Download ilstric Function

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CHAP
ilstric Function
the food digestion that was initiated by mastication and
salivaryenzymesin the mouth. In addition, they help)
from injury. The stomach also has several important DI
regulatethe intake of food, its mixing with gastric stcre
in particle size, and the exit of partially digested matel
num. Moreover,the stomach produces two important
gastrin and somatostatin that have both endocrine an .
These peptidesare primarily important in the regulation of gastric..seeretion.
Although these functions are important in the maintenance of
health, the stomach is neverthelessnot required for
who have had their entire stomach removed (Le., total
non-neoplasticreasonscan maintain adequatenutrition and achieve
lent longevity.
-
.,
FUNCTIONAL ANATOMY OF THE STOMACH
The Mucosa Is Composed of Surface Epithel1alCells and
Glands
The basic structure of the stomach wall is similar to that
of the gastrointestinal(GI) tract (see Fig. 40-2); there£
the stomachconsistsof both mucosal and muscle layers. l
be divided. based on its gross anatomy. into three major
41-1): (l) A specializedportion of the stomachcalledt1l.e
just distal to the gastroesophageal
junction and is i!eV(
secretingparietal cells. (2) The body or corpus is the large
stomach; its most proximal region is called the fundus
portion of the stomachis called the antrum. The surfacea
mucosais substantiallyincreasedby the presenceof gastri
consistof a pit. a neck. and a base.These glands contain severalcell Wpt.s,
including mucous, parietal. chief, and endocrine cells; endocrine cells are
891
892
41 / GastricFunction
Pit
III
m
Stem/regenerative cell
If!:~
Parietal (oxyntic) cell
Gland
-----Chief cell
Muscularls------mucosae
I I!II
~
Gastric gland
in corpus
Submucosa
II
Endocrine
FIGURE
section
41 - 1. Anatomy
through
of the stomach.
the wall of the body
Shown
are the macroscopic
divisions
of the stomach,
as well
as two
progressively
magnified
cell
views
of a
of the stomach.
found only in the antrum. The .surface epithelial cells,
which have their own distinct structure and function,
secreteHCO} and mucus.
Marked cellular heterogeneity exists not only within
segments(e.g., glands versus surface epithelial cells) but
also between segmentsof the stomach. For instance, as
discussedlater, the structure and function of the mucosal
epithelial cells in the antrum and body are quite distinct.
Similarly. although the smooth muscle in the proximal
and distal portions of the stomach appear structurally
similar, their functions and pharmacologicproperties differ substantially.
With Increasing Rates of Secretion of Gastric
Juice, the H+ Concentration
Rises and the
Na+ Concentration
Falls
The glands of the stOmachtypically secreteapproximately
2 liters/day of a fluid that is approximatelyisotonic with
blood plasma.As a consequenceof the heterogeneityof
gastric mucosal function, early investigatorsrecognized
that gastric secretionconsistsof two distinct components:
parietal- and nonparietal-cellsecretion.According to this
hypothesis, gastric secretion consists of (1) an Na+-rich
basal secretionthat originates from nonparietalcells, and
(2) a stimulated component that representsa pure parietal-cell secretion that is rich in H+. This model helps
explain the inverse relationshipbetweenthe luminal concentrations of H+ and Na+ as a function of the rate of
gastric secretion (Fig. 41-2). Thus, at high rates of gastric secretion-for example, when gastrin or histamine
stimulates parietal cells-intraluminal
[H+l is high
whereasintraluminal [Na+1is relatively low. At low rates
of secretion or in clinical situations in which maximal
acid secretionis reduced(e.g., perniciousanemia,seebox
on p. 971). intraluminal [H+] is low but intraluminal
[Na+1is high.
Gastric Function I 41
893
secreteeither acid or intrinsic factor. Glandsin the antral
mucosacontain chief cells and endocrine cells; the endocrine cells include the so-called G cells and D cells,
which secretegastrin and somatostatin,respectively(see
Table 40-1). These two peptide hormones function as
both endocrineand paracrineregulatorsof acid secretion.
As discussedin more detail later, gastrin stimulatesgastric-acid secretionby two mechanismsand is also a major
trophic or growth factor for GI epithelial-cellproliferation.
As discussedmore fully later, somatostatin also has several important regulatory functions, but its primary role
in gastric physiologyis to inhibit both gastrin releaseand
parietal-cellacid secretion.
In addition to the cells of the gastric glands,the stomach also contains superficial epithelial cells that cover the
gastric pits, as well as the surface in between the pits.
Thesecells secreteHCO).
FIGURE41-2. The effect of the gastric secretion rate on the composition of the gastric juice.
The Proximal Portion of the Stomach
SecretesAcid, Pepsinogens,Intrinsic Factor,
Bicarbonate, and Mucus, Whereas the Distal
Part ReleasesGastrin and Somatostatin
CORPUS.The primarysecretoryproductsof
the proxi-
mal pan of the stomach-acid (protons). pepsinogens.
and intrinsic factor-.-are made by distinct cells from
glands in the corpus of the stomach. The two primary
cell typesin the gastric glandsof the body of the stomach
are parietalcells and chief cells.
Parietal cells (or oxyntic cells) secreteboth acid and
intrinsic factor, a glycoprotein that is required for cobalamin (vitamin Bu) absorption in the ileum (p. 970). The
parietal cell has a very distinctive morphology (see Fig.
41-1). It is a large triangular cell with a centrally located
nucleus,an abundanceof mitochondria, intracellular tubulovesicular membranes,and canalicular structures. We
discussH+ secretionin the next subchapterand intrinsic
factor in Chapter44.
Chief cells (or peptic cells) secretepepsinogens,but
not acid. These epithelial cells are substantially smaller
than parietal cells. A close relationship exists among pH,
pepsin secretion, and function. Pepsfns are endopeptidases(Le., they hydrolyze "interior" peptide bonds) and
initiate protein digestion by hydrolyzing specific peptide
linkages.The basal luminal pH of the stomachis 4 to 6;
with stimulation, the pH of gastric secretionsis usually
reducedto less than 2. At pH valuesthat are less than 3,
pepsinogensare rapidly activated to pepsins. A low gastric pH also helps prevent bacterial colonization of the
small intestine.
In addition to parietal and chief cells, glands from the
corpus of the stomach also contain mucus-secreting
cells, which are confined to the neck of the gland (see
Fig. 41-1), and five or six endocrine cells. Among the
latter are enterochromaffin-like(ECL) cells, which release
histamine.
ANTRUM.The glands in the antrum of the stomach do
not contain parietal cells. Therefore,the antrum does not
The Stomach Accommodates Food, Mixes It
with Gastric Secretions, Grinds It, and
Empties the Chyme into the Duodenum
In addition to its secretoryproperties, the stomach also
has multiple motor functions. These functions are the
result of gastric smooth-muscleactivity. which is integrated by both neural and hormonal signals.Gastricmotor functions include both propulsive and retrograde
movementof food and liquid. as well as a nonpropulsive
movementthat increasesintragastricpressure.
Similar to the heterogeneityof gastric epithelial cells,
considerablediversity is seen in both the regulation and
contractility of gastricsmooth muscle.The stomachhas at
least tWo distinct areas of motor activity; the proximal
and distal portions of the stomachbehaveas separate,but
coordinated,entities. At least four eventscan be identified
in the overall processof gastric filling and emptying: (1)
receivingand providing temporary storageof dietary food
GASTRIC pH AND PNEUMONIA
Many patientshospitalizedin the intensivecare unit
(ICU) receiveprophylacticantiulcertreatment(e.g.,
histamine-2receptorantagpnists,suchas cimetidine)
that either neutralizeexistingacid or block its secretion and thereby raisegastricpH. Patientsin the ICU
who are mechanicallyventilatedor havecoagulopathies are highly susceptibleto hemorrhagefrom gastric stressulcers,a complicationthat can contribute
significantlyto overallmorbidity and mortality.These
different antiulcerregimensdo effectivelylessenthe
risk of developingstressulcers.However,by raising
gastricpH, theseagentsalso lower the barrierto
gram-negativebacterialcolonizationof the stomach.
Esophagealreflux and subsequentaspirationof these
organismsare common in thesevery sickpatients,
many of whom are alreadyimmunocompromisedor
even mechanicallycompromisedby the presenceof a
ventilator tube. If thesebacteriaare aspiratedinto the
airway,pneumoniacan result.The higher the gastric
pH, the greaterthe risk of pneumonia.
894
41 / GastricFunction
and liquids; (2) mixing of food and water with gastric
secretoryproducts, including pepsin and acid; (3) grinding of food so that panicle size is reduced to enhance
digestionand pennit passagethrough the pylorus; and (4)
regulatingthe exit of retained material from the stomach
into the duodenum (i.e., gastric emptying of "chyme") in
responseto variousstimuli.
The mechanismsby which the stomach receivesand
emptiesliquids and solids are significantly different. Emptying of liquids is primarily a function of the smooth
muscleof the proximalpan of the stomach,whereasemptying of solidsis regulatedby antral smooth muscle.
Lumen
~A
~.
HCI
Interstitial
space
.2~
~.
ACID SECRETION
The Parietal Cell Has a Specialized
Tubulovesicular Structure That Increases
Apical Membrane Area When the Cell Is
Stimulated to SecreteAcid
In the basalstate, the rate of acid secretionis low. Tubulovesicularmembranesare presentin the apical portion of
the resting, nonstimulated parietal cell and contain the
H-K pump (or H,K-adenosinetriphosphatase[ATPase])
that is responsiblefor acid secretion. Upon stimulation,
cytoskeletal rearrangement causes the tubulovesicular
membranesthat contain the H-K pump to fuse into the
canalicular membrane (Fig. 41-3). The result is a substantial increase(50- to lOa-fold) in the surface area of
the apical membraneof the parietal cell, as well as the
appearanceof microvilli. This fusion is accompaniedby
insertion of the H-K pumps, as well as K+ and Cl- channels, into the canalicularmembrane.The large number of
mitochondria in the parietal cell is consistent with the
high rate of glucoseoxidation and O2 consumption that is
neededto support acid secretion.
An H-K Pump Is Responsiblefor Gastric Acid
Secretion by Parietal Cells
The parietal cell H-K pump is a member of the gene
family of P-typeATPases(p. 63) that includes the ubiquitous Na-K pump (Na,K-ATPase)
, which is present at the
,
A
RESTING
Tubulovesicles
B ACTIVE
Canaliculus
\
FIGURE 41- 3. Parietal cell: resting and stimulated.
..~o
FIGURE41-4. Acid secretionby parietal cells. When the parietalcell is
Stimulated.H-K pumps (fueled by ATP hydrolysis) extrude W into the
lumen of the gastric gland in exchangefor K+. The K+ recyclesback
into the lumen via K+ channels. a- exits through channels In the
luminal membrane.completingthe net processof HO secretion.The H+
neededby the H-K pump is provided by the entry of CO2 and Hp.
which are convened to Wand HCO) by carbonic anhydrase.The
HCO) exits across the basolateral membrane via the CI-HCO} exchanger.ATP, adenosinetriphosphate.
basolateralmembraneof vinually all mammalianepithelial
cells and at the plasma membraneof nonpolarizedcells.
Similar to other membersof this ATPasefamily, the parietal cell H-K pump requires both an a subunit and a fJ
subunit for full activity. The catalytic function of the H-K
pump residesin the a subunit; however,the fJ subunit is
required for targeting to the apical membrane.The two .
subunits form a heterodimerwith close interaction at the
extracellulardomain.
The activity of theseP-type ATPases,including the gastric H-K pump, is affectedby inhibitors that are clinically
important in the control of gastric acid secretion.The two
types of gastric H-K pump inhibitors are (1) substituted
benzimidazoles(e.g., omeprazole), which act by binding
covalently to cysteineson the extracytoplasmicsurface,
and (2) substancesthat act as competitive inhi6itors of
the K+ binding site (e.g., the experimentaldrug Schering
28080). Omeprazole (see.the box titled Gastrinomaor
Zollinger-EllisonSyndrome)is a potent inhibitor of parietal-cell H-K pump activity and is an extremely effective
drug in the control of gastric-acidsecretionin both normal subjects and patients with hypersecretorystates. In
addition, H-K pump inhibitors have been useful in furthering understanding of the function of these pumps.
Thus, ouabain,a potent inhibitor of the Na-K pump, does
not inhibit the gastric H-K pump, whereasomeprazole
does not inhibit the Na-K pump. The colonicH-K pump,
whose a subunit has an amino-acidsequencethat is similar to that of both the Na-K 'pump and the parietal-cell
H-K pump, is partially inhibited by ouabain but not by
omeprazole.
According to the model presentedin Figure 41-4, the
Gastric Function / 41
(ECL) cells and possibly from mast cells (histaminocytes)
in the lamina propria. The central role of histamine and
ECl cells is consistent with the observationthat histamine-2 receptor antagonists(Le., H2 blockers), such as
cimetidine and ranitidine, not only block the direct action
of histamine on parietal cells but also substantiallyinhibit
the acid secretion stimulated by ACh and gastrin. The
effectivenessof H2 blockers in controlling acid secretion
after stimulation by most agonists is well establishedin
studies of both humans and experimentalanimals.These
drugs are widely prescribed to treat active peptic ulcer
disease.
key step in gastric-acidsecretionis extrusion of H+ into
the lumen of the gastric gland in exchangefor K+. The
K+ taken up into the parietal cells is recycled to the
lumen through' K+ channels.The final component of the
processis passivemovementof CI- into the gland lumen.
The apical membrane H-K pump energizes the entire
process,the net result of which is the active secretionof
HC!. Secretionof acid acrossthe apical membraneby the
H-K pump results in a rise in parietal cell pH. The adaptive responseto this rise in pH includes passiveuptake of
CO2 and H2O, which the enzyme carbonic anhydrase
(seebox on p. 637) converts to HCO) and H+. The H+
is the substrateof the H-K pump. The HCO)" exits across
the basolateralmembrane via the CI-HCO3 exchanger.
This latter processalso provides the CI- required for net
HCI movement across the apicaVcanalicularmembrane.
The basolateralNa-H exchangermay panicipate in intracellular pH regulation,especiallyin the basalstate.
The Three Acid Secretagogues Act Through
Either Ca2+/Diacylglycerol or Cyclic
Adenosine Monophosphate
Stimulation of acid secretionby ACh, gastrin, and histamine, is mediatedby a seriesof intracellular signal-transduction processessimilar to those responsiblefor the action of other agonists in other cell systems.All three
secretagogues
bind to specific G-protein-coupled receptors on the parietal-cellmembrane(Fig. 41-6).
Acetylcholine binds to an M3 muscarinic receptor (p.
387) on the parietal cell basolateralmembrane.This ACh
receptor couples to a guanosinetriphosphate(GTP)-binding protein (Gaq) and activatesphospholipaseC (PLC),
which converts phosphatidylinositol 4,5-biphosphate
(PIP2) to inositol 1,4,5-triphosphate(IP3) and diacylglycerol (DAG, p. 100). IP3 causesinternal stores to release
Ca2+,which then probably acts via calmodulin-dependent
protein kinase (p. 102). DAG activatesprotein kinase C
(PKC). The M3 receptoralso activatesa Ca2+channel.
Gastrin binds to a specific parietal-cell receptor that
has been identified as the gastrin-cholecystokinin B
(CCKJ receptor. Two related CCK receptorshave been
identified, CCKA and CCKe. Their amino-acid sequences
are approximately 50% identical, and both are G-protein
Three Secretagogues(Acetylcholine, Gastrin,
and Histamine) Directly and Indirectly Induce
Acid Secretion by Parietal Cells
The action of secretagogues
on gastric-acidsecretionoccurs via at least two parallel and perhaps redundant
mechanisms(Fig. 41-5). In the first, acetylcholine(ACh).
gastrin. and histamine bind directly to their respective
membrane receptors on the parietal cell and synergistically stimulate and potentiate acid secretion. ACh (see
Fig. 15-8) is releasedfrom endings of the vagus nerve
(cranial nerve X), and as we shall see in the next section.
gastrin is releasedfrom D cells. Histamine is synthesized
from histidine (seeFig. 12-9). The documentedpresence
of ACh, gastrin, and histamine receptors.at least on the
canine parietal cell, provides the primary support for this
view. In the second mechanism.ACh and gastrin indirectly induce acid secretionas a result of their stimulation of histamine release from enterochromaffin-like
In the direct pathway,acetylcholine,gastrin
and histaminestimulatethe parietalcell,
triggeringthe secretionof H+ into the lumen.
,Ch
t..
---
895
-
Fromvagusnerve-
M3
receptors)
- . . . ..
..
"'~ (h~~ne
_r).-..
--CCKe
-
(gastrin
"'- ..... ~
receptors)
...Gastrin.. .
Interstitial space
FIGURE 41-5. The direct and indirect actions of the three add secretagogues: acetylcholine. gastrin. and histamine. ACh. acetylcholine: CCKa.
cholecystokinin B; ECl. enterochromaffin-like; ENS. enteric nervous system.
896
4'
I Gastric Function
.
~ ';'~
. '
~
PlP2
T
~-
Lumen
.K+
.
r
1
. .
cr+
of antrum
G
E
R
.
...r
/.
-.
:
coupled. The CCKe receptor has equal affinity for
gastrin and cO<. In contrast, the CCKAreceptor'sa
for CCK is three orders of magnitude higher than
affinity for gastrin. Theseobservationsand the availa "
of
antagonists
are effects
beginning
to clarify
leI,receptor
but at times
opposite,
of gastrin
andthe
CCK
Gastrin
/
Ms
receptor
/~
ee2.
pIes to Ga'Jand activatesthe same PLC pathway as A
-- ea2+
does, which leads to both an increasein lCa2+),
various aspect>of GI function. The CO<, RCCpto,
.
activationof PKC
The histamine receptor on the parietal cell is an Ii
receptor that is coupled to the Ga. GTP-bindingprotein
-
~
I.
'---4
H-K pump
Parietal
cell
;-
Histamineactivationof the receptorcomplexstimulateS~
\.
.
the enzymeadenylyl cyclase,which in turn generateseye-.
,-
lic adenosine
monophosphate
(cAMP).The resultingacti-i
@)
pR)8ta-
vation of protein kinaseA leadsto the phosphorylationor
a number of parietal-ceIl-specificproteins. including the
H-K pump.
'
Gastrin Is Releasedby Both Antral and
FIGURE41-6. ~ceptors
andsignal-transduction
pathways
in theparietal cell. The pariela! cell has separatereceptors for three acid secretagogues. Acetykholine
Duodenal
G Cells, and Histamine
Is Released
by Enterochromaffln-like Cells In the Corpus
(ACh) and gaslrin each bind to specific receptors
(M) and CCt<..respectMly)that~ coupledto ~ G proteinGa,..The
resultis ac:nvationof phospholipaseC (PlC), which ultimately
to
the ICtIvatlonof protemkinaseC (PKC)and ~ releaseof Ca . The
~
histamine binds to an H1 receptor, coupled through Ga, to adenylyl
cyclase(AC).The resultis productionof cAMPand activationof PKA.
Two inhibitorsof acid secretionalso act directlyon the pariela!cell.
Somatostatin
and prostaglandins
bind to separatereceptorsthat ~
linkedto Ga;.The5cagentS
thusopposethe actionsof histamine.
cAMP,
cyclic adenosine monophosphate; CCK". cholecystokinin B; DAG. diacyl-
glycerol;ER. endoplasmicreticulum;PIP1.phosphatidylinositol 4,5-
blphosphate.
The presence of a gastric honnone that stimulates acid
secretionwas initially proposed in 1905. Direct evidence
of such a factor was obtained in 1938, and in 1964
...
Gregory and Tracey iSOlated and punfied gastnn and detennined its amino-acid sequence. Gastrin has three major
effects on GI cells: (1) stimulation of acid secretion by
parietal cells (see Fig. "1- 5) (2) release of histamine by
lls d (3) reguIanon
.'
f
I
h'
EQ ce ,an
0 "-,ucosa groWl 10 the
corpus of the stomach,as well as 10 the small and large
intestine .
Gastrin exists in several different rorms, but the two
major rorms are G-17, or "little gastrin; a 17-amino acid
linear peptide (Fig. 41- 7A), and G-34, or '"big gastrin,"a
34-amino acid peptide (see Fig. 41- 78). A single gene
encodesa peptide or 101 amino acids. Severalcleavage
steps and C-terminal amidation (i.e., addition or a -NH2
A
"LITTLE GASTRIN" OR G-17 (ANTRAl AND DUODENAL)
N
B
-.eoeo.
o.
Amkfe
a
.
Minimalfragment
for strongactivity
PyroGIu-PymgIuIamy1
Gastrin I, A=H
Gastrin II, A.SO4
CCK, A=SO4
-&IG GASTRIN" OR G-34 (DUODENAL)
N
-80..
.00 QDO
.0
00
C CCK (DUOOENAL AND JEJUNAL)
N
-o..o.~oo=.o~co o~c~oo~oo
..,.
IJ
Amide
Identicalto
Amide
Minimal fragment
for strong activity
FIGURE41-7. Amino acid sequencesof the:gastrins and CCK. A, A single gene encodesa lOl-amlno-acid peptide that Is processedto both G-17
and G-34. The N-tennlnal glutamine Is modified to create a pyroglutamyl tUidue. The C-tennlnal phenylalanineIs amidated.Thesemodifications
mau the:hormone resistantto carboxy- and amlnopeptldases.B, The final 16 amino adds of G-34 are identical to the final 16 amino acids In G.17.
Both G-17 and G.}t may Ix either not sulfaltd (Gastrin 1) or sulJaltd(Gastrin 11).C. The five final amino acids of CCK art identical 10 lhose of G-l7
and G-34. CCK. cholecystokinin.
GastricFunctionI 41
GastricFunctionI 4'
to the C terminus) occur during gastrin's post-translaC
occur during
gastrin's
post-translac tenninus)
tional:he
modification,
a process
that occurs
in the
endoal reticulum,
modification,
a process
that occurs
in the
endoplasmic
trans-Golgi
apparatus,
and both
immamic
reticulum,
trans-Golgi
apparatus,
and
both
immature and
mature
secretory
granules.
The
final
product
ofof
. and
mature
secretory
granules.
The
final
product
this post-translational
modification is either G-17 or
post-translational
modification
is either
G-17
G-34. The
tyrosine residue
may be either
sulfated
(so-or
The
tyrosine
residue
may
be
either
sulfated
(50calledgastrinII) or nonsulfated
(gastrin1);the two forms
:d gastrin II) or nonsulfated(gastrin I); the two forms
~
197
897
are equally active and are presentin equal amounts.Gasequally
active and are
presenthormone,
in equal amounts.
Gastrinare
and
cholttystokinin,
a related
have identiand cholecystokinin.
a related hormone,
caltrin
C-terminal
tetrapeptide sequences
(see Fig.have
41- identi70
calpossess
C-terminal
tetrapeptide
sequences
(seegastrin
Fig. 417C)
that
all the
biologic activities
of both
and
that
possess
all
the
biologic
activities
of
both
gastrin
and
CCK.Both G-17 and G-34 are presentin blood plasma,
CCK.
G-17
andprimarily
G-34 arereflect
present
in blood
plasma,
and
theirBoth
plasma
levels
their
degradation
andThus,
their plasma
levels
primarily
reflect than
their G-34,
degradation
rates.
although
G-17
is moreactive
the
rates.Thus, although G-17 is more active than G-34, the
Distentionof stomach
DI8ten1Ion
of 8Iomach
PregarV~,\
(fromvagusnerve)
Preganglionic
--;1\
neNe)
Corpu8
Corpus
\ \1P~liOnlc
T1-ENS
ENS
Postganglionic
/
PostganglIonic
/
.
ACh
I
.~
~
~
ScIm8IDetaIkI
EndocfIn8
AnIruIn
Antrum
DIgested protein ,
Lumen
aminoacids
~
~a
...
...
.
Somatostatin
Somatostatin
receptor
receptor
Somatoetdn
Somatostatin
..
o~
Iu:-~
0'1D
FIGURE 41-8. Regulationof gulrlc-acid secretion. In the corpus of the stomach,the vagus nerve Qot only stimulates the parielal cell directly by
releasing ACh, it also stimulates bolh ECl and D cells. Vagal stimulation of the ECl cells enhances gulric-acid secretion via Increased histamine
relrase. Vagal stimulation of the D cells also pl'Ol11Olesgastric-acid secretion by inhibiting the release of somatostatin. which would othe~
Inhibitby paracrine mechanisms- the relrase of histamine from Eel cells and the secretion of acid by perietal cells.
In the antrum of the stomach,the vagus stimulatesboth G cells and D cells. The vagus stimulatesthe G cells via GRP(gastrin-releasingpeptide).
promoting gastrin relrase.This gastrin promotesgastric-acidsecretionby two endocrinemechanisms:directly via the parielal cell and Indirectly via the
Eel cell, which relraseshistamine. The vagal stimuI.lion of D cells via ACh inhibits the releaseof somatostatin,which would otht~
inhibit-by
parac1'inemechanisms-the releaseof gastrin from G cells and-by an endocrine mechanism-acid secretionby parietal cells. luminal W directly
stimulates the D cells to release5Omat05latin.which Inhibits gastrin releasefrom the G cells, thereby reducing gulric-acid secretion (negative
feedbKk). In addition. products or protein digestion (i.e.. peptidesand amino acids) directly stimulate tht G crUs to rdwc gastrin. which sdmulatc
gastric-acidsecretion(positive feedback).ACh. acetylcholine;CCI<..cholecystokinin8; Eel. emerochromaffin-IIu; ENS.enteric nervoussystem.
898
41 / GastricFunction
latter is degradedat a substantiallylower rate than G-17.
As a consequence,the infusion of equal amountsof G-17
or G-34 produces comparable increasesin gastric-acid
secretion.
Specializedendocrine cells (G cells) in both the antrum and duodenum make each of the two gastrins.Antral G cells are the primary source of G-17, whereas
duodenal G cells are the primary source of G-34. Antral
G cells are unusual in that they respond to both luminal
and basolateralstimuli (Fig. 41-8). Antral G cells have
microvilli on their apical membranesurface and are referred to as an' "open-type" endocrine cell. These G cells
releasegastrin in responseto luminal peptidesand amino
acids, as well as in responseto gastrin-releasing peptide
(GRP),a 27-amino acid peptide that is releasedby vagal
nerve endings.As discussedlater, gastrin releaseis inhibited by somatostatin,which is releasedfrom adjacent D
cells.
Somatostatin, Releasedby Gastric D Cells, Is
the Central Mechanism of Inhibition of Acid
Secretion
Gastric-acidsecretion is under close control of not only
the stimulatory pathways discussedearlier but also the
inhibitory pathways. The major inhibitory pathway involves the releaseof somatostatin, a polypeptide hormone made by D cells in the antrum and corpus of the
stomach.Somatostatinis also made by the 8 cells of the
pancreaticislets (p. 1084) and by neurons in the hypothalamus(p. 1026). SomatostatinexistSin two forms, 5528 and 55-14, which have identical C termini. 55-28 is
the predominantform in the GI tract.
Somatostatininhibits gastric-acidsecretionby both direct and indirect mechanisms(see Fig. 41-8). In the
direct pathway, somatostatincoming from two different
sources binds to a G~-coupled receptor (55T) on the
basolateralmembraneof the parietal cell and inhibits adenylyl cyclase.The net effect is to antagonizethe stimulatory effectof histamineand thus inhibit gastric-acidsecretion by parietal cells. The source of this somatostatincan
either be paraaine (i.e.,D cells present in the corpus of
the stomach,near the parietal cells) or tndocrint (i.e., D
cells in the antrum). However,there is a major difference
in what triggers the D cells in the cOrpusand antrum.
Neural and hormonal mechanismsstimulate D cells in the
corpus(which cannot senseintraluminal pH), whereaslow
intraluminal pH stimulatesD cells in the antrum.
Somatostatinalso acts via two indirect pathways, both
of which are paracrine in nature. In the corpus of the
stomach, D cells release somatostatin that inhibits the
releaseof histaminefrom ECl cells (see Fig. 41-8). Becausehistamineis an acid secretagogue,
somatostatinthus
reducesgastric-acidsecretion.In the antrum of the stomach, D cells releasesomatostatinthat inhibits the release
of gastrin from G cells. Becausegastrin is another acid
secretagogue,
somatostatinalso reducesgastric-acidsecretion by this route. Note that the gastrin releasedby the G
cell feedsback on itself by stimulating D cells to release
the inhibitory somatostatin.
The presenceof multiple mechanismsby which soma-
tostatin inhibits acid secretionis another exampleof the
redundantregulatorypathwaysthat control acid secretion.
An understandingof the regulationof somatostatinrelease
from D cells is slowly evolving, but it appearsthat gastrin
stimulates somatostatinreleasewhereas cholinergic agonists inhibit somatostatinrelease.
Several Enteric Hormones ("Enterogastrone")
and Prostaglandins Inhibit Gastric-Acid
Secretion
Multiple processesin the duodenum and jejunum panicipate in the negative-feedbackmechanismsthat inhibit
gastric-acidsecretion. Fat, acid, and hyperosmolarsolutions in the duodenum are potent inhibitors of gastricacid secretion. Of these inhibitors, lipids are the most
potent, but acid is also quite imponant. Severalcandidate
hormones have been suggestedas the prime mediator of
this acid inhibition (Table 41-1). Theseinclude CCK (p.
920), secretin(p. 921), vasoactiveintestinal peptide (VIP),
gastric inhibitory peptide (GIP p. 899), neurotensin,and
peptide YY (p. 924). Although eachinhibits acid secretion
after systemicadministration,none has been unequivocally
establishedas the sole physiologic"enterogastrone."
Evidence suggeststhat secretin, which is releasedby
duodenal 5 cells, may have a prime role in inhibiting
gastric acid secretionafter the entry of fat and acid into
the duodenum. Secretinappearsto reduce acid secretion
by at least three mechanisms:(1) inhibition of antral
gastrin release, (2) stimulation of somatostatin release,
and (3) direct downregulationof the parietal-cellH+ secretory process.
The presenceof luminal fatty acids causesenteroendocrine cells in the duodenum and the proximal pan of the
TABLE 41-1
CCK (cholecystokinin)
I cellsof duodenum
and jejunumand
neuronsin ileum and
colon
Secretin
S cells in small intestine
VIP (vasoactive intestinal
peptide)
ENSneurons
GIP (gastric inhibitory
peptide, or glucose-dependent insulinotropic
polypeptide)
Neurotensin
K cells in duodenum
and jejunum
PeptideYY
Endocrine cells in ileum
and colon
Somatostatin
D cellsof stomachand
duodenum,6 cellsof
pancreaticislets
ENS,enteric nervous system.
Endocrine cells in ileum
GastricFunction/ 41
899
intestine to releaseboth GIP and CCK. GIP reduces
acid secretiondirectly by inhibiting parietal-cell acid secretion and indirectly by inhibiting the antral releaseof
gastrin.GIP also has the important function of stimulating
insUlin releasefrom pancreaticislet cells in responseto
duodenal glucose and fatty acids and is therefore often
referred to as glucose-dependentinsulinotropic polypeptide (p. 1073). CCK panicipatesin feedbackinhibition of
acid secretionby directly reducing parietal-cellacid secretion. Finally, some evidenceindicates that a neural reflex
elicited in the duodenum in responseto acid also inhibits
gastric-acidsecretion.
Prostaglandin El (PGE2)inhibits parietal-cell acid secretion, probably by inhibiting histamine's activation of
parietal-cellfunction at a site that is distal to the histamine receptor. PGE2appearsto bind to an EP3 receptor
on the basolateralmembraneof the parietal cell (see Fig.
41-6) and stimulatesGCIt,which in turn inhibits adenylyl
cyclase.In addition, prostaglandinsalso indirectly inhibit
gastric-acidsecretionby reducing histamine releasefrom
ECl cells and gastrin releasefrom antral G cells.
variability in basalacid secretionis also seenamongnormal individuals, and the resting intragastricpH can range
from 3 to 7.
In contrast to the low rate of acid secretionduring the
basal or interdigestiveperiod, acid secretionis enhanced
several-foldby eating (Fig. 41-9). It is important to note
that regulationof gastric-acidsecretionis most often studied in the fasting state,a state in which intragasnicpH is
relatively low becauseof the basal H+ secretoryrate and
the absenceof food that would otherwise buffer the secreted gastric acid. Experimentaladministration of a secretagoguein the fastedstate thus stimulatesparietal cells
and funher lowers intragastric pH. However, the time
courseof intragastricpH after a meal can vary considerably despite stimulation of acid secretion. The reason is
that intragastric pH dependsnot only on gastric-acidsecretion but also on the buffering power (p. 635) of food
and the rate of gastricemptying of both acid and panially
digestedmaterialinto the duodenum.
Regulationof acid secretionduring a meal can be best
characterizedby three separate,but interrelated phases:
the cephalic, the gastric, and the intestinal phases.The
.
cephalic and gastric phasesare of primary importance.
There Are Four 'phases of Acid Secretion. A
Regulationof acid secretionincludes both the stimulatory
Basal (or Interdlgestlve)
Phase and Three
and inhibitory mechanismsthat we discussedearlier (see
Phases Associated with Eating
Fig. 41-8). ACh, gastrin, and histamine all promote acid
BASALSTA1L Gastric-acidsecretion occurs throughout
secretionwhereassomatostatininhibits gastric-acidsecrethe day and night. Substantialincreasesin acid secretion tion.
occur after meals,whereasthe rate of acid secretionbeNote that although dividing acid secretion during a
tween meals is low (Le., the interdigestive phase). This
meal into three phaseshas been used for decades,it is
interdigestiveperiod follows a circadian rhythm; acid sesomewhatanmcial becauseof considerableoverlap in the
cretion is lowest in the morning before awakening and
regulationof acid secretion.For example,the vagusnerve
highest in the evening.Acid secretionis a direct function
is the central player in the cephalic phase,but it is also
of the number of parietal cells, which is also influenced,
imponant for the vagovagalreflex that is pan of the
at least in part, by body weight. Thus, men have higher
gastric phase.Similarly. gastrin releaseis a major comporatesof basalacid secretionthan women do. Considerable nent of the gastric phase,but vagalstimulation during the
800
800
~
Volume
(ml)
400
RaIleof H+
20 MCretlon(meqlhr)
[Hl (meqlllter)
~
10
0
0
1
Ingest
food
2
3
4
S
Time
(tv)
...therateofW
eecretion
n-.
FIGURE
41-9.
Effect
of eatingon acid secretion.Ingestingfood causes. markedWI in gastric[WI beaUStthe roodbuffersthe pre~
Howcvcr.as the food leavesthe stomachand as the rate of W secretionincreases.(H+( slowly risesto its "interdigestive"level.
W.
900
41 I Gastric Function
cephalic phasealso induces the releaseof antral gastrin,
Finally, the developmentof a consensusmodel has long
been hamperedby considerabledifferencesin regulation
of the gastric phase of acid secretion in humans, dogs,
and rodents,
.
CIPIIAUCPIIASL The smell, sight, taste, thought, and
swallowing of food initiate the cephalic phase,which is
primarily mediated by the vagus nerve (see Fig. 41-8).
Although the cephalic phase has long been studied in
experimental animals, especially dogs, recent studies of
sham feeding have confinned and extended the understanding of the mechanismof the cephalic phaseof acid
secretionin humans. The aforementionedsensorystimuli
activatethe dona! motor nucleus of the vagus nerve in
the medulla (p, 381), thus activatingparasympatheticpreganglionic efferent nerves. Insulin-induced hypoglycemia
also stimulatesthe vagusnerve and in so doing promotes
acid secretion,
Stimulation of the vagus nerve results in four distinct
physiologicalevents-which we have already introduced
in Figure 41-8-that togetherresult in enhancedgastricacid secretion. First, in the body of the stomach, vagal
postganglionic muscarinic nerves release acetylcholine,
which stimulates parietal-cell H+ secretion directly. Second, in the lamina propria of the body of the stomach,
the ACh releasedfrom vagal endings triggers histamine
releasefrom EQ cells, which stimulates acid secretion,
Third, in the antrum, peptidergicpostganglionicparasympathetic vagal neurons, as well as other enteric nervous
system (ENS) neurons, releaseGRP, which induces gastrin releasefrom antral G cells. This gastrin stimulates
.~
,,'8NI,
......
,
'c..
,'~1"~
FIGURE 41- 1O. GIstric phase or gastric-acid secretion. Food in the
stomach stlmula1es pstric-8cid secrttlon by two major mechanisms: mechanical stretch and the presence or digested pJ'O(ein rragments ("peptones"), ECl, enterochromaffin-like; ENS, enteric nervous system; GRP.
gastrin-releasing peptide.
FIGURE41 - 11. InteStinalphaseof gastric-acidsecretion.DIgestedprotein fragments(peptones)in the proximal small Intestinestimulate gastric-acid secretionby three major mechanisms.
gastric-acidsecretionboth directly by acting on the parietal cell and indirectly by promoting histamine release
from ECL cells. Founh. in both the antrum and the
corpus. the vagus nerve inhibits D cells. thus reducing
their releaseof somatostatinand reducing the background
inhibition of gastrin release.Thus. the cephalic phase
stimulatesacid secretiondirectly and indirectly by acting
on the parietal cell. The cephalic phaseaccountsfor approximately30% of total acid secretionand occurs before
the entry of any food into the stomach.
One of the surgical approachesfor the treatment of
peptic ulcer diseaseis cutting the vagus nerves (vagotomy) to inhibit gastric-acidsecretion. Rarely performed,
largely because of the many effective pharmacologic
agents available to treat peptic ulcer disease.the technique has neverthelessproved to be effectivein selected
cases.Becausevagus-nervestimulation affects severalGI
functions besidesparietal-cellacid secretion,the side effeas of vagotomyinclude a delay in gastricemptying and
diarrhea. To minimize these untoward events.there have
been successfulattempts to perform more Kselective"vagotomies, severing only those vagal fibers going to the
parietal cell.
CAS11IICPHASE.Entry of food into the stomach initiates
the two primary stimuli for the gastric phase of add
secretion (Fig. 41-10A). First, the food distendsthe gastric mucosa, which activates a vagovagal reflex as well as
local ENS reflexes. Second, partially digested proteins
stimulate antral G cells.
Distention of the gastric wall-both
in the corpus and
antrum-secondary to entry of food into the stomach
elidts
two distinct neurally mediated pathways.The first
is activation of a vagovagal re8ex (p. 884), in which
gastric-wall distention activatesa vagal afferentpathway,
which in turn stimulates a vagal efferent response in the
GastricFunction/ 41
dorsal nucleus of the vagus nerve. Stimulation of acid
secretionin responseto this vagalefferentstimulus occurs
via the same four parallel pathways that are operative
when the vagus nerve is activated during the cephalic
phase(seeFig. 41-8). Second,gastric-walldistention also
activatesa local ENS pathway that releasesACh, which
in turn stimulatesparietal-cellacid secretion.
The presenceof partially digested proteins (peptones)
or amino acids in the antrum directly stimulatesG cells
to releasegastrin (seeFig. 41-8). Intact proteins have no
effect. Acid secretion and activation of pepsinogen are
linked in a positive-feedbackrelationship. As discussed
later, low pH eriliancesthe conversion of pepsinogento
pepsin. Pepsin digests proteins to peptones,which promote gastrin release.Finally, gastrin promotes acid secretion, which closes the positive-feedbackloop. There is
little evidencethat either carbohydrateor lipid participate
in the regulation of gastric-acidsecretion.Componentsof
wine, beer, and coffee stimulate acid secretionby this Gcell mechanism.
In addition to the tWo stimulatory pathwaysacting during the gastricphase,a third pathway inhibitsgastric-acid
secretionby a c1assicnegative feedback mechanism, already noted earlier in our discussion of Figure 41-8.
(meq/hr)
After
SERUM
GASTRIN
Normal
Duodenalulcer
901
("1m.)"".
35
0.5-2.0
Pentagastrin
20-35
50
1.5-7.0
25-60
Gastrinoma
500
15-25
30-75
Perniciousanemia
350
0
0
Low intragastric pH stimulates antral D cells to release
somatostatin.Becausesomatostatininhibits the releaseof
gastrin by G cells, the net effect is a reduction in gastricacid secretion.The effectivenessof low pH in inhibiting
gastrin releaseis emphasizedby the following observation: Although peptonesare normally a potent stimulus
for gastrin release,they fail to stimulate gastrin release
either when the intraluminal pH of the antrum is maintained at 1.0 or when somatostatinis infused.
The gastric phase of acid secretion,which occurs primarily as a result of gastrin release.accountsfor 50% to
60%of total gastricacidsecretion.
THE INTESTINALPHASE. The presence of amino acids
and panially digested pep tides in the proximal ponion of
the small intestine stimulates acid secretion by three
mechanisms (Fig. 41-11). First, these peptones stimulate
duodenal G cells to secrete gastrin, just as peptones stimulate antral G cells in the gastric phase. Second, peptones
stimulate an unknown endocrine cell to release an additional humoral signal that has been referred to as "enterooxyntin." The chemical nature of this agent has not yet
been identified. Third, amino acids absorbed by the proximal pan of the small intestine stimulate acid secretion by
mechanisms that require funher definition.
Of interest, gastric-acid secretion mediated by the intestinal phase is enhanced after a ponacaval shunt. Such a
shunt-which
is used in the treatment of ponal hypertension caused by chronic liver disease-divens the portal blood that drains the small intestine around the liver
on its return to the hean. Thus, the signal released from
the small intestine during the "intestinal phase" is probably-in
normal individuals-removed
in pan by the
liver before reaching its target, the corpus of the stomach.
Approximately 5% to 10% oj total gastric acid secretionis
a result of the intestinal phase.
PEPSINOGEN SECRETION
Chief Cells, Triggered by Both cAMP and
Ca2+Pathways, Secrete Multiple Pepsinogens
That Initiate Protein Digestion
The chief cells in gastric glands, as well as mucous cells,
secretepepsinogens, a group of proteolytic proenyzmes
~
902
41 / GastricFunction
(Le., zymogensor inactive enzymeprecursors)that belong
to the generalclassof asparticproteinases.They are activated to pepsins by cleavageof an N-terminal peptide.
Pepsins are endepeptidasesthat initiate the hydrolysis of
ingestedprotein in the stomach.Although eight pepsinogen isoforms were initially identified on electrophoresis,
recent classificationsare based on immunologic identity,
so pepsinogensare most often classifiedas group I pepsinogens,group II pepsinogens,and cathepsinE. Group I
pepsinogenspredominate. They are secretedfrom chief
cells located at the base of glands in the corpus of the
stomach. Group II pepsinogensare also secreted from
chief cells but, in addition, are secreted from mucous
neck cells in the cardiac,corpus, and antral regions.
Pepsinogensecretionin the basalstate is approximately
20% of its maximal secretionafter stimulation. Although
pepsinogensecretion generally parallels the secretion of
acid, the ratio of maximal to basal pepsinogensecretionis
considerablyless than that for acid secretion. Moreover,
the cellular mechanismof pepsinogenreleaseis quite distinct from that of H+ secretionby parietal cells. Releaseof
pepsinogenacrossthe apical membraneis the result of a
novel processcalled compound exocytosis, in which secretory granules fuse with both the plasma membrane
and other secretorygranules.This processpermits rapid
and sustainedsecretionof pepsinogen.After stimulation,
the initial peak in pepsinogensecretion is followed by a
persistentlower rate of secretion.This pattern of secretion
has been interpreted as reflecting an initial secretion of
preformedpepsinogen,
followedby the secretionof newly
synthesized
pepsinogen.However, recent in vitro studies
suggestthat a feedbackmechanismmay account for the
subsequentreducedrate of pepsinogensecretion.
Two groups of agonistsstimulate chief cells to secrete
pepsinogen.One group acts through adenylyl cyclaseand
cAMP,and the other acts through increasesin [Ca2+Jj.
AGONISTSAcnNG VIA cAMP. Chief cells have receptors
for secretinIVIP, ~-adrenergic receptors, and EP2 receptors for PGE2. All these receptors activate adenylyl cyclase. At lower concentrations than those required to
stimulate pepsinogen secretion, PGE2 can also inhibit pepsinogen secretion, probably by binding to another receptor subtype.
AGONISTS
AcnNG VIA C,.z+.Chie('cells also have M3
muscarinic receptors for acetylcholine, as well as receptors for the gastrinlCCK family of peptides. Unlike gastric-acid secretion,which is stimulated via the CCKs receptor, pepsinogensecretion is stimulated via the CCKA
receptor,which has a much higher affinity for CCK than
for gastrin.Activation of both the M3 and CCKAreceptors
causesCaH releasefrom intracellular stores via IP3 and
thereby raises [CaH),. However, uncertainty exists about
whether increasedCaH influx is also required and about
whether PKC also has a role.
Of the agonistsjust listed, the most important for pepsinogen secretion is ACh releasedin responseto vagal
stimulation. Not only does ACh stimulate chief cells to
releasepepsinogen,it also stimulates parietal cells to secrete acid. This gastric acid produces additional pepsinogen secretionvia two different mechanisms.First, in the
stomach,a fall in pH elicits a local cholinergicreflex that
results in funher stimulation of chief cells to releasepepsinogen. Thus, the ACh that stimulates chief cells can
come both from the vagus and from the local reflex.
Second, in the duodenum, acid triggers the releaseof
secretin from S cells. By an endocrineeffect, this secretin
stimulatesthe chief cells to releasemore pepsinogen.The
exact role or roles of histamine and gastrin in pepsinogen
secretionare unclear.
low pH Is Required for Both Pepsinogen
Activation and Pepsin Activity
Pepsinogenis inactive and requires activation to a protease, pepsin, to initiate protein digestion. This activation
occurs by spontaneouscleavageof a small N-terminal
peptide fragment (the activation peptide), but only at a
pH that is less than 5.0 (Fig. 41-12). BetweenpH 5.0
and 3.0, spontaneousactivation of pepsinogenis slow,
but it is extremely rapid at a pH that is less than 3.0. In
addition, pepsinogenis also autoactivated;that is, newly
formed pepsin itself cleavespepsinogento pepsin.
Once pepsin is formed, its activity is also pH dependent. It has optimal activity at a pH between1.8 and 3.5;
the precise optimal pH depends on the specific pepsin,
type and concentrationof substrate,and osmolalityof the
solution. pH valuesabove 3.5 reversiblyinactivatepepsin,
and pH values above 7.2 irreversiblyinactivate the enzyme. These considerationsare sometimesuseful for establishing optimal antacid treatment regimens in peptic
ulcer disease.
Pepsinis an endopeptidasethat initiates the processof
protein digestion in the stomach.Pepsinaction results in
the releaseof small peptidesand amino acids (peptones)
that, as noted earlier, stimulate the releaseof gastrin from
antral G cells; thesepeptonesalso stimulate CCK release
from duodenal I cells. As previously mentioned,the peptones generatedby pepsin stimulate the very acid secretion required for pepsin activation and action. Thus, the
peptides that pepsin releasesare imponant in initiating a
coordinated responseto a meal. However, most protein
entering the duodenum remains as large peptides, and
nitrogen balanceis not impaired after total gastrectomy.
Digestiveproducts of both carbohydratesand lipid are
also found in the stomach, although secretion of their
respectivedigestive enzymeseither does not occur or is
not a major function of gastric epithelial cells. Carbohy-
Pepsinogen !I
r
->,.
Pepsin
~
FIGURE41-12. Activation of the pepsinogensto pepsins.At pH values
from 5 to 3. pepsinogensspontaneouslyactivate to pepsins by the
removal of an N-terminal "activation peptide." This spontaneousactivation is even faster at pH values that are below 3. The newly formed
pepsins themselves-which are active only at pH values below 3.5also can catalyze the activation of pepsinogens.
GastricFunctionI 41
drate digestion.is initiated in the mouth by salivary
amylase. However, after this enzyme is swallowed, the
stomachbecomesa more imponant site for starch hydrolysis than the mouth. There is no evidence of gastric
secretionof enzymesthat hydrolyze starch or other saccharides.Similarly, although lipid digestion is also initiated in the mouth by lingual lipase, significant lipid digestion occurs in the stomach as a result of both the
lingual lipase that is swallowedand gastric lipase, both
of which havean acid pH optimum (p. 962).
PROTECTION OF THE GASTRIC SURFACE
EPITHELIUM AND NEUTRALIZATION OF
ACID IN THE DUODENUM
At maximal rates of H+ secretion, the parietal cell can
drive the intraluminal pH of the stomach to 1 or less
(i.e., [Ht) > 100 mM) for long periods. The gastric
epithelium r.nust maintain an H + concentration gradient
of over a million-fold because the intracellular pH of
gastric epithelial cells is approximately 7.2 (Le., [H+) ==
60 nM) and plasma pH is about 7.4 (Le., [H+) ae 40
nM). Simultaneously,there is a substantialplasma-to-Iumen Na+ -concentrationgradient of approximately 30 becauseplasma [Na+) is 140 mM whereasintragastric [Na+)
can reach values as low as 5 mM, but only at high
secretoryrates (seeFig. 41-2). How is the stomachable
to maintain these gradients?How is it that the epithelial
cells are not destroyedby this acidity? Moreover,why do
pepsins in the gastric lumen not digest the epithelial
cells? The answer to all three questions is the so-called
gastric diffusion barrier.
Although the nature of the gastric diffusion barrier had
been controversial,it is now recognizedthat the diffusion
barrier is both physiologic and anatomic. Moreover, it is
apparentthat the diffusion barrier representsat least three
components: (1) relative impermeability to acid of the
apical membraneand epithelial cell tight junctions in the
gastricglands;(2) a mucous-gellayer varying in thickness
between 50 and 200 J.l.moverlying the surfaceepithelial
cells; and (3) an HCO) -containing microclimate adjacent
to the surface epithelial cells that maintains a relatively
high local pH.
:..
Vagal Stimulation and Irritation Stimulate
Gastric Mucous Cells to Secrete Mucin, a
Glycoprotein That Is Part of the Mucosal
Barrier
The mucus layer is largely composedof mucin, phospholipids. electrolytes,and water. Mucin is the high-molecular-weight glycoprotein (p. 40) that contributes to the
formation of a protective layer over the gastric mucosa.
Gastric mucin is a tetramer consisting of four identical
peptidesjoined by disulfide bonds. Each of the four peptide chains is linked to long polysaccharides,which are
often sulfated and thus mutually repulsive. The ensuing
high carbohydratecontent is responsiblefor the viscosity
of mucus, which explains,in large part, its protective role
in gastricmucosalphysiology.
903
Mucus is secretedby three different mucouscells: surface mucous cells (i.e., on the surface of the stomach),
mucous neck cells (i.e., at the point where a gastric pit
joins a gastric gland), and glandular mucouscells (i.e., in
the gastric glands in the antrum). The type of mucus
secretedby these cells differs; mucus that is synthesized
and secretedin the glandular cells is a neutral glycoprotein, whereasthe mucous cells on the surfaceand in the
gastric pits secreteboth neutral and acidic glycoproteins.
Mucin fonns a mucous-gel layer in combination with
phospholipids, electrolytes,and water. This mucous-gel
layer provides protection againstinjury from noxious luminal substances,including acid, pepsins,bile acids, and
ethanol. Mucin also lubricatesthe gastricmucosato minimize the abrasiveeffectsof intraluminal food.
The mucus barrier is not static. Abrasionscan remove
pieces of mucus. When mucus comes in contact with a
solution with a very low pH, the mucus precipitatesand
sloughs off. Thus, the mucous cells must constantly secrete mucus. Regulation of mucus secretion by gastric
mucosalcells is lesswell understoodthan is regulationof
the secretion of acid, pepsinogens,and other substances
by gastric cells. The two primary stimuli for inducing
mucus secretion are vagal stimulation and physical and
chemicalirritation of the gastricmucosaby ingestedfood.
The current model of mucus secretionsuggeststhat vagal
stimulation induces the releaseof ACh, which leads to
increasesin [Ca2+]1and thus stimulatesmucus secretion.
In contrast to acid and pepsinogensecretion,cAMP does
not appearto be a secondmessengerfor mucus secretion.
Gastric SurfaceCells Secrete HCOi,
Stimulated by Acetylcholine, Acids, and
Prostaglandins
Surface epithelial cells both in the corpus and in the
antrum of the stomach secreteHCO). Despite the relatively low rate of HCO) secretion-in comparisonto
acid secretion-HCO) is extremely important as part of
the gastric mucosalprotective mechanism.The mucus-gel
layer provides an unstirred layer under which the secreted HCO) remains trapped and maintains a local pH
of approximatelyof 7.0 versusan intraluminal pH in the
bulk phaseof 1 to 3. As illustrated in Figure 41-13A, an
electrogenic Na/HCO3 cotransporter (NBC) appears to
mediate the uptake of HCO) acrossthe basolateralmembrane of surfaceepithelial cells. The mechanismof HCO)
exit from the cell into the apical mucus layer is unknown
but may be mediatedby a channel.
Similar to the situation for mucus secretion,relatively
limited information is available about the regulation of
HCO) secretion. The present model suggeststhat vagal
stimulation mediated by ACh leads to an increase in
[CaHJ" which in turn stimulates HCO) secretion.Sham
feeding is a potent stimulus for HCO) secretionvia this
pathway. A second powerful stimulus of gastric HCO)
secretionis intraluminalacid. The mechanismof stimulation by acid appearsto be secondaryto both activationof
neural reflexesand local production of PGE2.Finally, evidence suggeststhat a humoral factor may also be involved in the induction of HCO) secretionby acid.
904
A
41 / GastricFunction
NORMAL SURFACE EPITHELIUM
1.5
pH
profile
7.0
7.4
Gastric lumen
Mast
up
'!f.
cell
..~
Mucus Protects the Gastric Surface
Epithelium by Trapping an HCOi-Rlch Fluid
Near the Apical Border of These Cells
Mucous cells on the surfaceof the stomach.as well as in
the gastric pits and neck ponions of the gastric glands.
secreteboth HCO) and mucus. Why is this barrier so
effective?First, the secretedmucus forms a mucous-gel
layer that is relatively impermeableto the diffusionof H+
from the gastric lumen to the surface cells. Second.beneath this layer of mucus is a microclimate that contains
fluid with a high pH and high IHCO) I. the result of
HCOj" secretionby gastricsurface epithelial cells (seeFig.
41-13A). Thus. this HCO) neutralizes most acid that
diffuses through the mucus layer. Mucosal integrity, including that of the mucosal diffusion barrier. is also
FIGURE 41- 13. DIffusion barrier in the surf8tt or the gastric mucosa.
A, The mucus secreted by the surface ceIls serves two runctions. First, it
acts
as a diffusion barrier ror H + and also pepsins.Second,the mucus
layer traps a relatively alkaline solUtion or HCO,. ThIs HCO] titrates
any W that diffuses into the sel layer rrom the stomach lumen. The
alkaline layer also inactivates any pepsin that penetrates Into the mucus.
B, 1£ W penetrates into the gastric epithelium, it damases mast cells.
which release histamine and other agents, setting up an inOammatory
response. 1£ the insult is mild. the ensuing increase in blood flow can
promote the production or both mucus and HCO, by the mucus cells.
1£ the insult is more severe, the inflammatory response leads to a decrease in blood flow and thus to ceIl injury.
maintained by PGE2,which-as we saw in the previous
section-stimulates mucosalHCO)"secretion.
Deep inside the gastric gland, where no obvious mucus
layer protects the parietal, chief, and ECl cells, the impermeability of the cells' apical barrier appearsto exclude
H+ even at pH valuesas low as 1. The paradox of how
HCI secretedby the parietal cells emergesfrom the gland
and into the gastriclumen may be explainedby a pr0ct5S
known as viscous fingering. Becausethe liquid emerging
from the gastric gland is both extremely acidic and presumably under pressure,it can tunnel through the mucous layer covering the opening of the gastric gland onto
the surface of the stomach.However, this stream of acid
apparently does not spread laterally, but rather rises to
the surfaceas a "finger" and thus does not neutralizethe
GastricFunctionI 41
905
- in the qUcroenvironmentbetween the surfaceepiI
cellsandthe mucus.
'{be mucous-gellayer and the trapped alkaline HCO)"
tion protectthe surfacecells not only from H+ but
from pepsin. The mucus per se acts as a pepsinn barrier. The relative alkalinity of the trapped
- inactivatesany pepsin that penetratesinto the mucus. Recall that pepsin is reversibly inactivated at pH
valuesthat are above approximately 3.5 and irreversibly
inactivatedby pH values approximatelyabove 7.2. Thus,
the mucus/tieD)" layer plays an important role in preventing "autodigestion"of the gastricmucosa.
Entry of Acid into the Duodenum Induces the
Releaseof Secretin From S Cells, Thus
Triggering the Secretion of HCOi by the
Pancreasand Duodenum, Which in Turn
Neutralizes Gastric Acid
The overall processof regulatinggastric-acidsecretioninvolves not only stimulation and inhibition of acid secretion-which we discussedearlier-but also neutralization of the gastric acid that passesfrom the stomachinto
the duodenum. The amount of secretedgastric acid is
reflected by a fall in intragastric pH. We have already
seen that this fall in pH servesas the signal to antral D
cells to releasesomatostatinand thus inhibit further acid
secretion, a classic negative-feedbackprocess. Ukewise,
low pH in the duodenum servesas a signal for the secretion of alkali to neutralizegastricacid in the duodenum.
The key playerin this neutralizationprocessis secretin, the same secretin that inhibits gastric-acidsecretion
and promotes pepsinogensecretionby chief cells. A low
duodenal pH, with a threshold of 4.5, triggersthe release
of secretinfrom S cells in the duodenum.However,the S
cells are probably not pH sensitive themselvesbut, instead, may respond to a signal from other cells that are
pH sensitive.As discussedin Chapter 42, secretinstimulates the secretion of fluid and HCOj" by the pancreas,
thus leading to intraduodenal neutralization of the acid
load from the stomach. Maximal HCOj" secretion is a
function of the amount of acid entering the duodenum,
as well as the length of duodenum exposedto acid. Thus,
high rates of gastric-acidsecretion trigger the releaseof
large amounts of secretin, which greatly stimulatespancreatic HCOj" secretion;the increasedHCOj" in turn neutralizesthe increasedduodenalacid load.
In addition to pancrtaticHCOj" secretion,the duodenal
acid load resulting from gastric-acidsecretionis partially
neutralized by duodenalHCOj" secretion. This duodenal
HCOj" secretion occurs in the proximal-but not the
distal- pan of the duodenum under the influence of
prostaglandins.Attention has been focused on duodenal
906
II
41 I GastricFunction
epithelial cells (villus and/or crypt cells) as the cellular
sourceof HG:O)"secretion,but the possibility that duodenal HCO)" originates,at least in part, from duodenal submucosalBrunner glands has not been excluded. Patients
with duodenal ulcer diseasetend to have both increased
gastric-acidsecretionand reduced duodenal HCO)" secretion. Thus, the increasedacid load in the duodenum is
only partially neutralized, so the duodenal mucosa has
increasedexposureto a low-pH solution.
FILLING AND EMPTYING OF THE STOMACH
Gastric Motor Activity Playsa Role in Filling,
Churning, and Emptying
Gastricmotor activity has three functions: (1) The receipt
of ingestedmaterial representsthe reservoir function of
the stomach and occurs as smooth muscle relaxes.This
responseoccurs primarily in the proximal portion of the
stomach. (2) lDgestedmaterial is ch11l'Dedand thus altered to a form that rapidly empties from the stomach
through the pylorus and facilitates normal jejunal digestion and absorption. Thus, in conjunction with gastric
acid and enzymes, the motor function of the stomach
helps initiate digestion. (3) The pyloric antrum, pylorus,
and proximal part of the duodenum function as a single
unit for emptying into the duodenum the modified gastric contents ("chyme"), consisting of both partially digestedfood material and gastric secretions.Gastric filling
and emptying are accomplishedby the coordinated activity of smooth muscle in the esophagus,lower esophageal
sphincter, and proximal and distal portions of the stomach, as well as the pylorus and duodenum.
The pattern of gastricsmooth-muscleactivity is distinct
during fasting and after eating. The pattern during fasting
is referred to as the migrating myoelectric (or motor)
complex (MMC), which we already discussedin connection with the small intestine (p. 889). This pattern is
terminatedby eating, at which ~int it is replacedby the
a vagovagalreflex, afferent fibers running with the va
nerve carry infonnation to the central nervous
(CNS), and efferentvagal fibers carry the signalfrom tht
CNS to the stomach and cause relaxation via a m~
nism that is neither cholinergic nor adrenergic.The resuW
is that intragastricvolume increaseswithoutan increasein
intragastric pressure.If vagal innervation to the stomach
is interrupted, gastricpressurerisesmuch more rapidly.
Quite apan from the receptiverelaxation of the stOIn-.
ach that anticipatesthe arrival of food after swallowing
and esophagealdistention, the stomachcan also relax in
responseto gastric filling per se. Thus. increasingintragastric volume, as a result of either food entering the
stomach or gastric secretion,does not produce a proportionate increasein inlragastric pressure.Instead,small increasesin volume do not cause increasesin intragastric
pressureuntil a threshold is reached.after which intragastric pressurerises steeply (Fig. 41-14A). This phenomenon is due to activedilatation of the fundus and has been
called gastric accommodation.Vagotomyabolishesa major portion of gastric accommodation,so increasesin intragastricvolume produce greaterincreasesin imragastric
pressure.However, the role of the vagusnerve in gastric
A
Intraluminal
60
pressure 40
(emHP)
20
so-calledfed pattern. Just as the proximal and distal
t'
regions of the stomach differ in secretoryfunction, they
also differ in the motor function responsiblefor storing,
processing,and emptying liquids and solids. The proximal part of the stomachis the primary location for storage of both liquids and solids. The distal portion of the
stomach is primarily responsible10r churning the solids
and generating smaller liquid-like material, which then
exits the stomach in a manner that is similar to that of
ingestedliquids. Thus, the gastric emptying of liquids and
solids is closelyintegrated.
~
Norm8I
0n
~
..",.
B
IIItV'I
---
AIV\
1 /W"I
OleatemeeI
Acid meal
Salinemeal
Filling of the Stomach Is Facilitated by Both
ReceptiveRelaxation and Gastric
Accommodation
I
~
Even a dry swallow relaxes both the lower esophageal
sphincter and the proximal part of the stomach. Of
course, the same happenswhen we swallow food. These
relaxationsfacilitate the entry of food into the stomach.
Relaxationin the fundus.is primarily regulatedby a vagovagal reflex and has been called receptive relaxation. In
0
10
20
Time (mln)
30
40
FIGURE 41-14. Guuic filling and emptying. (Pant:1B. dala rrom
Dooley CP. Reznick}B. Valenzuela}E: VariationsIn gastric and duodenal motility during gastric emptying or liquid mealsin humans.Gastroenterology87:1114-1119.1984.)
GastricFunctionI 41
he antrum
I\urnsthe
'appedmaterial,
)
)mach on its coments.
907
musculaturebefore delivery of the bolus. This increasein
pyloric resistancerepresentsthe coordinated responseof
antral. pyloric. and duodenalmotor activity. Once a bolus
of material is trapped near the antrum, it is churned to
help reduce the size of the panicles. a processtermed
grinding (see Fig. 41-15B). Only a small ponion of
gastric material-that containing particlessmaller than 2
mm- is propelled through the pylorus to the duodenum.
Thus. most of the gastric contents are retUrned to the
body of the stomach for pulverization and shearing of
solid panicles. a processknown as retropulsion (seeFig.
41-15C). These processesof propulsion. grinding. and
retropulsion repeat multiple times until the gastric contents are emptied. Panicleslarger than 2 mm are initially
retained in the stomachbut are eventuallyemptied into
the duodenum by MMCs during the interdigestiveperiod
that beginsapproximately2 hours or more after eating.
Modification of gastric contents is associatedwith the
activation of multiple feedback mechanisms.This feedback usually arisesfrom the duodenum (and beyond) and
almost alwaysresultsin a delay in gastricemptying.Thus.
as small squirts of gastricfluid leavethe stomach.chemoreceptorsand mechanoreceptors-primarily in the proximal but also in the distal ponion of the small intestinesenselow pH. a high content of calories.lipid, or some
amino acids (i.e., tryptophan). or changesin osmolarity.
Thesesignalsall decreasethe rate of gastric emptying by
a combination of neural and hormonal signals,including
the vagus nerve. secretin, CCK. and GIP releasedfrom
duodenal mucosa. Delayed gastric emptying represents:
the coordinated function of fundic relaxation; inhibition
of antral motor activity; stimulation of isolated. phasic
contractionsof the pyloric sphincter; and alteredintestinal
motor activity.
Books and Reviews
DelValle J. Todisco A: Gastric KCntion. In Yamada T (ed): Textbook of
Gutroenterology, Vol I, 3rd ed. Philadelphia, J8 lippincott. WlDiams
6r Wilkins, 1999. pp 278-319.
Dockray GJ. Varro A, Dimaline R: Gastric endocrine cells: Gene expression. processing and targeting of active products. Physiol Rev 76:767798. 1996.
Hasler Wl: The physiology of gastric motility and gastric emptying. In
Yamada T (ed): Textbook of Gastroenterology, Vol I, 3rd ed. Philadelphia. J8 lipplncott. Williams 6r Wilkins, 1999. pp 188-21'4.
Heney 5J. Sachs G: Gastric acid secretion. Physiol R£v 75:155-189,
1995.
Lichtenberger LM: The hydrophobic barrier propenies of gastrointestinal
mucus. Annu Rev Physlol 57:565-583, 1995.
Sachs G. Prinz C: Gastric enterochromaffin-llke cells and the regulation
of acid secretion. News Physiol Sd 11:57-62, 1996.
Sachs G. Zeng N. Prinz C: Physiology of isolated gastric endocrine cells.
Annu Rev Physiol 59:243-256, 1997.
Sawada M. Dickinson Cj: The G celL Annu Rev Physlol 59:273-298,
1997.
Journal Articles
Doo~ CP. ReznickjB, ValenzuelajE: Variationsin gastric and duode.
nal motility during gastricemptying of liquid mealsIn humans.Gastroenterology87:1114-1119.1984.
Waisbren 5j. Geibel jP, Modlin 1M. Boron WF: Unusual permeability
propcnies of gastricgland cells. Nature 368:332-335. 1994.