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Gastric Function
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. (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 are present in both corpus and antrum. The surface epithelial cells, which have their own distinct structure and function, secrete 
and mucus.
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 below, the structure and function of the mucosal epithelial cells in the antrum and body are quite distinct. Likewise, 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. Accordingly, 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 
N42-1 ), intraluminal [H + ] is low but intraluminal [Na + ] is high.
N42-1
Pernicious Anemia
The close relationship between acid and gastrin release is clearly manifested in individuals with impaired acid secretion. In pernicious anemia, atrophy of the gastric mucosa in the corpus and an absence of parietal cells result in a lack in the secretion of both gastric acid and intrinsic factor (IF). Many patients with pernicious anemia exhibit antibody-mediated immunity against their parietal cells, and many of these patients also produce anti-IF autoantibodies.
Because IF is required for cobalamin absorption in the ileum, the result is impaired cobalamin absorption. In contrast, the antrum is normal. Moreover, plasma gastrin levels are markedly elevated as a result of the absence of intraluminal acid, which normally triggers gastric D cells to release somatostatin (see pp. 868–870 ); this, in turn, inhibits antral gastrin release (see Box 42-1 ). Because parietal cells are absent, the elevated plasma gastrin levels are not associated with enhanced gastric acid secretion.
The clinical complications of cobalamin deficiency evolve over a period of years. Patients develop megaloblastic anemia (in which the circulating red blood cells are enlarged), a distinctive form of glossitis, and a neuropathy. The earliest neurological findings are those of peripheral neuropathy, as manifested by paresthesias and slow reflexes, as well as impaired senses of touch, vibration, and temperature. If untreated, the disease will ultimately involve the spinal cord, particularly the dorsal columns, thus producing weakness and ataxia. Memory impairment, depression, and dementia can also result. Parenteral administration of cobalamin reverses and prevents the manifestations of pernicious anemia, but it does not influence parietal cells or restore gastric secretion of either IF or intraluminal acid.
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 in glands of the corpus. 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 B 12 ) absorption in the ileum (see pp. 935-937 ). The parietal cell has a very distinctive morphology (see 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 subchapter and intrinsic factor on page 937 .
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 <2. At pH values that are <3, pepsinogens are rapidly activated to pepsins. A low gastric pH also helps to prevent bacterial colonization of the small intestine. N42-2
N42-2
Gastric pH and Pneumonia
Many patients hospitalized in the intensive care unit (ICU) receive prophylactic anti-ulcer treatments (e.g., proton pump inhibitors, such as omeprazole) that inhibit proton 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 anti-ulcer 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 the risk of pneumonia.
In addition to parietal and chief cells, glands from the corpus of the stomach also contain mucus-secreting cells, which are confined to the neck of the gland (see Fig. 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 below, 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 below, 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 
.
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 food and water with gastric secretory products, including pepsin and acid; (3) grinding 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.
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 O 2 consumption that is needed to support acid secretion.
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. N42-3 The two subunits form a heterodimer with close interaction at the extracellular domain.
N42-3
Gastric H-K Pump
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 anemia 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 CO 2 and H 2 O, which the enzyme carbonic anhydrase (see p. 630 ) converts to 
and H + . The H + is the substrate of the H-K pump. The 
exits across the basolateral membrane via a Cl-HCO 3 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.
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. 13-8 B ). In the second mechanism, ACh and gastrin indirectly induce acid secretion as a result of their stimulation of histamine release from ECL cells.
The three acid secretagogues act through either Ca 2+ /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 ).
ACh binds to an M 3 muscarinic receptor (see pp. 341–342 ) on the parietal-cell basolateral membrane. This ACh receptor couples to a GTP-binding protein (Gα q ) and activates phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG; see p. 58 ). IP 3 causes internal stores to release Ca 2+ , which then probably acts via calmodulin-dependent protein kinase (see p. 60 ). DAG activates protein kinase C (PKC). The M 3 receptor also activates a Ca 2+ channel.
Gastrin binds to a specific parietal-cell receptor that has been identified as the gastrin-cholecystokinin type 2 (CCK 2 ) receptor. Two related CCK receptors have been identified, CCK 1 and CCK 2 . Their amino-acid sequences are ~50% identical, and both are G protein coupled. The CCK 2 receptor has equal affinity for both gastrin and CCK. In contrast, the CCK 1 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 CCK 2 receptor couples to Gα q and activates the same PLC pathway as does ACh; this process leads to both an increase in [Ca 2+ ] i and activation of PKC.
The histamine receptor on the parietal cell is an H 2 receptor that is coupled to the Gα s 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.
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