The stomach, located on the left side of the abdominal cavity just below the diaphragm, lies between the esophagus and small intestine. As with the esophagus, it has a sphincter at either end: the previously mentioned LES at the entrance to the stomach and the pyloric sphincter at the exit of the stomach into the duodenum of the small intestine. The LES is normally closed except during swallowing. The pyloric sphincter is subject to tonic contraction, which keeps it almost, but not completely, closed so that fluids may easily pass through it. The movement of food materials through this sphincter requires strong gastric contractions. Even then, only a few milliliters are pushed through at a time. Gastric contractions mash the food materials and thoroughly mix them with gastric secretions. This produces a thick, semifluid mixture referred to as chyme.

Three regions make up the stomach:

• Fundus: uppermost region of the stomach located above the junction with the esophagus

• Body: middle or main portion of the stomach

• Antrum: terminal region of the stomach leading to the gastroduode-nal junction

The stomach performs several important functions:

• Stores ingested food until it can be processed by the remainder of the digestive tract

• Mechanically mashes ingested food and mixes it with gastric secretions

• Begins the process of protein digestion

Food is stored in the body of the stomach, which may expand to hold as much as 1 l of chyme. As food enters the stomach, it undergoes a reflex relaxation referred to as receptive relaxation. It enhances the ability of the stomach to accommodate an increase in volume with only a small increase in stomach pressure. The fundus does not typically store food because it is located above the esophageal opening into the stomach. Instead, it usually contains a pocket of gas.

Gastric motility. In addition to the circular and longitudinal layers of smooth muscle, the stomach contains an extra layer of smooth muscle. Beginning at the UES, the oblique layer of smooth muscle fans out across the anterior and posterior surfaces of the stomach and fuses with the circular layer in the lower region. This extra layer of muscle enhances gastric motility and therefore mixing and mashing of food.

Contraction of gastric smooth muscle occurs in the form of peristalsis. Peristaltic contractions begin in the body of the stomach and proceed in a wave-like fashion toward the duodenum. These contractions are weak in the upper portion of the stomach where the muscle layers are relatively thin. The contractions become much stronger in the lower portion of the stomach as the muscle layers become thicker. As the wave of contraction sweeps through the antrum, a small amount of chyme is pushed through the partially open pyloric sphincter. When the peristaltic contraction actually reaches the pyloric sphincter, it closes and the rest of the chyme in this region is forced back toward the body of the stomach where more mixing and mashing takes place.

It may take many hours for the contents of the stomach to be processed and moved into the small intestine. Several factors influence gastric motility and therefore the rate of gastric emptying. These include:

• Volume of chyme in the stomach

• Fluidity of chyme

• Volume and chemical composition of chyme in the duodenum

The major gastric factor that affects motility and the rate of emptying is the volume of chyme in the stomach. As the volume of chyme increases, the wall of the stomach becomes distended and mechanoreceptors are stimulated. This elicits reflexes that enhance gastric motility by way of the intrinsic and vagus nerves. The release of the hormone gastrin from the antral region of the stomach further contributes to enhanced motility.

The degree of fluidity of chyme also affects the rate of gastric emptying. Ingested liquids move through the pyloric sphincter and begin to empty almost immediately. Ingested solids must first be converted into a semifluid mixture of uniformly small particles. The faster the necessary degree of fluidity is achieved, the more rapidly the contents of the stomach may empty into the duodenum.

The most important factors that regulate gastric motility and the rate of emptying of the stomach involve the volume and chemical composition of chyme in the duodenum. Receptors in the duodenum are sensitive to:

• Distension

• Chyme osmolarity

The ultimate goal of these duodenal factors is to maintain a rate of gastric emptying consistent with the proper digestion and absorption of nutrient molecules in the small intestine. In other words, emptying must be regulated so that the duodenum has adequate opportunity to process the chyme that it already contains before it receives more from the stomach. Regulation occurs by way of the enterogastric reflex, which inhibits gastric motility, increases contraction of the pyloric sphincter, and therefore decreases rate of gastric emptying. This reflex is mediated through the intrinsic and vagus nerves. Regulation also occurs by way of a hormonal response that involves the release of the enterogastrones from the duodenum. These hormones, secre-tin, cholecystokinin and gastric inhibitory peptide, travel in the blood to the stomach where they inhibit gastric contractions.

As the volume of the chyme in the duodenum increases, it causes distension of the duodenal wall and stimulation of mechanoreceptors. This receptor stimulation elicits reflex inhibition of gastric motility mediated through the intrinsic and vagus nerves. Distension also causes release of gastric inhibitory peptide from the duodenum, which contributes to inhibition of gastric contractions.

Duodenal receptors are also sensitive to the chemical composition of chyme and are able to detect the presence of lipids, excess hydrogen ion, and hyperosmotic chyme. These conditions also elicit the enterogastric reflex and release of the enterogastrones in order to decrease the rate of gastric emptying.

Of the three major categories of nutrients, lipids are the slowest to be digested and absorbed. Furthermore, these processes take place only in the small intestine, so in order to ensure complete lipid digestion and absorption, the rate of movement of lipid from the stomach to the duodenum must be carefully regulated. The presence of lipid in the duodenum stimulates intestinal chemo receptors. This receptor stimulation elicits reflex inhibition of gastric motility and slows the addition of more lipid from the stomach. Lipid also causes the release of cholecystokinin and gastric inhibitory peptide from the duodenum. These hormones contribute to inhibition of gastric contractions. The significance of the inhibitory effect of lipid is illustrated by the comparison between a high-fat meal (up to 6 h for gastric emptying) and a meal consisting of carbohydrates and protein (3 h for gastric emptying). Therefore, a fatty meal is "more filling" than a low-fat meal due its effect on gastric motility.

An important gastric secretion is the hydrochloric acid that performs a number of functions in the stomach. This stomach acid is neutralized by pancreatic bicarbonate ion in the duodenum. Excess acid in the chyme stimulates chemoreceptors in the duodenum. This receptor stimulation elicits reflex inhibition of gastric motility. Excess acid also causes the release of secretin and gastric inhibitory peptide from the duodenum. These hormones contribute to inhibition of gastric contractions so that the neutralization process may be completed before additional acid arrives in chyme from the stomach.

Chyme within the duodenum has, by this point, undergone some degree of carbohydrate and protein digestion. Salivary amylase has fragmented starch molecules and, as will be discussed, pepsin from the stomach has fragmented proteins. Therefore, the number of disaccharides and small pep-tides has increased, which leads to an increase in the osmolarity of the chyme. The rate of absorption of these smaller molecules must keep pace with the rate of digestion of the larger molecules. If not, the stimulation of osmorecep-tors in the duodenum by the hyperosmotic chyme will inhibit gastric motility and gastric emptying. This effect is mediated through reflex inhibition as well as the release of gastric inhibitory peptide from the duodenum.

Gastric secretion. The human stomach secretes 1 to 2 l of gastric juice per day. The gastric mucosa, which produces these secretions, is divided into two functional regions:

• Oxyntic gland area

• Pyloric gland area

The oxyntic gland area is located in the proximal 80% of the stomach. These glands consist of three types of cells:

• Mucous neck cells

• Parietal cells

The pyloric gland area is located in the remaining distal 20% of the stomach. Secretions of the stomach include:

• Hydrochloric acid

• Pepsinogen

• Intrinsic factor

Hydrochloric acid (HCl), a strong acid that dissociates into an H+ and a Cl- ion, is produced by the parietal cells. These ions are actively transported into the lumen of the stomach by the proton pump. Functions of HCl include:

• Activation of pepsinogen, the precursor for the pepsin enzyme

• Assisting in breakdown of connective tissue and muscle fibers within ingested food

• Killing of most types of microorganisms ingested with food

Pepsinogen is produced by the chief cells. Within the lumen of the stomach, this precursor molecule is split by HCl to form the active enzyme pepsin. Optimally active at an acidic pH (pH = 2), pepsin begins protein digestion by fragmenting proteins into smaller peptide chains.

Mucus is produced by the mucus neck cells and by the surface epithelial cells of the stomach wall. A thick layer of mucus adheres to the wall of the stomach, forming the gastric mucosal barrier. The function of this barrier is to protect the gastric mucosa from injury — specifically, from the corrosive actions of HCl and pepsin. Together with bicarbonate ion released into the lumen of the stomach, mucus neutralizes the acid and maintains the mucosal surface at a nearly neutral pH.

Pharmacy application: drug-induced gastric disease

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil®), and acetaminophen (para-aminophenol derivative, Tylenol®). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer.

Unfortunately, frequent exposure to NSAIDS may also cause two detrimental effects. These agents inhibit the activity of cyc-lo-oxygenase, an important enzyme in synthesis of gastroprotec-tive prostaglandins. More importantly, NSAIDS may cause breaks in the gastric mucosal barrier. The normal gastric mucosa is relatively impermeable to H+ ion. When the gastric mucosal barrier is weakened or damaged, H+ ion leaks into the mucosa in exchange for Na+ ion. As H+ ion accumulates in the mucosa, intra-cellular buffer systems become saturated, the pH decreases, and cell injury and cell death occur. These damaged cells then secrete more HCl, which causes more injury, and so on, resulting in a positive feedback cycle. An ulcer may form when injury from the gastric secretions, HCl and pepsin, overwhelms the ability of the mucosa to protect itself and replace damaged cells. Local capillaries are also damaged, causing bleeding or hemorrhage into the gastric lumen.

Intrinsic factor is produced by the parietal cells. Within the stomach, it combines with vitamin B12 to form a complex necessary for absorption of this vitamin in the ileum of the small intestine. Vitamin B12 is an essential factor in the formation of red blood cells. Individuals unable to produce intrinsic factor cannot absorb vitamin B12 and red blood cell production is impaired. This condition, referred to as Pernicious anemia, occurs as a result of an autoimmune disorder involving destruction of parietal cells.

Gastrin is a hormone produced by gastric endocrine tissue — specifically, the G cells in the pyloric gland area. It is released into the blood and carried back to the stomach. The major function of gastrin is to enhance acid secretion by directly stimulating parietal cells (HCl) and chief cells (pepsinogen). Gastrin also stimulates the local release of histamine from enterochromaf-fin-like cells in the wall of the stomach. Histamine stimulates parietal cells to release HCl.

The three major phases of gastric secretion are:

• Cephalic phase: 20 to 30% of gastric secretory response to a meal

• Gastric phase: 60 to 70% of gastric secretory response to a meal

• Intestinal phase: approximately 10% of gastric secretory response to a meal

The cephalic phase of gastric secretion occurs before food even enters the stomach. Thoughts of food; sensory stimuli such as the smell, sight, or taste of food; and activities such as chewing and swallowing enhance gastric secretion. The cephalic phase is mediated by the vagus nerve and gastrin, which is released in response to vagal stimulation. These mechanisms promote secretion of HCl and pepsinogen.

The gastric phase is elicited by the presence of food in the stomach. Distension of the stomach wall, as well as the presence of protein, caffeine, and alcohol, enhances gastric secretion. This phase is mediated by the intrinsic nerves, the vagus nerve, and gastrin. Each of these mechanisms promotes secretion of HCl and pepsinogen.

Pharmacy application: pharmacological treatment of gastric ulcers

The pharmacological treatment of ulcers involves the inhibition of gastric acid secretion. However, more than one approach may be used to accomplish this goal: H2-receptor antagonists and proton pump inhibitors. Histamine does not play a role in normal acid production; however, it may stimulate release of HCl under pathological conditions. In the case of an ulcer, when H+ ion enters the gastric mucosa, it stimulates the release of histamine from local mast cells. The histamine then stimulates H2-receptors on the parietal cells to release more HCl. Therefore, excess acid release may be prevented with the administration of H2-receptor antagonists such as cimetidine (Tagamet®) and famotidine (Pepcid®). However, the inhibition of histamine-induced acid secretion is not adequate in all patients. More recently, proton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®) have been used to treat ulcers and gastroesophageal reflux disease (GERD). These drugs bind irreversibly to the proton pump (H+, K+-ATPase), which is found only in the parietal cell. This causes permanent inhibition of enzyme activity and, as a result, the secretion of H+ ions into the lumen of the stomach is inhibited. The secretion of acid resumes only after new molecules of H+, K+-ATPase are inserted into the gastric mucosa.

The intestinal phase has two components that influence gastric secretion:

• Excitatory

• Inhibitory

The excitatory component involves the release of intestinal gastrin that occurs in response to the presence of products of protein digestion in the duodenum. Intestinal gastrin travels in the blood to the stomach, where it enhances the secretion of HCl and pepsinogen. The magnitude of this effect is very small, however, because it accounts only for approximately 10% of the acid secretory response to a meal. In contrast to the excitatory component, the inhibitory component of the intestinal phase has a very strong influence on gastric secretion. As with gastric motility, the volume and composition of the chyme in the duodenum affect gastric secretion. Distension of the duodenal wall, as well as the presence of lipids, acid, and hyperosmotic chyme, inhibits secretion by way of the enterogastric reflex and the release of enterogastrones.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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