ilstric Function

the food digestion that was initiated by mastication andsalivary enzymes in the mouth. In addition, they help)from injury. The stomach also has several important DIregulate the intake of food, its mixing with gastric stcrein particle size, and the exit of partially digested matelnum. Moreover, the stomach produces two importantgastrin and somatostatin - that have both endocrine an .These peptides are primarily important in the regulation of gastric.. seere-tion.

Although these functions are important in the maintenance ofhealth, the stomach is nevertheless not required forwho have had their entire stomach removed (Le., totalnon-neoplastic reasons can maintain adequate nutrition and achievelent longevity.

.,FUNCTIONAL ANATOMY OF THE STOMACH

The Mucosa Is Composed of Surface Epithel1al Cells andGlandsThe basic structure of the stomach wall is similar to thatof the gastrointestinal (GI) tract (see Fig. 40-2); there£the stomach consists of both mucosal and muscle layers. lbe divided. based on its gross anatomy. into three major41-1): (l) A specialized portion of the stomach calledt1l.ejust distal to the gastroesophageal junction and is i!eV(secreting parietal cells. (2) The body or corpus is the largestomach; its most proximal region is called the fundusportion of the stomach is called the antrum. The surface amucosa is substantially increased by the presence of gastriconsist of a pit. a neck. and a base. These glands contain several cell Wpt.s,including mucous, parietal. chief, and endocrine cells; endocrine cells are

891

~

CHAP

~

892 41 / Gastric Function

IIIm

If!:~

Gland ------

Muscularls-------mucosae

II! II

II

Submucosa

FIGURE 41 - 1. Anatomy of the stomach. Shown are the macroscopic divisions of the stomach, as well as two progressively magnified views of a

section through the wall of the body of the stomach.

found only in the antrum. The .surface epithelial cells,which have their own distinct structure and function,secrete HCO} and mucus.

Marked cellular heterogeneity exists not only withinsegments (e.g., glands versus surface epithelial cells) butalso between segments of the stomach. For instance, asdiscussed later, the structure and function of the mucosalepithelial cells in the antrum and body are quite distinct.Similarly. although the smooth muscle in the proximaland distal portions of the stomach appear structurallysimilar, their functions and pharmacologic properties dif-fer substantially.

With Increasing Rates of Secretion of GastricJuice, the H+ Concentration Rises and theNa+ Concentration FallsThe glands of the stOmach typically secrete approximately2 liters/day of a fluid that is approximately isotonic with

Pit

Stem/regenerative cell

Parietal (oxyntic) cell

Chief cell

~

Gastric glandin corpus

Endocrine cell

blood plasma. As a consequence of the heterogeneity ofgastric mucosal function, early investigators recognizedthat gastric secretion consists of two distinct components:parietal- and nonparietal-cell secretion. According to thishypothesis, gastric secretion consists of (1) an Na+-richbasal secretion that originates from nonparietal cells, and(2) a stimulated component that represents a pure parie-tal-cell secretion that is rich in H+. This model helpsexplain the inverse relationship between the luminal con-centrations of H+ and Na+ as a function of the rate ofgastric secretion (Fig. 41-2). Thus, at high rates of gas-tric secretion-for example, when gastrin or histaminestimulates parietal cells-intraluminal [H+l is highwhereas intraluminal [Na+1 is relatively low. At low ratesof secretion or in clinical situations in which maximalacid secretion is reduced (e.g., pernicious anemia, see boxon p. 971). intraluminal [H+] is low but intraluminal[Na+1 is high.

The effect of the gastric secretion rate on the composi-

The Proximal Portion of the StomachSecretes Acid, Pepsinogens, Intrinsic Factor,Bicarbonate, and Mucus, Whereas the DistalPart Releases Gastrin and Somatostatin

CORPUS. The primary secretory products of the proxi-mal pan of the stomach-acid (protons). pepsinogens.and intrinsic factor-.-are made by distinct cells fromglands in the corpus of the stomach. The two primarycell types in the gastric glands of the body of the stomachare parietal cells and chief cells.

Parietal cells (or oxyntic cells) secrete both acid andintrinsic factor, a glycoprotein that is required for cobala-min (vitamin Bu) absorption in the ileum (p. 970). Theparietal cell has a very distinctive morphology (see Fig.41-1). It is a large triangular cell with a centrally locatednucleus, an abundance of mitochondria, intracellular tub-ulovesicular membranes, and canalicular structures. Wediscuss H+ secretion in the next subchapter and intrinsicfactor in Chapter 44.

Chief cells (or peptic cells) secrete pepsinogens, butnot acid. These epithelial cells are substantially smallerthan parietal cells. A close relationship exists among pH,pepsin secretion, and function. Pepsfns are endopepti-dases (Le., they hydrolyze "interior" peptide bonds) andinitiate protein digestion by hydrolyzing specific peptidelinkages. The basal luminal pH of the stomach is 4 to 6;with stimulation, the pH of gastric secretions is usuallyreduced to less than 2. At pH values that are less than 3,pepsinogens are rapidly activated to pepsins. A low gas-tric pH also helps prevent bacterial colonization of thesmall intestine.

In addition to parietal and chief cells, glands from thecorpus of the stomach also contain mucus-secretingcells, which are confined to the neck of the gland (seeFig. 41-1), and five or six endocrine cells. Among thelatter are enterochromaffin-like (ECL) cells, which releasehistamine.

ANTRUM. The glands in the antrum of the stomach donot contain parietal cells. Therefore, the antrum does not

FIGURE 41-2.tion of the gastric juice.

Gastric Function I 41 893

secrete either acid or intrinsic factor. Glands in the antralmucosa contain chief cells and endocrine cells; the en-docrine cells include the so-called G cells and D cells,which secrete gastrin and somatostatin, respectively (seeTable 40-1). These two peptide hormones function asboth endocrine and paracrine regulators of acid secretion.As discussed in more detail later, gastrin stimulates gas-tric-acid secretion by two mechanisms and is also a majortrophic or growth factor for GI epithelial-cell proliferation.As discussed more fully later, somatostatin also has sev-eral important regulatory functions, but its primary rolein gastric physiology is to inhibit both gastrin release andparietal-cell acid secretion.

In addition to the cells of the gastric glands, the stom-ach also contains superficial epithelial cells that cover thegastric pits, as well as the surface in between the pits.These cells secrete HCO).

The Stomach Accommodates Food, Mixes Itwith Gastric Secretions, Grinds It, andEmpties the Chyme into the DuodenumIn addition to its secretory properties, the stomach alsohas multiple motor functions. These functions are theresult of gastric smooth-muscle activity. which is inte-grated by both neural and hormonal signals. Gastric mo-tor functions include both propulsive and retrogrademovement of food and liquid. as well as a nonpropulsivemovement that increases intragastric pressure.

Similar to the heterogeneity of gastric epithelial cells,considerable diversity is seen in both the regulation andcontractility of gastric smooth muscle. The stomach has atleast tWo distinct areas of motor activity; the proximaland distal portions of the stomach behave as separate, butcoordinated, entities. At least four events can be identifiedin the overall process of gastric filling and emptying: (1)receiving and providing temporary storage of dietary food

GASTRIC pH AND PNEUMONIA

Many patients hospitalized in the intensive care unit(ICU) receive prophylactic antiulcer treatment (e.g.,histamine-2 receptor antagpnists, such as cimetidine)that either neutralize existing acid or block its secre-tion and thereby raise gastric pH. Patients in the ICUwho are mechanically ventilated or have coagulopa-thies are highly susceptible to hemorrhage from gas-tric stress ulcers, a complication that can contributesignificantly to overall morbidity and mortality. Thesedifferent antiulcer regimens do effectively lessen therisk of developing stress ulcers. However, by raisinggastric pH, these agents also lower the barrier togram-negative bacterial colonization of the stomach.Esophageal reflux and subsequent aspiration of theseorganisms are common in these very sick patients,many of whom are already immunocompromised oreven mechanically compromised by the presence of aventilator tube. If these bacteria are aspirated into theairway, pneumonia can result. The higher the gastricpH, the greater the risk of pneumonia.

894 41 / Gastric Function

and liquids; (2) mixing of food and water with gastricsecretory products, including pepsin and acid; (3) grind-ing of food so that panicle size is reduced to enhancedigestion and pennit passage through the pylorus; and (4)regulating the exit of retained material from the stomachinto the duodenum (i.e., gastric emptying of "chyme") inresponse to various stimuli.

The mechanisms by which the stomach receives andempties liquids and solids are significantly different. Emp-tying of liquids is primarily a function of the smoothmuscle of the proximal pan of the stomach, whereas emp-tying of solids is regulated by antral smooth muscle.

ACID SECRETION

The Parietal Cell Has a SpecializedTubulovesicular Structure That IncreasesApical Membrane Area When the Cell IsStimulated to Secrete AcidIn the basal state, the rate of acid secretion is low. Tubu-lovesicular membranes are present in the apical portion ofthe resting, nonstimulated parietal cell and contain theH-K pump (or H,K-adenosinetriphosphatase [ATPase])that is responsible for acid secretion. Upon stimulation,cytoskeletal rearrangement causes the tubulovesicularmembranes that contain the H-K pump to fuse into thecanalicular membrane (Fig. 41-3). The result is a sub-stantial increase (50- to lOa-fold) in the surface area ofthe apical membrane of the parietal cell, as well as theappearance of microvilli. This fusion is accompanied byinsertion of the H-K pumps, as well as K+ and Cl- chan-nels, into the canalicular membrane. The large number ofmitochondria in the parietal cell is consistent with thehigh rate of glucose oxidation and O2 consumption that isneeded to support acid secretion.

An H-K Pump Is Responsible for Gastric AcidSecretion by Parietal CellsThe parietal cell H-K pump is a member of the genefamily of P-type ATPases (p. 63) that includes the ubiqui-tous 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.

Lumen Interstitialspace

~A ~.HCI~.

.2~

..~oFIGURE 41-4. Acid secretion by parietal cells. When the parietal cell isStimulated. H-K pumps (fueled by ATP hydrolysis) extrude W into thelumen of the gastric gland in exchange for K+. The K+ recycles backinto the lumen via K+ channels. a- exits through channels In theluminal membrane. completing the net process of HO secretion. The H+needed by the H-K pump is provided by the entry of CO2 and Hp.which are convened to Wand HCO) by carbonic anhydrase. TheHCO) exits across the basolateral membrane via the CI-HCO} ex-changer. ATP, adenosine triphosphate.

basolateral membrane of vinually all mammalian epithelialcells and at the plasma membrane of nonpolarized cells.Similar to other members of this ATPase family, the parie-tal cell H-K pump requires both an a subunit and a fJsubunit for full activity. The catalytic function of the H-Kpump resides in the a subunit; however, the fJ subunit is

.required for targeting to the apical membrane. The twosubunits form a heterodimer with close interaction at theextracellular domain.

The activity of these P-type ATPases, including the gas-tric H-K pump, is affected by inhibitors that are clinicallyimportant in the control of gastric acid secretion. The twotypes of gastric H-K pump inhibitors are (1) substitutedbenzimidazoles (e.g., omeprazole) , which act by bindingcovalently to cysteines on the extracytoplasmic surface,and (2) substances that act as competitive inhi6itors ofthe K+ binding site (e.g., the experimental drug Schering28080). Omeprazole (see. the box titled Gastrinoma orZollinger-Ellison Syndrome) is a potent inhibitor of parie-tal-cell H-K pump activity and is an extremely effectivedrug in the control of gastric-acid secretion in both nor-mal subjects and patients with hypersecretory states. Inaddition, H-K pump inhibitors have been useful in fur-thering understanding of the function of these pumps.Thus, ouabain, a potent inhibitor of the Na-K pump, doesnot inhibit the gastric H-K pump, whereas omeprazoledoes not inhibit the Na-K pump. The colonic H-K pump,whose a subunit has an amino-acid sequence that is simi-lar to that of both the Na-K 'pump and the parietal-cellH-K pump, is partially inhibited by ouabain but not byomeprazole.

According to the model presented in Figure 41-4, the

,

key step in gastric-acid secretion is extrusion of H+ intothe lumen of the gastric gland in exchange for K+. TheK+ taken up into the parietal cells is recycled to thelumen through' K+ channels. The final component of theprocess is passive movement of CI- into the gland lumen.The apical membrane H-K pump energizes the entireprocess, the net result of which is the active secretion ofHC!. Secretion of acid across the apical membrane by theH-K pump results in a rise in parietal cell pH. The adap-tive response to this rise in pH includes passive uptake ofCO2 and H2O, which the enzyme carbonic anhydrase(see box on p. 637) converts to HCO) and H+. The H+is the substrate of the H-K pump. The HCO)" exits acrossthe basolateral membrane via the CI-HCO3 exchanger.This latter process also provides the CI- required for netHCI movement across the apicaVcanalicular membrane.The basolateral Na-H exchanger may panicipate in intra-cellular pH regulation, especially in the basal state.

Three Secretagogues (Acetylcholine, Gastrin,and Histamine) Directly and Indirectly InduceAcid Secretion by Parietal CellsThe action of secretagogues on gastric-acid secretion oc-curs via at least two parallel and perhaps redundantmechanisms (Fig. 41-5). In the first, acetylcholine (ACh).gastrin. and histamine bind directly to their respectivemembrane receptors on the parietal cell and synergisti-cally stimulate and potentiate acid secretion. ACh (seeFig. 15-8) is released from endings of the vagus nerve(cranial nerve X), and as we shall see in the next section.gastrin is released from D cells. Histamine is synthesizedfrom histidine (see Fig. 12-9). The documented presenceof ACh, gastrin, and histamine receptors. at least on thecanine parietal cell, provides the primary support for thisview. In the second mechanism. ACh and gastrin indi-rectly induce acid secretion as a result of their stimula-tion of histamine release from enterochromaffin-like

In the direct pathway, acetylcholine, gastrinand histamine stimulate the parietal cell,triggering the secretion of H+ into the lumen.

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.

Gastric Function / 41 895

(ECL) cells and possibly from mast cells (histaminocytes)in the lamina propria. The central role of histamine andECl cells is consistent with the observation that hista-mine-2 receptor antagonists (Le., H2 blockers), such ascimetidine and ranitidine, not only block the direct actionof histamine on parietal cells but also substantially inhibitthe acid secretion stimulated by ACh and gastrin. Theeffectiveness of H2 blockers in controlling acid secretionafter stimulation by most agonists is well established instudies of both humans and experimental animals. Thesedrugs are widely prescribed to treat active peptic ulcerdisease.

The Three Acid Secretagogues Act ThroughEither Ca2+ /Diacylglycerol or CyclicAdenosine MonophosphateStimulation of acid secretion by ACh, gastrin, and hista-mine, is mediated by a series of intracellular signal-trans-duction processes similar to those responsible for the ac-tion of other agonists in other cell systems. All threesecretagogues bind to specific G-protein-coupled recep-tors on the parietal-cell membrane (Fig. 41-6).

Acetylcholine binds to an M3 muscarinic receptor (p.387) on the parietal cell basolateral membrane. This AChreceptor couples to a guanosine triphosphate (GTP)-bind-ing protein (Gaq) and activates phospholipase C (PLC),which converts phosphatidylinositol 4,5-biphosphate(PIP 2) to inositol 1,4 ,5-triphosphate (IP 3) and diacylglyc-erol (DAG, p. 100). IP3 causes internal stores to releaseCa2+, which then probably acts via calmodulin-dependentprotein kinase (p. 102). DAG activates protein kinase C(PKC). The M3 receptor also activates a Ca2+ channel.

Gastrin binds to a specific parietal-cell receptor thathas been identified as the gastrin-cholecystokinin B(CCKJ receptor. Two related CCK receptors have beenidentified, CCKA and CCKe. Their amino-acid sequencesare approximately 50% identical, and both are G-protein

,Cht..

- From vagus nerve-

--- M3receptors)- . . . .. ..

"'~ (h~~ne _r).-..

(gastrin -"'- ~...Gastrin.. .

.....

--CCKereceptors)

4' I Gastric Function896

~ coupled. The CCKe receptor has equal affinity forgastrin and cO<. In contrast, the CCKA receptor's a

PlP2 r Ms for CCK is three orders of magnitude higher thanT G / receptor affinity for gastrin. These observations and the availa "~ . of receptor antagonists are beginning to clarify the- 1 leI, but at times opposite, effects of gastrin and CCK

Lumen ';'~ various aspect> of GI function. The CO<, RCCpto,of antrum~ . . . . E - ee2. pIes to Ga'J and activates the same PLC pathway as

. A.K+ cr+ R does, which leads to both an increase in lCa2+),. ' activation of PKC...r - The histamine receptor on the parietal cell is an Ii

/. I. ~ receptor that is coupled to the Ga. GTP-binding proteinH-K pump '---4 Histamine activation of the receptor complex stimulateS~

Parietal the enzyme adenylyl cyclase, which in turn generates eye-.cell ;- \. ,- lic adenosine monophosphate (cAMP). The resulting acti-i

. @) vation of protein kinase A leads to the phosphorylation orpR)8ta- ' a number of parietal-ceIl-specific proteins. including the

H-K pump.

Gastrin Is Released by Both Antral andFIGURE 41-6. ~ceptors and signal-transduction pathways in the parie- Duodenal G Cells, and Histamine Is Releasedtal cell. The pariela! cell has separate receptors for three acid secreta- by Enterochromaffln-like Cells In the Corpusgogues. Acetykholine (ACh) and gaslrin each bind to specific receptors(M) and CCt<.. respectMly) that ~ coupled to ~ G protein Ga,.. The The presence of a gastric honnone that stimulates acidresult is ac:nvation of phospholipase C (PlC), which ultimately ~ to secretion was initially proposed in 1905. Direct evidencethe ICtIvatlon of protem kinase C (PKC) and ~ release of Ca . The of such a factor was obtained in 1938, and in 1964histamine binds to an H1 receptor, coupled through Ga, to adenylyl ...cyclase (AC). The result is production of cAMP and activation of PKA. Gregory and Tracey iSOlated and punfied gastnn and de-Two inhibitors of acid secretion also act directly on the pariela! cell. tennined its amino-acid sequence. Gastrin has three majorSomatostatin and prostaglandins bind to separate receptors that ~ effects on GI cells: (1) stimulation of acid secretion bylinked to Ga;. The5c agentS thus oppose the actions of histamine. cAMP, parietal cells (see Fig. "1- 5) (2) release of histamine bycyclic adenosine monophosphate; CCK". cholecystokinin B; DAG. diacyl- lls d ( ) I .' f I h' thglycerol; ER. endoplasmic reticulum; PIP1. phosphatidyl inositol 4,5- EQ ce ,an 3 regu anon 0 "-,ucosa groWl 10 eblphosphate. corpus of the stomach, as well as 10 the small and large

intestine .

A "LITTLE GASTRIN" OR G-17 (ANTRAl AND DUODENAL)

-.eoeo. o. Amkfe

a Minimal fragment. for strong activity

N

B -&IG GASTRIN" OR G-34 (DUODENAL)

-80.. .00 QDO .0 00 ..,. AmideIJ

N

C CCK (DUOOENAL AND JEJUNAL)

-o..o.~oo=.o~coN

Minimal fragmentfor strong activity

FIGURE 41-7. Amino acid sequences of the: gastrins and CCK. A, A single gene encodes a lOl-amlno-acid peptide that Is processed to both G-17and G-34. The N-tennlnal glutamine Is modified to create a pyroglutamyl tUidue. The C-tennlnal phenylalanine Is amidated. These modificationsmau the: hormone resistant to 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-l7and G-34. CCK. cholecystokinin.

: - . Gastrin

/~

- ea2+

Gastrin exists in several different rorms, but the twomajor rorms are G-17, or "little gastrin; a 17 -amino acidlinear peptide (Fig. 41- 7A), and G-34, or '"big gastrin," a34-amino acid peptide (see Fig. 41- 78). A single geneencodes a peptide or 101 amino acids. Several cleavagesteps and C-terminal amidation (i.e., addition or a -NH2

PyroGIu-PymgIuIamy1Gastrin I, A=HGastrin II, A.SO4CCK, A=SO4

Identical to

o~c~oo~oo Amide

Gastric Function I 41 197

to the C terminus) occur during gastrin's post-transla- are equally active and are present in equal amounts. Gas-tional modification, a process that occurs in the endo- trin and cholttystokinin, a related hormone, have identi-plasmic reticulum, trans-Golgi apparatus, and both imma- cal C-terminal tetrapeptide sequences (see Fig. 41- 70ture and mature secretory granules. The final product of that possess all the biologic activities of both gastrin andthis post-translational modification is either G-17 or CCK. Both G-17 and G-34 are present in blood plasma,G-34. The tyrosine residue may be either sulfated (so- and their plasma levels primarily reflect their degradationcalled gastrin II) or nonsulfated (gastrin 1); the two forms rates. Thus, although G-17 is more active than G-34, the

Distention of stomach Corpu8~ PregarV~,\ neNe)

PostganglIonic \ 1- ENS/

AChI

.~~ ~ScIm8IDetaIk I

EndocfIn8

AnIruIn

DIgested protein ,Lumen amino acids

~ ~a...SomatostatinreceptorSomatoetdn

...

FIGURE 41-8. Regulation of gulrlc-acid secretion. In the corpus of the stomach, the vagus nerve Qot only stimulates the parielal cell directly byreleasing ACh, it also stimulates bolh ECl and D cells. Vagal stimulation of the ECl cells enhances gulric-acid secretion via Increased histaminerelrase. Vagal stimulation of the D cells also pl'Ol11Oles gastric-acid secretion by inhibiting the release of somatostatin. which would othe~ Inhibit-by 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 stimulates both G cells and D cells. The vagus stimulates the G cells via GRP (gastrin-releasing peptide).promoting gastrin relrase. This gastrin promotes gastric-acid secretion by two endocrine mechanisms: directly via the parielal cell and Indirectly via theEel cell, which relrases histamine. The vagal stimuI.lion of D cells via ACh inhibits the release of somatostatin, which would otht~ inhibit-byparac1'ine mechanisms-the release of gastrin from G cells and-by an endocrine mechanism-acid secretion by parietal cells. luminal W directlystimulates the D cells to release 5Omat05latin. which Inhibits gastrin release from the G cells, thereby reducing gulric-acid secretion (negativefeedbKk). In addition. products or protein digestion (i.e.. peptides and amino acids) directly stimulate tht G crUs to rdwc gastrin. which sdmulatcgastric-acid secretion (positive feedback). ACh. acetylcholine; CCI<.. cholecystokinin 8; Eel. emerochromaffin-IIu; ENS. enteric nervous system.

c:he C tenninus) occur during gastrin's post-transla-al modification, a process that occurs in the endo-mic reticulum, trans-Golgi apparatus, and both imma-. and mature secretory granules. The final product of

post-translational modification is either G-17 orThe tyrosine residue may be either sulfated (50-

:d gastrin II) or nonsulfated (gastrin I); the two forms

.

Gastric Function I 4' 897

are equally active and are present in equal amounts. Gas-trin and cholecystokinin. a related hormone, have identi-cal C-terminal tetrapeptide sequences (see Fig. 41- 7C)that possess all the biologic activities of both gastrin andCCK. Both G-17 and G-34 are present in blood plasma,and their plasma levels primarily reflect their degradationrates. Thus, although G-17 is more active than G-34, the

CorpusDI8ten1Ion of 8Iomach(from vagus nerve)

Preganglionic --;1 \P~liOnlc \ T 1- ENSPostganglionic

/

Antrum

...Somatostatinreceptor

Somatostatin

o~Iu:-~

0'1D

898 41 / Gastric Function

latter is degraded at a substantially lower rate than G-1 7.As a consequence, the infusion of equal amounts of G-17or G-34 produces comparable increases in gastric-acidsecretion.

Specialized endocrine cells (G cells) in both the an-trum and duodenum make each of the two gastrins. An-tral G cells are the primary source of G-17, whereasduodenal G cells are the primary source of G-34. AntralG cells are unusual in that they respond to both luminaland basolateral stimuli (Fig. 41-8). Antral G cells havemicrovilli on their apical membrane surface and are re-ferred to as an' "open-type" endocrine cell. These G cellsrelease gastrin in response to luminal peptides and aminoacids, as well as in response to gastrin-releasing peptide(GRP), a 27 -amino acid peptide that is released by vagalnerve endings. As discussed later, gastrin release is inhib-ited by somatostatin, which is released from adjacent Dcells.

Somatostatin, Released by Gastric D Cells, Isthe Central Mechanism of Inhibition of AcidSecretionGastric-acid secretion is under close control of not onlythe stimulatory pathways discussed earlier but also theinhibitory pathways. The major inhibitory pathway in-volves the release of somatostatin, a polypeptide hor-mone made by D cells in the antrum and corpus of thestomach. Somatostatin is also made by the 8 cells of thepancreatic islets (p. 1084) and by neurons in the hypo-thalamus (p. 1026). Somatostatin existS in two forms, 55-28 and 55-14, which have identical C termini. 55-28 isthe predominant form in the GI tract.

Somatostatin inhibits gastric-acid secretion by both di-rect and indirect mechanisms (see Fig. 41-8). In thedirect pathway, somatostatin coming from two differentsources binds to a G~-coupled receptor (55T) on thebasolateral membrane of the parietal cell and inhibits ad-enylyl cyclase. The net effect is to antagonize the stimula-tory effect of histamine and thus inhibit gastric-acid secre-tion by parietal cells. The source of this somatostatin caneither be paraaine (i.e.,D cells present in the corpus ofthe stomach, near the parietal cells) or tndocrint (i.e., Dcells in the antrum). However, there is a major differencein what triggers the D cells in the cOrpus and antrum.Neural and hormonal mechanisms stimulate D cells in thecorpus (which cannot sense intraluminal pH), whereas lowintraluminal pH stimulates D cells in the antrum.

Somatostatin also acts via two indirect pathways, bothof which are paracrine in nature. In the corpus of thestomach, D cells release somatostatin that inhibits therelease of histamine from ECl cells (see Fig. 41-8). Be-cause histamine is an acid secretagogue, somatostatin thusreduces gastric-acid secretion. In the antrum of the stom-ach, D cells release somatostatin that inhibits the releaseof gastrin from G cells. Because gastrin is another acidsecretagogue, somatostatin also reduces gastric-acid secre-tion by this route. Note that the gastrin released by the Gcell feeds back on itself by stimulating D cells to releasethe inhibitory somatostatin.

The presence of multiple mechanisms by which soma-

tostatin inhibits acid secretion is another example of theredundant regulatory pathways that control acid secretion.An understanding of the regulation of somatostatin releasefrom D cells is slowly evolving, but it appears that gastrinstimulates somatostatin release whereas cholinergic ago-nists inhibit somatostatin release.

Several Enteric Hormones ("Enterogastrone")and Prostaglandins Inhibit Gastric-AcidSecretionMultiple processes in the duodenum and jejunum panici-pate in the negative-feedback mechanisms that inhibitgastric-acid secretion. Fat, acid, and hyperosmolar solu-tions in the duodenum are potent inhibitors of gastric-acid secretion. Of these inhibitors, lipids are the mostpotent, but acid is also quite imponant. Several candidatehormones have been suggested as the prime mediator ofthis acid inhibition (Table 41-1). These include CCK (p.920), secretin (p. 921), vasoactive intestinal peptide (VIP),gastric inhibitory peptide (GIP p. 899), neurotensin, andpeptide YY (p. 924). Although each inhibits acid secretionafter systemic administration, none has been unequivocallyestablished as the sole physiologic "enterogastrone."

Evidence suggests that secretin, which is released byduodenal 5 cells, may have a prime role in inhibitinggastric acid secretion after the entry of fat and acid intothe duodenum. Secretin appears to reduce acid secretionby at least three mechanisms: (1) inhibition of antralgastrin release, (2) stimulation of somatostatin release,and (3) direct downregulation of the parietal-cell H+ se-cretory process.

The presence of luminal fatty acids causes enteroendo-crine cells in the duodenum and the proximal pan of the

TABLE 41-1

CCK (cholecystokinin) I cells of duodenumand jejunum andneurons in ileum andcolon

Secretin S cells in small intestine

ENS neuronsVIP (vasoactive intestinalpeptide)

K cells in duodenumand jejunum

GIP (gastric inhibitorypeptide, or glucose-de-pendent insulinotropicpolypeptide)

Endocrine cells in ileumNeurotensin

Peptide YY Endocrine cells in ileumand colon

Somatostatin D cells of stomach andduodenum, 6 cells ofpancreatic islets

ENS, enteric nervous system.

Gastric Function / 41 899

intestine to release both GIP and CCK. GIP reduces variability in basal acid secretion is also seen among nor-acid secretion directly by inhibiting parietal-cell acid se- mal individuals, and the resting intragastric pH can rangecretion and indirectly by inhibiting the antral release of from 3 to 7.gastrin. GIP also has the important function of stimulating In contrast to the low rate of acid secretion during theinsUlin release from pancreatic islet cells in response to basal or interdigestive period, acid secretion is enhancedduodenal glucose and fatty acids and is therefore often several-fold by eating (Fig. 41-9). It is important to notereferred to as glucose-dependent insulinotropic polypep- that regulation of gastric-acid secretion is most often stud-tide (p. 1073). CCK panicipates in feedback inhibition of ied in the fasting state, a state in which intragasnic pH isacid secretion by directly reducing parietal-cell acid secre- relatively low because of the basal H+ secretory rate andtion. Finally, some evidence indicates that a neural reflex the absence of food that would otherwise buffer the se-elicited in the duodenum in response to acid also inhibits creted gastric acid. Experimental administration of a se-gastric-acid secretion. cretagogue in the fasted state thus stimulates parietal cells

Prostaglandin El (PGE2) inhibits parietal-cell acid se- and funher lowers intragastric pH. However, the timecretion, probably by inhibiting histamine's activation of course of intragastric pH after a meal can vary considera-parietal-cell function at a site that is distal to the hista- bly despite stimulation of acid secretion. The reason ismine receptor. PGE2 appears to bind to an EP3 receptor that intragastric pH depends not only on gastric-acid se-on the basolateral membrane of the parietal cell (see Fig. cretion but also on the buffering power (p. 635) of food41-6) and stimulates GCIt, which in turn inhibits adenylyl and the rate of gastric emptying of both acid and paniallycyclase. In addition, prostaglandins also indirectly inhibit digested material into the duodenum.gastric-acid secretion by reducing histamine release from Regulation of acid secretion during a meal can be bestECl cells and gastrin release from antral G cells. characterized by three separate, but interrelated phases:

the cephalic, the gastric, and the intestinal phases. The. cephalic and gastric phases are of primary importance.

There Are Four 'phases of Acid Secretion. A Regulation of acid secretion includes both the stimulatoryBasal (or Interdlgestlve) Phase and Three and inhibitory mechanisms that we discussed earlier (seePhases Associated with Eating Fig. 41-8). ACh, gastrin, and histamine all promote acid

BASAL STA1L Gastric-acid secretion occurs throughout secretion whereas somatostatin inhibits gastric-acid secre-the day and night. Substantial increases in acid secretion tion.occur after meals, whereas the rate of acid secretion be- Note that although dividing acid secretion during atween meals is low (Le., the interdigestive phase). This meal into three phases has been used for decades, it isinterdigestive period follows a circadian rhythm; acid se- somewhat anmcial because of considerable overlap in thecretion is lowest in the morning before awakening and regulation of acid secretion. For example, the vagus nervehighest in the evening. Acid secretion is a direct function is the central player in the cephalic phase, but it is alsoof the number of parietal cells, which is also influenced, imponant for the vagovagal reflex that is pan of theat least in part, by body weight. Thus, men have higher gastric phase. Similarly. gastrin release is a major compo-rates of basal acid secretion than women do. Considerable nent of the gastric phase, but vagal stimulation during the

800

800 ~

Volume RaIle of H+(ml) 400 20 MCretlon (meqlhr)

[Hl (meqlllter)

~ 10

00 1 2 3 4 S

Ingest Timefood (tv)

...therateofWeecretion n-.

FIGURE 41-9. Effect of eating on acid secretion. Ingesting food causes . marked WI in gastric [WI beaUSt the rood buffers the pre~ W.Howcvcr. as the food leaves the stomach and as the rate of W secretion increases. (H+( slowly rises to its "interdigestive" level.

900 41 I Gastric Fu nction

cephalic phase also induces the release of antral gastrin,Finally, the development of a consensus model has longbeen hampered by considerable differences in regulationof the gastric phase of acid secretion in humans, dogs,and rodents,

CIPIIAUC PIIASL The smell, sight, taste, thought, andswallowing of food initiate the cephalic phase, which isprimarily mediated by the vagus nerve (see Fig. 41-8).Although the cephalic phase has long been studied in

. experimental animals, especially dogs, recent studies ofsham feeding have confinned and extended the under-standing of the mechanism of the cephalic phase of acidsecretion in humans. The aforementioned sensory stimuliactivate the dona! motor nucleus of the vagus nerve inthe medulla (p, 381), thus activating parasympathetic pre-ganglionic efferent nerves. Insulin-induced hypoglycemiaalso stimulates the vagus nerve and in so doing promotesacid secretion,

Stimulation of the vagus nerve results in four distinctphysiological events-which we have already introducedin Figure 41-8-that together result in enhanced gastric-acid secretion. First, in the body of the stomach, vagalpostganglionic muscarinic nerves release acetylcholine,which stimulates parietal-cell H+ secretion directly. Sec-ond, in the lamina propria of the body of the stomach,the ACh released from vagal endings triggers histaminerelease from EQ cells, which stimulates acid secretion,Third, in the antrum, peptidergic postganglionic parasym-pathetic vagal neurons, as well as other enteric nervoussystem (ENS) neurons, release GRP, which induces gas-trin release from antral G cells. This gastrin stimulates

.~,,'8NI,......

, ' c..

,'~1"~FIGURE 41- 1 O. GIstric phase or gastric-acid secretion. Food in thestomach stlmula1es pstric-8cid secrttlon by two major mechanisms: me-chanical stretch and the presence or digested pJ'O(ein rragments ("pep-tones"), ECl, enterochromaffin-like; ENS, enteric nervous system; GRP.

gastrin-releasing peptide.

FIGURE 41 - 11. InteStinal phase of gastric-acid secretion. DIgested pro-tein fragments (peptones) in the proximal small Intestine stimulate gas-tric-acid secretion by three major mechanisms.

gastric-acid secretion both directly by acting on the parie-tal cell and indirectly by promoting histamine releasefrom ECL cells. Founh. in both the antrum and thecorpus. the vagus nerve inhibits D cells. thus reducingtheir release of somatostatin and reducing the backgroundinhibition of gastrin release. Thus. the cephalic phasestimulates acid secretion directly and indirectly by actingon the parietal cell. The cephalic phase accounts for ap-proximately 30% of total acid secretion and occurs beforethe entry of any food into the stomach.

One of the surgical approaches for the treatment ofpeptic ulcer disease is cutting the vagus nerves (vagot-omy) to inhibit gastric-acid secretion. Rarely performed,largely because of the many effective pharmacologicagents available to treat peptic ulcer disease. the tech-nique has nevertheless proved to be effective in selectedcases. Because vagus-nerve stimulation affects several GIfunctions besides parietal-cell acid secretion, the side ef-feas of vagotomy include a delay in gastric emptying anddiarrhea. To minimize these untoward events. there havebeen successful attempts to perform more Kselective" va-gotomies, severing only those vagal fibers going to theparietal cell.

CAS11IIC PHASE. Entry of food into the stomach initiatesthe two primary stimuli for the gastric phase of addsecretion (Fig. 41-10A). First, the food distends the gas-tric mucosa, which activates a vagovagal reflex as well aslocal ENS reflexes. Second, partially digested proteinsstimulate antral G cells.

Distention of the gastric wall-both in the corpus andantrum-secondary to entry of food into the stomachelidts two distinct neurally mediated pathways. The firstis activation of a vagovagal re8ex (p. 884), in whichgastric-wall distention activates a vagal afferent pathway,which in turn stimulates a vagal efferent response in the

dorsal nucleus of the vagus nerve. Stimulation of acidsecretion in response to this vagal efferent stimulus occursvia the same four parallel pathways that are operativewhen the vagus nerve is activated during the cephalicphase (see Fig. 41-8). Second, gastric-wall distention alsoactivates a local ENS pathway that releases ACh, whichin turn stimulates parietal-cell acid secretion.

The presence of partially digested proteins (peptones)or amino acids in the antrum directly stimulates G cellsto release gastrin (see Fig. 41-8). Intact proteins have noeffect. Acid secretion and activation of pepsinogen arelinked in a positive-feedback relationship. As discussedlater, low pH eriliances the conversion of pepsinogen topepsin. Pepsin digests proteins to peptones, which pro-mote gastrin release. Finally, gastrin promotes acid secre-tion, which closes the positive-feedback loop. There islittle evidence that either carbohydrate or lipid participatein the regulation of gastric-acid secretion. Components ofwine, beer, and coffee stimulate acid secretion by this G-cell mechanism.

In addition to the tWo stimulatory pathways acting dur-ing the gastric phase, a third pathway inhibits gastric-acidsecretion by a c1assic negative feedback mechanism, al-ready noted earlier in our discussion of Figure 41-8.

901Gastric Function / 41

(meq/hr)After

SERUMGASTRIN("1m.)"". Pentagastrin

Normal 35 0.5-2.0 20-35

Duodenal ulcer 50 1.5-7.0 25-60

Gastrinoma 500 15-25 30-75

Pernicious anemia 350 0 0

Low intragastric pH stimulates antral D cells to releasesomatostatin. Because somatostatin inhibits the release ofgastrin by G cells, the net effect is a reduction in gastric-acid secretion. The effectiveness of low pH in inhibitinggastrin release is emphasized by the following observa-tion: Although peptones are normally a potent stimulusfor gastrin release, they fail to stimulate gastrin releaseeither when the intraluminal pH of the antrum is main-tained at 1.0 or when somatostatin is infused.

The gastric phase of acid secretion, which occurs pri-marily as a result of gastrin release. accounts for 50% to60% of total gastric acid secretion.

THE INTESTINAL PHASE. The presence of amino acidsand panially digested pep tides in the proximal ponion ofthe small intestine stimulates acid secretion by threemechanisms (Fig. 41-11). First, these peptones stimulateduodenal G cells to secrete gastrin, just as peptones stim-ulate antral G cells in the gastric phase. Second, peptonesstimulate an unknown endocrine cell to release an addi-tional humoral signal that has been referred to as "entero-oxyntin." The chemical nature of this agent has not yetbeen identified. Third, amino acids absorbed by the prox-imal pan of the small intestine stimulate acid secretion bymechanisms that require funher definition.

Of interest, gastric-acid secretion mediated by the intes-tinal phase is enhanced after a ponacaval shunt. Such ashunt-which is used in the treatment of ponal hyper-tension caused by chronic liver disease-divens the por-tal blood that drains the small intestine around the liveron its return to the hean. Thus, the signal released fromthe small intestine during the "intestinal phase" is proba-bly-in normal individuals-removed in pan by theliver before reaching its target, the corpus of the stomach.

Approximately 5% to 10% oj total gastric acid secretion isa result of the intestinal phase.

PEPSINOGEN SECRETION

Chief Cells, Triggered by Both cAMP andCa2+ Pathways, Secrete Multiple PepsinogensThat Initiate Protein DigestionThe chief cells in gastric glands, as well as mucous cells,secrete pepsinogens, a group of proteolytic proenyzmes

902 41 / Gastric Function

(Le., zymogens or inactive enzyme precursors) that belongto the general class of aspartic proteinases. They are acti-vated to pepsins by cleavage of an N-terminal peptide.Pepsins are endepeptidases that initiate the hydrolysis ofingested protein in the stomach. Although eight pepsino-gen isoforms were initially identified on electrophoresis,recent classifications are based on immunologic identity,so pepsinogens are most often classified as group I pep-sinogens, group II pepsinogens, and cathepsin E. Group Ipepsinogens predominate. They are secreted from chiefcells located at the base of glands in the corpus of thestomach. Group II pepsinogens are also secreted fromchief cells but, in addition, are secreted from mucousneck cells in the cardiac, corpus, and antral regions.

Pepsinogen secretion in the basal state is approximately20% of its maximal secretion after stimulation. Althoughpepsinogen secretion generally parallels the secretion ofacid, the ratio of maximal to basal pepsinogen secretion isconsiderably less than that for acid secretion. Moreover,the cellular mechanism of pepsinogen release is quite dis-tinct from that of H+ secretion by parietal cells. Release ofpepsinogen across the apical membrane is the result of anovel process called compound exocytosis, in which se-cretory granules fuse with both the plasma membraneand other secretory granules. This process permits rapidand sustained secretion of pepsinogen. After stimulation,the initial peak in pepsinogen secretion is followed by apersistent lower rate of secretion. This pattern of secretionhas been interpreted as reflecting an initial secretion ofpreformed pepsinogen, followed by the secretion of newlysynthesized pepsinogen. However, recent in vitro studiessuggest that a feedback mechanism may account for thesubsequent reduced rate of pepsinogen secretion.

Two groups of agonists stimulate chief cells to secretepepsinogen. One group acts through adenylyl cyclase andcAMP, and the other acts through increases in [Ca2+Jj.

AGONISTS AcnNG VIA cAMP. Chief cells have receptorsfor secretinIVIP, ~-adrenergic receptors, and EP2 recep-tors for PGE2. All these receptors activate adenylyl cy-clase. At lower concentrations than those required tostimulate pepsinogen secretion, PGE2 can also inhibit pep-sinogen secretion, probably by binding to another recep-tor subtype.

AGONISTS AcnNG VIA C,.z+. Chie('cells also have M3muscarinic receptors for acetylcholine, as well as recep-tors for the gastrinlCCK family of peptides. Unlike gas-tric-acid secretion, which is stimulated via the CCKs re-ceptor, pepsinogen secretion is stimulated via the CCKAreceptor, which has a much higher affinity for CCK thanfor gastrin. Activation of both the M3 and CCKA receptorscauses CaH release from intracellular stores via IP3 andthereby raises [CaH),. However, uncertainty exists aboutwhether increased CaH influx is also required and aboutwhether PKC also has a role.

Of the agonists just listed, the most important for pep-sinogen secretion is ACh released in response to vagalstimulation. Not only does ACh stimulate chief cells torelease pepsinogen, it also stimulates parietal cells to se-crete acid. This gastric acid produces additional pepsino-gen secretion via two different mechanisms. First, in the

stomach, a fall in pH elicits a local cholinergic reflex thatresults in funher stimulation of chief cells to release pep-sinogen. Thus, the ACh that stimulates chief cells cancome both from the vagus and from the local reflex.Second, in the duodenum, acid triggers the release ofsecretin from S cells. By an endocrine effect, this secretinstimulates the chief cells to release more pepsinogen. Theexact role or roles of histamine and gastrin in pepsinogensecretion are unclear.

low pH Is Required for Both PepsinogenActivation and Pepsin Activity

Pepsinogen is inactive and requires activation to a prote-ase, pepsin, to initiate protein digestion. This activationoccurs by spontaneous cleavage of a small N-terminalpeptide fragment (the activation peptide), but only at apH that is less than 5.0 (Fig. 41-12). Between pH 5.0and 3.0, spontaneous activation of pepsinogen is slow,but it is extremely rapid at a pH that is less than 3.0. Inaddition, pepsinogen is also autoactivated; that is, newlyformed pepsin itself cleaves pepsinogen to pepsin.

Once pepsin is formed, its activity is also pH depen-dent. It has optimal activity at a pH between 1.8 and 3.5;the precise optimal pH depends on the specific pepsin,type and concentration of substrate, and osmolality of thesolution. pH values above 3.5 reversibly inactivate pepsin,and pH values above 7.2 irreversibly inactivate the en-zyme. These considerations are sometimes useful for es-tablishing optimal antacid treatment regimens in pepticulcer disease.

Pepsin is an endopeptidase that initiates the process ofprotein digestion in the stomach. Pepsin action results inthe release of small peptides and amino acids (peptones)that, as noted earlier, stimulate the release of gastrin fromantral G cells; these peptones also stimulate CCK releasefrom duodenal I cells. As previously mentioned, the pep-tones generated by pepsin stimulate the very acid secre-tion required for pepsin activation and action. Thus, thepeptides that pepsin releases are imponant in initiating acoordinated response to a meal. However, most proteinentering the duodenum remains as large peptides, andnitrogen balance is not impaired after total gastrectomy.

Digestive products of both carbohydrates and lipid arealso found in the stomach, although secretion of theirrespective digestive enzymes either does not occur or isnot a major function of gastric epithelial cells. Carbohy-

~

!I PepsinPepsinogen

r->,. ~FIGURE 41-12. Activation of the pepsinogens to pepsins. At pH valuesfrom 5 to 3. pepsinogens spontaneously activate to pepsins by theremoval of an N-terminal "activation peptide." This spontaneous activa-tion is even faster at pH values that are below 3. The newly formedpepsins themselves-which are active only at pH values below 3.5-also can catalyze the activation of pepsinogens.

drate digestion. is initiated in the mouth by salivaryamylase. However, after this enzyme is swallowed, thestomach becomes a more imponant site for starch hydrol-ysis than the mouth. There is no evidence of gastricsecretion of enzymes that hydrolyze starch or other sac-charides. Similarly, although lipid digestion is also initi-ated in the mouth by lingual lipase, significant lipid di-gestion occurs in the stomach as a result of both thelingual lipase that is swallowed and gastric lipase, bothof which have an acid pH optimum (p. 962).

PROTECTION OF THE GASTRIC SURFACEEPITHELIUM AND NEUTRALIZATION OFACID IN THE DUODENUM

At maximal rates of H+ secretion, the parietal cell candrive the intraluminal pH of the stomach to 1 or less(i.e., [Ht) > 100 mM) for long periods. The gastricepithelium r.nust maintain an H + concentration gradientof over a million-fold because the intracellular pH ofgastric epithelial cells is approximately 7.2 (Le., [H+) ==60 nM) and plasma pH is about 7.4 (Le., [H+) ae 40nM). Simultaneously, there is a substantial plasma-to-Iu-men Na + -concentration gradient of approximately 30 be-cause plasma [Na+) is 140 mM whereas intragastric [Na+)can reach values as low as 5 mM, but only at highsecretory rates (see Fig. 41-2). How is the stomach ableto maintain these gradients? How is it that the epithelialcells are not destroyed by this acidity? Moreover, why dopepsins in the gastric lumen not digest the epithelialcells? The answer to all three questions is the so-calledgastric diffusion barrier.

Although the nature of the gastric diffusion barrier hadbeen controversial, it is now recognized that the diffusionbarrier is both physiologic and anatomic. Moreover, it isapparent that the diffusion barrier represents at least threecomponents: (1) relative impermeability to acid of theapical membrane and epithelial cell tight junctions in thegastric glands; (2) a mucous-gel layer varying in thicknessbetween 50 and 200 J.l.m overlying the surface epithelialcells; and (3) an HCO) -containing microclimate adjacentto the surface epithelial cells that maintains a relativelyhigh local pH. :..

Vagal Stimulation and Irritation StimulateGastric Mucous Cells to Secrete Mucin, aGlycoprotein That Is Part of the MucosalBarrierThe mucus layer is largely composed of mucin, phospho-lipids. electrolytes, and water. Mucin is the high-molecu-lar-weight glycoprotein (p. 40) that contributes to theformation of a protective layer over the gastric mucosa.Gastric mucin is a tetramer consisting of four identicalpeptides joined by disulfide bonds. Each of the four pep-tide chains is linked to long polysaccharides, which areoften sulfated and thus mutually repulsive. The ensuinghigh carbohydrate content is responsible for the viscosityof mucus, which explains, in large part, its protective rolein gastric mucosal physiology.

Gastric Function I 41 903

Mucus is secreted by three different mucous cells: sur-face mucous cells (i.e., on the surface of the stomach),mucous neck cells (i.e., at the point where a gastric pitjoins a gastric gland), and glandular mucous cells (i.e., inthe gastric glands in the antrum). The type of mucussecreted by these cells differs; mucus that is synthesizedand secreted in the glandular cells is a neutral glycopro-tein, whereas the mucous cells on the surface and in thegastric pits secrete both neutral and acidic glycoproteins.Mucin fonns a mucous-gel layer in combination withphospholipids, electrolytes, and water. This mucous-gellayer provides protection against injury from noxious lu-minal substances, including acid, pepsins, bile acids, andethanol. Mucin also lubricates the gastric mucosa to mini-mize the abrasive effects of intraluminal food.

The mucus barrier is not static. Abrasions can removepieces of mucus. When mucus comes in contact with asolution with a very low pH, the mucus precipitates andsloughs off. Thus, the mucous cells must constantly se-crete mucus. Regulation of mucus secretion by gastricmucosal cells is less well understood than is regulation ofthe secretion of acid, pepsinogens, and other substancesby gastric cells. The two primary stimuli for inducingmucus secretion are vagal stimulation and physical andchemical irritation of the gastric mucosa by ingested food.The current model of mucus secretion suggests that vagalstimulation induces the release of ACh, which leads toincreases in [Ca2+]1 and thus stimulates mucus secretion.In contrast to acid and pepsinogen secretion, cAMP doesnot appear to be a second messenger for mucus secretion.

Gastric Surface Cells Secrete HCOi,Stimulated by Acetylcholine, Acids, andProstaglandinsSurface epithelial cells both in the corpus and in theantrum of the stomach secrete HCO). Despite the rela-tively low rate of HCO) secretion-in comparison toacid secretion-HCO) is extremely important as part ofthe gastric mucosal protective mechanism. The mucus-gellayer provides an unstirred layer under which the se-creted HCO) remains trapped and maintains a local pHof approximately of 7.0 versus an intraluminal pH in thebulk phase of 1 to 3. As illustrated in Figure 41-13A, anelectrogenic Na/HCO3 co transporter (NBC) appears tomediate the uptake of HCO) across the basolateral mem-brane of surface epithelial cells. The mechanism of HCO)exit from the cell into the apical mucus layer is unknownbut may be mediated by a channel.

Similar to the situation for mucus secretion, relativelylimited information is available about the regulation ofHCO) secretion. The present model suggests that vagalstimulation mediated by ACh leads to an increase in[CaHJ" which in turn stimulates HCO) secretion. Shamfeeding is a potent stimulus for HCO) secretion via thispathway. A second powerful stimulus of gastric HCO)secretion is intraluminal acid. The mechanism of stimula-tion by acid appears to be secondary to both activation ofneural reflexes and local production of PGE2. Finally, evi-dence suggests that a humoral factor may also be in-volved in the induction of HCO) secretion by acid.

904 41 / Gastric Function

A NORMAL SURFACE EPITHELIUM

Gastric lumen

Mast cell

..~up'!f.

Mucus Protects the Gastric SurfaceEpithelium by Trapping an HCOi-Rlch FluidNear the Apical Border of These CellsMucous cells on the surface of the stomach. as well as inthe gastric pits and neck ponions of the gastric glands.secrete both HCO) and mucus. Why is this barrier soeffective? First, the secreted mucus forms a mucous-gellayer that is relatively impermeable to the diffusion of H+from the gastric lumen to the surface cells. Second. be-neath this layer of mucus is a microclimate that containsfluid with a high pH and high IHCO) I. the result ofHCOj" secretion by gastric surface epithelial cells (see Fig.41-13A). Thus. this HCO) neutralizes most acid thatdiffuses through the mucus layer. Mucosal integrity, in-cluding that of the mucosal diffusion barrier. is also

1.5

pHprofile

7.0

7.4

FIGURE 41- 13. DIffusion barrier in the surf8tt or the gastric mucosa.A, The mucus secreted by the surface ceIls serves two runctions. First, itacts as a diffusion barrier ror H + and also pepsins. Second, the mucuslayer traps a relatively alkaline solUtion or HCO,. ThIs HCO] titratesany W that diffuses into the sel layer rrom the stomach lumen. Thealkaline 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 inOammatoryresponse. 1£ the insult is mild. the ensuing increase in blood flow canpromote the production or both mucus and HCO, by the mucus cells.1£ the insult is more severe, the inflammatory response leads to a de-crease in blood flow and thus to ceIl injury.

maintained by PGE2, which-as we saw in the previoussection-stimulates mucosal HCO)" secretion.

Deep inside the gastric gland, where no obvious mucuslayer protects the parietal, chief, and ECl cells, the im-permeability of the cells' apical barrier appears to excludeH+ even at pH values as low as 1. The paradox of howHCI secreted by the parietal cells emerges from the glandand into the gastric lumen may be explained by a pr0ct5Sknown as viscous fingering. Because the liquid emergingfrom the gastric gland is both extremely acidic and pre-sumably under pressure, it can tunnel through the mu-cous layer covering the opening of the gastric gland ontothe surface of the stomach. However, this stream of acidapparently does not spread laterally, but rather rises tothe surface as a "finger" and thus does not neutralize the

- in the qUcroenvironment between the surface epi-I cells and the mucus.

'{be mucous-gel layer and the trapped alkaline HCO)"tion protect the surface cells not only from H + butfrom pepsin. The mucus per se acts as a pepsin-

n barrier. The relative alkalinity of the trapped- inactivates any pepsin that penetrates into the mu-

cus. Recall that pepsin is reversibly inactivated at pHvalues that are above approximately 3.5 and irreversiblyinactivated by pH values approximately above 7.2. Thus,the mucus/tieD)" layer plays an important role in pre-venting "autodigestion" of the gastric mucosa.

Entry of Acid into the Duodenum Induces theRelease of Secretin From S Cells, ThusTriggering the Secretion of HCOi by thePancreas and Duodenum, Which in TurnNeutralizes Gastric AcidThe overall process of regulating gastric-acid secretion in-volves not only stimulation and inhibition of acid secre-tion-which we discussed earlier-but also neutraliza-tion of the gastric acid that passes from the stomach into

905Gastric Function I 41

the duodenum. The amount of secreted gastric acid isreflected by a fall in intragastric pH. We have alreadyseen that this fall in pH serves as the signal to antral Dcells to release somatostatin and thus inhibit further acidsecretion, a classic negative-feedback process. Ukewise,low pH in the duodenum serves as a signal for the secre-tion of alkali to neutralize gastric acid in the duodenum.

The key player in this neutralization process is secre-tin, the same secretin that inhibits gastric-acid secretionand promotes pepsinogen secretion by chief cells. A lowduodenal pH, with a threshold of 4.5, triggers the releaseof secretin from S cells in the duodenum. However, the Scells are probably not pH sensitive themselves but, in-stead, may respond to a signal from other cells that arepH sensitive. As discussed in Chapter 42, secretin stimu-lates the secretion of fluid and HCOj" by the pancreas,thus leading to intraduodenal neutralization of the acidload from the stomach. Maximal HCOj" secretion is afunction of the amount of acid entering the duodenum,as well as the length of duodenum exposed to acid. Thus,high rates of gastric-acid secretion trigger the release oflarge amounts of secretin, which greatly stimulates pan-creatic HCOj" secretion; the increased HCOj" in turn neu-tralizes the increased duodenal acid load.

In addition to pancrtatic HCOj" secretion, the duodenalacid load resulting from gastric-acid secretion is partiallyneutralized by duodenal HCOj" secretion. This duodenalHCOj" secretion occurs in the proximal-but not thedistal- pan of the duodenum under the influence ofprostaglandins. Attention has been focused on duodenal

41 I Gastric Function906

epithelial cells (villus and/or crypt cells) as the cellularsource of HG:O)" secretion, but the possibility that duode-nal HCO)" originates, at least in part, from duodenal sub-mucosal Brunner glands has not been excluded. Patientswith duodenal ulcer disease tend to have both increasedgastric-acid secretion and reduced duodenal HCO)" secre-tion. Thus, the increased acid load in the duodenum isonly partially neutralized, so the duodenal mucosa hasincreased exposure to a low-pH solution.

II

FILLING AND EMPTYING OF THE STOMACH

Gastric Motor Activity Plays a Role in Filling,Churning, and Emptying

~

Gastric motor activity has three functions: (1) The receiptof ingested material represents the reservoir function ofthe stomach and occurs as smooth muscle relaxes. Thisresponse occurs primarily in the proximal portion of thestomach. (2) lDgested material is ch11l'Ded and thus al-tered to a form that rapidly empties from the stomachthrough the pylorus and facilitates normal jejunal diges-tion and absorption. Thus, in conjunction with gastricacid and enzymes, the motor function of the stomachhelps initiate digestion. (3) The pyloric antrum, pylorus,and proximal part of the duodenum function as a singleunit for emptying into the duodenum the modified gas-tric contents ("chyme"), consisting of both partially di-gested food material and gastric secretions. Gastric fillingand emptying are accomplished by the coordinated activ-ity of smooth muscle in the esophagus, lower esophagealsphincter, and proximal and distal portions of the stom-ach, as well as the pylorus and duodenum.

The pattern of gastric smooth-muscle activity is distinctduring fasting and after eating. The pattern during fastingis referred to as the migrating myoelectric (or motor)complex (MMC), which we already discussed in connec-tion with the small intestine (p. 889). This pattern isterminated by eating, at which ~int it is replaced by theso-called fed pattern. Just as the proximal and distalregions of the stomach differ in secretory function, theyalso differ in the motor function responsible for storing,processing, and emptying liquids and solids. The proxi-mal part of the stomach is the primary location for stor-age of both liquids and solids. The distal portion of thestomach is primarily responsible 10r churning the solidsand generating smaller liquid-like material, which thenexits the stomach in a manner that is similar to that ofingested liquids. Thus, the gastric emptying of liquids andsolids is closely integrated.

~

It'

Filling of the Stomach Is Facilitated by BothReceptive Relaxation and GastricAccommodationEven a dry swallow relaxes both the lower esophagealsphincter and the proximal part of the stomach. Ofcourse, the same happens when we swallow food. Theserelaxations facilitate the entry of food into the stomach.Relaxation in the fundus. is primarily regulated by a vago-vagal reflex and has been called receptive relaxation. In

I

~

a vagovagal reflex, afferent fibers running with the va ~

nerve carry infonnation to the central nervous(CNS), and efferent vagal fibers carry the signal from thtCNS to the stomach and cause relaxation via a m~nism that is neither cholinergic nor adrenergic. The resuWis that intragastric volume increases without an increase inintragastric pressure. If vagal innervation to the stomachis interrupted, gastric pressure rises much more rapidly.

Quite apan from the receptive relaxation of the stOIn- .ach that anticipates the arrival of food after swallowingand esophageal distention, the stomach can also relax inresponse to gastric filling per se. Thus. increasing intra-gastric volume, as a result of either food entering thestomach or gastric secretion, does not produce a propor-tionate increase in inlragastric pressure. Instead, small in-creases in volume do not cause increases in intragastricpressure until a threshold is reached. after which intragas-tric pressure rises steeply (Fig. 41-14A). This phenome-non is due to active dilatation of the fundus and has beencalled gastric accommodation. Vagotomy abolishes a ma-jor portion of gastric accommodation, so increases in in-tragastric volume produce greater increases in imragastricpressure. However, the role of the vagus nerve in gastric

Intraluminal 60

pressure 40(em HP)

20 Norm8I

0n ~ ..",. IIItV'I AIV\ 1 /W"I

A

B

Oleate meeIAcid mealSaline meal

---

0 10 20 30 40Time (mln)

FIGURE 41-14. Guuic filling and emptying. (Pant:1 B. dala rromDooley CP. Reznick }B. Valenzuela }E: Variations In gastric and duode-nal motility during gastric emptying or liquid meals in humans. Gastro-enterology 87:1114-1119.1984.)

907Gastric Function I 41

musculature before delivery of the bolus. This increase inpyloric resistance represents the coordinated response ofantral. pyloric. and duodenal motor activity. Once a bolusof material is trapped near the antrum, it is churned tohelp reduce the size of the panicles. a process termedgrinding (see Fig. 41-15B). Only a small ponion ofgastric material-that containing particles smaller than 2mm - is propelled through the pylorus to the duodenum.Thus. most of the gastric contents are retUrned to thebody of the stomach for pulverization and shearing ofsolid panicles. a process known as retropulsion (see Fig.41-15C). These processes of propulsion. grinding. andretropulsion repeat multiple times until the gastric con-tents are emptied. Panicles larger than 2 mm are initiallyretained in the stomach but are eventually emptied intothe duodenum by MMCs during the interdigestive periodthat begins approximately 2 hours or more after eating.

Modification of gastric contents is associated with theactivation of multiple feedback mechanisms. This feed-back usually arises from the duodenum (and beyond) andalmost always results in a delay in gastric emptying. Thus.as small squirts of gastric fluid leave the stomach. chemo-receptors and mechanoreceptors-primarily in the proxi-mal but also in the distal ponion of the small intestine-sense low pH. a high content of calories. lipid, or someamino acids (i.e., tryptophan). or changes in osmolarity.These signals all decrease the rate of gastric emptying bya combination of neural and hormonal signals, includingthe vagus nerve. secretin, CCK. and GIP released fromduodenal mucosa. Delayed gastric emptying represents:the coordinated function of fundic relaxation; inhibitionof antral motor activity; stimulation of isolated. phasiccontractions of the pyloric sphincter; and altered intestinalmotor activity.

he an trumI\urns the'apped material,

))mach on its coments.

Books and ReviewsDelValle 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 expres-

sion. processing and targeting of active products. Physiol Rev 76:767-

798. 1996.Hasler Wl: The physiology of gastric motility and gastric emptying. In

Yamada T (ed): Textbook of Gastroenterology, Vol I, 3rd ed. Phila-delphia. 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,

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Journal ArticlesDoo~ CP. Reznick jB, Valenzuela jE: Variations in gastric and duode.

nal motility during gastric emptying of liquid meals In humans. Gas-troenterology 87:1114-1119.1984.

Waisbren 5j. Geibel jP, Modlin 1M. Boron WF: Unusual permeabilitypropcnies of gastric gland cells. Nature 368:332-335. 1994.