Identify the secretory products of the stomach, their cells of origin, and their functions.
Understand the mechanisms making it possible for the stomach to secrete 150 mN hydrochloric acid.
Describe the electrolyte composition of gastric secretion and how it varies with the rate of secretion.
Identify the major stimulants of the parietal cell and explain their interactions.
Discuss the phases involved in the stimulation of gastric acid secretion and the processes acting in each.
Identify factors that both stimulate and inhibit the release of the hormone gastrin.
Explain the processes that result in the inhibition of gastric acid secretion following the ingestion of a meal and its emptying from the stomach.
Describe the processes resulting in gastric and duodenal ulcer diseases.
Five constituents of gastric juice— intrinsic factor , hydrogen ion (H + ), pepsin , mucus , and water —have physiologic functions. They are secreted by the various cells present within the gastric mucosa. The only indispensable ingredient in gastric juice is intrinsic factor, required for the absorption of vitamin B 12 by the ileal mucosa. Acid is necessary for the conversion of inactive pepsinogen to the enzyme pepsin. Acid and pepsin begin the digestion of protein, but in their absence pancreatic enzymes hydrolyze all ingested protein, so no nitrogen is wasted in the stools. Acid also kills a large number of bacteria that enter the stomach, thereby reducing the number of organisms reaching the intestine. In cases of severely reduced or absent acid secretion, the incidence of intestinal infections is greater. Mucus lines the wall of the stomach and protects it from damage. Mucus acts primarily as a lubricant, protecting the mucosa from physical injury. Together with bicarbonate ( <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HCO−3HCO3−
HCO 3 −
), mucus neutralizes acid and maintains the surface of the mucosa at a pH near neutrality. This is part of the gastric mucosal barrier that protects the stomach from acid and pepsin digestion. Water acts as the medium for the action of acid and enzymes and solubilizes many of the constituents of a meal.
Gastric juice and many of its functions originally were described by a young army surgeon, William Beaumont, stationed at a fort on Mackinac Island in northern Michigan. Beaumont was called to treat a French Canadian, Alexis St. Martin, who had been accidentally shot in the side at close range with a shotgun. St. Martin unexpectedly survived but was left with a permanent opening into his stomach from the outside (gastric fistula). The accident occurred in 1822, and during the ensuing 3 years Beaumont nursed St. Martin back to health. Beaumont retained St. Martin “for the purpose of making physiological experiments,” which were begun in 1825. Beaumont’s observations and conclusions, many of which remain unchanged today, include the description of the juice itself and its digestive and bacteriostatic functions, the identification of the acid as hydrochloric, the realization that mucus was a separate secretion, the realization that mental disturbances affected gastric function, a direct study of gastric motility, and a thorough study of the ability of gastric juices to digest various foodstuffs.
Functionally, the gastric mucosa is divided into the oxyntic gland area and the pyloric gland area ( Fig. 8.1 ). The oxyntic gland mucosa secretes acid and is located in the proximal 80% of the stomach. It includes the body and the fundus. The distal 20% of the gastric mucosa, referred to as the pyloric gland mucosa, synthesizes and releases the hormone gastrin. This area of the stomach often is designated the antrum .
The gastric mucosa is composed of pits and glands ( Fig. 8.2 ). The pits and surface itself are lined with mucous or surface epithelial cells. At the base of the pits are the openings of the glands, which project into the mucosa toward the outside or serosa. The oxyntic glands contain the acid-producing parietal cells and the peptic or chief cells , which secrete the enzyme precursor pepsinogen . Pyloric glands contain the gastrin-producing G cells and mucous cells, which also produce pepsinogen. Mucous neck cells are present where the glands open into the pits. Each gland contains a stem cell in this region. These cells divide; one daughter cell remains anchored as the stem cell, and the other divides several times. The resulting new cells migrate both to the surface, where they differentiate into mucous cells, and down into the glands, where they become parietal cells in the oxyntic gland area. Endocrine cells such as the G cells also differentiate from stem cells. Peptic cells are capable of mitosis, but evidence indicates that they also can arise from stem cells during the repair of damage to the mucosa. Cells of the surface and pits are replaced much more rapidly than are those of the glands.
The parietal cells secrete hydrochloric acid (HCl) and, in humans, intrinsic factor. In some species the chief cells also secrete intrinsic factor. The normal human stomach contains approximately 1 billion parietal cells, which produce acid at a concentration of 150 to 160 mEq/L. The number of parietal cells determines the maximal secretory rate and accounts for interindividual variability. The human stomach secretes 1 to 2 L of gastric juice per day. Because the pH of the final juice at high rates of secretion may be less than 1 and that of the blood is 7.4, the parietal cells must expend a large amount of energy to concentrate H + . The energy for the production of this more than a million-fold concentration gradient comes from adenosine triphosphate (ATP), which is produced by the numerous mitochondria located within the cell ( Fig. 8.3 ).
During the resting state, the cytoplasm of the parietal cells is dominated by numerous tubulovesicles. There is also an intracellular canaliculus that is continuous with the lumen of the oxyntic gland. The tubulovesicles contain the enzymes carbonic anhydrase (CA) and H + , potassium (K + )-ATPase (H + ,K + -ATPase), necessary for the production and secretion of acid, on their apical membranes. Thus in the resting parietal cell, any basal secretion is directed into the lumen of the tubulovesicles and not into the cytoplasm of the cell. Stimulation of acid secretion causes the migration of the tubulovesicles and their incorporation into the membrane of the canaliculus as microvilli. As a result, the surface area of the canaliculus is greatly expanded to occupy much of the cell. The activities of the enzymes, which are now in the canalicular membrane, increase significantly during acid secretion. Acid secretion begins within 10 minutes of administering a stimulant. This lag time probably is expended in the morphologic conversion and enzyme activations described previously. Following the removal of stimulation, the tubulovesicles reform and the canaliculus regains its resting configuration.
The surface epithelial mucous cells are recognized primarily by the large number of mucous granules at their apical surfaces. During secretion, the membranes of the granules fuse with the cell membrane and expel mucus.
Peptic cells contain a highly developed endoplasmic reticulum for the synthesis of pepsinogen. The proenzyme is packaged into zymogen granules by the numerous Golgi structures within the cytoplasm. The zymogen granules migrate to the apical surface, where, during secretion, they empty their contents into the lumen by exocytosis. This entire procedure of enzyme synthesis, packaging, and secretion is discussed in greater detail in Chapter 9 .
Endocrine cells of the gut also contain numerous granules. Unlike in the peptic and mucous cells, however, these hormone-containing granules are located at the base of the cell. The hormones are secreted into the intercellular space, from which they diffuse into the capillaries. The endocrine cells have numerous microvilli extending from their apical surface into the lumen. Presumably the microvilli contain receptors that sample the luminal contents and trigger hormone secretion in response to the appropriate stimuli.
Secretion of Acid
The transport processes involved in the secretion of HCl are shown in Fig. 8.4 . The exact biochemical steps for the production of H + are not known, but the reaction can be summarized as follows:
HOH → OH − + H +
H + is pumped actively into the lumen and <SPAN role=presentation tabIndex=0 id=MathJax-Element-3-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−¿’>HCO−¿3HCO3−¿
HCO 3 − ¿
diffuses into the blood, thus giving gastric venous blood a higher pH than that of arterial blood when the stomach is secreting. Step 2 is catalyzed by CA. Inhibition of this enzyme decreases the rate but does not prevent acid secretion. Metabolism produces much of the carbon dioxide (CO 2 ) used to neutralize hydroxyl (OH – ), but at high secretory rates, CO 2 from the blood also is required. The active transport of H + across the mucosal membrane is catalyzed by H + ,K + -ATPase, and H + is pumped into the lumen in exchange for K + . Within the cell, K + is accumulated by the sodium (Na + ),K + -ATPase in the basolateral membrane. Accumulated K + moves down its electrochemical gradient and leaks across both membranes. Luminal K + is therefore recycled by the H + ,K + -ATPase. Chloride (Cl − ) enters the cell across the basolateral membrane in exchange for <SPAN role=presentation tabIndex=0 id=MathJax-Element-4-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−¿’>HCO−¿3HCO3−¿
HCO 3 − ¿
. The pumping of H + out of the cell allows OH – to accumulate and form <SPAN role=presentation tabIndex=0 id=MathJax-Element-5-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−¿’>HCO−¿3HCO3−¿
HCO 3 − ¿
from CO 2 , a step catalyzed by CA. The <SPAN role=presentation tabIndex=0 id=MathJax-Element-6-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−¿’>HCO−¿3HCO3−¿
HCO 3 − ¿
entering the blood causes the blood’s pH to increase, so the gastric venous blood from the actively secreting stomach has a higher pH than arterial blood. The production of OH – is facilitated by the low intracellular Na + concentration established by the Na + ,K + -ATPase. Some Na + moves down its gradient back into the cell in exchange for H + , thus further increasing OH – production. This process in turn increases <SPAN role=presentation tabIndex=0 id=MathJax-Element-7-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−¿’>HCO−¿3HCO3−¿
HCO 3 − ¿
production and enhances the driving force for the entry of Cl − and its uphill movement from the blood into the lumen. Thus the movement of Cl − from blood to lumen against both electrical and chemical gradients is the result of excess OH – in the cell after the H + has been pumped out.
The H + ,K + -ATPase catalyzes the pumping of H + out of the cytoplasm into the secretory canaliculus in exchange for K + . The exchange of H + for K + has a 1:1 stoichiometry and is therefore electrically neutral. In the resting cell, the H + ,K + -ATPase is found in the membranes of the tubulovesicles. As noted previously, following a secretory stimulus, the tubulovesicles fuse with the canaliculus, thus greatly increasing the surface area of the secretory membrane and the number of “pumps” in it. When acid secretion ends, the tubulovesicles form again, and the canaliculus shrinks. Although there has been some controversy over whether the tubulovesicles are separate structures or whether they are collapsed canalicular membrane, current evidence indicates that they are separate structures that fuse with the canaliculus and undergo recycling following secretion. H + ,K + -ATPase, like Na + , K + -ATPase, with which it has a 60% amino acid homology, is a member of the P-type ion-transporting ATPases, which also include the calcium (Ca 2+ )-ATPase. Inhibition of the H + ,K + -ATPase totally blocks gastric acid secretion. Drugs such as omeprazole, a substituted benzimidazole, are accumulated in acid spaces and are activated at low pH. They then bind irreversibly to sulfhydryl groups of the H + ,K + -ATPase and inactivate the enzyme. These pump inhibitors are the most potent of the different types of acid secretory inhibitors and are effective agents in the treatment of peptic ulcer, even ulcer caused by gastrinoma (Zollinger-Ellison syndrome).