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Gastric Physiology
The stomach stores food and facilitates digestion through
a variety of secretory and motor functions. Important
secretory functions include the production of acid,
pepsin, intrinsic factor, mucus, and gastrointestinal hormones. Important motor functions include food storage
(receptive relaxation and accommodation), grinding and
mixing, controlled emptying of ingested food, and periodic interprandial “housekeeping.”
Hydrochloric acid (HCl) stimulates both mechanical and biochemical breakdown of ingested food. In
an acidic environment, pepsin and HCl facilitate proteolysis. Gastric acid also inhibits the proliferation of
ingested bacteria and stimulates secretin release when
it enters the duodenum. Parietal cells secrete HCl
when one of three membrane receptor types is stimulated by acetylcholine (from vagal nerve fibers), gastrin
(from G cells), or histamine (from enterochromaffinlike
[ECL] cells). Somatostatin from mucosal D cells inhibits
gastric acid secretion. The enzyme H+/K+-ATPase is the
proton pump that is stored within the intracellular
tubulovesicles and is the final common pathway for
gastric acid secretion. Although electroneutral, this is an
energy-requiring process, because the hydrogen is
secreted against a gradient of at least 1 millionfold,
which explains why the parietal cell is the most mitochondria-dense mammalian cell (about one third by
volume). During acid production, K+ and Cl− are also
secreted into the secretory canaliculus through separate
channels.
Food ingestion is the physiologic stimulus for acid
secretion. The acid secretory response occurs in three
phases: cephalic, gastric, and intestinal. The cephalic or
vagal phase begins with the thought, sight, smell, and/or
taste of food. These stimuli activate several cortical and
hypothalamic sites, and signals are transmitted to the
stomach by the vagal nerves. Acetylcholine is released,
leading to stimulation of ECL cells and parietal cells. The
cephalic phase accounts for 30% of total acid secretion
in response to a meal.
The gastric phase begins when food reaches the
stomach and lasts until the stomach is empty. It accounts
for 60% of the total acid secretion. The gastric phase of
acid secretion has several components. Amino acids and
small peptides directly stimulate antral G cells to secrete
gastrin, which is carried in the bloodstream to the parietal cells and stimulates acid secretion in an endocrine
fashion. In addition, proximal gastric distention stimulates acid secretion via a vagovagal reflex arc, which is
abolished by truncal or highly selective vagotomy. Antral
distention also stimulates antral gastrin secretion. Acetylcholine stimulates gastrin release, and gastrin stimulates
histamine release from ECL cells. Enterochromaffin-like
cells play a key role in the regulation of gastric acid secretion. A large part of the acid-stimulatory effects of both
acetylcholine and gastrin are mediated by histamine
released from mucosal ECL cells. This explains why H2blockers are effective inhibitors of acid secretion, even
though histamine is only one of three parietal cell stimulants. The mucosal D cells release somatostatin, which
inhibits histamine release from ECL cells and gastrin
release from D cells. The function of D cells is inhibited
by Helicobacter pylori infection and leads to an exaggerated acid secretory response.
The intestinal phase of gastric secretion is poorly
understood and is thought to be mediated by an unknown
hormone from the proximal small bowel mucosa in
response to luminal chyme. This phase starts when gastric
emptying begins and continues as long as nutrients
remain in the proximal small intestine. It accounts for
about 10% of meal-induced acid secretion.
Interprandial basal acid secretion is 2 to 5 mEq of HCl
per hour, about 10% of maximal acid output, and it is
greater at night. Basal acid secretion probably contributes to the relatively low bacterial counts found in the
stomach. Basal acid secretion is reduced 75% to 90% by
vagotomy or H2-receptor blockade.
Pepsinogen secretion from chief cells is primarily stimulated by food ingestion; acetylcholine is the most impor201
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tant mediator. Somatostatin inhibits pepsinogen secretion. Pepsinogen I is produced by chief cells in acidproducing glands; pepsinogen II is produced by chief cells
in both acid-producing and gastrin-producing antral
glands. Pepsinogen is cleaved to the active pepsin enzyme
in an acidic environment and is maximally active at a pH
of 2.5. The enzyme catalyzes the hydrolysis of proteins
and is denatured at alkaline pH. Activated parietal cells
secrete intrinsic factor in addition to HCl. Intrinsic factor
binds to luminal vitamin B12, and the complex is absorbed
in the terminal ileum via mucosal receptors.
Gastric Mucosal Barrier
The stomach’s durable resistance to autodigestion by
caustic HCl and active pepsin is multifaceted. When these
defenses break down, ulceration occurs. The mucus and
bicarbonate secreted by surface epithelial cells form an
unstirred mucous gel with a favorable pH gradient. Cell
membranes and tight junctions prevent hydrogen ions
from gaining access to the interstitial space. Hydrogen
ions that occasionally break through are buffered by the
alkaline tide created by basolateral bicarbonate secretion
from stimulated parietal cells. Any sloughed or denuded
surface epithelial cells are rapidly replaced by migration
of adjacent cells via a process called restitution. Mucosal
blood flow is crucial in maintaining a healthy mucosa by
providing nutrients and oxygen for the cellular functions
involved in cytoprotection. “Back-diffused” hydrogen is
buffered and rapidly removed by the rich blood supply.
When barrier breakers such as bile or aspirin lead to
increased back-diffusion of hydrogen ions from the
lumen into the lamina propria and submucosa, there is
a protective increase in mucosal blood flow. If this protective response is blocked, gross ulceration can occur.
Important mediators of these protective mechanisms
include prostaglandins, nitric oxide, intrinsic nerves,
and peptides such as calcitonin gene–related peptide
and gastrin. Misoprostol is a commercially available
prostaglandin E analogue that prevents gastric mucosal
damage in chronic nonsteroidal anti-inflammatory drug
users. In addition to these local defenses, there are important protective factors in swallowed saliva, duodenal
secretions, and pancreatic and biliary secretions.
Gastric Hormones
Gastrin is produced by antral G cells and is the major
hormonal stimulant of acid secretion during the gastric
phase. A variety of molecular forms exist: the large
majority of gastrin released by the human antrum is G17.
Luminal peptides and amino acids are the most potent
stimulants of gastrin release, and luminal acid is the most
potent inhibitor of gastrin secretion. The inhibitor effect
Part XII. Gastrointestinal Disorders
is mediated in a paracrine fashion by somatostatin
released from antral D cells. Gastrin also is trophic to
gastric parietal cells and to other gastrointestinal mucosal
cells. Important causes of hypergastrinemia include pernicious anemia, acid-suppressive medication, gastrinoma,
retained antrum following distal gastrectomy and Billroth II surgery, and vagotomy.
Somatostatin is produced by D cells located throughout the gastric mucosa. The major stimulus for somatostatin release is antral acidification; acetylcholine from
vagal nerve fibers inhibits its release. Somatostatin
inhibits acid secretion from parietal cells, gastrin release
from G cells, and histamine release from ECL cells. The
primary effect of somatostatin is mediated in a paracrine
fashion, but an endocrine (bloodstream) effect is possible also.
Gastrin-releasing peptide (GRP) in the antrum stimulates both gastrin and somatostatin release by binding to
receptors on the G and D cells. Nerve terminals end near
the mucosa in the gastric body and antrum, which are rich
in GRP immunoreactivity. When GRP is given peripherally it stimulates acid secretion, but when it is given centrally into the cerebral ventricles of animals, it inhibits
acid secretion, apparently via a pathway involving the
sympathetic nervous system.
Ghrelin is a small peptide that is produced primarily in
the stomach. Ghrelin is a potent secretagogue of pituitary
growth hormone but not adrenocorticotropic hormone,
follicle-stimulating hormone, luteinizing hormone, prolactin, or thyroid-stimulating hormone. Ghrelin appears
to be an orexigenic regulator of appetite. When ghrelin
is elevated, appetite is stimulated, and when it is suppressed, appetite is suppressed. The gastric bypass operation is associated with suppression of plasma ghrelin
levels and appetite.
Gastric Motility and Emptying
Gastric motor function has several purposes. Interprandial motor activity clears undigested debris, sloughed
cells, and mucus. When feeding begins, the stomach
relaxes to accommodate the meal. Regulated motor
activity breaks down food into small particles and controls the output into the duodenum. The stomach accomplishes this via coordinated smooth muscle relaxation
and contraction of the proximal, distal, and pyloric gastric
segments. Smooth muscle myoelectric potentials are
translated into muscular activity, which is modulated by
extrinsic and intrinsic innervation and hormones.
The intrinsic innervation consists of ganglia and nerves
constituting the enteric nervous system with a variety of
neurotransmitters. Important excitatory neurotransmitters include acetylcholine, the tachykinins, substance P,
and neurokinin A. Important inhibitory neurotransmit-
83. Gastric Physiology
ters include nitric oxide and vasoactive intestinal peptide.
Serotonin has been shown to modulate both contraction
and relaxation. A variety of other molecules affect motility, including GRP, histamine, neuropeptide Y, norepinephrine, and endogenous opioids.
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Specialized cells in the muscularis propria, interstitial
cells of Cajal, also are important modulators of gastrointestinal motility. They amplify both cholinergic excitatory
and nitrergic inhibitory input to the smooth muscle of the
stomach and intestine.