstruction or be induced experimentally.

Gastrin stimulates acid secretion by acting directly on the parietal cell and by releasing histamine

from enterochromaffin cells. Gastrin stimulates the growth of the oxyntic gland mucosa of the

stomach and also stimulates colonic mucosa growth. This physiologic effect initially produced

great concern for clinicians who prescribe potent acid suppressing medication (proton pump

inhibitors) which cause gastrin elevations who worried that this could result in increased risk for

colon cancer. Fortunately, this has not been the case. Gastrin secretion is inhibited by antral

acidification (pH less than 3) and also by somatostatin (somatostatin inhibits just about

everything).

Question 20

How does CCK differ from gastrin? Which cells release it? Where are these cells located? What are the functions of CCK? What is the most potent stimulator for its release? What are some other stimulators?

Answer 20

Grouped in the same family, CCK is structurally related to gastrin. Like gastrin, the c-terminal is

required for biological activity. The 5 c-terminal amino acids of CCK are identical to those of

gastrin. Several forms of CCK have been isolated, CCK-8, CCK-33, CCK-39, CCK-58. The

feature differentiating the activity of CCK versus gastrin is the location of the tyrosyl residue.

Sulfation of the tyrosyl residue is required for CCK activity. This is not the case for gastrin.

CCK is released from the I cells of the duodenum and proximal jejunum. High concentrations of

CCK are also present in neurons, including neurons in the brain.

CCK stimulates gallbladder contraction and relaxes the sphincter of Oddi. CCK is a

potent stimulator of pancreatic enzyme secretion. It augments secretin stimulated water and

bicarbonate pancreatic secretion. CCK has a trophic effect on the pancreas. The release of CCK

is stimulated by digested protein (peptides and single amino acids, especially Trp, Phe). The

most potent stimulus for CCK release is fatty acids or their monoglycerides (free fatty acid; > 9

carbons). Note that carbohydrates do not stimulate CCK release. Acid is a weak stimulus for

CCK release.

Question 21

Which cells release secretin? Where are they located? What are the functions of secretin? What stimulates secretin secretion?

Answer 21

Secretin is a member of a large peptide family with homology to glucagon. Secretin is a linear

peptide containing 27 amino acids. Fourteen of these amino acids are identical to those of

glucagon. Members of this family require all amino acids to be present for biological activity

(fragments alone are not active). Secretin is released from S cells in the duodenum and proximal

jejunum. The primary physiological effect of secretin is the stimulation of large volume,

bicarbonate rich pancreatic secretion and water secretion. Secretin inhibits gastric acid secretion.

Along with CCK, secretin stimulates the growth of the exocrine pancreas. Secretin also

stimulates pepsin secretion from the stomach. The most important stimulus for secretin secretion

is acid (pH < 4-5). To a much lesser degree, secretin secretion is stimulated by fatty acids.

Question 22

What is the pharmalogic effect of GIP? What is its physiologic function? What can cause GIP to be released? Where is it released from?

Answer 22

GIP is also a member of the secretin-glucagon family. It is composed of 9 amino acids that are

identical to those of secretin. In pharmacologic doses, GIP has actions similar to secretin and

glucagons. Although called a “gastric inhibitory peptide” for its effect on inhibiting gastric acid

secretion, this is more a function of pharmacologic effects in the laboratory. Its physiologic

function is the stimulation of insulin release in the presence of luminal (not intravenous) glucose.

This is termed an “insulinotropic” effect. Hydrolyzed fat, amino acids (Arg, His, Leu, Lys)

release GIP. The location of GIP release is the duodenum and proximal jejunum.

Question 23

What causes motilin to be released? What is its function?

Answer 23

Motilin is a peptide that does not fit neatly into the other families of peptides. It is a linear

22 amino-acid peptide that is released approximately every 90 minutes during fasting. It is

regulated by a cholinergic pathway such that acetylcholine inhibitors its release. It is a potent

stimulator of upper gut motility. This includes initiating the phase three of the interdigestive

migrating motor complex during fasting (see motility discussion below).

Question 24

What is the function of somatostatin? Which cells is it released from? Where are they located? What stimulates its release?

Answer 24

Paracrine peptides are released in concentrations sufficient to act on nearby cells,

predominantly through diffusion. Although it can act as a hormone and neurocrine, somatostatin

is the only GI paracrine peptide and this is its primary function. It inhibits the release of all

peptide hormones and also inhibits gastrointestinal motility. Additional clinically important

effects include inhibition of gastrin release, gastric acid secretion, pancreatic secretion, intestinal secretion and motility. Somatostatin is released from D cells in pancreatic islets, from stomach

and the entire bowel. Somatostatin release is stimulated by luminal acid. Somatostatin is also

present in nerves in the central nervous system and peripheral nervous system.

Question 25

What are the functions of VIP? Where is it found? What are its targets? How might it be mediated?

Answer 25

VIP biochemically is a member of the secretin-glucagon family. It is found only in nerves and

mediates smooth muscle relaxation in the gut including lower esophageal sphincter relaxation,

internal anal sphincter relaxation and receptive relaxation of the proximal stomach. VIP may also

relax vascular smooth muscle, increasing intestinal blood flow. The effects of VIP on smooth

muscle relaxation may be mediated by nitric oxide. VIP also stimulates pancreatic and intestinal

secretion. Islet cell tumors containing VIP (VIPoma) produce a watery diarrhea syndrome. This

results in a massive secretory diarrhea with hypokalemia.

Question 26

What is GRP? What is its function? Where is it located? What stimulates its release?

Answer 26

Bombesin is the name of the biologically active peptide originally isolated from amphibian skin.

The human counterpart of bombesin is called gastrin releasing peptide (GRP). GRP is located in

nerves of the gastric mucosa and is released by vagal stimulation. This vagal stimulated GRP

release stimulates gastrin release.

Question 27

What receptors do enkephalins act at? What are their functions?

Answer 27

Met- and Leu-enkephalin activate opiate receptors. They are widely distributed in the nerves of

the mucosa and smooth muscle of the gut. Enkephalin release results in smooth muscle

contraction of sphincters (LES, pyloric and ileocecal sphincters). The enkephalins may also play

a role in peristalsis as inhibitory interneurons. They function to inhibit intestinal secretion and

inhibit intestinal motility.

Question 28

List the candidate hormones? What are their possible functions? What stimulates their release? etc?

Answer 28

The roles of these hormones are still being evaluated: enteroglucagon, neurotensin, pancreatic

polypeptide and peptide YY. Enteroglucagon is located in the distal small bowel and is released

into the blood stream. Physiologic action is unknown but may mediate the “ileal break”. The

ileal break describes what happens when undigested fats reach the distal small bowel and

proximal motility is slowed. Glucagon like peptide-1 (GLP-1) is an enteroglucagon that may

stimulate insulin release. Its role is not clearly established. Pancreatic polypeptide is an islet cell

peptide that inhibits pancreatic exocrine secretion. Its release is stimulated by all food. It is also

released in response to the cephalic phase of digestion. Its release occurs from vagal stimulation.

Although pancreatic polypeptide inhibits pancreatic enzyme and bicarbonate secretion in

pharmacologic doses, its clinical significance is not clear. Peptide YY is found in ileal and

colonic mucosa and is released by meals, especially fat. Its release

emptying and may also be important in the ileal break.

Question 29

What is the function of NO in the GI tract?

Answer 29

Nitric oxide is an important mediator of gastrointestinal relaxation. It is both a central and

peripheral “neurotransmitter.” It is a colorless, odorless gas with a very short half-life

(<5seconds). In the gastrointestinal tract, it diffuses into adjacent cells. It is very lipophilic,

easily penetrating biological membranes. It binds guanylate cyclase which increases cGMP.

Like its effect on vascular smooth muscles, it mediates intestinal smooth muscle relaxation

through cGMP.

Question 30

Describe the interdigestive period. What secretions occur during the interdigestive period and what are they like?

Answer 30

 Low basal level of motor, secretory and digestive activity, attributed to low levels of

parasympathetic imput and circulating hormones

 Occurs 12-15 hours per day

 Endocrine cells replenish hormones during this time

 Exocrine cells replenish enzymes

 Continuous cellular exfoliation and regeneration of the mucosal epithelium

Secretion during interdigestive period

Saliva - Secreted at basal rate to moisten the mouth

Gastric Juice - Low level of secretion of HCL

• Low vagal tone and low gastrin
• Decreased pH (food acts as a buffer) so gastrin release is suppressed by antral acidification

Pancreas - Low bicarbonate, low enzyme juice secreted as low vagal tone and low CCK
- Secretion of alkaline juice buffers small amount of acidic gastric juice emptied into small intestine

Bile - Low concentration of bile salts in portal venous blood, and high hepatic bile salt synthesis
- Bile is stored in gallbladder, water is absorbed and bile is concentrated

Question 31

What occurs during the cephalic phase of digestion? What secretions occur and what are they like?

Answer 31

Digestive Period: Cephalic Phase

Anticipation, thought, sight, and smell of food activate parasympathetic efferent nerves, stimulating secretion by digestive glands to prepare the intestine for food.

Secretion during cephalic phase

Saliva - Increased secretion for lubrication for comfortable mastication and swallowing

Gastric Juice - Vagus stimulates acid secretion directly through parietal cells and indirectly through gastrin
- Cephalic phase accounts for 30% of meal stimulated acid release

Pancreas - Direct vagal stimulation of low volume, enzyme rich juice

Biliary - Hepatic bile synthesis similar to fasting as portal vein bile salt concentration is low
- Vagus relaxes Sphincter of Oddi, contracts gallbladder and 30% of stored bile empties into intestine

Question 32

Describe what the gastric phase of digestion is like? What secretions occur and what are they like?

Answer 32

The gastric phase is that period of time during which food is in the stomach.Parasympathetic influence is waning as gastrin becomes a more dominant stimulus.

Secretion during gastric phase

Saliva - Decreases back to basal state

Gastric Juice - Distention stimulates stretch receptors initiating vago-vagal reflex which maintains parietal cell secretion
- Peptides stimulate gastrin - a major stimulus of HCL secretion

Pancreas - Gastric distension evokes high enzyme, low volume secretion (antropancreatic reflex).
Partially neurally mediated; gastrin is a very weak pancreatic stimulant.

Bile - Gallbladder continues to empty but at a slower rate because of reduced parasympathetic drive.

Question 33

Describe the intestinal phase. What secretions occur and what are they like?

Answer 33

The intestinal phase is the period of time that chyme is present in the small intestine. This phase overlaps with the gastric phase. The intestinal phase is characterized by the release of intestinal hormones (CCK, secretin) and digestion and absorption of all three nutrients (carbohydrate, fat and protein).

Secretion during intestinal phase

Stomach - As the stomach empties, buffer is lost and antral acidification inhibits further gastrin release
- Duodenal acidity stimulates secretin release which further decreases parietal cell secretion.

Pancreas - Acid stimulates secretin which causes pancreatic bicarbonate secretion

• Fat and protein in chyme stimulates CCK to cause pancreatic enzyme secretion
• Secretin and CCK potentiate each other to cause maximal pancreatic secretion of bicarbonate and enzymes
• Bicarbonate increases the pH of the small intestine for optimal pH of pancreatic enzymes

Bile - CCK causes intense contraction of the gallbladder and relaxation of the Sphincter of Oddi with 80% of gallbladder bile emptied.
- Secretin causes bicarbonate rich biliary secretion

Question 34

What secretions occur in the late intestinal phase and what are they like?

Answer 34

Secretion during late intestinal phase

Gastric - Falls to basal level

Pancreas - Falls to basal level

Bile - Enterohepatic circulation 2-3 cycles/meal

• Bile salts reabsorbed in terminal ileum, and as the concentration of bile salts in the portal vein increases, bile salts synthesis decreases.
• Bile flow increases, Sphincter of Oddi contracts so the gallbladder begins to fill