Secretory Functions of the Alimentary Tract

Sympathetic Stimulation Has a Dual Effect on the Alimentary Tract Glandular Secretion Rate.

Stimula­tion of the sympathetic nerves going to the gastrointestinal tract causes a slight to moderate increase in secretion by some of the local glands. However, sympathetic stimulation also results in constriction of the blood vessels that supply the glands. Therefore, sympathetic stimulation can have a dual effect: (1) sympathetic stimulation alone usually slightly increases secretion and (2) if parasympathetic or hormonal stimulation is already causing copious secretion by the glands, superimposed sympathetic stimulation usually reduces the secretion, sometimes significantly so, mainly because of vasoconstrictive reduction of the blood supply.

Regulation of Glandular Secretion by Hormones.

In the stomach and intestine, several different gastrointestinal hormones help regulate the volume and character of the secretions. These hormones are liberated from the gastrointestinal mucosa in response to the presence of food in the lumen of the gut. The hormones are then absorbed into the blood and carried to the glands, where they stimulate secretion. This type of stimulation is particularly valuable to increase the output of gastric juice and pancreatic juice when food enters the stomach or duodenum.

Chemically, the gastrointestinal hormones are polypeptides or polypeptide derivatives and will be discussed in more detail later.

Secretion of Organic Substances.

Although all the basic mechanisms by which glandular cells function are not known, experimental evidence points to the following principles of secretion, as shown in Figure 65-1.

Water and Electrolyte Secretion.

A second necessity for glandular secretion is secretion of sufficient water and electrolytes to go along with the organic substances. Secretion by the salivary glands, discussed in more detail later, provides an example of how nervous stimulation causes water and salts to pass through the glandular cells in great profusion, washing the organic substances through the secretory border of the cells at the same time. It is believed that hormones acting on the cell membrane of some glandular cells also cause secretory effects similar to those caused by nervous stimulation.

Saliva Contains a Serous Secretion and a Mucus Secretion.

The principal glands of salivation are the parotid, submandibular, and sublingual glands; in addition, there are many tiny buccal glands. Daily secretion of saliva normally ranges between 800 and 1500 milliliters, as shown by the average value of 1000 milliliters in Table 65-1.

Saliva contains two major types of protein secretion: (1) a serous secretion that contains ptyalin (an α-amylase), which is an enzyme for digesting starches, and (2) mucus secretion that contains mucin for lubricating and for surface protective purposes.

The parotid glands secrete almost entirely the serous type of secretion, whereas the submandibular and sublingual glands secrete both serous secretion and mucus. The buccal glands secrete only mucus. Saliva has a pH between 6.0 and 7.0, which is a favorable range for the digestive action of ptyalin.

Secretion of Ions in Saliva.

Saliva contains especially large quantities of potassium and bicarbonate ions. Conversely, the concentrations of both sodium and chloride ions are several times less in saliva than in plasma. One can understand these special concentrations of ions in the saliva from the following description of the mechanism for secretion of saliva.

Figure 65-2 shows secretion by the submandibular gland, a typical compound gland that contains acini and salivary ducts. Salivary secretion is a two-stage operation: The first stage involves the acini, and the second stage involves the salivary ducts. The acini secrete a primary secretion that contains ptyalin and/or mucin in a solution of ions with concentrations not greatly different from those of typical extracellular fluid. As the primary secretion flows through the ducts, two major active transport processes take place that markedly modify the ionic composition of the fluid in the saliva.

First, sodium ions are actively reabsorbed from all the salivary ducts and potassium ions are actively secreted in exchange for the sodium. Therefore, the sodium ion concentration of the saliva becomes greatly reduced, whereas the potassium ion concentration becomes increased. However, there is excess sodium reabsorption compared with potassium secretion, which creates electrical negativity of about −70 millivolts in the salivary ducts; this negativity in turn causes chloride ions to be reabsorbed passively. Therefore, the chloride ion concentration in the salivary fluid falls to a very low level, matching the ductal decrease in sodium ion concentration.

Second, bicarbonate ions are secreted by the ductal epithelium into the lumen of the duct. This secretion is at least partly caused by the passive exchange of bicarbonate for chloride ions, but it may also result partly from an active secretory process.

The net result of these transport processes is that under resting conditions, the concentrations of sodium and chloride ions in the saliva are only about 15 mEq/L each, about one seventh to one tenth their concentrations in plasma. Conversely, the concentration of potassium ions is about 30 mEq/L, seven times as great as in plasma, and the concentration of bicarbonate ions is 50 to 70 mEq/L, about two to three times that of plasma.

During maximal salivation, the salivary ionic concentrations change considerably because the rate of formation of primary secretion by the acini can increase as much as 20-fold. This acinar secretion then flows through the ducts so rapidly that the ductal reconditioning of the secretion is considerably reduced. Therefore, when copious quantities of saliva are being secreted, the sodium chloride concentration is about one half or two thirds that of plasma, and the potassium concentration rises to only four times that of plasma.

Function of Saliva for Oral Hygiene.

Under basal awake conditions, about 0.5 milliliter of saliva, almost entirely of the mucous type, is secreted each minute; however, during sleep, little secretion occurs. This secretion plays an exceedingly important role for maintaining healthy oral tissues. The mouth is loaded with pathogenic bacteria that can easily destroy tissues and cause dental caries. Saliva helps prevent the deteriorative processes in several ways:

Parietal Cells of the Oxyntic Glands Are the Only Cells That Secrete Hydrochloric Acid.

As noted earlier in the chapter, the acidity of the fluid secreted by the parietal cells of the oxyntic glands can be great, with pH as low as 0.8. However, secretion of this acid is under continuous control by both endocrine and nervous signals. Furthermore, the parietal cells operate in close association with another type of cell called enterochromaffin-like cells (ECL cells), the primary function of which is to secrete histamine.

The ECL cells lie in the deep recesses of the oxyntic glands and therefore release histamine in direct contact with the parietal cells of the glands. The rate of formation and secretion of hydrochloric acid by the parietal cells is directly related to the amount of histamine secreted by the ECL cells. In turn, the ECL cells are stimulated to secrete histamine by the hormone gastrin, which is formed almost entirely in the antral portion of the stomach mucosa in response to proteins in the foods being digested. The ECL cells may also be stimulated by hormones secreted by the enteric nervous system of the stomach wall. We will first discuss the gastrin mechanism for control of the ECL cells and their subsequent control of parietal cell secretion of hydrochloric acid.

Stimulation of Acid Secretion by Gastrin.

Gastrin is a hormone secreted by gastrin cells, also called G cells. These cells are located in the pyloric glands in the distal end of the stomach. Gastrin is a large polypeptide secreted in two forms: a large form called G-34, which contains 34 amino acids, and a smaller form, G-17, which contains 17 amino acids. Although both of these forms are important, the smaller form is more abundant.

When meats or other foods containing protein reach the antral end of the stomach, some of the proteins from these foods have a special stimulatory effect on the gastrin cells in the pyloric glands to cause release of gastrin into the blood to be transported to the ECL cells of the stomach. The vigorous mixing of the gastric juices transports the gastrin rapidly to the ECL cells in the body of the stomach, causing release of histamine directly into the deep oxyntic glands. The histamine then acts quickly to stimulate gastric hydrochloric acid secretion.

Cephalic Phase.

The cephalic phase of gastric secretion occurs even before food enters the stomach, especially while it is being eaten. It results from the sight, smell, thought, or taste of food, and the greater the appetite, the more intense is the stimulation. Neurogenic signals that cause the cephalic phase of gastric secretion originate in the cerebral cortex and in the appetite centers of the amygdala and hypothalamus. They are transmitted through the dorsal motor nuclei of the vagi and thence through the vagus nerves to the stomach. This phase of secretion normally accounts for about 30 percent of the gastric secretion associated with eating a meal.

Gastric Phase.

Once food enters the stomach, it excites (1) long vagovagal reflexes from the stomach to the brain and back to the stomach, (2) local enteric reflexes, and (3) the gastrin mechanism, all of which cause secretion of gastric juice during several hours while food remains in the stomach. The gastric phase of secretion accounts for about 60 percent of the total gastric secretion associated with eating a meal and therefore accounts for most of the total daily gastric secretion of about 1500 milliliters.

Intestinal Phase.

The presence of food in the upper portion of the small intestine, particularly in the duodenum, will continue to cause stomach secretion of small amounts of gastric juice, probably partly because of small amounts of gastrin released by the duodenal mucosa. This secretion accounts for about 10 percent of the acid response to a meal.

Gastric Secretion During the Interdigestive Period.

The stomach secretes a few milliliters of gastric juice each hour during the “interdigestive period,” when little or no digestion is occurring anywhere in the gut. The secretion that does occur is usually almost entirely of the nonoxyntic type, composed mainly of mucus but little pepsin and almost no acid.

Emotional stimuli may increase interdigestive gastric secretion (which is highly peptic and acidic) to 50 milliliters or more per hour, in much the same way that the cephalic phase of gastric secretion excites secretion at the onset of a meal. This increase of secretion in response to emotional stimuli is believed to contribute to the development of peptic ulcers, as discussed in Chapter 67.

Secretion of Trypsin Inhibitor Prevents Digestion of the Pancreas.

It is important that the proteolytic enzymes of the pancreatic juice not become activated until after they have been secreted into the intestine because the trypsin and the other enzymes would digest the pancreas. Fortunately, the same cells that secrete proteolytic enzymes into the acini of the pancreas simultaneously secrete another substance called trypsin inhibitor. This substance, which is formed in the cytoplasm of the glandular cells, prevents activation of trypsin both inside the secretory cells and in the acini and ducts of the pancreas. In addition, because it is trypsin that activates the other pancreatic proteolytic enzymes, trypsin inhibitor prevents activation of the other enzymes as well.

When the pancreas becomes severely damaged or when a duct becomes blocked, large quantities of pancreatic secretion sometimes become pooled in the damaged areas of the pancreas. Under these conditions, the effect of trypsin inhibitor is often overwhelmed, in which case the pancreatic secretions rapidly become activated and can literally digest the entire pancreas within a few hours, giving rise to the condition called acute pancreatitis. This condition is sometimes lethal because of accompanying circulatory shock; even if it is not lethal, it usually leads to a subsequent lifetime of pancreatic insufficiency.

Cephalic and Gastric Phases.

During the cephalic phase of pancreatic secretion, the same nervous signals from the brain that cause secretion in the stomach also cause acetylcholine release by the vagal nerve end­ings in the pancreas. This signaling causes moderate amounts of enzymes to be secreted into the pancreatic acini, accounting for about 20 percent of the total secretion of pancreatic enzymes after a meal. However, little of the secretion flows immediately through the pancreatic ducts into the intestine because only small amounts of water and electrolytes are secreted along with the enzymes.

During the gastric phase, the nervous stimulation of enzyme secretion continues, accounting for another 5 to 10 percent of pancreatic enzymes secreted after a meal. However, again, only small amounts reach the duodenum because of continued lack of significant fluid secretion.

Intestinal Phase.

After chyme leaves the stomach and enters the small intestine, pancreatic secretion becomes copious, mainly in response to the hormone secretin.

Secretin Stimulates Copious Secretion of Bicarbonate Ions, Which Neutralizes Acidic Stomach Chyme.

Secretin is a polypeptide containing 27 amino acids (with a molecular weight of about 3400). It is present in an inactive form, prosecretin, in so-called S cells in the mucosa of the duodenum and jejunum. When acid chyme with a pH less than 4.5 to 5.0 enters the duodenum from the stomach, it causes duodenal mucosal release and activation of secretin, which is then absorbed into the blood. The one truly potent constituent of chyme that causes this secretin release is the hydrochloric acid from the stomach.

Secretin in turn causes the pancreas to secrete large quantities of fluid containing a high concentration of bicarbonate ion (up to 145 mEq/L) but a low concentration of chloride ion. The secretin mechanism is especially important for two reasons: First, secretin begins to be released from the mucosa of the small intestine when the pH of the duodenal contents falls below 4.5 to 5.0, and its release increases greatly as the pH falls to 3.0. This mechanism immediately causes copious secretion of pancreatic juice that contains abundant amounts of sodium bicarbonate. The net result is then the following reaction in the duodenum:

HCl+NaHCO3→NaCl+H2CO3

The carbonic acid then immediately dissociates into carbon dioxide and water. The carbon dioxide is absorbed into the blood and expired through the lungs, thus leaving a neutral solution of sodium chloride in the duodenum. In this way, the acid contents that are emptied into the duodenum from the stomach become neutralized, and thus further peptic digestive activity by the gastric juices in the duodenum is immediately blocked. Because the mucosa of the small intestine cannot withstand the digestive action of acid gastric juice, this protective mechanism is essential to prevent the development of duodenal ulcers, as is discussed in further detail in Chapter 67.

Bicarbonate ion secretion by the pancreas provides an appropriate pH for action of the pancreatic digestive enzymes, which function optimally in a slightly alkaline or neutral medium, at a pH of 7.0 to 8.0. Fortunately, the pH of the sodium bicarbonate secretion averages 8.0.

Cholecystokinin Contributes to Control of Digestive Enzyme Secretion by the Pancreas.

The presence of food in the upper small intestine also causes a second hormone, cholecystokinin (CCK), a polypeptide containing 33 amino acids, to be released from yet another group of cells, the I cells, in the mucosa of the duodenum and upper jejunum. This release of CCK results especially from the presence of proteoses and peptones (products of partial protein digestion) and long-chain fatty acids in the chyme coming from the stomach.

CCK, like secretin, passes by way of the blood to the pancreas, but instead of causing sodium bicarbonate secretion, it mainly causes secretion of much more pancreatic digestive enzymes by the acinar cells. This effect is similar to that caused by vagal stimulation but is even more pronounced, accounting for 70 to 80 percent of the total secretion of the pancreatic digestive enzymes after a meal.

The differences between the pancreatic stimulatory effects of secretin and CCK are shown in Figure 65-9, which demonstrates (1) intense sodium bicarbonate secretion in response to acid in the duodenum, stimulated by secretin; (2) a dual effect in response to soap (a fat); and (3) intense digestive enzyme secretion (when peptones enter the duodenum) stimulated by CCK.

Figure 65-10 summarizes the more important factors in the regulation of pancreatic secretion. The total amount secreted each day is about 1 liter.

Storing and Concentrating Bile in the Gallbladder.

Bile is secreted continually by the liver cells, but most of it is normally stored in the gallbladder until it is needed in the duodenum. The maximum volume that the gallbladder can hold is only 30 to 60 milliliters. Nevertheless, as much as 12 hours of bile secretion (usually about 450 milliliters) can be stored in the gallbladder because water, sodium, chloride, and most other small electrolytes are continually absorbed through the gallbladder mucosa, concentrating the remaining bile constituents that contain the bile salts, cholesterol, lecithin, and bilirubin.

Most of this gallbladder absorption is caused by active transport of sodium through the gallbladder epithelium, and this transport is followed by secondary absorption of chloride ions, water, and most other diffusible constituents. Bile is normally concentrated in this way about 5-fold, but it can be concentrated up to a maximum of 20-fold.

Composition of Bile.

Table 65-2 lists the composition of bile when it is first secreted by the liver and then after it has been concentrated in the gallbladder. By far the most abundant substances secreted in the bile are bile salts, which account for about one half of the total solutes also in the bile. Also secreted or excreted in large concentrations are bilirubin, cholesterol, lecithin, and the usual electrolytes of plasma.

In the concentrating process in the gallbladder, water and large portions of the electrolytes (except calcium ions) are reabsorbed by the gallbladder mucosa; essentially all other constituents, especially the bile salts and the lipid substances cholesterol and lecithin, are not reabsorbed and, therefore, become highly concentrated in the gallbladder bile.

Cholecystokinin Stimulates Gallbladder Emptying.

When food begins to be digested in the upper gastrointestinal tract, the gallbladder begins to empty, especially when fatty foods reach the duodenum about 30 minutes after a meal. The mechanism of gallbladder emptying is rhythmical contractions of the gallbladder wall, but effective emptying also requires simultaneous relaxation of the sphincter of Oddi, which guards the exit of the common bile duct into the duodenum.

By far the most potent stimulus for causing the gallbladder contractions is the hormone CCK. This is the same CCK discussed earlier that causes increased secretion of digestive enzymes by the acinar cells of the pancreas. The stimulus for CCK entry into the blood from the duodenal mucosa is mainly the presence of fatty foods in the duodenum.

The gallbladder is also stimulated less strongly by acetylcholine-secreting nerve fibers from both the vagi and the intestinal enteric nervous system. They are the same nerves that promote motility and secretion in other parts of the upper gastrointestinal tract.

In summary, the gallbladder empties its store of concentrated bile into the duodenum mainly in response to the CCK stimulus that is initiated mainly by fatty foods. When fat is not in the food, the gallbladder empties poorly, but when significant quantities of fat are present, the gallbladder normally empties completely in about 1 hour. Figure 65-11 summarizes the secretion of bile, its storage in the gallbladder, and its ultimate release from the bladder to the duodenum.

Enterohepatic Circulation of Bile Salts.

About 94 percent of the bile salts are reabsorbed into the blood from the small intestine, about one half of this by diffusion through the mucosa in the early portions of the small intestine and the remainder by an active transport process through the intestinal mucosa in the distal ileum. They then enter the portal blood and pass back to the liver. Upon reaching the liver and during first passage through the venous sinusoids, these salts are absorbed almost entirely back into the hepatic cells and are then resecreted into the bile.

In this way, about 94 percent of all the bile salts are recirculated into the bile, so on average these salts make the entire circuit some 17 times before being carried out in the feces. The small quantities of bile salts lost into the feces are replaced by new amounts formed continually by the liver cells. This recirculation of the bile salts is called the enterohepatic circulation of bile salts.

The quantity of bile secreted by the liver each day is highly dependent on the availability of bile salts—the greater the quantity of bile salts in the enterohepatic circulation (usually a total of only about 2.5 grams), the greater the rate of bile secretion. Indeed, ingestion of supplemental bile salts can increase bile secretion by several hundred milliliters per day.

If a bile fistula empties the bile salts to the exterior for several days to several weeks so they cannot be reabsorbed from the ileum, the liver increases its production of bile salts 6- to 10-fold, which increases the rate of bile secretion most of the way back to normal. This demonstrates that the daily rate of liver bile salt secretion is actively controlled by the availability (or lack of availability) of bile salts in the enterohepatic circulation.

Role of Secretin in Controlling Bile Secretion.

In addition to the strong stimulating effect of bile acids to cause bile secretion, the hormone secretin—which also stimulates pancreatic secretion—increases bile secretion, sometimes more than doubling its secretion for several hours after a meal. This increase in secretion consists almost entirely of secretion of a sodium bicarbonate–rich watery solution by the epithelial cells of the bile ductules and ducts and does not represent increased secretion by the liver parenchymal cells themselves. The bicarbonate in turn passes into the small intestine and joins the bicarbonate from the pancreas in neutralizing the hydrochloric acid from the stomach. Thus, the secretin feedback mechanism for neutralizing duodenal acid operates not only through its effects on pancreatic secretion but also to a lesser extent through its effect on secretion by the liver ductules and ducts.

Mechanism of Secretion of the Watery Fluid.

The exact mechanism that controls the marked secretion of watery fluid by the crypts of Lieberkühn is still unclear, but it is believed to involve at least two active secretory processes: (1) active secretion of chloride ions into the crypts and (2) active secretion of bicarbonate ions. The secretion of both ions causes electrical drag of positively charged sodium ions through the membrane and into the secreted fluid as well. Finally, all these ions together cause osmotic movement of water.

Digestive Enzymes in the Small Intestinal Secretion.

When secretions of the small intestine are collected without cellular debris, they have almost no enzymes. The enterocytes of the mucosa, especially those that cover the villi, contain digestive enzymes that digest specific food substances while they are being absorbed through the epithelium. These enzymes are the following: (1) several peptidases for splitting small peptides into amino acids; (2) four enzymes—sucrase, maltase, isomaltase, and lactase—for splitting disaccharides into monosaccharides; and (3) small amounts of intestinal lipase for splitting neutral fats into glycerol and fatty acids.

The epithelial cells deep in the crypts of Lieberkühn continually undergo mitosis, and new cells migrate along the basement membrane upward out of the crypts toward the tips of the villi, thus continually replacing the villus epithelium and also forming new digestive enzymes. As the villus cells age, they are finally shed into the intestinal secretions. The life cycle of an intestinal epithelial cell is about 5 days. This rapid growth of new cells also allows rapid repair of excoriations that occur in the mucosa.

Mucus Secretion.

The mucosa of the large intestine, like that of the small intestine, has many crypts of Lieberkühn; however, unlike the small intestine, it contains no villi. The epithelial cells secrete almost no digestive enzymes. Instead, they contain mucous cells that secrete only mucus. This mucus contains moderate amounts of bicarbonate ions secreted by a few non–mucus-secreting epithelial cells. The rate of secretion of mucus is regulated principally by direct, tactile stimulation of the epithelial cells lining the large intestine and by local nervous reflexes to the mucous cells in the crypts of Lieberkühn.

Stimulation of the pelvic nerves from the spinal cord, which carry parasympathetic innervation to the distal one half to two thirds of the large intestine, also can cause a marked increase in mucus secretion. This increase occurs along with an increase in peristaltic motility of the colon, which was discussed in Chapter 64.

During extreme parasympathetic stimulation, often caused by emotional disturbances, so much mucus can occasionally be secreted into the large intestine that the person has a bowel movement of ropy mucus as often as every 30 minutes; this mucus often contains little or no fecal material.

Mucus in the large intestine protects the intestinal wall against excoriation, but in addition, it provides an adherent medium for holding fecal matter together. Furthermore, it protects the intestinal wall from the great amount of bacterial activity that takes place inside the feces, and, finally, the mucus plus the alkalinity of the secretion (a pH of 8.0 caused by large amounts of sodium bicarbonate) provides a barrier to keep acids formed in the feces from attacking the intestinal wall.

Diarrhea Caused by Excess Secretion of Water and Electrolytes in Response to Irritation.

Whenever a segment of the large intestine becomes intensely irritated, as occurs when bacterial infection becomes rampant during enteritis, the mucosa secretes extra large quantities of water and electrolytes in addition to the normal viscid alkaline mucus. This secretion acts to dilute the irritating factors and to cause rapid movement of the feces toward the anus. The result is diarrhea, with loss of large quantities of water and electrolytes. However, the diarrhea also washes away irritant factors, which promotes earlier recovery from the disease than might otherwise occur.