The dorsal surface of the tongue contains numerous mucosal projections called lingual papillae (Figure 15-1). Each lingual papilla is formed by a highly vascular connective tissue core and a covering layer of stratified squamous epithelium. According to their shape, lingual papillae can be divided into four types: (1) filiform papillae (narrow conical), the most abundant; (2) fungiform papillae (mushroom-shaped); (3) circumvallate papillae; and (4) foliate papillae (leaf-shaped), rudimentary in humans but well developed in rabbits and monkeys.

Figure 15-1 Tongue

Taste buds are found in all lingual papillae except the filiform papillae. Taste buds are barrel-shaped epithelial structures containing chemosensory cells called gustatory receptor cells. Gustatory receptor cells are in synaptic contact with the terminals of the gustatory nerves.

Circumvallate (wall-like) papillae are located in the posterior part of the tongue, aligned in front of the sulcus terminalis. The circumvallate papilla occupies a recess in the mucosa and, therefore, it is surrounded by a circular furrow or trench.

Serous glands, or Ebner’s glands, in the connective tissue, in contact with the underlying muscle, are associated with the circumvallate papilla. The ducts of Ebner’s glands open into the floor of the circular furrow.

The sides of the circumvallate papilla and the facing wall of furrow contain several taste buds. Each taste bud, depending on the species, consists of 50 to 150 cells, with its narrow apical ends extending into a taste pore. A taste bud has three cell components (Figure 15-2): (1) taste receptor cells, (2) supporting cells (or immature taste cells), and (3) precursor cells (or basal cells).

Figure 15-2 Taste bud

Taste receptor cells have a life span of 10 to 14 days. Precursor cells give rise to supporting cells (or immature taste cells) which, in turn, become mature taste receptor cells. The basal portion of a taste receptor cell makes contact with an afferent nerve terminal derived from neurons in the sensory ganglia of the facial, glossopharyngeal, and vagus nerves.

Sweet, sour, bitter, and salty are the four classic taste sensations. A fifth taste is umami (the taste of monosodium glutamate). A specific taste sensation is generated by specific taste receptor cells. The facial nerve carries the five taste sensations; the glossopharyngeal nerve carries sweet and bitter sensations.

Taste is initiated when soluble chemicals, called tastants, diffuse through the taste pore and interact with the G-protein α, β, and γ subunits (called gustducin) linked to the taste receptors (designated TR1 and TR2), present in the apical microvilli of the taste receptor cells. As we discussed in Chapter 3, Cell Signaling, guanosine triphosphate (GTP) binding to the α subunit of the G-protein complex activates target molecules (ion channels in the taste receptor cells). Ionic changes within taste cells cause either depolarization (see Figure 15-2) or hyperpolarization of the receptor cells. An increase in intracellular Ca²⁺ triggers the release of neurotransmitters at the afferent synapse with the afferent nerve terminal. Some taste receptor cells respond to only one of the basic taste substances. Others are sensitive to more than one taste substance.

TOOTH

In the adult human, dentition consists of 32 permanent teeth. The 16 upper teeth are embedded in alveolar processes of the maxilla. The lower 16 teeth are embedded in similar alveolar processes of the mandible. The permanent dentition is preceded by a set of 20 deciduous teeth, also called milk or baby teeth. Deciduous teeth appear at about 6 months of age and the entire set is present by age 6 to 8 years. The deciduous teeth are replaced between ages 10 and 12 by the 32 permanent teeth. This replacement process ends at about age 18.

Each of the several types of teeth has a distinctive shape and function: incisors are specialized for cutting; canines, for puncturing and holding; and molars, for crushing.

Each tooth consists of a crown and either single or multiple roots (Figure 15-3). The crown is covered by highly calcified layers of enamel and dentin. The outer surface of the root is covered by another calcified tissue called cementum. The dentin forms the bulk of the tooth and contains a central chamber filled with soft tissue, the pulp. The pulp chamber opens at the apical foramen into the bony alveolar process by the root canal. Blood vessels, nerves, and lymphatics enter and leave the pulp chamber through the apical foramen. Myelinated nerve fibers run along with the blood vessels.

Figure 15-3 Longitudinal section of the tooth

TOOTH DEVELOPMENT

The ectoderm, cranial neural crest, and mesenchyme contribute to the development of the tooth (Figure 15-4). Ameloblasts derive from the ectoderm. Odontoblasts derive from the cranial neural crest. Cementocytes derive from the mesenchyme.

Figure 15-4 Stages of tooth development

Secreted signaling molecules—activin βA, fibroblast growth factor, and bone morphogenetic proteins—mediate the interaction between the dental epithelium and the mesenchyme during tooth morphogenesis. Figure 15-4 illustrates the relevant steps of tooth development.

ODONTOBLASTS

A layer of odontoblasts is present at the periphery of the pulp. Odontoblasts are active secretory cells that synthesize and secrete collagen and noncollagenous material, the organic components of the dentin.

The odontoblast is a columnar epithelial-like cell located at the inner side of the dentin, in the pulp cavity (Figure 15-5). The apical cell domain is embedded in predentin, a nonmineralized layer of dentin-like material. The apical domain projects a main apical cell process that becomes enclosed within a canalicular system just above the junctional complexes linking adjacent odontoblasts.

Figure 15-5 Odontoblasts

A well-developed rough endoplasmic reticulum and Golgi apparatus as well as secretory granules are found in the apical region of the odontoblast. The secretory granules contain procollagen. When procollagen is released from the odontoblast, it is enzymatically processed to tropocollagen, which aggregates into type I collagen fibrils.

Predentin is the layer of den tin adjacent to the odontoblast cell body and processes. Predentin is nonmineralized and consists mainly of collagen fibrils that will become covered (mineralized) by hydroxyapatite crystals in the dentin region. A demarcation mineralization front separates predentin from dentin. Dentin consists of 20% organic material, mainly type I collagen; 70% inorganic material, mainly crystals of hydroxyapatite and fluoroapatite; and 10% water.

Coronal dentin dysplasia (also known as dentin dysplasia, type II) is a rare inherited autosomal defect characterized by abnormal development of dentin, extremely short roots (rootless teeth), and obliterated pulp chambers.

The pulp consists of blood vessels, nerves, and lymphatics surrounded by fibroblasts and mesenchyme-like extracellular elements. Blood vessels (arterioles) branch into a capillary network among the cell bodies of the odontoblasts. An inflammation in the pulp causes swelling and pain. Because there is no space for swelling in the pulp cavity, the blood supply is suppressed by compression, leading rapidly to the death of the pulpal cells.

Cementum

The cementum is a bonelike mineralized tissue covering the outer surface of the root. Like bone, the cementum consists of calcified collagenous fibrils and trapped osteocyte-like cells called cementocytes.

The cementum meets the enamel at the cementoenamel junction and separates the crown from the root at the neck region of the tooth. The outermost layer of the cementum is uncalcified and is produced by cementoblasts in contact with the periodontal ligament, a collagen- and fibroblast-rich and vascularized suspensory ligament holding the tooth in the sockets of the alveolar bone (see Figure 15-3). The strength of the periodontal ligament fibers gives teeth mobility and strong bone attachment, both useful in orthodontic treatment.

AMELOBLASTS

Ameloblasts are enamel-producing cells present only during tooth development. The ameloblast (Figure 15-6) is a polarized columnar cell with mitochondria and a nucleus present in the basal region of the cell. The supranuclear region contains numerous cisternae of rough endoplasmic reticulum and Golgi apparatus.

Figure 15-6 Ameloblasts

Beyond apical junctional complexes joining contiguous ameloblasts, the apical domain displays a broad process, Tomes’ process, in proximity to the calcified enamel matrix. The apical domain has abundant secretory granules containing glycoprotein precursors of the enamel matrix. Electron microscopic examination shows that the enamel consists of thin undulated enamel rods separated by an interrod region with a structure similar to that of the enamel rods but with its crystals oriented in a different direction. Each rod is coated with a thin layer of organic matrix, called the rod sheath.

The enamel is the hardest substance found in the body. About 95% of the enamel is composed of crystals of hydroxyapatite; less than 5% is protein. The newly secreted enamel contains a high content of protein (about 30%), whose concentration decreases to 1% during enamel mineralization. The extracellular matrix of the developing enamel contains two classes of proteins: amelogenin and enamelin.

Amelogenin is the major constituent, unique to the developing enamel. It controls the calcification of the enamel. Enamelin is a minor component; it has ameloprotease activity, which breaks down amelogenin during enamel assembly. Amelogenesis imperfecta is an X chromosome–linked inherited disease affecting the synthesis of amelogenin required for the formation of the tooth enamel; affected enamel does not attain its normal thickness, hardness, and color. Autosomal-dominant amelogenesis imperfecta is caused by a mutation of the enamelin gene.

GENERAL ORGANIZATION OF THE DIGESTIVE, OR ALIMENTARY, TUBE

Although we study each segment of the digestive or alimentary tube separately, it is important to discuss first the general organization of the tube to understand that each segment does not function as an independent unit.

We start with the common histologic features of the digestive tube by indicating that, except for the oral cavity, the digestive tube has a uniform histologic organization. This organization is characterized by distinct and significant structural variations reflecting changes in functional activity.

After the oral cavity, the digestive tube is differentiated into four major organs: esophagus, stomach, small intestine, and large intestine. Each of these organs is made up of four concentric layers (Figure 15-7): (1) the mucosa, (2) the sub-mucosa, (3) the muscularis, and (4) the adventitia, or serosa.

Figure 15-7 Overall histologie organization of the digestive tube

The mucosa has three components: a lining epithelium, an underlying lamina propria consisting of a vascularized loose connective tissue, and a thin layer of smooth muscle, the muscularis mucosae.

Lymphatic nodules and scattered immunocompetent cells (lymphocytes, plasma cells, and macrophages) are present in the lamina propria. The lamina propria of the small and large intestines is a relevant site of immune responses (see Chapter 16, Lower Digestive Segment).

The lining epithelium invaginates to form glands, extending into the lamina propria (mucosal glands) or submucosa (submucosal glands), or ducts, transporting secretions from the liver and pancreas through the wall of the digestive tube (duodenum) into its lumen.

In the stomach and small intestine, both the mucosa and submucosa extend into the lumen as folds, called rugae and plicae, respectively. In other instances, the mucosa alone extends into the lumen as fingers, or villi. Mucosal glands increase the secretory capacity, whereas villi increase the absorptive capacity of the digestive tube.

The mucosa shows significant variations from segment to segment of the digestive tract. The submucosa consists of a dense irregular connective tissue with large blood vessels, lymphatics, and nerves branching into the mucosa and muscularis. Glands are present in the submucosa of the esophagus and duodenum.

The muscularis contains two layers of smooth muscle: the smooth muscle fibers of the inner layer are arranged around the tube lumen (circular layer); fibers of the outer layer are disposed along the tube (longitudinal layer). Contraction of the smooth fibers of the circular layer reduces the lumen; contraction of the fibers of the longitudinal layer shortens the tube. Skeletal muscle fibers are present in the upper esophagus and the anal sphincter.

The adventitia of the digestive tract consists of several layers of connective tissue continuous with adjacent connective tissues. When the digestive tube is suspended by the mesentery or peritoneal fold, the adventitia is covered by a mesothelium (simple squamous epithelium) supported by a thin connective tissue layer, together forming a serosa, or serous membrane.

Microvasculature of the digestive tube

We start our discussion with the microvasculature of the stomach. The microcirculation of the small intestine and differences from the gastric microcirculation are discussed in Chapter 16, Lower Digestive Segment (see Figure 16-3).

Blood and lymphatic vessels and nerves reach the walls of the digestive tube through the supporting mesentery or the surrounding tissues. After entering the walls of the stomach, arteries organize three arterial networks: the subserosal, intramuscular, and submucosal plexuses (Figure 15-8). Some branches from the plexuses run longitudinally in the muscularis and submucosa; other branches extend perpendicularly into the mucosa and muscularis.

Figure 15-8 Gastric microvasculature

In the mucosa, arterioles derived from the submucosal plexus supply a bed of fenestrated capillaries around the gastric glands and anastomose laterally with each other. The fenestrated nature of the capillaries facilitates bicarbonate delivery to protect the surface epithelial cells against hydrochloric acid damage (see Figure 15-17).

Collecting venules descend from the mucosa into the submucosa as veins, leave the digestive tube through the mesentery, and drain into the splenic and superior mesenteric veins. Mesenteric veins drain into the portal vein, leading to the liver (see Chapter 17, Digestive Glands).

Clinical significance: Gastric microcirculation and gastric ulcers

As we discuss later in this chapter, gastric microcirculation plays a significant role in the protection of the integrity of the gastric mucosa. A breakdown in this protective mechanism, including mucus and bicarbonate secretion, allows the destructive action of hydrochloric acid and pepsin and bacterial infection, leading to peptic ulcer disease (PUD). PUD includes a group of disorders characterized by a partial or total loss of the mucosal surface of the stomach or duodenum or both.

The rich blood supply to the gastric mucosa is of considerable significance in understanding bleeding associated with stress ulcers. Stress ulcers are superficial gastric mucosal erosions observed after severe trauma or severe illness and after the long-term use of aspirin and corticosteroids. In most cases, stress ulcers are clinically asymptomatic and are detected only when they cause severe bleeding.

Nerve supply of the digestive tube

The digestive tube is innervated by the autonomic nervous system (ANS). The ANS consists of an extrinsic component (the parasympathetic and sympathetic innervation) and an intrinsic, or enteric, component.

Sympathetic nerve fibers derive from the thoracic and lumbar spinal cord. Parasympathetic nerve fibers derive from the vagal dorsal motor nucleus of the medulla oblongata. Visceral sensory fibers originate in the spinal dorsal root ganglia.

The intrinsic or enteric innervation is represented by two distinct interconnected neuronal circuits formed by sensory and motor neurons linked by inter-neurons: (1) the submucosal plexus of Meissner, present in the submucosa; and (2) the myenteric plexus of Auerbach (Figure 15-9), located between the inner circular and outer longitudinal layers of the muscularis.

Figure 15-9 Innervation of the digestive tube

Neurons and interneurons of the plexuses give off axons that branch to form the networks. The plexuses are connected to the extrinsic sympathetic and parasympathetic ANS: the plexuses of Auerbach and Meissner receive preganglionic axons of the parasympathetic neurons and postganglionic axons of sympathetic neurons.

The intrinsic or enteric nervous system enables the digestive tube to respond to both local stimuli and input from extrinsic nerves of the ANS. The integrated extrinsic and intrinsic (enteric) networks regulate and control (1) peristaltic contractions of the muscularis and movements of the muscularis mucosae and (2) secretory activities of the mucosal and submucosal glands. Stimulation of preganglionic parasympathetic nerve fibers (cholinergic terminals) of the muscularis causes increased motility as well as glandular secretory activity. Stimulation of postganglionic sympathetic nerve fibers (adrenergic terminals) on the smooth muscle cells causes decreased motility.

ESOPHAGUS

The esophagus is a muscular tube linking the pharynx to the stomach. It runs through the thorax, crosses the diaphragm, and enters the stomach. Contractions of the muscularis propel the food down the esophagus—in about 2 seconds. At this velocity, changes of pressure and volume within the thorax are minimal. No disruption of respiration and cardiopulmonary circulation takes place.

The esophageal mucosa consists of a stratified squamous epithelium overlying a lamina propria with numerous connective tissue papillae (Figure 15-10). The muscularis mucosae is not present in the upper portion of the esophagus, but it becomes organized near the stomach. Both the mucosa and the submucosa in the undistended esophagus form longitudinal folds that give the lumen an irregular outline. As the bolus of food moves down the esophagus, the folds disappear transiently and then are restored by the recoil of the elastic fibers of the submucosa.

Figure 15-10 Esophagus

The submucosa contains a network of collagen and elastic fibers and many small blood vessels. At the lower end of the esophagus, submucosal venous plexuses drain into both the systemic venous system and the portal venous system. An increase in pressure in the portal venous system, caused by chronic liver disease, results in dilation of the submucosal venous sinuses and the formation of esophageal varices. Rupture of the varices or ulceration of the overlying mucosa can produce hemorrhage into the esophagus and stomach, often causing vomiting (hematemesis).

Mucosal and submucosal glands are found in the esophagus. Their function is to produce continuously a thin layer of mucus that lubricates the surface of the epithelium.

The mucosal tubular glands, restricted to the lamina propria, resemble the cardiac glands of the stomach and are called cardiac esophageal glands.

The submucosal tubuloacinar glands, found in the submucosa just beneath the muscularis mucosae, are organized into small lobules drained by a single duct (see Figure 15-10). The acini are lined by two secretory cell types: a mucous and a serous cell type, the latter with secretory granules containing lysozyme.

The composition of the inner circumferential (or circular) and outer longitudinal layers of the muscularis shows segment-dependent variations. In the upper third of the esophagus, both layers consist of striated muscle. In the middle third, smooth muscle fibers can be seen deep to the striated muscle. In the lower third, both layers of the muscularis contain smooth muscle cells.

Clinical significance: The mechanism of swallowing and dysphagia

The esophagus has two sphincters: (1) the anatomically defined upper esophageal sphincter (UES), or cricopharyngeal sphincter, and (2) the functionally defined lower esophageal sphincter (LES), or gastroesophageal sphincter. The UES participates in the initiation of swallowing. The LES prevents reflux of gastric contents into the esophagus.

Because the esophageal stratified squamous lining epithelium at the epithelial transformation zone may be replaced at the lower end by a poorly resistant columnar epithelium, a reflux of acidic gastric secretions causes chronic inflammation (reflux esophagitis) or ulceration and difficulty in swallowing (dysphagia).

When the esophageal hiatus in the diaphragm does not close entirely during development, a hiatus hernia enables a portion of the stomach to move into the thoracic cavity. In sliding hiatus hernia, the stomach protrudes through the diaphragmatic hiatus, normally occupied by the lower esophagus. Reflux esophagitis and peptic ulceration in the intrathoracic portion of the stomach and lower esophagus leads to difficulty in swallowing and the feeling of a lump in the throat. This condition, commonly seen in family practice patients, affects young and middle-aged women in particular.

The movements involved in swallowing are coordinated by nerves from the cervical and thoracic sympathetic trunks, forming plexuses in the submucosa and in between the inner and outer layers of the muscularis. Diseases affecting this neuromuscular system may result in muscle spasm, difficulty in swallowing, and substernal pain.

STOMACH

The stomach extends from the esophagus to the duodenum. At the gastroesophageal junction, the epithelium changes from stratified squamous to a simple columnar type. The muscularis mucosae of the esophagus is continuous with that of the stomach. However, the submucosa does not have a clear demarcation line, and glands from the cardiac portion of the stomach may extend under the stratified squamous epithelium and contact the esophageal cardiac glands.

The function of the stomach is to homogenize and chemically process the swallowed semisolid food. Both the contractions of the muscular wall of the stomach and the acid and enzymes secreted by the gastric mucosa contribute to this function. Once the food is transformed into a thick fluid, it is released gradually into the duodenum.

Four regions are recognized in the stomach: (1) the cardia, a 2- to 3-cm-wide zone surrounding the esophageal opening; (2) the fundus, projecting to the left of the opening of the esophagus; (3) the body, an extensive central region; and (4) the pyloric antrum (Greek pyloros, gatekeeper), ending at the gastroduodenal orifice. Based on the motility characteristics of the stomach, the orad area, consisting of the fundus and the upper part of the body, relaxes during swallowing. The caudad area, consisting of the lower portion of the body and the antrum, participates in the regulation of gastric emptying.

The empty stomach shows gastric mucosal folds, or rugae, covered by gastric pits or foveolae (Figure 15-11). A gastric mucosal barrier, produced by surface mucous cells, protects the mucosal surface. The surface mucous cells contain apical periodic acid–Schiff (PAS)–positive granules and are linked to each other by apical tight junctions.

Cardia region

Glands of the cardia region are tubular, with a coiled end and an opening continuous with the gastric pits (Figure 15-12). A mucus-secreting epithelium lines the cardiac glands.

Figure 15-11 Stomach: Ruga

Figure 15-12 Stomach: Cardiac region

Functions of the gastric gland

Gastric glands of the fundus-body region are the major contributors to the gastric juice. About 15 million gastric glands open into 3.5 million gastric pits. From two to seven gastric glands open into a single gastric pit, or foveola.

A gastric gland consists of three regions (Figure 15-13): (1) the pit, or foveola, lined by surface mucous cells; (2) the neck, containing mucous neck cells, mitotically active stem cells, and parietal cells; and (3) the body, representing the major length of the gland. The upper and lower portions of the body contain different proportions of cells lining the gastric gland.

Figure 15-13 Stomach: Gastric gland

The surface mucous cells line the surface of the gastric mucosa and the gastric pits (Figure 15-14; see also Figure 15-13).

Figure 15-14 Gastric gland: Surface and neck cells

The gastric glands proper house five major cell types: (1) mucous neck cells (see Figure 15-13), (2) chief cells (also called peptic cells), (3) parietal cells (also called oxyntic cells), (4) stem cells, and (5) gastroenteroendocrine cells (called enterochromaffin cells because of their staining affinity for chromic acid salts).

The upper portion of the main body of the gastric gland contains abundant parietal cells. Chief cells and gastroenteroendocrine cells predominate in the lower portion (see Figure 15-13).

The gastric mucosa of the fundus-body has two classes of mucus-producing cells (see Figure 15-14): (1) the surface mucous cells lining the pit and (2) the mucous neck cells located at the opening of the gastric gland into the pit. Both cells produce mucins, glycoproteins with high molecular mass. A mucus layer, containing 95% water and 5% mucins, forms an insoluble gel that attaches to the surface of the gastric mucosa, forming a 100-μm-thick protective gastric mucosal barrier. This protective mucus blanket traps bicarbonate ions and neutralizes the microenvironment adjacent to the apical region of the surface mucous cells to an alkaline pH.

Na⁺, K⁺, and Cl⁻ are additional constituents of the protective mucosal barrier. Patients with chronic vomiting or undergoing continuous aspiration of gastric juice require intravenous replacement of NaCl, dextrose, and K⁺ to prevent hypokalemic metabolic acidosis.

Chief cells (Figure 15-15) predominate in the lower third of the gastric gland. Chief cells are not present in cardiac glands and are seldom found in the pyloric antrum. Chief cells have a structural similarity to the zymogenic cells of the exocrine pancreas: the basal region of the cytoplasm contains an extensive rough endoplasmic reticulum. Pepsinogen-containing secretory granules (zymogen granules) are observed in the apical region of the cell. Pepsinogen, a proenzyme stored in the zymogen granules, is released into the lumen of the gland and converted in the acid environment of the stomach to pepsin, a proteolytic enzyme capable of digesting most proteins. Exocytosis of pepsinogen is rapid and stimulated by feeding (after fasting).

Figure 15-15 Gastric gland: Chief and parietal cells

Parietal cells predominate near the neck and in the upper segment of the gastric gland and are linked to chief cells by junctional complexes. Parietal cells produce the hydrochloric acid of the gastric juice and intrinsic factor, a glycoprotein that binds to vitamin B₁₂. Vitamin B₁₂ binds in the stomach to the transporting binding protein intrinsic factor. In the small intestine, the vitamin B₁₂-intrinsic factor complex binds to intrinsic factor receptor on the surface of enterocytes in the ileum and is transported to the liver through the portal circulation.

Autoimmune gastritis is caused by autoantibodies to H⁺,K⁺-dependent ATPase, a parietal cell antigen, and intrinsic factor. Destruction of parietal cells causes a reduction in hydrochloric acid in the gastric juice (achlorhydria) and a lack of synthesis of intrinsic factor. The resulting vitamin B₁₂ deficiency disrupts the formation of red blood cells in the bone marrow, leading to a condition known as pernicious anemia, identified by examination of peripheral blood as megaloblastic anemia characterized by macrocytic red blood cells and hypersegmented large neutrophils (see Chapter 6, Blood and Hematopoiesis).

Parietal cells have three distinctive features (see Figure 15-15): (1) abundant mitochondria, which occupy about 40% of the cell volume and provide the adenosine triphosphate (ATP) required to pump H⁺ ions into the lumen of the intracellular canaliculus; (2) an intracellular canaliculus, formed by an invagination of the apical cell surface and continuous with the lumen of the gastric gland, which is lined by numerous microvilli; and (3) an H⁺,K⁺-dependent ATPase-rich tubulovesicular system, which is distributed along the secretory canaliculus during the resting state of the parietal cell.

After stimulation, the tubulovesicular system fuses with the membrane of the secretory canaliculus, and numerous microvilli project into the canalicular space. Membrane fusion increases the amount of H⁺,K⁺-ATPase and expands the intracellular canaliculus. H⁺,K⁺-ATPase represents about 80% of the protein content of the plasma membrane of the microvilli.

Secretion of hydrochloric acid by parietal cells

Parietal cells produce an acidic secretion (pH 0.9 to 2.0) rich in hydrochloric acid, with a concentration of H⁺ ions one million times greater than that of blood (Figure 15-16). The release of H⁺ ions and Cl⁻ by the parietal cell involves the membrane fusion of the tubulovesicular system with the intracellular canaliculus.

Figure 15-16 Hydrochloric acid secretion by parietal cells

The parasympathetic mediator acetylcholine and the peptide gastrin, produced by enteroendocrine cells of the pyloric antrum, stimulate parietal cells to secrete HCl (see Figure 15-19). Acetylcholine also stimulates the release of gastrin. Histamine potentiates the effects of acetylcholine and gastrin on parietal cell secretion after binding to the histamine H₂ receptor. Histamine is produced by enterochromaffin-like (ECL) cells within the lamina propria surrounding the gastric glands. Cimetidine is an H₂ receptor antagonist that inhibits histamine-dependent acid secretion.

H⁺,K⁺-dependent ATPase facilitates the exchange of H⁺ and K⁺. Cl⁻ and Na⁺ (derived from the dissociation of NaCl) are actively transported into the lumen of the intracellular canaliculus, leading to the production of HCl. K⁺ and Na⁺ are recycled back into the cell by separate pumps once H⁺ has taken their place. Omeprazole, with binding affinity to H⁺,K⁺-dependent ATPase, inactivates acid secretion and is an effective agent in the treatment of peptic ulcer.