H

activities are discussed in Chapter 35, which is concerned with the digestion and absorption of nutrients.

Between meals, pancreatic enzymes are stored in zymogen granules that have migrated to an area near the apical membrane of the acinar cell. A secretory stimulus results in the fusion of the granule membrane with the apical membrane of the cell and the secretion of enzyme contents into the lumen. This process of exocytosis is the only step in the synthesis of the proteins, formation of granules, and secretion of the enzymes known to be controlled by neural and hormonal input.

The steps involved in the synthesis and secretion of pancreatic enzymes are outlined in Fig. 21. In general, these same steps are involved in the production and secretion of salivary enzymes and of pepsin from the

FIGURE 21 Schematic diagram of a pancreatic acinar cell illustrating the primary steps in the synthesis and secretion of enzymes.

stomach. Step 1 is the actual synthesis of the enzyme protein on the polysomes attached to the cisternae of the rough endoplasmic reticulum. As the protein is being synthesized, it elongates and, directed by a leader sequence of hydrophobic amino acids, enters the cisternae of the rough endoplasmic reticulum, where it is collected and where it may undergo some post-translational modification (step 2). Once within the lumen, the enzymes remain membrane bound until they are secreted from the cell. In step 3, the enzymes are transferred to the Golgi complex. This transfer may involve the budding off of enzyme-containing transition elements from the rough endoplasmic reticulum. After association with the Golgi vesicles, the enzymes are transported to condensing vacuoles (step 4), where they are concentrated to form zymogen granules (step 5). The enzymes are then stored in the zymogen granules until a secretory stimulus triggers their expulsion into the lumen of the acinus (step 6). Energy is required for the transport of the enzymes through the endoplasmic reticulum and Golgi vesicles to the condensing granules. Steps 1 through 5 occur without a secretory stimulus.

The process just outlined is accepted by most authorities in this field. However, acini that have been depleted of granules by constant stimulation are still capable of secreting enzymes. The interrelationship of these two mechanisms has not been explained experimentally.

Normally, the pancreatic proteases are not activated until they are secreted into the duodenum. There, enterokinase, an enzyme present in the apical membranes of the enterocytes, converts inactive trypsinogen to the active enzyme trypsin. Trypsin then catalyzes the conversion of the other protease proenzymes to active enzymes. Numerous measures are in place to ensure that proteases are not activated in the cytoplasm of the acinar cell where

Clinical Note

Pancreatitis

Pancreatitis, or inflammation of the pancreas, occurs when activated pancreatic proteases digest pancreatic tissue itself. The most common causes of this condition are excessive consumption of alcohol and blockage of the pancreatic or common duct. Duct blockage is usually due to gallstones and frequently occurs at the ampulla of Vater. Pancreatic secretions build up behind the obstruction, trypsin accumulates, and activates the other pancreatic proteases as well as additional trypsin. Eventually the normal defense mechanisms are overwhelmed and digestion of pancreatic tissue begins.

Approximately 10% of pancreatitis is hereditary. Mutations of the genes associated with the normal defense mechanisms have been identified as accounting for most of these cases. Two mutations occur in the trypsinogen gene itself. One (R122H) enhances trypsin activity by impairing its autodigestion. The other (N29I) leads to an increased rate of autoactivation. In addition, mutations in the predominant native trypsin inhibitor have been shown to increase the risk of disease.

they can digest the pancreas itself. First, and foremost, the proteases are synthesized as inactive precursors. Second, pancreatic enzymes are membrane bound from the time of synthesis until they are secreted from zymogen granules. Third, acinar cells contain a trypsin inhibitor which destroys active trypsin. Fourth, trypsin itself is capable of autodigestion.

Regulation of Secretion

The secretion of the aqueous component (fluid and bicarbonate) is regulated by the amount of acid entering the duodenum. Because the function of this component of pancreatic secretion is to neutralize the intestinal contents, this operates as another negative feedback system for the regulation of a gastrointestinal secretion. Similarly, the secretion of the enzymatic component is regulated by the amount of fat and protein in the intestinal contents. Most stimulation of pancreatic secretion is initiated during the intestinal phase, although stimuli from both the cephalic and gastric phases also contribute. The primary agents involved in stimulating the pancreatic cells are secretin, CCK, and acetylcholine acting via vagovagal reflexes.

In humans, there is little basal pancreatic secretion. The aqueous component is secreted at rates of 2-3% of maximal, and the enzymatic component at 10-15% of maximal. The stimuli involved in basal pancreatic secretion are unknown, and basal secretion may be an intrinsic property of the organ.

Cephalic Phase

Truncal vagotomy decreases the pancreatic secretory response to a meal by approximately 60%. Most of this reduction, however, is due to the interruption of vagovagal reflexes initiated during the intestinal phase.

The stimuli for the cephalic phase of pancreatic secretion are identical to those discussed previously for gastric secretion and contribute approximately 20% of the pancreatic response. Vagal efferents to the pancreas release acetylcholine at both the ductule and acinar cells (Fig. 22). Stimulation has a greater effect on the enzymatic component (acinar cells) than on the aqueous component. This results in the production of a low volume of secretion with a high enzymatic content. In humans, gastrin plays little or no role in the cephalic phase of pancreatic secretion.

Gastric Phase

Distension of either the proximal or distal regions of the stomach stimulates pancreatic secretion by initiating vagovagal reflexes. Because these are mediated by

Vagus Nucleus Vagus Nerve

Conditioned reflexes Smell, Taste Chewing Swallowing Hypoglycemia

Vagus Nucleus Vagus Nerve

Conditioned reflexes Smell, Taste Chewing Swallowing Hypoglycemia

^Acinar Cells f DucfCell^Acinar Cells

^ - — Gastrin - ' FIGURE 22 Mechanisms involved in the stimulation of pancreatic secretion during the cephalic phase. Dashed lines represent mechanisms of little importance in humans. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

^Acinar Cells f DucfCell^Acinar Cells

^ - — Gastrin - ' FIGURE 22 Mechanisms involved in the stimulation of pancreatic secretion during the cephalic phase. Dashed lines represent mechanisms of little importance in humans. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

acetylcholine, secretion is primarily the low-volume enzymatic component. There is no strong evidence that gastrin contributes to the human pancreatic response. The percentage of pancreatic secretion due to the gastric phase is small, amounting to only 5-10% of the total.

Intestinal Phase

Hydrogen ion and fat and protein digestion products in the lumen of the small intestine account for 70-80% of the human pancreatic secretory response to a meal. Acid releases secretin from the S cells of duodenal mucosa, and secretin is the principal stimulant of the aqueous component. Fat and protein digestion products release CCK from duodenal I cells. CCK is the primary humoral stimulant of the enzymatic component. The enzymatic component is also stimulated by acetylcholine via vagovagal reflexes initiated by acid, fatty acids, and peptides and amino acids acting on receptors present in the duodenal mucosa. Neither CCK nor acetylcholine has much effect on the ductule cells in the absence of secretin. However, both potentiate the effects of secre-tin, allowing the pancreas to secrete large amounts of water and bicarbonate. The mechanisms involved in the stimulation of pancreatic secretion during the intestinal phase are summarized in Fig. 23.

FIGURE 23 Mechanisms involved in the stimulation of pancreatic secretion during the intestinal phase. Dashed lines indicate potentiative interactions with secretin. (Modified from Johnson LR, ed., Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

Secretin is released when the duodenal mucosa is acidified to pH 4.5 or lower (Fig. 24). As the pH of the duodenal contents is lowered to 3.0, secretin release increases linearly. Below pH 3.0, secretin release does not depend on the pH, but depends only on the amount of titratable acid entering the duodenum. As more acid enters the duodenum, more S cells are acidified to release secretin. Therefore, below pH 3.0, secretin release depends on only the area of mucosa acidified. Secretin can also be released by high concentrations of fatty acids. This mechanism, however, is not nearly as important physiologically as release by hydrogen ion.

During the response to a normal meal, the pH of duodenal contents rarely drops below 3.5 or 4, and only the duodenal bulb and proximal duodenum are sufficiently acidified to release secretin. Therefore, even though secretin is present in relatively equal amounts throughout the duodenal and jejunal mucosa, little is released. In fact, the amount released is, by itself, sufficient to account for only a small fraction of the bicarbonate and water secreted by the pancreas. However, in the presence of fat and protein digestion products, lowering the duodenal pH even slightly below 4.5 leads to near maximal increases in water and bicarbonate secretion. This magnified response is due to the potentiation of small amounts of secretin by CCK and acetylcholine. The potentiation of secretin effects is an important physiologic interaction either between two hormones or between a hormone and a neurocrine.

Potentiation allows maximal effects to be produced with small amounts of hormones, leading in turn to a conservation of hormone supplies. Because only small amounts of hormone circulate, potentiation also ensures that "pharmacologic" effects of the peptides do not occur.

CCK is released by L-isomers of amino acids and by fatty acids containing eight or more carbon atoms. Not all amino acids are strong releasers of CCK. In humans, phenylalanine, methionine, and tryptophan appear to be the most potent. Three peptides, all containing glycine, are also effective releasers of CCK. These are glycyl-phenylalanine, glycyltryptophan, and phenylalanylgly-cine. Interestingly, dipeptides of glycine and glycine itself are not effective stimuli for CCK release. There is evidence that additional peptides, some containing at least four amino acids, also release CCK. Fatty acids longer than eight carbon atoms release CCK. Lauric, palmitic, stearic, and oleic acids are potent and equally effective. All of these protein and fat digestion products, as well as hydrogen ion, also initiate vagovagal reflexes. CCK is present in equal concentrations throughout the mucosa of the duodenum and jejunum. Digestion products are equally effective at stimulating pancreatic enzyme secretion when applied to any segment of this part of the small intestine.

Response to a Meal

As digestion proceeds in the stomach, much of the gastric acid is buffered by proteins. As mixing, digestion, and secretion continue, the buffers become saturated and the pH drops to around 2. As the stomach empties, the maximal load of titratable acid delivered to the duodenum may be as great as 20-30 mmol/hr. This includes both free H+ and that bound to buffers. This

FIGURE 24 Pancreatic bicarbonate output in response to the acidification of a fixed length of duodenum. Bicarbonate output is used as an index of secretin release.

Duodenal pH

FIGURE 24 Pancreatic bicarbonate output in response to the acidification of a fixed length of duodenum. Bicarbonate output is used as an index of secretin release.

Clinical Note

A number of conditions in which the pancreas is directly involved decrease pancreatic secretion. These include pancreatitis, cystic fibrosis, and tumors of the pancreas. Pancreatic secretion is reduced by severe protein deficiency as in kwashiorkor. Chronic pancreatitis usually results in decreased volume and bicarbonate output, whereas individuals with cystic fibrosis or kwashiorkor exhibit decreases in both components. Cystic fibrosis is a relatively common, lethal, autosomal recessive disorder that causes viscid mucous secretion by pancreatic, airway and intestinal epithelia as well as a generalized disorder of fluid and electrolyte transport. In the pancreas the result is generalized pancreatic exocrine insufficiency. The critical abnormality is defective regulation of apical membrane Cl" channels (see Fig. 20). In cystic fibrosis the gene product is apparently normal, however, Cl" conductance is not inserted into the apical membrane. Thus, the problem is in protein trafficking. This defect results in the inability of cAMP to stimulate Cl" secretion and a severe decrease in secretion of the aqueous component. As a result proteinacious acinar secretions become concentrated and finally block the lumen of the duct, eventually destroying the gland. Pancreatic exocrine function is determined by collecting the duodenal content with a doublelumen nasogastric tube. One lumen is used to evacuate potentially contaminating gastric juice and the other to collect duodenal content, which is presumed to be primarily pancreatic in origin. Symptomatically, pancreatic insufficiency may show up as steatorrhea, the presence of fat in the stool. Pancreatic enzyme secretion must be reduced to less than 20% of normal before enough fat is left undigested to appear in the stool. Thus, pancreatic enzymes are secreted in great excess. Steatorrhea can be the result of a number of problems beside insufficient pancreatic lipase. To determine whether the condition is pancreatic in origin, it is necessary only to measure the concentration of any pancreatic enzyme in the jejunal content after a meal.

rate of delivery approximates the maximal acid secretory rate of the stomach, which in turn equals the maximal rate of bicarbonate secretion by the pancreas. In the first part of the duodenum, both the free acid and bound acid are rapidly neutralized by bicarbonate and the pH is raised from 2 at the pylorus to around 4 beyond the duodenal bulb. Within the remainder of the proximal duodenum, the pH of chyme is quickly increased to near neutrality. Most of the neutralization is accomplished by pancreatic bicarbonate, but an additional amount of bicarbonate is secreted by the duodenal mucosa and the liver. A small amount of hydrogen ion is absorbed directly by the mucosa.

Pancreatic enzyme secretion increases abruptly shortly after chyme enters the stomach, and peaks within 30 min to levels equal to 70-80% of those attainable with maximal stimulation by CCK and cholinergic reflexes. Enzyme secretion continues at this rate as chyme enters the duodenum. The enzyme response may be kept below the maximal possible rate by inhibitors such as pancreatic polypeptide.

Changes in the proportion of the nutrients in the diet change the proportion of enzymes in pancreatic secretion. For example, ingestion of a high-protein, low-carbohydrate diet for several days results in an increase in the proportion of proteases and a decrease in the proportion of amylase in pancreatic secretion. Adaptation of pancreatic juice to the diet is now known to be mediated by hormones at the level of gene expression. CCK increases the expression of the protease genes. GIF and secretin increase the expression of the lipase gene. In diabetics, insulin regulates amylase gene expression, but we do not know how amylase expression is regulated normally.

Molecular Basis for Potentiation

After the delivery of a secretory stimulus, the entire chain of intracellular events leading to secretion has not been identified. However, the concept of potentiation requires that the stimuli bind to different receptors and trigger different chains of events. Some of the steps involved have been elucidated using isolated rodent acini and are diagrammed schematically in Fig. 25. Secretin triggers an increase in cAMP formation after it binds to its membrane receptor. Acetylcholine binds to a receptor different from that of secretin and increases the formation of inositol trisphosphate, which in turn mobilizes Ca2+ from intracellular stores. CCK binds to a third distinct receptor and also increases intracellular

FIGURE 25 Diagram of the mechanisms leading to potentiation of enzyme secretion from the rodent pancreatic acinar cell. Similar potentiative interactions occur in human ductule cells but not in human acinar cells. (Modified from Johnson LR, Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

FIGURE 25 Diagram of the mechanisms leading to potentiation of enzyme secretion from the rodent pancreatic acinar cell. Similar potentiative interactions occur in human ductule cells but not in human acinar cells. (Modified from Johnson LR, Gastrointestinal physiology, 6th ed. St. Louis: CV Mosby, 2001.)

free Ca2+ via the inositol trisphosphate pathway. Interactions between secretin and acetylcholine or secretin and CCK, therefore, result in potentiation. The effects of combining acetylcholine and CCK, which trigger identical mechanisms, are only additive. Obviously, at some point the different intracellular mechanisms must interact to produce the potentiated response. The point of this interaction and the actual events producing potentiation are not understood. VIP and glucagon also increase cAMP levels, and substance P, GRP, and gastrin increase Ca2+ levels in acinar cells. There is no evidence, however, that any of these agents is released in sufficient quantities to be a physiologically significant regulator of pancreatic secretion.

As previously mentioned, these interactions have been elucidated for isolated rodent acini. However, a similar situation is likely to exist in the human ductule cell for the potentiation of the effect of secretin by CCK and acetylcholine. Why secretin does not potentiate CCK and acetylcholine effects on human acinar cells is not known.

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