Gastric Secretion

Four components of gastric juice—hydrochloric acid, pepsin, mucus, and intrinsic factor—have physiologic functions. Acid is necessary for the conversion of inactive pepsinogen to the active enzyme pepsin. Acid and pepsin begin the digestion of dietary protein. However, in the absence of the stomach, pancreatic enzymes hydrolyze all ingested proteins, so that they are totally absorbed. Gastric acid is bacteriostatic, and most bacteria entering the gastrointestinal tract with ingested food are killed in the stomach. Without gastric acid or in cases in which its secretion is severely reduced, there is a higher incidence of bacterial infections of the intestines. Mucus is secreted as a protective coating for the stomach and serves as a physical lubricant and barrier between the cells and ingested material. Mucus and bicarbonate trapped in the mucus layer also maintain the mucosal surface at a near -neutral pH. This is part of the so-called gastric mucosal barrier that protects the stomach from acid and pepsin. Intrinsic factor binds vitamin B12 and is necessary for its absorption in the ileum. This is the only indispensable substance in gastric juice. Patients who have undergone a total gastrectomy must take injections of vitamin B12.

Functional Anatomy of the Stomach

The stomach is divided into two regions according to secretory function. The proximal 80% consists of acid-secreting oxyntic gland mucosa. The remaining distal 20% does not secrete acid but contains endocrine cells that synthesize and release the hormone gastrin. The mucosa in this region is referred to as the pyloric gland mucosa, and the region itself is often called the antrum

The gastric mucosa contains glands that open into pits in the mucosal surface (Fig. 7). The pits of the oxyntic gland area are shallow and lined with mucous or surface epithelial cells, which line the surface as well. At the bases of the pits are the openings of the glands.

FIGURE 6 Anatomic and functional divisions of the stomach. In discussions of secretion, the stomach is divided into the acid-secreting oxyntic gland area and the gastrin-producing pyloric gland area.

FIGURE 7 Oxyntic gland and surface pit, showing the positions of the various cell types.


FIGURE 6 Anatomic and functional divisions of the stomach. In discussions of secretion, the stomach is divided into the acid-secreting oxyntic gland area and the gastrin-producing pyloric gland area.

FIGURE 7 Oxyntic gland and surface pit, showing the positions of the various cell types.

The glands project into the mucosa toward the serosa and account for approximately three-fourths of the total mucosal thickness. The oxyntic glands contain acid-producing, parietal, or oxyntic cells and the chief or peptic cells, which synthesize and secrete the enzyme precursor pepsinogen (Fig. 7). Pyloric glands contain the hormone-producing gastrin (G) cells and mucous cells, which also secrete pepsinogen. The oxyntic glands contain mucous neck cells, located primarily where the glands open into the pits. These cells secrete soluble mucus, which is thinner than the visible mucus produced by the surface epithelial cells. Each gland also contains a stem cell located in the area of the mucous neck cells. These are proliferative cells: After division, one daughter cell remains anchored as the new stem cell. The other undergoes a number of divisions and the resulting cells may migrate to the surface, where they differentiate into surface epithelial cells, or they may migrate down into the glands, where they become parietal cells. The pits of the pyloric gland area are much deeper than those of the oxyntic gland area, occupying about two-thirds of the mucosa. Stem cells are found both in the neck regions and in the glands themselves. In the pyloric gland area, daughter cells differentiate into mucous cells or into G cells. Peptic cells normally arise by mitosis, but during times when damaged mucosa is being repaired, they may also differentiate from stem cells.

Parietal cells secrete hydrochloric acid at concentrations ranging from 150-160 mmol/L in amounts of 1-2 L/day. The human stomach contains approximately 1 billion parietal cells, and the number of parietal cells determines the secretory capacity of the stomach. Because the pH of this solution is less than 1 and that of the blood is 7.4, it means that the parietal cells concentrate H+ several million times. The energy required for this process comes from adenosine triphos-phate (ATP) produced by the numerous mitochondria within the cells (Fig. 8A). In humans, parietal cells also secrete intrinsic factor. In some species, intrinsic factor is produced by the chief cells.

The ultrastructure of the parietal cell is unique and reflects its function. The cytoplasm of the nonsecreting parietal cell (Fig. 8A) contains a branching intracellular or secretory canaliculus that is closed to the lumen of the gland. The canaliculi are lined by short microvilli, which are not prominent. The cytoplasm of the resting cell also contains an elaborate system of tubular and vesicular membranes called tubulovesicles. These are usually concentrated in the apical region of the cell. Within a few minutes after the stimulation of secretion, the secretory canaliculus (the apical membrane) begins to expand and becomes open to the lumen. The microvilli increase greatly in number and length, actually becoming filamentous, so that the surface area of the apical membrane may increase 6- to 10-fold (Fig. 8B). This expansion is matched by a decrease in the surface area of the membranes of the tubulovesicles. Removal of the secretory stimulus leads to a collapse of the canaliculi and reappearance of the tubulovesicles. This morphologic transformation is a complex process, and several theories have been proposed to account for it. Most evidence favors a membrane recycling process that proposes that the tubulovesicles fuse with the apical plasma membrane when the cell is stimulated, increasing its surface area. After stimulation, the surface membrane is believed to be reincorporated into tubulo-vesicles by a process of endocytosis.

The active transport mechanism responsible for the secretion of H+ is the (H + ,K + )-ATPase enzyme, which in the resting cell is located in the membranes of the tubulovesicles. Thus, during the stimulation of secretion, the H + pump is relocated to the apical or secretory membrane. The activities of (H + ,K + )-ATPase and carbonic anhydrase, another enzyme involved in acid secretion, increase after the stimulation of secretion. Acid secretion begins within 10 min of administering a stimulant. The lag time is believed to be due to the morphologic conversion described and the activation of these enzymes.

FIGURE 8 (A) Nonsecreting parietal cell is characterized by numerous tubulovesicles and an internalized distended intracellular canaliculus, that has few microvilli. (B) In the secreting parietal cell, the tubulovesicles have fused with the membrane of intracellular canaliculus, which now opens into the lumen of the gland. The fusion has produced abundant, long microvilli within the canaliculus. (Modified from Ito S., Functional gastric morphology. In Johnson LR, ed., Physiology of the gastrointestinal tract. New York: Raven Press, 1981, p 531.)

FIGURE 8 (A) Nonsecreting parietal cell is characterized by numerous tubulovesicles and an internalized distended intracellular canaliculus, that has few microvilli. (B) In the secreting parietal cell, the tubulovesicles have fused with the membrane of intracellular canaliculus, which now opens into the lumen of the gland. The fusion has produced abundant, long microvilli within the canaliculus. (Modified from Ito S., Functional gastric morphology. In Johnson LR, ed., Physiology of the gastrointestinal tract. New York: Raven Press, 1981, p 531.)

The surface epithelial or mucous cells are cuboidal and contain large numbers of mucous granules at their apical surfaces. During secretion, the membranes of the granules fuse with the plasma membrane, releasing mucus into the lumen.

Like other cells that synthesize and secrete enzymes, the peptic or chief cells have a highly developed endoplasmic reticulum. After synthesis by the rough endoplasmic reticulum, the enzyme precursor pepsinogen molecules are transported to the numerous Golgi structures and packaged into zymogen granules. The granules migrate to the apical region of the cell, where they are stored in the cytoplasm. A secretory stimulus triggers membrane fusion and exocytosis of pepsinogen. This entire process of enzyme synthesis, packaging, and secretion is discussed later in this chapter in the section concerning the pancreas.

Electrolytes of Gastric Juice

At all rates of secretion, gastric juice is essentially isotonic to plasma. The ionic composition of gastric juice, however, varies with the rate of secretion (Fig. 9). At basal (unstimulated) rates of secretion, gastric juice is primarily a solution of NaCl with small amounts of H + and K+. As the rate of secretion increases, the concentration of Na+ decreases and the concentration of H+ increases, so that at peak rates gastric juice is primarily HC1 with small amounts of K+ and Na+. At all rates of secretion, H+ and Cl are secreted against their electrochemical gradients. It is important to realize that even at basal secretory rates, gastric juice is extremely acidic. The concentration of H+ may range from 10-20 mmol/L basally up to 130-150 mmol/L at peak rates. In other words, the pH will range from pH 2 to pH < 1.

The changes in ionic composition with the rate of gastric secretion are due to the manner in which the juice is produced. There are actually two separate secretions. A nonparietal secretion contains primarily Na+ and Cl" with K+ and HCO" present in amounts approximately

equal to their concentrations in plasma. In the absence of all H+ secretion, HCO" may be detected in gastric juice in concentrations up to 30 mmol/L. This nonpari-etal component is produced continually at a constant low rate. The parietal component, which is a solution of 150 mmol/L HC1 plus 10-20 mmol/L KC1, is secreted against this background at rates depending on the degree of stimulation. Therefore, at all rates of secretion, gastric juice is a mixture of these two components. At low rates, the nonparietal component predominates. As the secretory rate increases, and because the increase is due only to the parietal cell component, gastric juice begins to resemble pure parietal cell secretion.

This so-called two-component theory of gastric secretion is probably an oversimplification. There is no doubt exchange of H+ for Na+ as the parietal secretion moves up the gland into the lumen. Although such changes are minimal at high rates of secretion, they contribute significantly to the final composition of the juice at lower rates, when more time is available for exchange.

Knowledge of the composition of gastric juice is important in treating a patient who has lost significant volumes of gastric juice by aspiration or chronic vomiting. Replacement of only NaCl will result in hypokalemic metabolic alkalosis.

Acid Secretory Process

The cellular processes that best explain the secretion of HC1 are shown in Fig. 10. The exact metabolic steps in the production of H + are not known. However, the reaction is summarized by

Medium Secretory Rate

FIGURE 9 Relationships between the concentrations of the principal ions in gastric juice and the rate of secretion.

The H+ is actively pumped across the apical membrane in exchange for luminal K+ by the (H + ,K + )-ATPase already discussed. K+ is accumulated within the cell by the (Na + ,K + )-ATPase in the basolateral membrane. The accumulated K+ moves down its electrochemical gradient, leaking through conductive pathways in both membranes. The K+ entering the luminal space is, therefore, being recycled by the (H + ,K + )-ATPase. Cl" enters the cell across the basolateral membrane in exchange for HCO". The HCO" is formed from CO2 and OH", which is accumulated within the cell as H+ is pumped out. Carbonic anhydrase (Ca) catalyzes the formation of HCO" from OH" and CO2. The HCCV is carried away by the blood. The pH of the venous blood from an actively secreting stomach may actually be higher than the pH of the arterial blood, because of this so-called alkaline tide. In addition, the (Na + -K + ) pump maintains a low intracellular Na+ concentration.

FIGURE 10 Cellular processes that best account for the production of HCl by the gastric parietal cell.

Some Na + moves down its concentration gradient, entering the cell across the basolateral membrane in exchange for H +. This is a secondary active transport of H+ out of the cell. This Na + is recycled by the sodium pump. The Na + -H + exchange also increases the amount of base in the cell, facilitating the entrance of Cl". Therefore, the movement of Cl" from the blood to the lumen against its electrochemical gradient is achieved by virtue of excess OH" in the cell after H+ has been pumped out. HCO" is produced from CO2 and OH" and diffuses down its concentration gradient in exchange for Cl" entering the cell. Water moves into the lumen by osmosis in response to the secretion of ions.

The potential difference across the resting gastric mucosa is approximately "70 to "80 mV lumen negative with respect to the blood. This significant charge difference is due to the active secretion of Cl" by surface epithelial cells as well as parietal cells (see Chapter 36 for a discussion of the Cl" secretory mechanism). When acid secretion is stimulated, the potential difference decreases to "30 or "40 mV because of the transport of positively charged H+ in the same direction as Cl". Thus, H+ is actually secreted down an electrical gradient, facilitating its transport against the concentration gradient of several million-fold.

The potential differences across the mucosa of the various regions of the gastrointestinal tract vary according to location, and this information is frequently used by physicians in locating the tips of catheters. For example, as a catheter with an attached electrode moves from the esophagus ("15 mV) into the stomach, the potential difference will increase dramatically. It will then decrease from approximately "80 to "5 mV as the tip passes the pylorus and enters the duodenum.

The secretion of H+ against such a great concentration gradient and the maintenance of an electrical gradient require minimal leakage of ions and acid back into the mucosa. The absence of significant leakage across the gastric mucosa is attributed to the so-called gastric mucosal barrier. When this barrier is disrupted by bile acids, alcohol, aspirin, or any of a number of other agents that damage the mucosa, the potential difference decreases considerably as ions leak down their electrochemical gradients. H+ then enters the mucosa and damage occurs. The anatomic nature of the barrier is not totally defined; its properties and role in mucosal damage are more fully discussed in the section on the pathophysiology of ulcer disease.

Stimulants of Acid Secretion

Only a few substances directly stimulate acid secretion from the parietal cells. These include the antral hormone gastrin, the parasympathetic mediator acetyl-choline, and the paracrine agent histamine. The amounts of gastrin and acetylcholine reaching the stomach vary in response to the digestive state and are responsible for the regulation of acid secretion. In addition to these three main stimulants, an unknown hormone of intestinal origin stimulates acid secretion. This peptide has been named enterooxyntin to denote both its origin and action. In humans, an additional amount of stimulation is caused by circulating amino acids after their absorption from the small intestine.

Histamine is released from the enterochromaffin-like cells (ECLs) within the lamina propria and diffuses through the extracellular fluid to the parietal cells. Histamine acts as a paracrine to stimulate acid secretion. Figure 11 illustrates the relationships between gastrin, acetylcholine, and histamine. The ECL cell contains receptors for gastrin and acetylcholine. Gastrin is the major regulator of the ECL cells. Acutely gastrin stimulates the release of histamine from the ECL cells and the synthesis of new histamine by increasing the activity of the enzyme, histidine decarboxylase. Over the longer term, gastrin stimulates the proliferation of the ECL cells. Although histamine release and synthesis are also increased by acetylcholine, its effects are not as pronounced as those of gastrin.

The parietal cell membrane has separate receptors for histamine, gastrin, and acetylcholine (Fig. 11).

Nerves Blood

FIGURE 11 Interactions of histamine, gastrin, and acetylcholine (Ach) on the parietal cell. This model accounts for the potentiation between stimuli and the inhibitory effects of atropine (At) and cimetidine (Cra).

Nerves Blood

FIGURE 11 Interactions of histamine, gastrin, and acetylcholine (Ach) on the parietal cell. This model accounts for the potentiation between stimuli and the inhibitory effects of atropine (At) and cimetidine (Cra).

The final rate of secretion, however, depends on the interactions of these secretagogues. At this point, it is important to understand the concept of potentiation. Potentiation occurs between two stimulants when the response to their simultaneous administration exceeds the sums of the responses to each agent administered separately. Another convenient definition is that the maximal response to the two agents acting together exceeds the maximal response to either agent alone. Potentiation allows small amounts of endogenous stimuli to produce near maximal effects, and within the gastrointestinal tract it is a common physiologic event.

At the parietal cell, histamine potentiates the actions of gastrin and acetylcholine. In a similar manner, potentiation also exists between gastrin and acetylcho-line. These interactions between stimuli are one reason why specific antihistamines that block acid secretion stimulated by histamine (H2-receptor blockers such as cimetidine) also block secretory responses to acetylcho-line and gastrin. As one would predict, atropine, the specific antagonist of the muscarinic actions of acet-ylcholine, also blocks secretion stimulated by histamine and gastrin. Thus, the effects of the H2 blockers on gastrin- or acetylcholine-stimulated secretion are due to the inhibition of the portion of the secretory response resulting from histamine potentiation as well as to the inhibition of histamine released by their actions on the ECL cells. Similarly, the inhibition of histamine- and gastrin-stimulated acid secretion by atropine is caused by removal of the potentiating interactions with acet-ylcholine. The points at which atropine and cimetidine affect the secretory process are indicated in Fig. 11. No specific and potent receptor blocker for gastrin is available for similar studies.

The exact intracellular events leading to potentiation are unknown. However, potentiation occurs only between those agents that act through different second messenger systems after binding to their receptors. Acetylcholine binds to the muscarinic receptor, resulting in the formation of inositol trisphosphate and the subsequent increase in intracellular Ca2+. Histamine binding activates adenylate cyclase, resulting in the formation of cAMP. The messenger system for gastrin has not been worked out, but appears to involve Ca2 + rather than cAMP and to be somewhat different from the cholinergic system.

Stimulation of Acid Secretion

Basal or interdigestive secretion is that which occurs in the absence of all gastrointestinal stimulation. Basal secretion is equal to about 10% of the maximal response to a meal. In humans, basal secretion shows a circadian rhythm, with the highest acid output in the evening and the lowest in the morning. The cause of this variation is unknown, but it is not matched by changes in plasma gastrin levels. In both dogs and humans, basal acid secretion is reduced by vagotomy, further reduced by antrectomy (removal of the source of gastrin), and inhibited by histamine H2 antagonists. These results indicate that the presence of background amounts of acetylcholine, gastrin, and histamine account for at least part of basal secretion.

Between meals, therefore, the emptied stomach contains a relatively small volume of gastric juice. The pH of this fluid, however, is usually less than 2.0, and the mucosa is acidified. Acidification of the antral mucosa prevents gastrin release, and the acidification of the oxyntic gland mucosa has an inhibitory effect on acid secretion. Both of these mechanisms appear to involve the acid-mediated release of somatostatin and the paracrine action of somatostatin on the G cells in the antrum and the parietal cells in the oxyntic gland area.

The stimulation of acid secretion is divided into the cephalic, gastric, and intestinal phases for convenience in understanding the different mechanisms involved. This division is based on the location of the receptors initiating the secretory responses. The division is somewhat artificial, for during most of the response to a meal stimulation is initiated simultaneously from more than one area. The stomach of a normal 70-kg man has the capacity to secrete about 20 mmol of acid per hour.

Cephalic Phase

Stimulation during the cephalic phase accounts for about 30% of the response to a meal. The presence of food in the mouth stimulates mechanoreceptors (pressure) and chemoreceptors (smell and taste) located in the tongue and the buccal and nasal cavities. Central pathways can also be activated by the thought of an appetizing meal or events triggering conditioned reflexes. In each case, afferent impulses are relayed to the vagal nucleus, and vagal efferent nerves carry impulses to the stomach (Fig. 12). The entire cephalic phase is therefore blocked by vagotomy.

The cephalic phase can be studied by a procedure known as sham feeding. A subject is given an appetizing meal and allowed to feed himself and chew but not to swallow the food. The cephalic phase can also be activated by direct vagal stimulation. In humans, this is mimicked by inducing hypoglycemia, which activates hypothalamic centers that stimulate secretion via vagal pathways. Hypoglycemia can be induced with insulin or tolbutamide or by giving glucose analogues, such as 3-methylglucose or 2-deoxyglucose, which interfere with glucose metabolism.

The vagus increases acid secretion through two mechanisms: It stimulates the parietal cells directly and stimulates the release of gastrin. The mediator at the parietal cell is acetylcholine, and the mediator at the G cell is bombesin, also called gastrin-releasing peptide (GRP). Atropine blocks the direct effects on the

FIGURE 12 Mechanisms stimulating gastric acid secretion during the cephalic phase. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

parietal cell, but does not block the release of gastrin. In humans, the direct effect on the parietal cell is more important, because selective vagotomy of the acid-secreting portion of the stomach abolishes the response to sham feeding, whereas antrectomy only moderately reduces it. During sham feeding experiments or other studies designed to examine the cephalic phase, gastrin release will not occur unless steps are taken to neutralize the acid present in the stomach. The mechanisms involved in the cephalic phase are outlined in Fig. 12.

Gastric Phase

As swallowed food enters the stomach, it mixes with the small volume of acid present. Buffers (primarily proteins) in the food neutralize the acid, raising the intragastric pH from around 2 to as high as 6. Because gastrin release is inhibited at antral pHs below 3, little or no gastrin is released from a stomach that does not contain food. When the pH increases above 3, vagal stimulation from the cephalic phase initiates gastrin release. Gastrin release is maintained during the gastric phase by both neural and chemical mechanisms. The gastric phase accounts for approximately 60% of the acid response to a meal.

Distension of the gastric wall activates mechano-receptors initiating extramural or vagovagal reflexes and intramural reflexes that stimulate both gastrin release and acid secretion. Distension of the oxyntic gland area stimulates the parietal cells directly via a local or intramural reflex mediated by acetylcholine. Extramural reflexes whose afferent and efferent paths are contained in the vagus nerve are also triggered. This vagovagal reflex results in effects identical to those of the cephalic phase, namely, parietal cell stimulation by acetylcholine and gastrin release mediated by GRP. Distension of the antrum causes gastrin release via a local, intramural reflex that appears to be mediated by acetylcholine. Antral distension also elicits a vagovagal reflex that results in both gastrin release via GRP and stimulation of the parietal cells directly via acetylcholine. All gastrin release stimulated by distension is blocked by acidifying the antral mucosa. Distension with acidified solutions, however, will still result in increased acid secretion through local and vagovagal reflexes, directly stimulating the parietal cells via acetylcholine. The reflexes are summarized in Fig. 13.

The only major nutrient that stimulates gastric acid secretion chemically is protein. To be effective, the protein must be partially digested to peptides and amino acids. The entire stimulation of acid secretion by protein digestion products appears to be due to the direct chemical release of gastrin. This release of gastrin is not blocked by vagotomy or atropine, but it is blocked by

Gastrin -

FIGURE 13 Mechanisms stimulating gastric acid secretion during the gastric phase. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

Gastrin -

FIGURE 13 Mechanisms stimulating gastric acid secretion during the gastric phase. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

acidifying the antral mucosa below pH 3. The most effective amino acids for releasing gastrin in humans are phenylalanine and tryptophan.

The only other commonly ingested agents known to stimulate acid secretion chemically are calcium, alcohol, and caffeine. In the human, calcium ions are a strong stimulus for gastrin release and acid secretion. High concentrations of ethanol release gastrin, and intravenous ethanol increases acid secretion by an unknown mechanism. In general, solutions of ethanol up to 15% have little or no effect on gastric secretion. Caffeine is a direct stimulant of acid secretion in humans. It probably acts by inhibiting the phosphodiesterase that breaks down cAMP. Caffeine, however, is not the major stimulant present in coffee, because decaffeinated coffee is as strong a stimulant of secretion as regular coffee.

Intestinal Phase

Acid secretion as a result of stimuli acting from the intestine is minor, accounting for only 10% of the total response to a meal. Protein digestion products in the duodenum stimulate acid secretion by at least two mechanisms. One seems to involve the release of an unidentified hormone by distension. This hormone has been named enterooxyntin to denote both its location and effect. Intravenously infused amino acids also stimulate acid secretion. Therefore, part of the intestinal phase of stimulation is due to the circulation of absorbed amino acids to the parietal cells. Intestinal mucosa contains gastrin, but it is not released under normal conditions in humans. The factors stimulating acid secretion during the entire response to a meal are summarized in Fig. 14. Note that histamine is present to stimulate the parietal cell and potentiate the other stimuli during all phases.

Regulation of Gastrin Release

A summary of the pathways believed to be involved in the regulation of gastrin release is depicted in Fig. 15. Endocrine cells containing somatostatin are located close to the gastrin-containing G cells. Somatostatin, acting as a paracrine, inhibits gastrin release. Vagal stimulation increases gastrin release via two mechanisms. First, some neurons release GRP (bombesin) at the G cells, stimulating them directly to release gastrin. Second, other inhibitory neurons go to the somatostatin cell, where they release acetylcholine, which inhibits somatostatin release. This dual pathway mechanism accounts for the observations that vagus-stimulated gastrin release is not blocked by atropine and that vagal stimulation decreases somatostatin release into mucosal perfusates. Digested protein and other chemicals act directly on the G cell to stimulate gastrin release. It is believed that the apical surface of the G cell contains specific receptors to recognize these stimulants. These receptors, however, have not been identified. Acid in the lumen resulting in a pH <3 acts directly on the somatostatin cell to stimulate somatostatin release. When somatostatin is released, it blocks the effect of all stimulants of gastrin release. Within the oxyntic gland area, somatostatin acts directly on the parietal cell to inhibit acid secretion.

Inhibition of Acid Secretion

The duration of the acid secretory response to a meal is determined primarily by the intragastric pH and the nature of the chyme entering the duodenum. As shown in Fig. 16, at the start of a meal the stomach contains a small volume of acidic gastric juice, which acidifies the antral mucosa. Somatostatin is released and acts through a paracrine mechanism to inhibit gastrin release and to inhibit directly the parietal cells as well. As a result, the

FIGURE 14 Summary of acid secretion.

Gastrin Ach

FIGURE 14 Summary of acid secretion.

ECL cell —► Histamine the mechanisms for stimulating gastric

FIGURE 15 Mechanism accounting for the regulation ot gastrin release.

rate of secretion is low (basal). As the meal is ingested, the small volume of acid is rapidly neutralized by buffers present in the food, intragastric pH increases to 5 or 6, and acid secretion begins. Secretion is initiated by the direct vagal component of the cephalic response, but as the intragastric pH rises above 3, gastrin release is triggered by stimuli of the cephalic and gastric phases. An hour after the meal, the rate of acid secretion is maximal, the buffering capacity of the meal is saturated, a significant portion of the meal has emptied from the stomach, and the pH of the contents has begun to decrease. As the pH of the contents continues to fall, gastrin release is inhibited, removing a significant factor for the stimulation of acid secretion, and somatostatin inhibits the parietal cells. This negative feedback mechanism is extremely important in the regulation of acid secretion.

As chyme enters the duodenum, it initiates a number of processes that inhibit acid secretion at the level of the parietal cell. These mechanisms are both neural and humoral and are triggered by the pH, osmolarity, and fat content of the chyme. Thus, these processes are similar, and some may be identical to those that inhibit gastric emptying. Large amounts of acid may release sufficient secretin from the duodenal mucosa to inhibit the parietal cells. Acid also triggers an inhibitory intramural neuroreflex. Hyperosmotic solutions and fatty acids release an as yet unidentified hormone or hormones that inhibit acid secretion. These substances are called enterogastrones, denoting their location and inhibitory effect on the stomach. Gastric inhibitory peptide (GIF) may also take part in the inhibition of both acid secretion and gastrin release. None of the hormonal mediators of these responses is firmly established. The important thing for the student to understand is that both neural and humoral mechanisms exist for the inhibition of acid secretion, and that these are triggered by chyme in the duodenum. Our knowledge of the inhibition of acid secretion is summarized in Fig. 17.


Pepsin is stored and secreted as the inactive precursor pepsinogen, which has a molecular weight of 42,500. At intragastric pH lower than 5, pepsinogen is split to form the active enzyme pepsin, which has a molecular weight of 35,000. Pepsin can catalyze the formation of


FIGURE 16 The relationship between gastric acid secretory rate, intragastric pH, and the volume of gastric contents during a meal.


FIGURE 16 The relationship between gastric acid secretory rate, intragastric pH, and the volume of gastric contents during a meal.




Inhibits gastrin release

Inhibits acid secretion

Oxyntic gland area

Acid (pH < 3.0)


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