Gastric motility is controlled centrally and by local neurohormonal control of muscle. The muscle layers include the outer longitudinal, middle circular and inner oblique fibers. Neuronal control involves the intrinsic myenteric plexus, the extrinsic postganglionic sympathetic fibers of the celiac plexus, and the preganglionic parasympathetic fibers of the vagus nerve. The vagal afferents are both relaxatory and excitatory. These vagal fibers are neither cholinergic nor adrenergic.

Factors that influence gastric motility may be classified as myogenic, neural and chemical. The resting potential difference of the gastric smooth muscle is 5-15 mV and there is a rhythmic depolarization, with this basic electrical rhythm being set by the gastric pacemaker, which gives rise to slow-wave activity. The action potential produces peristalsis and is influenced by gastrin. The force of the contraction is increased with vagal activity, gastrin and motilin, and is decreased with gastric secretion.

Gastric distention by food or liquid stimulates both intrinsic nerves and vagal afferents. There is increased spike burst activity, more forceful peristaltic contractions and increased gastric emptying. Pyloric sphincter relaxation occurs so that the antral lumen is not occluded by peristaltic waves. Gastric contents are propelled both forward and backward toward the body of the stomach and are thoroughly mixed. Gastrin delays gastric emptying by decreasing gastric motility and at the same time increasing duodenal motility and pyloric tone (events that are mediated by fat, protein or acid in the duodenum). This increase in duodenal motility and pyloric tone is effected by stimulation of duodenal osmoreceptors and by the release of secretin, cholecysto- kinin (CCK) and gastric inhibitory polypeptide (GIP).

Gastric motility is inhibited for the stomach to accommodate food. Vagal relaxatory fibers are stimulated by swallowing, esophageal or gastric distention, and neurogenic stimulation. Sympathetic and adrenergic fibers influence these cholinergic neurons.

The emptying of the stomach is influenced by the substance, volume, osmolality and composition of the ingested meal. Liquids empty more rapidly than solids. The rate of gastric emptying is related to the square root of the volume, so that a constant proportion of the gastric contents empties per unit time. Stimulation of duodenal osmoreceptors with triglycerides, fatty acids or hydrochloric acid slows gastric emptying.

The gastric body serves as a reservoir, whereas the antrum has the function of mixing, churning and emptying. A high-pressure gradient exists at the gastroduodenal junction, with the pyloric sphincter playing an important role in the coordinated activity of emptying the antral contents into the duodenum.

When the volume of the stomach increases with relaxation, the intragastric pressure does not increase, because of receptive relaxation mediated by way of a vagal reflex and the splanchnic nerves. Receptive relaxation occurs primarily in the gastric fundus and body. Vagotomy, fundoplication and extensive involvement of the stomach by adenocarcinoma result in a loss of this capacity, leading to early satiety. Gastric fundal contractions are infrequent, and of large amplitude and long duration (45 seconds). These contractions propel contents to the body and antrum for mixing to occur.

The distal two-thirds of the stomach is under intrinsic myogenic control. Electrical slow-wave activity can be detected on the greater curvature, with aboral contractions passing from the greater to the lesser curvature at a rate of about 3 per minute. Although antral contractions occur only in response to neural stimulation, the muscle will contract only when a slow wave occurs. The gastric pacemaker controls the frequency and direction of propagated contractions. This control can be altered by the insertion of an electrical pacemaker, potentially changing the frequency of contraction and reversing its direction. It is possible that some clinical disorders of gastric emptying may give rise to chronic nausea, vomiting, fullness and distention.

As antral contractions pass distally, velocity increases, with near simultaneous contractions of distal antrum and pylorus. A small amount of gastric chyme may enter the duodenum, but most passes back into the stomach, where further mixing and churning takes place.

The pyloric sphincter is recognized macroscopically by thickening of the distal circular antral muscle, forming a muscular ring. However, it is difficult to accept this as a true physiologic sphincter, since in its resting phase it is open, and the rapid closure with antral peristalsis serves more to retard than to facilitate the aboral passage of gastric chyme. The pylorus acts to limit duodenogastric reflux. Duodenal acidification or infusion of secretin results in an increase in pyloric sphincter pressure. Patients with gastric ulcer or bile gastritis experience increased reflux of duodenal contents (including bile and pancreatic enzymes) into the stomach, apparently secondary to a pyloric defect. If the sphincter is ablated by pyloroplasty for duodenal ulcer disease, bile reflux is inevitable.

3.2.1 GASTRIC ACID SECRETION

It is generally accepted that acid secretion is activated by three separate pathways: the neural, hormonal and paracrinal (local) pathways. The major chemical transmitter substances are acetylcholine, gastrin and histamine.

The vagus and branches from the celiac plexus and ganglia traveling along the celiac artery are the major extrinsic nervous supply to the acid-secreting portion of the stomach. The postganglionic neurons of the vagi that terminate in the oxyntic gland near the oxyntic cells are predominantly cholinergic. These cholinergic fibers are rarely seen in contact with the oxyntic cells, and therefore acetylcholine released by these nerve endings must diffuse a relatively long distance to the cells. There are two types of muscarinic binding sites on oxyntic cells: M₁ and M₂ receptors. The cholinergic binding results in a dose-dependent acid secretory response. Additionally, there may be muscarinic receptors on histamine-containing cells resulting in indirect stimulation by histamine release on paracrine cells.

Histamine has a direct stimulatory action on oxyntic cells via an H₂ receptor. The stimulatory action of histamine on oxyntic cells is competitively antagonized by a group of histamine analogues (such as cimetidine, ranitidine, famotidine, nizatidine and others) that specifically interact with the H₂ receptor. The histamine antagonists binding to the H₁ receptor can decrease gastric histamine, but at much higher doses.

Gastrin, the other major secretagogue, also interacts with oxyntic cells via a gastrin receptor. The weak stimulatory effect of gastrin on acid production can be competitively inhibited by proglumide, a glutamic acid derivative known to antagonize CCK. Since CCK binds with the same affinity and produces a similar weak secretory response, the question has been raised whether the receptor may be a CCK receptor instead of a gastrin receptor, or whether the receptor may be related to the well-known trophic effect of gastrin rather than the acid-secreting effects.

The binding of secretagogues to the oxyntic cell receptors is coupled to at least two possible intracellular messengers, Ca⁺⁺ and cyclic AMP. Cholinergic action controls the influx of extracellular Ca⁺⁺ into the oxyntic cell, with subsequent activation of undefined intracellular events resulting in acid secretion. The weak stimulatory effect of gastrin is also Ca⁺⁺ dependent. Histamine does not require extracellular Ca⁺⁺ for stimulation of acid secretion. Cyclic AMP is the intracellular messenger coupling the effect of histamine to hydrogen ion production and secretion.

After the oxyntic cells have been stimulated, intracellular endoplasmic tubular structures known as tubulovesicles disappear from the cytoplasm, while the microvilli in the secretory canaliculi increase in length to enlarge the secretory surface. The tubulovesicle membranes contain H⁺/K⁺ -ATPase, the enzyme responsible for driving the H+pump, exchanging K⁺ for H⁺. These membranes have a low permeability to K⁺ and, at rest, prevent sufficient K⁺ from entering the lumen of the tubulovesicles, thus preventing H⁺ transport. Stimulatory activity occurs only with a cellular signal from secretagogues.

It is evident that the overall process of acid secretion is controlled by a complex interaction of a number of pathways that will be further elucidated in the future.

3.2.2 PEPSINOGEN SECRETION

Pepsinogens are present in the mucous cells of cardiac glands, in the chief and mucous neck cells of oxyntic glands, in the mucous cells of pyloric glands and in the mucus cells of duodenal Brunner's glands. These proenzymes are secreted and activated by acids to the active form, pepsin. Furthermore, pepsin can activate additional pepsinogen autocatalytically.

The mucosal lining of the stomach contains four types of immunologically distinct pepsinogens with the ability to digest proteins at acid pH. Pepsinogens and hydrochloric acid secretion respond to much the same stimulants. Cephalic-vagal stimulation strongly stimulates pepsinogen secretion. Anticholinergics, histamine H₂-receptor antagonists and vagotomy decrease pepsinogen secretion. Elevated serum type 1 pepsinogen has been associated with duodenal ulcer and gastrinoma, while atrophic gastritis (with or without pernicious anemia) has been associated with low levels of type 1 pepsinogen.

3.2.3 INTRINSIC FACTOR SECRETION

Intrinsic factor (IF) is a glycoprotein secreted by oxyntic cells. It is important in vitamin B₁₂ absorption. B₁₂ is released from dietary protein by gastric acid and pepsin; it binds to IF and to R protein, which is secreted into saliva. B₁₂ binds more efficiently to the R proteins at low pH, so most of the B₁₂ is initially complexed with the R proteins. In the upper small bowel, pancreatic enzymes cleave the complexes and the free B₁₂ binds to IF, which eventually binds to a specific ileal receptor and is subsequently absorbed and transported to the tissues by another B₁₂-binding protein, transcobalamin II.

Stimulants of acid secretion also stimulate IF secretion. Patients with low or absent acid secretion often have reduced IF secretion. Continued IF secretion is low but the amounts may be adequate to prevent vitamin B₁₂ deficiency and pernicious anemia. Rarely, IF secretion can be absent with normal acid secretion. Circulating antibodies to IF and oxyntic cells are found in many patients with atrophic gastritis, achlorhydria or hypochlorhydria, and pernicious anemia.

The tight junctions between the surface epithelial cells seal off the paracellular route for transport between cells. Transport can also occur across the bilipid layer membrane at the apical surface of the mucosal epithelial cells. The fluidity of this membrane can vary and influence permeability to various macromolecules. While there is active and passive transport of H⁺, Na⁺ and K⁺ ions, an electric potential difference exists across the mucosa. With disruption of this barrier, a fall in potential difference occurs.

In the presence of luminal acid, the gastroduodenal pH approaches pH 2, while the immediately adjacent epithelium may be near neutral (pH 7). This pH gradient, which plays some role in protection from acid-peptic digestion, is probably dependent on the combined secretion of mucus and bicarbonate. How the gastric mucosa secretes acid while maintaining a near-neutral pH adjacent to the surface epithelium requires elucidation.

Gastric mucus consists of about 95% water and 5% glycoprotein. It provides lubrication for food particles and its gel-like nature retains water and bicarbonate close to the surface epithelium. Mucus is secreted by exocytosis, apical expulsion and exfoliation, and formed with bicarbonate in the surface epithelial cells, in the epithelial cells of the gastric gland neck and by the Brunner's glands of the duodenum. The mucus layer varies in thickness but averages about 100mm. The role of mucus in protection against acid-peptic activity is unclear. It does provide a relatively thick unstirred layer adjacent to the mucosa, allowing a rate of diffusion of H⁺ ions four times slower than through a similar thickness of unstirred water. This contributes to the maintenance of a hydrogen ion gradient between the gastric lumen and the surface epithelium. That is, when the pH in the gastric lumen is 2, the pH at the gastric membrane will be 6.8 to 7. ASA and nonsteroidal anti-inflammatory agents inhibit mucus synthesis and release, while prostaglandins increase mucus synthesis. Mucus synthesis is decreased after stress and may play a role in stress ulceration. Mucus limits the diffusion of pepsin and other large molecules, thus preventing further injury.

Bicarbonate secretion is an active process dependent on the metabolic integrity of a healthy epithelium. Secretion is stimulated by acetylcholine, prostaglandins, glucagon and cyclic GMP, and inhibited by a-adrenergic agonists and GIP. Luminal acid also appears to stimulate gastric and duodenal bicarbonate secretion. Low concentrations of bile salts in the stomach inhibit gastric bicarbonate secretion.

Prostaglandins probably play an important role in mucosal defense. These saturated, oxygenated fatty acids are derived from arachidonic acid. They may protect the mucosa by maintaining or increasing gastric mucosal blood flow and hence stimulating mucus production and bicarbonate secretion, and increasing protein synthesis (which is necessary for the maintenance and regeneration of cells). It is not known whether prostaglandins play a role in the maintenance of normal membrane function and tight junctions, but they probably maintain sulfhydryl groups, which act as oxidative scavengers.

The development of gastritis and gastric ulcer is thought to arise as a result of defective defense mechanisms. There may be increased degradation of mucus by pepsinogen 1, bile or pancreatic secretions; by infection with Helicobacter pylori; or through mechanical factors. A quantitatively or qualitatively defective secretion of mucus is also possible. Bicarbonate secretion may be reduced or mucosal blood flow and/or mucosal metabolism compromised, as occurs in stress ulceration.

Gastrin is the most important peptide in the regulation of gastric acid secretion. Under physiologic conditions gastrin is released continually, with increased amounts appearing in the blood at mealtimes. Gastrin is a hormone that increases the rate of oxyntic cell secretion of H⁺ and peptic cell secretion of pepsinogen. Gastrin increases contraction of antral smooth muscle and increases mucosal blood flow.

Extragastric actions of gastrin include contraction of the lower esophageal sphincter, stimulation of pancreatic enzyme secretion, gallbladder contraction, increased small intestine motility, and the regulation of glucose-stimulated insulin release. Gastrin is a trophic hormone that stimulates protein synthesis and growth of certain gastrointestinal tissues, such as the mucosal lining of the stomach and gut, and the parenchyma of the pancreas.

Somatostatin inhibits the release of gastrin from the G cells, probably acting as a paracrine substance. In addition, the nerves of the gastric mucosa contain vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP or bombesin). VIP is probably responsible for mediating the relaxation of gastric smooth muscle. Bombesin mediates the release of gastrin in response to vagal stimulation.

Maximal acid output refers to the total acid output during the hour after stimulation with pentagastrin (6 µg/kg IM or SC) or histamine (40 µg/kg SC). This value is determined by adding the results of either four 15-minute or six 10-minute sample collections after stimulation. The normal range is 25-55 mEq HCl per hour.

Peak acid output reflects the two highest consecutive 15-minute periods of stimulated output, multiplied by a factor of 2 to yield a value for a one-hour output.