CHAPTER 26Overview of Gastrointestinal Function & Regulation 443HORMONES/PARACRINES
Biologically active polypeptides that are secreted by nerve cells
and gland cells in the mucosa act in a paracrine fashion, but
they also enter the circulation. Measurement of their concen-
trations in blood after a meal has shed light on the roles these
gastrointestinal hormones play in the regulation of gas-
trointestinal secretion and motility.
When large doses of the hormones are given, their actions
overlap. However, their physiologic effects appear to be relatively
discrete. On the basis of structural similarity (Table 26–6) and,
to a degree, similarity of function, the key hormones fall into
one of two families: the gastrin family, the primary members of
which are gastrin and CCK; and the secretin family, the primary
members of which are secretin, glucagon, glicentin (GLI), vaso-
active intestinal peptide (VIP; actually a neurotransmitter, or
neurocrine), and gastric inhibitory polypeptide (also known as
glucose-dependent insulinotropic peptide, or GIP). There are
also other hormones that do not fall readily into these families.
ENTEROENDOCRINE CELLS
More than 15 types of hormone-secreting enteroendocrine
cells have been identified in the mucosa of the stomach, small
intestine, and colon. Many of these secrete only one hormone
and are identified by letters (G cells, S cells, etc). Others man-
ufacture serotonin or histamine and are called enterochromaf-
fin or enterochromaffin-like (ECL) cells, respectively.
GASTRIN
Gastrin is produced by cells called G cells in the antral portion
of the gastric mucosa (Figure 26–22). G cells are flask-shaped,
with a broad base containing many gastrin granules and a nar-
row apex that reaches the mucosal surface. Microvilli project
from the apical end into the lumen. Receptors mediating gas-
trin responses to changes in gastric contents are present on the
microvilli. Other cells in the gastrointestinal tract that secrete
hormones have a similar morphology.
Gastrin is typical of a number of polypeptide hormones in
that it shows both macroheterogeneity and microheteroge-
neity. Macroheterogeneity refers to the occurrence in tissues
and body fluids of peptide chains of various lengths; microhet-
erogeneity refers to differences in molecular structure due to
derivatization of single amino acid residues. Preprogastrin is
processed into fragments of various sizes. Three main frag-
ments contain 34, 17, and 14 amino acid residues. All have the
same carboxyl terminal configuration (Table 26–6). These
forms are also known as G 34, G 17, and G 14 gastrins, respec-
tively. Another form is the carboxyl terminal tetrapeptide, and
there is also a large form that is extended at the amino terminal
and contains more than 45 amino acid residues. One form of
derivatization is sulfation of the tyrosine that is the sixth
amino acid residue from the carboxyl terminal. Approximately
equal amounts of nonsulfated and sulfated forms are present in
blood and tissues, and they are equally active. Another deriva-
tization is amidation of the carboxyl terminal phenylalanine.
What is the physiologic significance of this marked hetero-
geneity? Some differences in activity exist between the various
components, and the proportions of the components also dif-
fer in the various tissues in which gastrin is found. This sug-
gests that different forms are tailored for different actions.
However, all that can be concluded at present is that G 17 is
the principal form with respect to gastric acid secretion. The
carboxyl terminal tetrapeptide has all the activities of gastrin
but only 10% of the strength of G 17.
G 14 and G 17 have half-lives of 2 to 3 min in the circula-
tion, whereas G 34 has a half-life of 15 min. Gastrins are inac-
tivated primarily in the kidney and small intestine.
In large doses, gastrin has a variety of actions, but its princi-
pal physiologic actions are stimulation of gastric acid and pep-
sin secretion and stimulation of the growth of the mucosa of
the stomach and small and large intestines (trophic action).
Gastrin secretion is affected by the contents of the stomach,
the rate of discharge of the vagus nerves, and bloodborne fac-
tors (Table 26–7). Atropine does not inhibit the gastrin
response to a test meal in humans, because the transmitter
secreted by the postganglionic vagal fibers that innervate the G
cells is gastrin-releasing polypeptide (GRP; see below) rather
than acetylcholine. Gastrin secretion is also increased by the
presence of the products of protein digestion in the stomach,
particularly amino acids, which act directly on the G cells.
Phenylalanine and tryptophan are particularly effective.
Acid in the antrum inhibits gastrin secretion, partly by a
direct action on G cells and partly by release of somatostatin,
a relatively potent inhibitor of gastrin secretion. The effect of
acid is the basis of a negative feedback loop regulating gastrin
secretion. Increased secretion of the hormone increases acid
secretion, but the acid then feeds back to inhibit further gas-
trin secretion. In conditions such as pernicious anemia in
which the acid-secreting cells of the stomach are damaged,
gastrin secretion is chronically elevated.CHOLECYSTOKININ
Cholecystokinin (CCK) is secreted by cells in the mucosa of
the upper small intestine. It has a plethora of actions in the
gastrointestinal system, but the most important appear to be
the stimulation of pancreatic enzyme secretion, the contrac-
tion of the gallbladder (the action for which it was named),
and relaxation of the sphincter of Oddi, which allows both bile
and pancreatic juice to flow into the intestinal lumen.
Like gastrin, CCK shows both macroheterogeneity and
microheterogeneity. Prepro-CCK is processed into many frag-
ments. A large CCK contains 58 amino acid residues (CCK
58). In addition, there are CCK peptides that contain 39
amino acid residues (CCK 39) and 33 amino acid residues
(CCK 33), several forms that contain 12 (CCK 12) or slightly
more amino acid residues, and a form that contains 8 amino
acid residues (CCK 8). All of these forms have the same 5
amino acids at the carboxyl terminal as gastrin (Table 26–6).