Medical Physiology, 3rd Edition

Acid Secretion

The parietal cell has a specialized tubulovesicular structure that increases apical membrane area when the cell is stimulated to secrete acid

In the basal state, the rate of acid secretion is low. Tubulovesicular membranes are present in the apical portion of the resting, nonstimulated parietal cell and contain the H-K pump (or H,K-ATPase) that is responsible for acid secretion. Upon stimulation, cytoskeletal rearrangement causes the tubulovesicular membranes that contain the H-K pump to fuse into the canalicular membrane (Fig. 42-3). The result is a substantial increase (50- to 100-fold) in the surface area of the apical membrane of the parietal cell, as well as the appearance of microvilli. This fusion is accompanied by insertion of the H-K pumps, as well as K+and Cl channels, into the canalicular membrane. The large number of mitochondria in the parietal cell is consistent with the high rate of glucose oxidation and O2 consumption that is needed to support acid secretion.

image

FIGURE 42-3 Parietal cell: resting and stimulated.

An H-K pump is responsible for gastric acid secretion by parietal cells

The parietal-cell H-K pump is a member of the gene family of P-type ATPases (see pp. 117-118) that includes the ubiquitous Na-K pump (Na,K-ATPase), which is present at the basolateral membrane of virtually all mammalian epithelial cells and at the plasma membrane of nonpolarized cells. Similar to other members of this ATPase family, the parietal-cell H-K pump requires both an α subunit and a β subunit for full activity. The catalytic function of the H-K pump resides in the α subunit; however, the β subunit is required for targeting to the apical membrane. image N42-3 The two subunits form a heterodimer with close interaction at the extracellular domain.

N42-3

Gastric H-K Pump

Contributed by Emile Boulpaep, and Walter Boron

The α subunit of the parietal-cell H-K pump has 1033 amino acids and 10 membrane-spanning segments. It is ~65% identical to the α subunit of the Na-K pump.

The β subunit, which consists of 290 amino acids, has only one membrane-spanning segment; it is 35% to 40% identical to the β subunit of the Na-K pump. The two subunits form a heterodimer with close interaction at the extracellular domain.

The activity of these P-type ATPases, including the gastric H-K pump, is affected by 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 cysteines on the extracytoplasmic surface; and (2) substances that act as competitive inhibitors of the K+-binding site (e.g., the experimental drug Schering 28080). Omeprazole is a potent inhibitor of parietal-cell H-K pump activity and is an extremely effective drug in the control of gastric acid secretion in both normal subjects and patients with hypersecretory states (Box 42-1). 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, whereas omeprazole does not inhibit the Na-K pump. The colonic H-K pump, whose α subunit has an amino-acid sequence that is similar but not identical to that of both the Na-K pump and the parietal-cell H-K pump, is partially inhibited by ouabain but not by omeprazole.

Box 42-1

Gastrinoma or Zollinger-Ellison Syndrome

On rare occasions, patients with one or more ulcers have very high rates of gastric acid secretion. The increased acid secretion in these patients is most often a result of elevated levels of serum gastrin, released from a pancreatic islet cell adenoma or gastrinoma (Table 42-1). This clinical picture is also known as Zollinger-Ellison (ZE) syndrome. Because gastrin released from these islet cell adenomas is not under physiological control, but rather is continuously released, acid secretion is substantially increased under basal conditions. However, the intravenous administration of pentagastrin—a synthetic gastrin consisting of the last four amino acids of gastrin plus β-alanine—produces only a modest increase in gastric acid secretion. Omeprazole, a potent inhibitor of the parietal-cell H-K pump, is now an effective therapeutic agent to control the marked enhancement of gastric acid secretion in patients with gastrinoma and thus helps to heal their duodenal and gastric ulcers.

In contrast to patients with gastrinoma or ZE syndrome, other patients with duodenal ulcer have serum gastrin levels that are near normal. Their basal acid-secretion rates are modestly elevated but increase markedly in response to pentagastrin.

Patients with pernicious anemiaimage N42-1 lack parietal cells and thus cannot secrete the H+ necessary to stimulate the antral D cell (see Fig. 42-8). Consequently, the release of somatostatin from the D cell is low, which results in minimal tonic inhibition of gastrin release from G cells. Thus, these patients have very high levels of serum gastrin, but virtually no H+ secretion (see Table 42-1).

TABLE 42-1

Serum Gastrin Levels and Gastric Acid Secretion Rates

 

SERUM GASTRIN (pg/mL)

H+ SECRETION (meq/hr)

BASAL

AFTER 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

The key step in gastric acid secretion is extrusion of H+ into the lumen of the gastric gland in exchange for K+ (Fig. 42-4). The K+ taken up into the parietal cells is recycled to the lumen through K+ channels. The final component of the process is passive movement of Cl into the gland lumen. The net result is the secretion of HCl. Secretion of acid across the apical membrane by the H-K pump results in a rise in parietal-cell pH. The adaptive response to this rise in pH includes passive uptake of CO2 and H2O, which the enzyme carbonic anhydrase (see p. 630) converts to image and H+. The H+ is the substrate of the H-K pump. The image exits across the basolateral membrane via a Cl-HCO3 exchanger (AE2 or SLC4A2), which also provides some of the Cl required for net HCl movement across the apical/canalicular membrane. The basolateral Na-H exchanger may participate in intracellular pH regulation, especially in the basal state.

image

FIGURE 42-4 Acid secretion by parietal cells. When the parietal cell is stimulated, H-K pumps extrude H+ into the lumen of the gastric gland in exchange for K+. The K+ recycles back into the lumen via K+ channels. Carbonic anhydrase (CA) provides the H+extruded by the H-K pump, as image exits via the basolateral anion exchanger (AE2). Cl enters across basolateral membrane via AE2, Na/K/Cl cotransporter NKCC1, and the electrogenic SLC26A7; Cl exits through apical CFTR (and perhaps ClC) channels.

Three secretagogues (acetylcholine, gastrin, and histamine) directly and indirectly induce acid secretion by parietal cells

The action of secretagogues on gastric acid secretion occurs via at least two parallel and perhaps redundant mechanisms (Fig. 42-5). In the first, acetylcholine (ACh), gastrin, and histamine bind directly to their respective receptors on the parietal-cell membrane and synergistically stimulate acid secretion. ACh (see Fig. 14-8) is released from endings of the vagus nerve (cranial nerve X), and as we will see below, gastrin is released from G cells. Histamine is synthesized from histidine in ECL cells of the lamina propria (see Fig. 13-8B). In the second mechanism, ACh and gastrin indirectly induce acid secretion as a result of their stimulation of histamine release from ECL cells.

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FIGURE 42-5 Direct and indirect actions of the three acid secretagogues: ACh, gastrin, and histamine.

The three acid secretagogues act through either Ca2+/diacylglycerol or cAMP

Stimulation of acid secretion by ACh, gastrin, and histamine is mediated by a series of intracellular signal-transduction processes similar to those responsible for the action of other agonists in other cell systems. All three secretagogues bind to specific G protein–coupled receptors on the parietal-cell membrane (Fig. 42-6).

image

FIGURE 42-6 Receptors and signal-transduction pathways in the parietal cell. The parietal cell has separate receptors for three acid secretagogues. ACh and gastrin each bind to specific receptors (M3 and CCK2, respectively) coupled to the G protein Gαq. The result is activation of PLC, which ultimately leads to the activation of PKC and the release of Ca2+. The histamine binds to an H2 receptor, coupled through Gαs to adenylyl cyclase (AC). The result is production of cAMP and activation of PKA. Two inhibitors of acid secretion, somatostatin and prostaglandins, bind to separate receptors coupled to Gαi. ER, endoplasmic reticulum.

ACh binds to an M3 muscarinic receptor (see pp. 341–342) on the parietal-cell basolateral membrane. This ACh receptor couples to a GTP-binding protein (Gαq) and activates phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG; see p. 58). IP3 causes internal stores to release Ca2+, which then probably acts via calmodulin-dependent protein kinase (see p. 60). DAG activates protein kinase C (PKC). The M3 receptor also activates a Ca2+ channel.

Gastrin binds to a specific parietal-cell receptor that has been identified as the gastrin-cholecystokinin type 2 (CCK2) receptor. Two related CCK receptors have been identified, CCK1 and CCK2. Their amino-acid sequences are ~50% identical, and both are G protein coupled. The CCK2 receptor has equal affinity for both gastrin and CCK. In contrast, the CCK1 receptor's affinity for CCK is three orders of magnitude higher than its affinity for gastrin. These observations and the availability of receptor antagonists are beginning to clarify the parallel, but at times opposite, effects of gastrin and CCK on various aspects of GI function. The CCK2 receptor couples to Gαq and activates the same PLC pathway as does ACh; this process leads to both an increase in [Ca2+]i and activation of PKC.

The histamine receptor on the parietal cell is an H2 receptor that is coupled to the Gαs GTP-binding protein. Histamine activation of the receptor complex stimulates the enzyme adenylyl cyclase, which, in turn, generates cAMP. The resulting activation of protein kinase A leads to the phosphorylation of certain parietal-cell proteins, including the H-K pump.

Antral and duodenal G cells release gastrin, whereas ECL cells in the corpus release histamine

The presence of a gastric hormone that stimulates acid secretion was initially proposed in 1905. Direct evidence of such a factor was obtained in 1938, and in 1964 Gregory and Tracey isolated and purified gastrin and determined its amino-acid sequence. Gastrin has three major effects on GI cells: (1) stimulation of acid secretion by parietal cells (see Fig. 42-5), (2) release of histamine by ECL cells, and (3) regulation of mucosal growth in the corpus of the stomach, as well as in the small and large intestine.

Gastrin exists in several different forms, but the two major forms are G-17, or “little gastrin,” a 17–amino-acid linear peptide (Fig. 42-7A), and G-34, or “big gastrin,” a 34–amino-acid peptide (see Fig. 42-7B). A single gene encodes a peptide of 101 amino acids. Several cleavage steps and C-terminal amidation (i.e., addition of an –NH2 to the C terminus) take place during gastrin's post-translational modification, a process that occurs in the endoplasmic reticulum, trans-Golgi apparatus, and both immature and mature secretory granules. The final product of this post-translational modification is either G-17 or G-34. The tyrosine residue may be either sulfated (so-called gastrin II) or nonsulfated (gastrin I); the two forms are equally active and are present in equal amounts. Gastrin and CCK, a related hormone, have identical C-terminal tetrapeptide sequences (see Fig. 42-7C) that possess all the biological activities of both gastrin and CCK. Both G-17 and G-34 are present in blood plasma, and their plasma levels primarily reflect their degradation rates. Thus, although G-17 is more active than G-34, the latter is degraded at a substantially lower rate than G-17. As a consequence, the infusion of an equal amount of G-17 or G-34 produces comparable increases in gastric acid secretion.

image

FIGURE 42-7 A, A single gene encodes a 101–amino-acid peptide that is processed to both G-17 (“little gastrin”) and G-34 (“big gastrin”). The N-terminal glutamine is modified to create a pyroglutamyl residue. The C-terminal phenylalanine is amidated. These modifications make the hormone resistant to carboxy- and aminopeptidases. B, The final 16 amino acids of G-34 are identical to the final 16 amino acids in G-17. Both G-17 and G-34 may be either not sulfated (gastrin I) or sulfated (gastrin II). C, The five final amino acids of CCK are identical to those of G-17 and G-34.

Specialized endocrine 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 basolateral stimuli (Fig. 42-8). Antral G cells have microvilli on their apical membrane surface and are referred to as an open-type endocrine cell. These G cells release gastrin in response to luminal peptides and amino acids, as well as in response to gastrin-releasing peptide (GRP), a 27–amino-acid peptide that is released by vagal nerve endings. As discussed below, gastrin release is inhibited by somatostatin, which is released from adjacent D cells.

image

FIGURE 42-8 Regulation of gastric acid secretion. In the corpus of the stomach, the vagus nerve not only stimulates the parietal cell directly by releasing ACh, it also stimulates both ECL and D cells. Vagal stimulation of the ECL cells enhances gastric acid secretion via increased histamine release. Vagal stimulation of the D cells also promotes gastric acid secretion by inhibiting the release of somatostatin, which would otherwise inhibit—by paracrine mechanisms—the release of histamine from ECL cells and the secretion of acid by parietal cells. In the antrum of the stomach, the vagus nerve stimulates both G cells and D cells. The vagus stimulates the G cells via GRP, promoting gastrin release. This gastrin promotes gastric acid secretion by two endocrine mechanisms: directly via the parietal cell and indirectly via the ECL cell, which releases histamine. The vagal stimulation of D cells via ACh inhibits the release of somatostatin, which would otherwise inhibit—by paracrine mechanisms—the release of gastrin from G cells and—by an endocrine mechanism—acid secretion by parietal cells. Luminal H+ directly stimulates the D cells to release somatostatin, which inhibits gastrin release from the G cells, thereby reducing gastric acid secretion (negative feedback). In addition, products of protein digestion (i.e., peptides and amino acids) directly stimulate the G cells to release gastrin, which stimulates gastric acid secretion (positive feedback).

ECL cells in the corpus of the stomach synthesize histamine. The central role of histamine and ECL cells is consistent with the observation that H2 receptor antagonists (i.e., H2 blockers), such as cimetidine and ranitidine, not only block the direct action of histamine on parietal cells but also substantially inhibit the acid secretion stimulated by ACh and gastrin (which activate ECL cells). The effectiveness of H2 blockers in controlling acid secretion after stimulation by most agonists is well established in humans.

Gastric D cells release somatostatin, the central inhibitor of acid secretion

Gastric acid secretion is under close control of not only the stimulatory pathways discussed above but also the inhibitory pathways. The major inhibitory pathway involves the release of somatostatin, a polypeptide hormone made by D cells in the antrum and corpus of the stomach. Somatostatin is also made by the δ cells of the pancreatic islets (see p. 1035) and by neurons in the hypothalamus (see pp. 993–994). Somatostatin exists in two forms, SS-28 and SS-14, which have identical C termini. SS-28 is the predominant form in the GI tract.

Somatostatin inhibits gastric acid secretion by both direct and indirect mechanisms (see Fig. 42-8). In the direct pathway, somatostatin coming from two different sources binds to a Gαi-coupled receptor (SST) on the basolateral membrane of the parietal cell and inhibits adenylyl cyclase. The net effect is to antagonize the stimulatory effect of histamine and thus inhibit gastric acid secretion by parietal cells. The source of this somatostatin can be either paracrine (i.e., D cells present in the corpus of the stomach, near the parietal cells) or endocrine (i.e., D cells in the antrum). However, there is a major difference in what triggers the D cells in the corpus and in the antrum. Neural and hormonal mechanisms stimulate D cells in the corpus (which cannot sense intraluminal pH), whereas low intraluminal pH stimulates D cells in the antrum.

Somatostatin also acts via two indirect pathways, both of which are paracrine. In the corpus of the stomach, D cells release somatostatin, which inhibits the release of histamine from ECL cells (see Fig. 42-8). Because histamine is an acid secretagogue, somatostatin thus reduces gastric acid secretion. In the antrum of the stomach, D cells release somatostatin, which inhibits the release of gastrin from G cells. Because gastrin is another acid secretagogue, somatostatin also reduces gastric acid secretion by this route. The gastrin released by the G cell feeds back on itself by stimulating D cells to release the inhibitory somatostatin.

The presence of multiple mechanisms by which somatostatin inhibits acid secretion is another example of the redundant regulatory pathways that control acid secretion. An understanding of the regulation of somatostatin release from D cells is slowly evolving, but it appears that gastrin stimulates somatostatin release, whereas cholinergic agonists inhibit somatostatin release.

Several enteric hormones (“enterogastrone”) and prostaglandins inhibit gastric acid secretion

Multiple processes in the duodenum and jejunum participate in the negative-feedback mechanisms that inhibit gastric acid secretion. Fat, acid, and hyperosmolar solutions in the duodenum are potent inhibitors of gastric acid secretion. Of these inhibitors, lipids are the most potent, but acid is also quite important. Several candidate hormones have been suggested as mediators of this acid inhibition (Table 42-2). These include CCK, secretin (see p. 889), vasoactive intestinal peptide (VIP; see Fig. 13-9), gastric inhibitory peptide (GIP), neurotensin (see Fig. 13-9), and peptide YY (see p. 892). Although each inhibits acid secretion after systemic administration, none has been unequivocally established as the sole physiological “enterogastrone.”

TABLE 42-2

Enteric Hormones that Inhibit Gastric H+ Secretion

HORMONE

SOURCE

CCK

I cells of duodenum and jejunum and neurons in ileum and colon

Secretin

S cells in small intestine

VIP

ENS neurons

GIP

K cells in duodenum and jejunum

Neurotensin

Endocrine cells in ileum

Peptide YY

Endocrine cells in ileum and colon

Somatostatin

D cells of stomach and duodenum, δ cells of pancreatic islets

Evidence suggests that secretin, which is released by duodenal S cells, may have a prime role in inhibiting gastric acid secretion after the entry of fat and acid into the duodenum. Secretin appears to reduce acid secretion by at least three mechanisms: (1) inhibition of antral gastrin release, (2) stimulation of somatostatin release, and (3) direct downregulation of the parietal-cell H+ secretory process.

The presence of luminal fatty acids causes enteroendocrine cells in the duodenum and the proximal part of the small intestine to release both GIP and CCK. GIP reduces acid secretion directly by inhibiting parietal-cell acid secretion and indirectly by inhibiting the antral release of gastrin. GIP also has the important function of stimulating insulin release from pancreatic islet cells in response to duodenal glucose and fatty acids and is therefore often referred to as glucose-dependent insulinotropic polypeptide (see p. 1041). CCK participates in feedback inhibition of acid secretion by directly reducing parietal-cell acid secretion. Finally, some evidence indicates that a neural reflex elicited in the duodenum in response to acid also inhibits gastric acid secretion.

Prostaglandin E2 (PGE2) inhibits parietal-cell acid secretion, probably by inhibiting histamine's activation of parietal-cell function at a site that is distal to the histamine receptor. PGE2 appears to bind to an EP3receptor on the basolateral membrane of the parietal cell (see Fig. 42-6) and stimulates Gαi, which, in turn, inhibits adenylyl cyclase. In addition, prostaglandins also indirectly inhibit gastric acid secretion by reducing histamine release from ECL cells and gastrin release from antral G cells.

A meal triggers three phases of acid secretion

Basal State

Gastric acid secretion occurs throughout the day and night. Substantial increases in acid secretion occur after meals, whereas the rate of acid secretion between meals is low (i.e., the interdigestive phase). This interdigestive period follows a circadian rhythm; acid secretion is lowest in the morning before awakening and is highest in the evening. Acid secretion is a direct function of the number of parietal cells, which is also influenced, at least in part, by body weight. Thus, men have higher rates of basal acid secretion than do women. Considerable variability in basal acid secretion is also seen among normal individuals, and the resting intragastric pH can range from 3 to 7 (see Box 42-1).

In contrast to the low rate of acid secretion during the basal or interdigestive period, acid secretion is enhanced several-fold by eating (Fig. 42-9). Regulation of gastric acid secretion is most often studied in the fasting state, a state in which intragastric pH is relatively low because of the basal H+ secretory rate and the absence of food that would otherwise buffer the secreted gastric acid. Experimental administration of a secretagogue in the fasted state thus stimulates parietal cells and further lowers intragastric pH. However, the time course of intragastric pH after a meal can vary considerably despite stimulation of acid secretion. The reason is that intragastric pH depends not only on gastric acid secretion but also on the buffering power (see p. 629) of food and the rate of gastric emptying of both acid and partially digested material into the duodenum.

image

FIGURE 42-9 Effect of eating on acid secretion. Ingesting food causes a marked fall in gastric [H+] because the food buffers the pre-existing H+. However, as the food leaves the stomach and as the rate of H+ secretion increases, [H+] slowly rises to its “interdigestive” level.

Regulation of acid secretion during a meal can be best characterized as including three separate but interrelated phases: the cephalic, the gastric, and the intestinal phases. The cephalic and gastric phases are of primary importance. Regulation of acid secretion includes both the stimulatory and inhibitory mechanisms that we discussed above (see Fig. 42-8). ACh, gastrin, and histamine all promote acid secretion, whereas somatostatin inhibits gastric acid secretion.

Although dividing acid secretion during a meal into three phases has been used for decades, it is somewhat artificial because of considerable overlap in the regulation of acid secretion. For example, the vagus nerve is the central factor in the cephalic phase, but it is also important for the vagovagal reflex that is part of the gastric phase. Similarly, gastrin release is a major component of the gastric phase, but vagal stimulation during the cephalic phase also induces the release of antral gastrin. Finally, the development of a consensus model has long been hampered by considerable differences in regulation of the gastric phase of acid secretion in humans, dogs, and rodents.

Cephalic Phase

The smell, sight, taste, thought, and swallowing of food initiate the cephalic phase, which is primarily mediated by the vagus nerve (see Fig. 42-8). Although the cephalic phase has long been studied in experimental animals, especially in dogs by Pavlov, imageN42-4 more recent studies of sham feeding have confirmed and extended the understanding of the mechanism of the cephalic phase of acid secretion in humans. The aforementioned sensory stimuli activate the dorsal motor nucleus of the vagus nerve in the medulla (see p. 339) and thus excite parasympathetic preganglionic efferent nerves. Insulin-induced hypoglycemia also stimulates the vagus nerve and in so doing promotes acid secretion.

N42-4

Ivan Petrovich Pavlov

Contributed by Emile Boulpaep, and Walter Boron

The classical experiments demonstrating the cephalic phase of salivary and gastric secretion in dogs were the work of Ivan Petrovich Pavlov. For his contributions to digestive physiology, Pavlov received the 1904 Nobel Prize in Physiology or Medicine. For more information about Pavlov and the work that led to his Nobel Prize, visit http://www.nobel.se/medicine/laureates/1904/index.html (accessed September 2014).

Reference

Wood JD. The first Nobel Prize for integrative systems physiology: Ivan Petrovich Pavlov, 1904. Physiology. 2004;19:326–330.

Stimulation of the vagus nerve results in four distinct physiological events (already introduced in Fig. 42-8) that together result in enhanced gastric acid secretion. First, in the body of the stomach, vagal postganglionic muscarinic nerves release ACh, which stimulates parietal-cell H+ secretion directly. Second, in the lamina propria of the body of the stomach, the ACh released from vagal endings triggers histamine release from ECL cells, which stimulates acid secretion. Third, in the antrum, peptidergic postganglionic parasympathetic vagal neurons, as well as other enteric nervous system (ENS) neurons, release GRP, which induces gastrin release from antral G cells. This gastrin stimulates gastric acid secretion both directly by acting on parietal cells and indirectly by promoting histamine release from ECL cells. Fourth, in both the antrum and the corpus, the vagus nerve inhibits D cells, thereby reducing their release of somatostatin and reducing the background inhibition of gastrin release. Thus, the cephalic phase stimulates acid secretion directly and indirectly by acting on the parietal cell. The cephalic phase accounts for ~30% of total acid secretion and occurs before the entry of any food into the stomach.

One of the surgical approaches for the treatment of peptic ulcer disease is cutting the vagus nerves (vagotomy) to inhibit gastric acid secretion. Rarely performed, largely because of the many effective pharmacological agents available to treat peptic ulcer disease, the technique has nevertheless proved effective in selected cases. Because vagal stimulation affects several GI functions besides parietal-cell acid secretion, the side effects of vagotomy include a delay in gastric emptying and diarrhea. Selective vagotomies—severing only those vagal fibers leading to the parietal cell—minimize these untoward events.

Gastric Phase

Entry of food into the stomach initiates the two primary stimuli for the gastric phase of acid secretion (Fig. 42-10). First, the food distends the gastric mucosa, which activates a vagovagal reflex as well as local ENS reflexes. Second, partially digested proteins stimulate antral G cells.

image

FIGURE 42-10 Gastric phase of gastric acid secretion. Food in the stomach stimulates gastric acid secretion by two major mechanisms: mechanical stretch and the presence of digested protein fragments (peptones).

Distention of the gastric wall—both in the corpus and antrum—secondary to entry of food into the stomach elicits two distinct neurally mediated pathways. The first is activation of a vagovagal reflex (see p. 857), in which gastric wall distention activates a vagal afferent pathway, resulting in a vagal efferent response in the dorsal nucleus of the vagus nerve. Stimulation of acid secretion in response to this vagal efferent stimulus occurs via the same four parallel pathways that are operative when the vagus nerve is activated during the cephalic phase (see Fig. 42-8). Second, gastric wall distention also activates a local ENS pathway that releases ACh, thereby activating parietal-cell acid secretion.

The presence of partially digested proteins (peptones) or amino acids in the antrum directly stimulates G cells to release gastrin (see Fig. 42-8). Intact proteins have no effect. Acid secretion and activation of pepsinogen are linked in a positive-feedback relationship. As discussed below, low pH enhances the conversion of pepsinogen to pepsin. Pepsin digests proteins to peptones, which promote gastrin release. Finally, gastrin promotes acid secretion, which closes the positive-feedback loop. Neither carbohydrate nor lipid participates in the regulation of gastric acid secretion. Components of wine, beer, and coffee stimulate acid secretion by this G-cell mechanism.

In addition to the two stimulatory pathways acting during the gastric phase, a third pathway inhibits gastric acid secretion by a classic negative-feedback mechanism, already noted above in our discussion of Figure 42-8. Low intragastric pH stimulates antral D cells to release somatostatin. Because somatostatin inhibits the release of gastrin by G cells, the net effect is a reduction in gastric acid secretion. The effectiveness of low pH in inhibiting gastrin release is emphasized by the following observation: Although peptones are 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 somatostatin is infused.

The gastric phase of acid secretion, which occurs primarily as a result of gastrin release, accounts for 50% to 60% of total gastric acid secretion.

Intestinal Phase

The presence of amino acids and partially digested peptides in the proximal portion of the small intestine stimulates acid secretion by three mechanisms (Fig. 42-11). 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 entero-oxyntin. The chemical nature of this agent has not yet been identified. Third, amino acids absorbed by the proximal part of the small intestine stimulate acid secretion by mechanisms that require further definition.

image

FIGURE 42-11 Intestinal phase of gastric acid secretion. Digested protein fragments (peptones) in the proximal small intestine stimulate gastric acid secretion by three major mechanisms.

Gastric acid secretion mediated by the intestinal phase is enhanced after a portacaval shunt. Such a shunt—used in the treatment of portal hypertension caused by chronic liver disease—diverts the portal blood that drains the small intestine around the liver on its return to the heart. Thus, the signal released from the small intestine during the intestinal phase is probably—in normal individuals—removed in part by the liver before reaching its target, the corpus of the stomach.

Approximately 5% to 10% of total gastric acid secretion is a result of the intestinal phase.