Twelve Flashcards
What are some functions that GI motility facilitates? What cells are involved?
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.
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?
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.
What are some results of disorders of motility? What are some causes?
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.
Where is smooth muscle found in the GI tract? How does it differ in the different parts? What are phasic contractions? Tonic contractions?
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).
Describe various properties common to all smooth muscle and how they affect function. How do they compare to skeletal muscle?
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.
What is gut smooth muscle like compared to other types of smooth muscle? What is it like electrically?
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.
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?
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.
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?
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.
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?
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.
What happens when one gut smooth muscle is depolarized? Describe phasic contractions. Describe two different types. Describe tonic contractions.
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.
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?
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.
What NTs are involved in the ENS? Which ones are inhibitory and which are excitatory?
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.
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?
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.
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?
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.
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?
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).
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?
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.
Describe the process of peristalsis including the different stimuli, NT, and neuroconnections involved.
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.
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?
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.
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?
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).
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?
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.
Which cells release secretin? Where are they located? What are the functions of secretin? What stimulates secretin secretion?
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.
What is the pharmalogic effect of GIP? What is its physiologic function? What can cause GIP to be released? Where is it released from?
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.
What causes motilin to be released? What is its function?
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).
What is the function of somatostatin? Which cells is it released from? Where are they located? What stimulates its release?
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.
What are the functions of VIP? Where is it found? What are its targets? How might it be mediated?
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.
What is GRP? What is its function? Where is it located? What stimulates its release?
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.
What receptors do enkephalins act at? What are their functions?
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.
List the candidate hormones? What are their possible functions? What stimulates their release? etc?
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.
What is the function of NO in the GI tract?
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.
Describe the interdigestive period. What secretions occur during the interdigestive period and what are they like?
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
What occurs during the cephalic phase of digestion? What secretions occur and what are they like?
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
Describe what the gastric phase of digestion is like? What secretions occur and what are they like?
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.
Describe the intestinal phase. What secretions occur and what are they like?
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
What secretions occur in the late intestinal phase and what are they like?
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
