Henry J. Binder
The stomach plays several important roles in human nutrition and has secretory, motor, and humoral functions. These activities are not separate and distinct, but rather represent integrated functions that are required to initiate the normal digestive process.
The stomach has several specific secretory products. In addition to the stomach’s best-known product—acid, these products include pepsinogen, mucus, bicarbonate, intrinsic factor, and water. These substances continue the food digestion that was initiated by mastication and the action of salivary enzymes in the mouth. In addition, they help protect the stomach from injury. The stomach also has several important motor functions that regulate the intake of food, its mixing with gastric secretions and reduction in particle size, and the exit of partially digested material into the duodenum. Moreover, the stomach produces two important humoral agents—gastrin and somatostatin—that have both endocrine and paracrine actions. These peptides are primarily important in the regulation of gastric secretion.
Although these functions are important in the maintenance of good health, the stomach is nevertheless not required for survival. Individuals who have had their entire stomach removed (i.e., total gastrectomy) for non-neoplastic reasons can maintain adequate nutrition and achieve excellent longevity.
FUNCTIONAL ANATOMY OF THE STOMACH
The mucosa is composed of surface epithelial cells and glands
The basic structure of the stomach wall is similar to that of other regions of the gastrointestinal (GI) tract (see Fig. 41-2); therefore, the wall of the stomach consists of both mucosal and muscle layers. The stomach can be divided, based on its gross anatomy, into three major segments (Fig. 42-1): (1) a specialized portion of the stomach called the cardia is located just distal to the gastroesophageal junction and is devoid of the acid-secreting parietal cells; (2) the body or corpus is the largest portion of the stomach; its most proximal region is called the fundus; and (3) the distal portion of the stomach is called the antrum. The surface area of the gastric mucosa is substantially increased by the presence of gastric glands, which consist of a pit, a neck, and a base. These glands contain several cell types, including mucous, parietal, chief, and endocrine cells; endocrine cells also present in both corpus and antrum. The surface epithelial cells, which have their own distinct structure and function, secrete HCO−3 and mucus.
Figure 42-1 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.
Marked cellular heterogeneity exists not only within segments (e.g., glands versus surface epithelial cells) but also between segments of the stomach. For instance, as discussed later, the structure and function of the mucosal epithelial cells in the antrum and body are quite distinct. Similarly, although the smooth muscle in the proximal and distal portions of the stomach appear structurally similar, their functions and pharmacological properties differ substantially.
With increasing rates of secretion of gastric juice, the H+ concentration rises, and the Na+ concentration falls
The glands of the stomach typically secrete ~2 L/day of a fluid that is approximately isotonic with blood plasma. As a consequence of the heterogeneity of gastric mucosal function, early investigators recognized that gastric secretion consists of two distinct components: parietal cell and nonparietal cell secretion. According to this hypothesis, gastric secretion consists of (1) an Na+-rich basal secretion that originates from nonparietal cells and (2) a stimulated component that represents a pure parietal cell secretion that is rich in H+. This model helps to explain the inverse relationship between the luminal concentrations of H+ and Na+ as a function of the rate of gastric secretion (Fig. 42-2). Thus, at high rates of gastric secretion—for example, when gastrin or histamine stimulates parietal cells—intraluminal [H+] is high, whereas intraluminal [Na+] is relatively low. At low rates of secretion or in clinical situations in which maximal acid secretion is reduced (e.g., pernicious anemia; see Chapter 44 for the box on that topic), intraluminal [H+] is low but intraluminal [Na+] is high.
Figure 42-2 The effect of the gastric secretion rate on the composition of the gastric juice.
The proximal portion of the stomach secretes acid, pepsinogens, intrinsic factor, bicarbonate, and mucus, whereas the distal part releases gastrin and somatostatin
Corpus The primary secretory products of the proximal part of the stomach—acid (protons), pepsinogens, and intrinsic factor—are made by distinct cells from glands in the corpus of the stomach. The two primary cell types in the gastric glands of the body of the stomach are parietal cells and chief cells.
Parietal cells (or oxyntic cells) secrete both acid and intrinsic factor, a glycoprotein that is required for cobalamin (vitamin B12) absorption in the ileum (see Chapter 45). The parietal cell has a very distinctive morphology (Fig. 42-1). It is a large, triangular cell with a centrally located nucleus, an abundance of mitochondria, intracellular tubulovesicular membranes, and canalicular structures. We discuss H+ secretion in the next major section and intrinsic factor in Chapter 45.
Chief cells (or peptic cells) secrete pepsinogens, but not acid. These epithelial cells are substantially smaller than parietal cells. A close relationship exists among pH, pepsin secretion, and function. Pepsins are endopeptidases (i.e., they hydrolyze “interior” peptide bonds) and initiate protein digestion by hydrolyzing specific peptide linkages. The basal luminal pH of the stomach is 4 to 6; with stimulation, the pH of gastric secretions is usually reduced to less than 2. At pH values that are less than 3, pepsinogens are rapidly activated to pepsins. A low gastric pH also helps to prevent bacterial colonization of the small intestine.
In addition to parietal and chief cells, glands from the corpus of the stomach also contain mucus-secreting cells, which are confined to the neck of the gland (Fig. 42-1), and five or six endocrine cells. Among these endocrine cells are enterochromaffin-like (ECL) cells, which release histamine.
Antrum The glands in the antrum of the stomach do not contain parietal cells. Therefore, the antrum does not secrete either acid or intrinsic factor. Glands in the antral mucosa contain chief cells and endocrine cells; the endocrine cells include the so-called G cells and D cells, which secrete gastrin and somatostatin, respectively (see Table 41-1). These two peptide hormones function as both endocrine and paracrine regulators of acid secretion. As discussed in more detail later, gastrin stimulates gastric acid secretion by two mechanisms and is also a major trophic or growth factor for GI epithelial cell proliferation. As discussed more fully later, somatostatin also has several important regulatory functions, but its primary role in gastric physiology is to inhibit both gastrin release and parietal cell acid secretion.
In addition to the cells of the gastric glands, the stomach also contains superficial epithelial cells that cover the gastric pits, as well as the surface in between the pits. These cells secrete HCO−3.
Gastric pH and Pneumonia
Many patients hospitalized in the intensive care unit (ICU) receive prophylactic antiulcer treatments (e.g., proton pump inhibitors, such as omeprazole) that either neutralize existing acid or block its secretion and thereby raise gastric pH. Patients in the ICU who are mechanically ventilated or who have coagulopathies are highly susceptible to hemorrhage from gastric stress ulcers, a complication that can contribute significantly to overall morbidity and mortality. These different antiulcer regimens do effectively lessen the risk of developing stress ulcers. However, by raising gastric pH, these agents also lower the barrier to gram-negative bacterial colonization of the stomach. Esophageal reflux and subsequent aspiration of these organisms are common in these very sick patients, many of whom are already immunocompromised or even mechanically compromised by the presence of a ventilator tube. If these bacteria are aspirated into the airway, pneumonia can result. The higher the gastric pH, the greater is the risk of pneumonia.
The stomach accommodates food, mixes it with gastric secretions, grinds it, and empties the chyme into the duodenum
In addition to its secretory properties, the stomach also has multiple motor functions. These functions are the result of gastric smooth muscle activity, which is integrated by both neural and hormonal signals. Gastric motor functions include both propulsive and retrograde movement of food and liquid, as well as a nonpropulsive movement that increases intragastric pressure.
Similar to the heterogeneity of gastric epithelial cells, considerable diversity is seen in both the regulation and contractility of gastric smooth muscle. The stomach has at least two distinct areas of motor activity; the proximal and distal portions of the stomach behave as separate, but coordinated, entities. At least four events can be identified in the overall process of gastric filling and emptying: (1) receiving and providing temporary storage of dietary food and liquids; (2) mixing of food and water with gastric secretory products, including pepsin and acid; (3) grinding of food so that particle size is reduced to enhance digestion and to permit passage through the pylorus; and (4) regulating the exit of retained material from the stomach into the duodenum (i.e., gastric emptying of chyme) in response to various stimuli.
The mechanisms by which the stomach receives and empties liquids and solids are significantly different. Emptying of liquids is primarily a function of the smooth muscle of the proximal part of the stomach, whereas emptying of solids is regulated by antral smooth muscle.
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. On 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.
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 Chapter 5) 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. The two subunits form a heterodimer with close interaction at the extracellular domain. (See Note: Gastric H-K Pump)
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 as follows: (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 (see the box titled Gastrinoma or Zollinger-Ellison Syndrome) 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 physiologically normal subjects and patients with hypersecretory states. 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.
According to the model presented in Figure 42-4, the key step in gastric acid secretion is extrusion of H+ into the lumen of the gastric gland in exchange for K+. 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 apical membrane H-K pump energizes the entire process, the net result of which is the active 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 CO2and H2O, which the enzyme carbonic anhydrase (see Chapter 28 for the box on this topic) converts to HCO−3 and H+. The H+ is the substrate of the H-K pump. The HCO−3 exits across the basolateral membrane through the Cl-HCO3 exchanger. This process also provides 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.
Figure 42-4 Acid secretion by parietal cells. When the parietal cell is stimulated, H-K pumps (fueled by ATP hydrolysis) extrude H+ into the lumen of the gastric gland in exchange for K+. The K+ recycles back into the lumen by K+ channels. Cl− exits through channels in the luminal membrane, thus completing the net process of HCl secretion. The H+ needed by the H-K pump is provided by the entry of CO2 and H2O, which are converted to H+ and HCO−3 by carbonic anhydrase. The HCO−3 exits across the basolateral membrane through the Cl-HCO3exchanger.
Three secretagogues (acetylcholine, gastrin, and histamine) directly and indirectly induce acid secretion by parietal cells
The action of secretagogues on gastric acid secretion occurs through at least two parallel and perhaps redundant mechanisms (Fig. 42-5). In the first, acetylcholine (ACh), gastrin, and histamine bind directly to their respective membrane receptors on the parietal cell and synergistically stimulate and potentiate acid secretion. ACh (see Fig. 14-8) is released from endings of the vagus nerve (cranial nerve X), and as we see in the next section, gastrin is released from G cells. Histamine is synthesized from histidine (see Fig. 13-8). The documented presence of ACh, gastrin, and histamine receptors, at least on the canine parietal cell, provides the primary support for this view. In the second mechanism, ACh and gastrin indirectly induce acid secretion as a result of their stimulation of histamine release from ECL cells in the lamina propria. The central role of histamine and ECL cells is consistent with the observation that histamine-2 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. The effectiveness of H2 blockers in controlling acid secretion after stimulation by most agonists is well established in studies of both humans and experimental animals. These drugs, but more importantly the proton pump inhibitors, are prescribed to treat active peptic ulcer disease.
Figure 42-5 The 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).
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 CCKB, respectively) that are coupled to the G protein Gaq. 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 Gas to adenylyl cyclase (AC). The result is production of cAMP and activation of PKA. Two inhibitors of acid secretion also act directly on the parietal cell. Somatostatin and prostaglandins bind to separate receptors that are linked to Gai. These agents thus oppose the actions of histamine. ER, endoplasmic reticulum.
ACh binds to an M3 muscarinic receptor (see Chapter 14) on the parietal cell basolateral membrane. This ACh receptor couples to a GTP-binding protein (Gaq) and activates phospholipase C (PLC), which converts phosphatidylinositol 4, 5-biphosphate (PIP2) to inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol (DAG; see Chapter 3). IP3 causes internal stores to release Ca2+, which then probably acts through calmodulin-dependent protein kinase (see Chapter 3). 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 B (CCKB) receptor. Two related CCK receptors have been identified: CCKA and CCKB. Their amino acid sequences are ~50% identical, and both are G protein coupled. The CCKB receptor has equal affinity for both gastrin and CCK. In contrast, the CCKA 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 CCKB receptor couples to Gaq and activates the same PLC pathway as does ACh, and 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 Gas 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–specific proteins, including the H-K pump.
Gastrin is released by both antral and duodenal G cells, and histamine is released by enterochromaffin-like cells in the corpus
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 (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 (Fig. 42-7B). A single gene encodes a peptide of 101 amino acids. Several cleavage steps and C-terminal amidation (i.e., addition of a −NH2 to the C terminus) occur 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 (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 equal amounts of G-17 or G-34 produces comparable increases in gastric acid secretion.
Figure 42-7 Amino acid sequences of the gastrins and CCK. A, A single gene encodes a 101–amino acid peptide that is processed to both G-17 and G-34. The N-terminal glutamine is modified to create a pyroglutamyl residue. The C-terminal phenylalanine is amidated. These modifications make the hormone resistant to carboxypeptidases 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 (G cells) in both the antrum and duodenum make each of the two gastrins. Antral G cells are the primary source of G-17, whereas duodenal G cells are the primary source of G-34. Antral G cells are unusual in that they respond to both luminal and 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 later, gastrin release is inhibited by somatostatin, which is released from adjacent D cells.
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 but also stimulates both ECL and D cells. Vagal stimulation of the ECL cells enhances gastric acid secretion through 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 stimulates both G cells and D cells. The vagus stimulates the G cells through GRP, thus promoting gastrin release. This gastrin promotes gastric acid secretion by two endocrine mechanisms: directly through the parietal cell and indirectly through the ECL cell, which releases histamine. The vagal stimulation of D cells by 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).
Somatostatin, released by gastric D cells, is the central mechanism of inhibition of acid secretion
Gastric acid secretion is under close control of not only the stimulatory pathways discussed earlier 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 Chapter 51) and by neurons in the hypothalamus (see Chapter 48). 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 (Fig. 42-8). In the direct pathway, somatostatin coming from two different sources binds to a Gai-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 either be 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 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 through two indirect pathways, both of which are paracrine. In the corpus of the stomach, D cells release somatostatin that inhibits the release of histamine from ECL cells (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 the prime mediator of this acid inhibition (Table 42-1). These include CCK, secretin, and peptide YY (see Chapter 43), as well as vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), and neurotensin. Although each inhibits acid secretion after systemic administration, none has been unequivocallyestablished as the sole physiological “enterogastrone.”
Table 42-1 Enteric Hormones That Inhibit Gastric H+ Secretion
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 down-regulation 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 Chapter 51). 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 (Fig. 42-6) and stimulates Gai, 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 physiologically normal individuals, and the resting intragastric pH can range from 3 to 7.
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 Chapter 28) of food and the rate of gastric emptying of both acid and partially digested material into the duodenum.
Figure 42-9 Effect of eating on acid secretion. Ingesting food causes a marked fall in gastric [H+] because the food buffers the preexisting 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 by 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 earlier (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 (Fig. 42-8). Although the cephalic phase has long been studied in experimental animals, especially dogs by Pavlov, 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 Chapter 14) and thus activate parasympathetic preganglionic efferent nerves. Insulin-induced hypoglycemia also stimulates the vagus nerve and in so doing promotes acid secretion. (See Note: Ivan Petrovich Pavlov)
Stimulation of the vagus nerve results in four distinct physiological events (already introduced in Figure 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 the parietal cell 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 vagus nerve stimulation affects several GI functions besides parietal cell acid secretion, the side effects of vagotomy include a delay in gastric emptying and diarrhea. To minimize these untoward events, successful attempts have been made to perform more selective vagotomies, severing only those vagal fibers leading to the parietal cell.
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.
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 Chapter 41), in which gastric 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 acid secretion in response to this vagal efferent stimulus occurs through the same four parallel pathways that are operative when the vagus nerve is activated during the cephalic phase (Fig. 42-8). Second, gastric wall distention also activates a local ENS pathway that releases ACh, which, in turn, stimulates parietal cell acid secretion.
The presence of partially digested proteins (peptones) or amino acids in the antrum directly stimulates G cells to release gastrin (Fig. 42-8). Intact proteins have no effect. Acid secretion and activation of pepsinogen are linked in a positive feedback relationship. As discussed later, 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. Little evidence indicates that either carbohydrate or 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 earlier 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.
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.
Gastrinoma or Zollinger-Ellison Syndrome
On rare occasion, 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 42-2). This clinical picture is also known as the Zollinger-Ellison 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 Zollinger-Ellison syndrome, other patients with duodenal ulcer have serum gastrin levels that are near normal. Their basal gastric acid secretion rates are modestly elevated, but they increase markedly in response to pentagastrin. Patients with pernicious anemia(see Chapter 45 for the box on this topic) lack parietal cells and thus cannot secrete H+. In the absence of a low luminal pH, the antral D cell is not stimulated by acid (Fig. 42-10). Consequently, the release of somatostatin from the D cell is low, and minimal tonic inhibition of gastrin release from G cells occurs. It is not surprising, then, that these patients have very high levels of serum gastrin, but virtually no H+ secretion (Table 42-2).
Table 42-2 Serum Gastrin Levels and Gastric Acid Secretion Rates
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.
Chief cells, triggered by both cAMP and Ca2+ pathways, secrete multiple pepsinogens that initiate protein digestion
The chief cells in gastric glands, as well as mucous cells, secrete pepsinogens, a group of proteolytic proenyzmes (i.e., zymogens or inactive enzyme precursors) that belong to the general class of aspartic proteinases. They are activated to pepsins by cleavage of an N-terminal peptide. Pepsins are endopeptidases that initiate the hydrolysis of ingested protein in the stomach. Although eight pepsinogen isoforms were initially identified on electrophoresis, recent classifications are based on immunological identity, so pepsinogens are most often classified as group I pepsinogens, group II pepsinogens, and cathepsin E. Group I pepsinogens predominate. They are secreted from chief cells located at the base of glands in the corpus of the stomach. Group II pepsinogens are also secreted from chief cells but, in addition, are secreted from mucous neck cells in the cardiac, corpus, and antral regions.
Pepsinogen secretion in the basal state is ~20% of its maximal secretion after stimulation. Although pepsinogen secretion generally parallels the secretion of acid, the ratio of maximal to basal pepsinogen secretion is considerably less than that for acid secretion. Moreover, the cellular mechanism of pepsinogen release is quite distinct from that of H+ secretion by parietal cells. Release of pepsinogen across the apical membrane is the result of a novel process called compound exocytosis, in which secretory granules fuse with both the plasma membrane and other secretory granules. This process permits rapid and sustained secretion of pepsinogen. After stimulation, the initial peak in pepsinogen secretion is followed by a persistent lower rate of secretion. This pattern of secretion has been interpreted as reflecting an initial secretion of preformed pepsinogen, followed by the secretion of newly synthesizedpepsinogen. However, more recent in vitro studies suggested that a feedback mechanism may account for the subsequent reduced rate of pepsinogen secretion.
Two groups of agonists stimulate chief cells to secrete pepsinogen. One group acts through adenylyl cyclase and cAMP, and the other acts through increases in [Ca2+]i.
Agonists Acting Through cAMP Chief cells have receptors for secretin/VIP, β2-adrenergic receptors, and EP2 receptors for PGE2 (see Chapter 3). All these receptors activate adenylyl cyclase. At lower concentrations than those required to stimulate pepsinogen secretion, PGE2 can also inhibit pepsinogen secretion, probably by binding to another receptor subtype.
Agonists Acting Through Ca2+ Chief cells also have M3 muscarinic receptors for ACh, as well as receptors for the gastrin/CCK family of peptides. Unlike gastric acid secretion, which is stimulated by the CCKBreceptor, pepsinogen secretion is stimulated by the CCKA receptor, which has a much higher affinity for CCK than for gastrin. Activation of both the M3 and CCKA receptors causes Ca2+ release from intracellular stores by IP3 and thereby raises [Ca2+]i. However, uncertainty exists about whether increased Ca2+ influx is also required and about whether PKC also has a role.
Of the agonists just listed, the most important for pepsinogen secretion is ACh released in response to vagal stimulation. Not only does ACh stimulate chief cells to release pepsinogen, but also it stimulates parietal cells to secrete acid. This gastric acid produces additional pepsinogen secretion by two different mechanisms. First, in the stomach, a fall in pH elicits a local cholinergic reflex that results in further stimulation of chief cells to release pepsinogen. Thus, the ACh that stimulates chief cells can come both from the vagus and from the local reflex. Second, in the duodenum, acid triggers the release of secretin from S cells. By an endocrine effect, this secretin stimulates the chief cells to release more pepsinogen. The exact role or roles of histamine and gastrin in pepsinogen secretion are unclear.
Low pH is required for both pepsinogen activation and pepsin activity
Pepsinogen is inactive and requires activation to a protease, pepsin, to initiate protein digestion. This activation occurs by spontaneous cleavage of a small N-terminal peptide fragment (the activation peptide), but only at a pH that is less than 5.0 (Fig. 42-12). Between pH 5.0 and 3.0, spontaneous activation of pepsinogen is slow, but it is extremely rapid at a pH that is less than 3.0. In addition, pepsinogen is also autoactivated; that is, newly formed pepsin itself cleaves pepsinogen to pepsin.
Figure 42-12 Activation of the pepsinogens to pepsins. At pH values from 5 to 3, pepsinogens spontaneously activate to pepsins by the removal of an N-terminal activation peptide. This spontaneous activation is even faster at pH values lower than 3. The newly formed pepsins themselves—which are active only at pH values lower than 3.5—also can catalyze the activation of pepsinogens.
Once pepsin is formed, its activity is also pH dependent. 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 the solution. pH values higher than 3.5 reversibly inactivate pepsin, and pH values higher than 7.2 irreversibly inactivate the enzyme. These considerations are sometimes useful for establishing optimal antacid treatment regimens in peptic ulcer disease.
Pepsin is an endopeptidase that initiates the process of protein digestion in the stomach. Pepsin action results in the release of small peptides and amino acids (peptones) that, as noted earlier, stimulate the release of gastrin from antral G cells; these peptones also stimulate CCK release from duodenal I cells. As previously mentioned, the peptones generated by pepsin stimulate the very acid secretion required for pepsin activation and action. Thus, the peptides that pepsin releases are important in initiating a coordinated response to a meal. However, most protein entering the duodenum remains as large peptides, and nitrogen balance is not impaired after total gastrectomy.
Digestive products of both carbohydrates and lipid are also found in the stomach, although secretion of their respective digestive enzymes either does not occur or is not a major function of gastric epithelial cells. Carbohydrate digestion is initiated in the mouth by salivary amylase. However, after this enzyme is swallowed, the stomach becomes a more important site for starch hydrolysis than the mouth. No evidence indicates gastric secretion of enzymes that hydrolyze starch or other saccharides. Similarly, although lipid digestion is also initiated in the mouth by lingual lipase, significant lipid digestion occurs in the stomach as a result of both the lingual lipase that is swallowed and gastric lipase, both of which have an acid pH optimum (see Chapter 45).
PROTECTION OF THE GASTRIC SURFACE EPITHELIUM AND NEUTRALIZATION OF ACID IN THE DUODENUM
At maximal rates of H+ secretion, the parietal cell can drive the intraluminal pH of the stomach to 1 or less (i.e., [H+] > 100 mM) for long periods. The gastric epithelium must maintain an H+ concentration gradient of more than a million-fold because the intracellular pH of gastric epithelial cells is ~7.2 (i.e., [H+] ≅ 60 nM) and plasma pH is ~7.4 (i.e., [H+] ≅ 40 nM). Simultaneously, a substantial plasma-to-lumen Na+ concentration gradient of ~30 is present because plasma [Na+] is 140 mM, whereas intragastric [Na+] can reach values as low as 5 mM, but only at high secretory rates (Fig. 42-2). How is the stomach able to maintain these gradients? How is it that the epithelial cells are not destroyed by this acidity? Moreover, why do pepsins in the gastric lumen not digest the epithelial cells? The answer to all three questions is the so-called gastric diffusion barrier.
Although the nature of the gastric diffusion barrier had been controversial, it is now recognized that the diffusion barrier is both physiological and anatomical. Moreover, it is apparent that the diffusion barrier represents at least three components: (1) relative impermeability to acid of the apical membrane and epithelial cell tight junctions in the gastric glands, (2) a mucous gel layer varying in thickness between 50 and 200 μm overlying the surface epithelial cells, and (3) an HCO−3-containing microclimate adjacent to the surface epithelial cells that maintains a relatively high local pH.
Vagal stimulation and irritation stimulate gastric mucous cells to secrete mucin, a glycoprotein that is part of the mucosal barrier
The mucus layer is largely composed of mucin, phospholipids, electrolytes, and water. Mucin is the high-molecular-weight glycoprotein (see Chapter 2) that contributes to the formation of a protective layer over the gastric mucosa. Gastric mucin is a tetramer consisting of four identical peptides joined by disulfide bonds. Each of the four peptide chains is linked to long polysaccharides, which are often sulfated and are thus mutually repulsive. The ensuing high carbohydrate content is responsible for the viscosity of mucus, which explains, in large part, its protective role in gastric mucosal physiology.
Mucus is secreted by three different mucous cells: surface mucous cells (i.e., on the surface of the stomach), mucous neck cells (i.e., at the point where a gastric pit joins a gastric gland), and glandular mucous cells (i.e., in the gastric glands in the antrum). The type of mucus secreted by these cells differs; mucus that is synthesized and secreted in the glandular cells is a neutral glycoprotein, whereas the mucous cells on the surface and in the gastric pits secrete both neutral and acidic glycoproteins. Mucin forms a mucous gel layer in combination with phospholipids, electrolytes, and water. This mucous gel layer provides protection against injury from noxious luminal substances, including acid, pepsins, bile acids, and ethanol. Mucin also lubricates the gastric mucosa to minimize the abrasive effects of intraluminal food.
The mucus barrier is not static. Abrasions can remove pieces of mucus. When mucus comes in contact with a solution with a very low pH, the mucus precipitates and sloughs off. Thus, the mucous cells must constantly secrete mucus. Regulation of mucus secretion by gastric mucosal cells is less well understood than is regulation of the secretion of acid, pepsinogens, and other substances by gastric cells. The two primary stimuli for inducing mucus secretion are vagal stimulation and physical and chemical irritation of the gastric mucosa by ingested food. The current model of mucus secretion suggests that vagal stimulation induces the release of ACh, which leads to increases in [Ca2+]i and thus stimulates mucus secretion. In contrast to acid and pepsinogen secretion, cAMP does not appear to be a second messenger for mucus secretion.
Gastric surface cells secrete HCO−3, stimulated by acetylcholine, acids, and prostaglandins
Surface epithelial cells both in the corpus and in the antrum of the stomach secrete HCO−3. Despite the relatively low rate of HCO−3 secretion—in comparison with acid secretion—HCO−3 is extremely important as part of the gastric mucosal protective mechanism. The mucus gel layer provides an unstirred layer under which the secreted HCO−3 remains trapped and maintains a local pH of ~of 7.0 versus an intraluminal pH in the bulk phase of 1 to 3. As illustrated in Figure 42-13A, an electrogenic Na/HCO3 cotransporter (NBC) appears to mediate the uptake of HCO−3 across the basolateral membrane of surface epithelial cells. The mechanism of HCO−3 exit from the cell into the apical mucus layer is unknown but may be mediated by a channel.
Figure 42-13 Diffusion barrier in the surface of the gastric mucosa. A, The mucus secreted by the surface cells serves two functions. First, it acts as a diffusion barrier for H+ and also pepsins. Second, the mucus layer traps a relatively alkaline solution of HCO−3. This HCO−3titrates any H+ that diffuses into the gel layer from the stomach lumen. The alkaline layer also inactivates any pepsin that penetrates into the mucus. B, If H+ penetrates into the gastric epithelium, it damages mast cells, which release histamine and other agents, thereby setting up an inflammatory response. If the insult is mild, the ensuing increase in blood flow can promote the production of both mucus and HCO−3 by the mucus cells. If the insult is more severe, the inflammatory response leads to a decrease in blood flow and thus to cell injury.
Similar to the situation for mucus secretion, relatively limited information is available about the regulation of HCO−3 secretion. The present model suggests that vagal stimulation mediated by ACh leads to an increase in [Ca2+]i, which, in turn, stimulates HCO−3 secretion. Sham feeding is a potent stimulus for HCO−3 secretion through this pathway. A second powerful stimulus of gastric HCO−3 secretion is intraluminal acid. The mechanism of stimulation by acid appears to be secondary to both activation of neural reflexes and local production of PGE2. Finally, evidence suggests that a humoral factor may also be involved in the induction of HCO−3 secretion by acid.
Mucus protects the gastric surface epithelium by trapping an HCO−3-rich fluid near the apical border of these cells
Mucous cells on the surface of the stomach, as well as in the gastric pits and neck portions of the gastric glands, secrete both HCO−3 and mucus. Why is this barrier so effective? First, the secreted mucus forms a mucous gel layer that is relatively impermeable to the diffusion of H+ from the gastric lumen to the surface cells. Second, beneath this layer of mucus is a microclimate that contains fluid with a high pH and high [HCO−3], the result of HCO−3 secretion by gastric surface epithelial cells (Fig. 42-13A). Thus, this HCO−3 neutralizes most acid that diffuses through the mucus layer. Mucosal integrity, including that of the mucosal diffusion barrier, is also maintained by PGE2, which—as discussed in the previous section—stimulates mucosal HCO−3 secretion.
Deep inside the gastric gland, where no obvious mucus layer protects the parietal, chief, and ECL cells, the impermeability of the cells’ apical barrier appears to exclude H+ even at pH values as low as 1. The paradox of how HCl secreted by the parietal cells emerges from the gland and into the gastric lumen may be explained by a process known as viscous fingering. Because the liquid emerging from the gastric gland is both extremely acidic and presumably under pressure, it can tunnel through the mucous layer covering the opening of the gastric gland onto the surface of the stomach. However, this stream of acid apparently does not spread laterally, but rather rises to the surface as a “finger” and thus does not neutralize the HCO−3 in the microenvironment between the surface epithelial cells and the mucus.
The mucous gel layer and the trapped alkaline HCO−3 solution protect the surface cells not only from H+ but also from pepsin. The mucus per se acts as a pepsin diffusion barrier. The relative alkalinity of the trapped HCO−3inactivates any pepsin that penetrates the mucus. Recall that pepsin is reversibly inactivated at pH values higher than ~3.5 and is irreversibly inactivated by pH values higher than ~7.2. Thus, the mucus HCO−3 layer plays an important role in preventing autodigestion of the gastric mucosa.
Breakdown of the Gastric Barrier
Integrity of the gastric-epithelial barrier can be conveniently judged by maintenance of a high lumen-negative transepithelial potential difference (PD) of ~−60 mV. Several agents that cause mucosal injury, including mucosal ulceration, can alter the mucosal diffusion barrier. Salicylates, bile acids, and ethanol all impair the mucosal diffusion barrier and result in H+ (acid) backdiffusion, an increase in intraluminal [Na+], a fall in PD, and mucosal damage (Fig. 42-13B). Three decades ago, Davenport proposed an attractive model to explain how H+, after having breached the mucosal diffusion barrier, produces injury to the gastric mucosa. Although several details of this original model have been modified during the ensuing years, it is still believed that entry of acid into the mucosa damages mast cells, which release histamine and other mediators of inflammation. The histamine and other agents cause local vasodilatation that increases blood flow. If the damage is not too severe, this response allows the surface cells to maintain their production of mucus and HCO−3. However, if the injury is more severe, inflammatory cells release a host of agents—including platelet-activating factor, leukotrienes, endothelins, thromboxanes, and oxidants—that reduce blood flow (ischemia) and result in tissue injury, including capillary damage.
Prostaglandins play a central role in maintaining mucosal integrity. For example, prostaglandins prevent or reverse mucosal injury secondary to salicylates, bile, and ethanol. This protective effect of prostaglandins is the result of several actions, including their ability to inhibit acid secretion, stimulate both HCO−3 and mucus secretion, increase mucosal blood flow, and modify the local inflammatory response induced by acid.
Entry of acid into the duodenum induces the release of secretin from S cells, thus triggering the secretion of HCO−3 by the pancreas and duodenum, which, in turn, neutralizes gastric acid
The overall process of regulating gastric acid secretion involves not only stimulation and inhibition of acid secretion (as discussed earlier), but also neutralization of the gastric acid that passes from the stomach into the duodenum. The amount of secreted gastric acid is reflected by a fall in intragastric pH. We have already seen that this fall in pH serves as the signal to antral D cells to release somatostatin and thus to inhibit further acid secretion, a classic negative feedback process. Similarly, low pH in the duodenum serves as a signal for the secretion of alkali to neutralize gastric acid in the duodenum.
During the past decade, our understanding of the etiology of duodenal and gastric ulcers has radically changed. Abundant evidence now indicates that most peptic ulcers are an infectious disease in that most (but not all) ulcers are caused by Helicobacter pylori, a gram-negative bacillus that colonizes the antral mucosa. Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for ~20% of ulcers. Although almost all ulcers that are not associated with NSAID use are secondary to H. pylori infestation, many, if not most, individuals with evidence of H. pylori infestation do not have peptic ulcer disease. The factors responsible for H. pylori–induced inflammation or ulceration are not known. However, the increase in gastric acid secretion that is present in most patients with duodenal ulcers may occur because H. pylori–induced antral inflammation inhibits the release of somatostatin by antral D cells. Because somatostatin normally inhibits gastrin release by antral G cells, the result would be increased gastrin release and thus increased gastric acid secretion. Indeed, as noted in Table 42-2, serum gastrin levels are modestly elevated in patients with duodenal ulcers.
Inhibition of acid secretion heals, but does not cure H. pylori–induced peptic ulcers. However, antibiotic therapy that eradicates H. pylori cures peptic ulcer disease.
The key factor in this neutralization process is secretin, the same secretin that inhibits gastric acid secretion and promotes pepsinogen secretion by chief cells. A low duodenal pH, with a threshold of 4.5, triggers the release of secretin from S cells in the duodenum. However, the S cells are probably not pH sensitive themselves but, instead, may respond to a signal from other cells that are pH sensitive. Secretin stimulates the secretion of fluid and HCO−3 by the pancreas, thus leading to intraduodenal neutralization of the acid load from the stomach. Maximal HCO−3 secretion is a function 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 of large amounts of secretin, which greatly stimulates pancreatic HCO−3secretion; the increased HCO−3, in turn, neutralizes the increased duodenal acid load.
In addition to pancreatic HCO−3 secretion, the duodenal acid load resulting from gastric acid secretion is partially neutralized by duodenal HCO−3 secretion. This duodenal HCO−3 secretion occurs in the proximal—but not the distal—part of the duodenum under the influence of prostaglandins. Attention has been focused on duodenal epithelial cells (villus or crypt cells) as the cellular source of HCO−3secretion, but the possibility that duodenal HCO−3 originates, at least in part, from duodenal submucosal Brunner’s glands has not been excluded. The mechanism of duodenal HCO−3 secretion involves both Cl-HCO3 exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane (see Fig. 43-6). Patients with duodenal ulcer disease tend to have both increased gastric acid secretion and reduced duodenal HCO−3 secretion. Thus, the increased acid load in the duodenum is only partially neutralized, so the duodenal mucosa has increased exposure to a low-pH solution.
FILLING AND EMPTYING OF THE STOMACH
Gastric motor activity plays a role in filling, churning, and emptying
Gastric motor activity has three functions. First, the receipt of ingested material represents the reservoir function of the stomach and occurs as smooth muscle relaxes. This response occurs primarily in the proximal portion of the stomach. Second, ingested material is churned and is thereby altered to a form that rapidly empties from the stomach through the pylorus and facilitates normal jejunal digestion and absorption. Thus, in conjunction with gastric acid and enzymes, the motor function of the stomach helps to initiate digestion. Third, the pyloric antrum, pylorus, and proximal part of the duodenum function as a single unit for emptying into the duodenum the modified gastric contents (chyme), consisting of both partially digested food material and gastric secretions. Gastric filling and emptying are accomplished by the coordinated activity of smooth muscle in the esophagus, lower esophageal sphincter, and proximal and distal portions of the stomach, as well as the pylorus and duodenum.
The pattern of gastric smooth muscle activity is distinct during fasting and after eating. The pattern during fasting is referred to as the migrating myoelectric (or motor) complex (MMC), as discussed in Chapter 41 in connection with the small intestine. This pattern is terminated by eating, at which point it is replaced by the so-called fed pattern. Just as the proximal and distal regions of the stomach differ in secretory function, they also differ in the motor function responsible for storing, processing, and emptying liquids and solids. The proximal part of the stomach is the primary location for storage of both liquids and solids. The distal portion of the stomach is primarily responsible for churning the solids and generating smaller liquid-like material, which then exits the stomach in a manner similar to that of ingested liquids. Thus, the gastric emptying of liquids and of solids is closely integrated.
Filling of the stomach is facilitated by both receptive relaxation and gastric accommodation
Even a dry swallow relaxes both the lower esophageal sphincter and the proximal part of the stomach. Of course, the same happens when we swallow food. These relaxations facilitate the entry of food into the stomach. Relaxation in the fundus is primarily regulated by a vagovagal reflex and has been called receptive relaxation. In a vagovagal reflex, afferent fibers running with the vagus nerve carry information to the central nervous system (CNS), and efferent vagal fibers carry the signal from the CNS to the stomach and cause relaxation by a mechanism that is neither cholinergic nor adrenergic. The result is that intragastric volume increases without an increase in intragastric pressure. If vagal innervation to the stomach is interrupted, gastric pressure rises much more rapidly.
Quite apart from the receptive relaxation of the stomach that anticipates the arrival of food after swallowing and esophageal distention, the stomach can also relax in response to gastric filling per se. Thus, increasing intragastric volume, as a result of either entry of food into the stomach or gastric secretion, does not produce a proportionate increase in intragastric pressure. Instead, small increases in volume do not cause increases in intragastric pressure until a threshold is reached, after which intragastric pressure rises steeply (Fig. 42-14A). This phenomenon is the result of active dilatation of the fundus and has been called gastric accommodation. Vagotomy abolishes a major portion of gastric accommodation, so increases in intragastric volume produce greater increases in intragastric pressure. However, the role of the vagus nerve in gastric accommodation is one of modulation. It is generally believed that the ENS (see Chapter 41) is the primary regulator permitting the storage of substantial amounts of solids and liquids in the proximal part of the stomach without major increases in intragastric pressure.
Figure 42-14 Gastric filling and emptying. (B, Data from Dooley CP, Reznick JB, Valenzuela JE: Variations in gastric and duodenal motility during gastric emptying of liquid meals in humans. Gastroenterology 1984; 87:1114-1119.)
The stomach churns its contents until the particles are small enough to be gradually emptied into the duodenum
The substance most rapidly emptied by the stomach is isotonic saline or water. Emptying of these liquids occurs without delay and is faster the greater the volume of fluid. Acidic and caloric fluids leave the stomach more slowly, whereas fatty materials exit even more slowly (Fig. 42-14B). Solids do not leave the stomach as such, but must first be reduced in size (i.e., trituration). Particles larger than 2 mm do not leave the stomach during the immediate postprandial digestive period. The delay in gastric emptying of solids occurs because solids must be reduced to less than 2 mm; at that point, they are emptied by mechanisms similar to those of liquids.
Vomiting, a frequent sign and symptom in clinical medicine, represents a complex series of multiple afferent stimuli coordinated by one or more brain centers, leading to a coordinated neuromuscular response. Nausea is the sensation that vomiting may occur. The act of emesisinvolves several preprogrammed coordinated smooth and striated muscle responses. The initial event is the abolition of intestinal slow-wave activity that is linked to propulsive peristaltic contractions. As the normal peristaltic contractions of the stomach and small intestine wane, they are replaced by retrogradecontractions, beginning in the ileum and progressing to the stomach. These retrograde contractions are accompanied by contraction of abdominal and inspiratory muscles (external intercostal muscles and diaphragm) against a closed glottis, thus resulting in an increase in intra-abdominal pressure. Relaxation of the diaphragmatic crural muscle and lower esophageal sphincter permits transmission of this increase in intra-abdominal pressure into the thorax, with expulsion of the gastric contents into the esophagus. Movement of the larynx upward and forward and relaxation of the upper esophageal sphincter are required for oral propulsion, whereas closure of the glottis prevents aspiration.
Three major categories of stimuli can potentially induce the foregoing series of events that lead to vomiting. First, gastric irritants and peritonitis, for example, probably act by vagal afferent pathways, presumably to rid the body of the irritant. Second, inner ear dysfunction or motion sickness acts through the vestibular nerve and vestibular nuclei. Third, drugs such as digitalis and certain cancer chemotherapeutic agents activate the area postrema in the brain (see Chapter 11). Pregnancy can also cause nausea and vomiting, by an unknown mechanism. Although several central loci receive these emetic stimuli, the primary locus is the area postrema, also called the chemoreceptor trigger zone. Although no single brainstem site coordinates vomiting, the nucleus tractus solitarii plays an important role in the initiation of emesis. Neurotransmitter receptors that are important in various causes of vomiting include neurokinin NK1 and substance P receptors in the nucleus tractus solitarii, 5-HT3 receptors in vagal afferents, and dopamine D2 receptors in the vestibular nucleus.
Movement of solid particles toward the antrum is accomplished by the interaction of propulsive gastric contractions and occlusion of the pylorus, a process termed propulsion (Fig. 42-15A). Gastric contractions are initiated by the gastric pacemaker, which is located on the greater curvature, approximately at the junction of the proximal and middle portions of the stomach. These contractions propel the luminal contents toward the pylorus, which is partially closed by contraction of the pyloric musculature before delivery of the bolus. This increase in pyloric resistance represents the coordinated response of antral, pyloric, and duodenal motor activity. Once a bolus of material is trapped near the antrum, it is churned to help reduce the size of the particles, a process termed grinding (Fig. 42-15B). Only a small portion of gastric material—that containing particles smaller than 2 mm—is propelled through the pylorus to the duodenum. Thus, most gastric contents are returned to the body of the stomach for pulverization and shearing of solid particles, a process known as retropulsion (Fig. 42-15C). These processes of propulsion, grinding, and retropulsion repeat multiple times until the gastric contents are emptied. Particles larger than 2 mm are initially retained in the stomach but are eventually emptied into the duodenum by MMCs during the interdigestive period that begins ~2 hours or more after eating.
Figure 42-15 Mechanical actions of the stomach on its contents.
Modification of gastric contents is associated with the activation of multiple feedback mechanisms. This feedback usually arises from the duodenum (and beyond) and almost always results in a delay in gastric emptying. Thus, as small squirts of gastric fluid leave the stomach, chemoreceptors and mechanoreceptors—primarily in the proximal but also in the distal portion of the small intestine—sense low pH, a high content of calories, lipid, or some amino acids (i.e., tryptophan), or changes in osmolarity. These signals all decrease the rate of gastric emptying by a combination of neural and hormonal signals, including the vagus nerve, secretin, CCK, and GIP released from duodenal mucosa. Delayed gastric emptying represents the following: the coordinated function of fundic relaxation; inhibition of antral motor activity; stimulation of isolated, phasic contractions of the pyloric sphincter; and altered intestinal motor activity.
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