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18. 1 Introduction




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gitated from the small intestine via the pylonc sphincter. Their detergent action may break down the mucosal barrier rendering it susceptible to erosion by the gastric acid. Stress may also con­tribute to the development of gastric ulcers in some individuals. However, a great many ulcers are now believed to be caused by acid-resistant bacteria, Helicobacter pylori, which adhere to the gastric epithelium and destroy the mucosal barrier to expose large, unprotected areas of mucosa.

Summary

  1. Gastric juice contains salts, water, hydrochloric acid, pepsinogen,
    intrinsic factor, and mucus. Gastric acid is secreted by the parietal
    cells of the gastric glands in response to food. Hydrogen ions move
    out of the cells against a massive concentration gradient. Chloride
    ions move against both an electrical and a chemical gradient.
    Bicarbonate ions are added to the plasma creating an 'alkaline tide' in
    the venous blood draining the stomach.

  2. A number of proteolytic enzymes are secreted by the chief cells of
    the gastric glands. They are released as inactive pepsinogens and
    activated by the acidic environment in the gastric lumen. They
    hydrolyze peptide bonds within protein molecules to liberate
    polypeptides.

  3. The parietal cells secrete a glycoprotein called intrinsic factor which
    is essential for the absorption of vitamin B]2 in the terminal ileum.

  4. The gastric mucosa creates a 'barrier' to protect itself from erosion by
    the gastric juice. Alkaline, mucus-rich fluid secreted by the gastric
    glands provides a protective coating for the mucosa. Prostagiandins
    of the E series inctease the thickness of this layer and stimulate the
    production of bicarbonate.

18.6 The regulation of gastric secretion

The secretion of hydrochloric acid and of pepsinogens by the glands of the gastric mucosa are regulated largely in parallel, and by the same factors. Both nervous and endocrine mechanisms are involved and interact at many levels. Gastric secretion is nor­mally considered to occur in three phases, the timing of which overlaps considerably. These are the cephalic, gastric, and intestinal phases.

The cephalic phase of gastric secretion

This takes place even before the entry of food into the stomach and results from the anticipation of food, its sight, smell, and taste. The relative contribution of the cephalic phase to overall gastric secretion in response to a meal is variable, and dependent upon mood and appetite, but may amount to as much as 30 per cent. Neurogenic signals originating in the cerebral cortex or the appetite centers of the amygdala and hypothalamus, are relayed to the stomach via efferent fibers whose cell bodies lie within the dorsal motor nuclei of the vagus.

^ Parasympathetic vagal activity influences gastric secretion both directly and indirectly

Postganglionic parasympathetic fibers in the myenteric plexus release acetylcholine and stimulate the output of the gastric glands. Vagal stimulation also causes the release of gastrin from the G-cells of the antral glands. Gastrin reaches the gastric glands by way of the bloodstream and stimulates them to secrete acid and pepsinogens. Furthermore, both vagal activity and gastrin stimulate the release of histamine from mast cells. Histamine acts on parietal cells via H2 receptors to stimulate hydrogen ion secretion. Thus, acetylcholine, gastrin, and hista­mine all enhance the secretion of gastric juice.

The gastric phase of gastric secretion

The arrival of food in the stomach stimulates the gastric phase of acid, pepsinogen, and mucus production, which accounts for more than 60 per cent of total gastric secretion. The two prin­cipal triggers are distension of the stomach wall and the chemical content of the food.

Distension of the stomach activates mechanoreceptors and initi­ates both local (short-loop) myenteric reflexes and long-loop vago-vagal reflexes. Both reflexes lead to the secretion of acetylcholine which stimulates the output of gastric juice by the secretory cells of the stomach. The importance of the vagally mediated reflexes is revealed by the 80 pet cent reduction in acid production in res­ponse to distension which is seen following vagotomy. Emotional stress, fear, anxiety, or any other state which triggers a sympathetic response will inhibit gastric secretion because the parasympathetic controls over the GI tract are temporarily overridden.

In addition to its direct cholinergic action, the vagus stimu­lates the output of gastrin from G-cells in response to distension of the body of the stomach. Gastrin is a powerful stimulus for acid secretion from the parietal cells and also enhances the release of enzymes and mucus from the gastric glands. Although intact proteins are without effect on the rate of gastric secretion, peptides and free amino acids stimulate the output of gastric juice through a direct action on the G-cells. The amino acids tryptophan and phenylalanine are particularly potent secreta-gogues, as are bile acids and short-chain fatty acids.

Gastrin secretion is inhibited when the pH of the gastric contents falls to between 2 and 3. Thus, gastrin secretion is maximal soon after entry of food into the stomach, when the pH is relatively high, but declines as acid secretion and protein diges­tion get under way and the pH of the gastric contents falls. The inhibition of gastrin secretion is mediated by an increase in the secretion of somatostatin from the D-cells of the gastric mucosa. In this way, gastric acid secretion is self-limiting and the gastric phase of gastric secretion normally lasts for 3-4 hours.

The intestinal phase of gastric secretion

A small proportion (5 per cent ot so) of the total gastric secretion in response to food takes place as partially digested food starts to enter the duodenum. This is believed to be due to the sectetion of

^ 406

18 The gut and nutrition


gastrin from G-cells in the intestinal mucosa which encourages the gastric glands to continue secreting. This effect is, however, short-lived and as acid chyme distends the duodenum, an entero-gastric reflex is initiated whereby gastric secretory activity is sup­pressed. A variety of hormones contribute to this reflex.

Secretin is secreted by the duodenal mucosa in response to acid. It reaches the stomach via the bloodstream and inhibits the release of gastrin. It also exerts a direct inhibitory action on the parietal cells to reduce their sensitivity to gastrin.

Two hormones are released in response to the presence of products of fat digestion in the duodenum and proximal jejunum. These are cholecystokinin (CCK) and gastric inhibitory peptide (GIP, also called glucose-dependent insulinotropic peptidej. Both inhibit the release of gastrin and gastric acid, although their relative importance is not clear. Figure 18.13 summarizes the factors regulating gastric secretion.

Disorders of gastric acid secretion

Reduced gastric secretion is a relatively rare condition generally restricted to elderly patients with atrophy of the gastric mucosa. Achlorhydria (a decrease in hydrochloric acid secretion) may occur as a result of a loss of parietal cells. Although digestive pro-

cesses are normally unaffected, achlorhydria can cause impaired absorption of substances requiring an acid environment.

A number of disorders, including stress in some individuals, are associated with abnormally high rates of gastric acid secre­tion and a variety of drugs and constituents of foods are known to stimulate the production of acid (e.g. caffeine and alcohol). A rarer condition, the Zollinger—Ellison syndrome is caused by a gastrin-secreting tumor of the non-/3 cells of the pancreatic islets. Here, gastric acid secretion reaches such high values that erosion of the gastric mucosal barrier occurs, leading to ulceration of the stomach wall.

Several strategies have been developed to treat excessive acid production and promote healing of the gastric mucosa. Specific H2-receptor antagonists such as cimetidine and ranitidine, which block parietal cell histamine receptors, may be used to inhibit acid secretion. Other agents, such as benzimidazoles, which are weak bases, are known to inhibit the activity of the proton pumps on the apical surface of the parietal cells. Drugs based on agents of this kind are used increasingly to treat patients with ulcers caused by the hypersecretion of gastric acid. Individuals whose gastric ulcers are caused by H. pylori are now treated with a course of antibiotics combined with antacid therapy.



Fig. 18.13 The major factors involved in the regulation of gastric secretion during the different phases of secretion. Secretin, CCK, and GIP are secreted by entero-endocrine cells in the duodenal epithelium and have an inhibitory action on gastrin secretion, as does a low pH in the lumen of the stomach.

18.7 Storage, mixing, and propulsion of gastric contents

407


Summary

  1. Nervous and endocrine mechanisms combine to regulate gastric
    secretion. Secretion occurs in three phases: cephalic, gastric, and
    intestinal.

  2. The cephalic phase of secretion occurs m response to the sight, smell,
    and anticipation of food. Parasympathetic vagal fibers stimulate
    secretion via the release of acetylcholine, both directly and by
    stimulating gastrin secretion.

  3. The arrival of food in the stomach initiates the gastric phase of secre­
    tion in which distension and the presence of amino acids and pep-
    tides stimulates the output of HCI and pepsinogen. Gastrin is an
    important mediator of this phase. Secretion is inhibited "when the pH
    of the gastric contents falls to around 2 or 3-

  4. As partially digested food enters the duodenum some gastrin is
    secreted from G-cells in the intestinal mucosa. This stimulates
    further secretion. However, secretin, OCK, and GIP all contribute to
    the inhibition of gastric secretion.

18.7 The storage, mixing, and propulsion of gastric contents

The motor functions of the stomach play an important role in the overall process of digestion. The stomach stores food until it can be accommodated by the lower regions of the GI tract. It also mixes the food with gastric secretions and, through its grinding action, breaks it down into smaller pieces until it forms semiliquid chyme. The stomach contents are then delivered to the duodenum at a rate compatible with digestion and absorp­tion. These functions are controlled by complex interactions between the enteric nervous system, the autonomic nervous system, and a number of hormones.

For the purposes of its motor function, the stomach may be divided into two parts. These are the proximal motor unit, con­sisting of the fundus and body of the stomach, and the distal motor unit, consisting of the antral and pyloric regions. The proximal motor unit carries out the reservoir functions of the stomach while the distal motor unit is responsible for the mixing of food and its propulsion into the duodenum.

Storage function of the stomach

The empty stomach has a volume of around 50 ml and an intra-gastric pressure of 0.6 kPa (5 mmHg) or less. Although it can stretch to accommodate large volumes of food, little increase in intragastric pressure is seen until the stomach volume exceeds 1 liter. There are several reasons for this. The smooth muscle of the stomach wall is able to increase its length significantly without altering its tone, a property known as plasticity. The stomach exhibits receptive relaxation. As it is stretched, a vagal reflex is triggered which inhibits muscle activity in the body of the stomach. This reflex is thought to be coordinated by the regions of the brainstem responsible for swallowing. Finally, the

shape of the stomach itself contributes to its effectiveness as a reservoir. As the diameter of the stomach increases during filling, the radius of curvature of its walls also increases. At a given pressure, the stretching force on the walls increases in pro­portion to this radius of curvature (Laplace's law, see also Section 16.4). As a result, intragastric pressure rises only slightly despite significant distension.

Contractile activity of the full stomach— mixing and propulsion

Gastric motility results from the coordinated contraction of the three smooth muscle layers which lie within the stomach wall. The different orientations of the longitudinal, circular, and oblique layers allow the stomach to perform a wide variety of different movements, including grinding, churning, kneading, and twisting, as well as propulsion.

During fasting, the stomach shows only weak contractile activity (though in extreme hunger there may be short periods of intense contractile activity experienced as hunger 'pangs'). After a meal, peristaltic contractions begin in the body of the stomach. These are very weak, rippling movements but as the contractions approach the pylorus, where the musculature is thicker, they become much more powerful, reaching a maximum close to the gastro-duodenal junction. Thus, the contents of the fundus remain relatively undisturbed while those of the pyloric regions receive a vigorous pummeling and mixing. Although the inten­sity of these peristaltic contractions may be modified by many factors, their rate remains fairly constant at around three contractions a minute.

The rate of propagation of the peristaltic wave accelerates as it nears the distal regions so that the smooth muscle of the antrum and pylorus contracts virtually simultaneously, pushing the gastric contents ahead of the peristaltic wave. As pressure in the antrum rises, the pyloric sphincter opens and a few milliliters of chyme are squirted through it into the first part of the duode­num, the duodenal bulb. The sphincter closes almost immedi­ately, thus preventing further emptying, and as a result of the continued high pressure in the antrum, some of the gastric con­tents are forced back into more proximal regions. This is called retropulsion and increases the effectiveness of mixing and break­down of food particles within the stomach.

Gastric motility is enhanced by many of the same nervous and hormonal factors that stimulate gastric secretion. Distension of the stomach wall by food activates stretch receptors and gastrin-secreting cells which both enhance the force of peristaltic contractions and thus increase the efficiency of mixing and emptying movements. The nervous control of gastric motility is not completely understood. Both parasympathetic (vagal) and sympathetic fibers supply the smooth muscle and, in general, it appears that parasympathetic activity increases, while sympathetic activity decreases, motility.

408

18 The gut and nutrition


The rate of gastric emptying is carefully controlled

If digestion and absorption are to proceed with optimum efficiency, it is essential that chyme is delivered to the duodenum at a rate that enables the small intestine to process it fully. Furthermore, it is important that duodenal contents are pre­vented from being regurgitated into the stomach. The gastric and duodenal environments are very different. The gastric mucosa is resistant to acid but may be eroded by bile, while the duodenum is resistant to the effects of bile but is unable to tolerate low pH. Consequently, gastric emptying which is too rapid may result in the formation of duodenal ulcers, while regurgitation of duodenal contents may result in gastric ulceration.

^ Many factors contribute to the regulation of gastric emptying

Emptying of the stomach depends upon the factors that influence motor activity throughout the GI tract—the inherent excitability of smooth muscle, intrinsic and extrinsic nervous pathways, and hormones. In general, the stomach empties at a rate that is propor­tional to gastric volume, i.e. the fuller the stomach the more rapidly it empties. In addition, the physical and chemical nature of the gastric contents affects the rate of emptying. Fats and proteins in the ingested food, a very acidic juice, and a hypertonic mixture of juice and food will all delay emptying. In general, the closer the contents are to isotonic saline, the more rapidly they will leave the stomach. The half-time for liquids remaining in the stomach is about 20 minutes as compared with about 2 hours for solids.

Receptors of various kinds are present within the duodenum and contribute to the regulation of gastric emptying via the so-called enterogastric reflex, a collective term used to describe all the hormonal and neural mechanisms that mediate intestinal control of gastric emptying.

The presence of fatty acids or monoglycerides in the duode­num causes an increase in the contractility of the pyloric sphinc­ter. This will tend to reduce the rate at which the gastric contents can be propelled through the sphincter into the small intestine. This is an important mechanism whereby the GI tract ensures that fats are not delivered to the duodenum more quickly than the bile salts can process them. The mechanism of action of fats is unclear but both CCK and GIP are released from the small intes­tine in response to fats and their digestion products, and both hormones have been shown to delay gastric emptying.

The products of protein digestion are also believed to exert their inhibitory effect on gastric emptying through endocrine pathways. Gastrin is secreted from G-cells in both the antrum and duodenum in response to peptides and amino acids. The action of gastrin is twofold. Although it stimulates contraction of the antrum, it also increases the degree of constriction of the pyloric sphincter so that the net effect of gastrin secretion is normally to delay emptying of the stomach.

The delay in gastric emptying seen when acid enters the duo­denum is probably mediated at least in part by the vagus nerve,

since vagotomy reduces the response. Secretin may also play a role. This hormone is released in response to acid in the duode­num and delays gastric emptying by inhibiting contraction of the antrum and constricting the pyloric sphincter. Secretin also stimulates the flow of bicarbonate-rich pancreatic juice, which neutralizes the acid within the duodenum. Indeed, all the known actions of secretin counteract duodenal acidification.

The electrical activity underlying gastric contractions

The regular peristaltic contractions shown by the stomach are the mechanical consequence of the basic electrical rhythm (BER) of smooth muscle cells. This basic rhythm is set by the sponta­neous activity of pacemaker cells in the longitudinal smooth muscle layer of the stomach wall in the region of the greater curvature. These cells show spontaneous depolarization and repo-larization every 20 seconds or so to establish the BER or 'slow-wave' rhythm of the stomach. The pacemaker cells are electrically coupled to the rest of the stomach muscle sheet by means of gap junctions and their rhythm is, therefore, transmitted to the entire muscularis.

The electrical properties of the gastric slow wave and its rela­tionship with the contractile force generated by the smooth muscle are illustrated in Fig. 18.14. The potential change is triphasic and similar to a cardiac muscle action potential, although it is about 10 times as long. The inward current responsible for initial depolarization is probably carried by calcium ions moving through voltage-gated channels while the plateau is maintained by the inward movement of both sodium and calcium ions. Repolarization is associated with a delayed outward potassium current.




Fig. 18.14 The relationship between contraction and the electrical activity of the smooth muscle of the stomach.


Despite the fact that action potentials are not normally associ­ated with the gastric pacemaker potentials in the proximal regions of the stomach, contraction of the smooth muscle occurs when the depolarization phase of the potential reaches the threshold for contraction (the mechanical threshold). The force of contraction is related to the degree of depolarization and the time for which the potential exceeds threshold. In the distal antrum and pyloric regions of the stomach, vigorous propulsive

^ 18.8 The small intestine
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