Gastrointestinal Secretion (Table 6.2) PDF

# IV. GASTROINTESTINAL SECRETION (TABLE 6.2) ## Table 6.2 Summary of Gastrointestinal (GI) Secretions | GI Secretion | Major Characteristics | Stimulated By | Inhibited By | |---|---|---|---| | Saliva | High HCO₃^-, High K⁺, Hypotonic, α-Amylase, Lingual Lipase | Pa...

# IV. GASTROINTESTINAL SECRETION (TABLE 6.2) ## Table 6.2 Summary of Gastrointestinal (GI) Secretions | GI Secretion | Major Characteristics | Stimulated By | Inhibited By | |---|---|---|---| | Saliva | High HCO₃^-, High K⁺, Hypotonic, α-Amylase, Lingual Lipase | Parasympathetic nervous system, Sympathetic nervous system | Sleep, Dehydration, Atropine | | Gastric Secretion | Pepsinogen, Intrinsic factor, High HCO₃^-, Isotonic | Gastrin, Parasympathetic nervous system, Histamine | ↓ Stomach pH, Chyme in duodenum (via secretin and GIP), Somatostatin, Atropine, Cimetidine, Omeprazole | | Pancreatic Secretion | Pancreatic lipase, amylase, proteases | Secretin, CCK (potentiates secretin), Parasympathetic nervous system | | | Bile | Bile salts, Bilirubin, Phospholipids, Cholesterol | CCK (causes contraction of gallbladder and relaxation of sphincter of Oddi), Parasympathetic nervous system (causes contraction of gallbladder) | Ileal resection | CCK = cholecystokinin; GIP = glucose-dependent insulinotropic peptide. ## A. Salivary Secretion 1. **Functions of saliva** a. Initial starch digestion by α-amylase (ptyalin) and initial triglyceride digestion by lingual lipase. b. Lubrication of ingested food by mucus. c. Protection of the mouth and esophagus by dilution and buffering of ingested foods. 2. **Composition of saliva** a. Saliva is characterized by: - High volume (relative to the small size of the salivary glands). - High K⁺ and HCO₃^- concentrations. - Low Na⁺ and Cl ^- concentrations. - Hypotonicity. - Presence of α-amylase, lingual lipase, and kallikrein. b. The composition of saliva varies with the salivary flow rate (**Figure 6.4**). - At the lowest flow rates, saliva has the lowest osmolarity and lowest Na⁺, Cl^-, and HCO₃^- concentrations but has the highest K⁺ concentration. - At the highest flow rates (up to 4 mL/min), the composition of saliva is closest to that of plasma. 3. **Formation of saliva (Figure 6.5)** - Saliva is formed by three major glands—the parotid, submandibular, and sublingual glands. - The structure of each gland is similar to a bunch of grapes. The acinus (the blind end of each duct) is lined with acinar cells and secretes an initial saliva. A branching duct system is lined with columnar epithelial cells, which modify the initial saliva. - When saliva production is stimulated, myoepithelial cells, which line the acinus and initial ducts, contract and eject saliva into the mouth. a. **The acinus** - Produces an initial saliva with a composition similar to plasma. - This initial saliva is isotonic and has the same Na+, K+, Cl^-, and HCO₃^- concentrations as plasma. b. **The ducts** - Modify the initial saliva by the following processes: - The ducts reabsorb Na⁺ and Cl^-; therefore, the concentrations of these ions are lower than their plasma concentrations. - The ducts secrete K⁺ and HCO₃^-; therefore, the concentrations of these ions are higher than their plasma concentrations. - Aldosterone acts on the ductal cells to increase the reabsorption of Na⁺ and the secretion of K⁺ (analogous to its actions on the renal distal tubule). - Saliva becomes hypotonic in the ducts because the ducts are relatively impermeable to water. Because more solute than water is reabsorbed by the ducts, the saliva becomes dilute relative to plasma. - The effect of flow rate on saliva composition is explained primarily by changes in the contact time available for reabsorption and secretion processes to occur in the ducts. - Thus, at **high flow rates**, saliva is most like the initial secretion from the acinus; it has the highest Na⁺ and Cl^- concentrations and the lowest K⁺ concentration.. - At **low flow rates**, saliva is least like the initial secretion from the acinus; it has the lowest Na⁺ and Cl ^- concentrations and the highest K⁺ concentration. - The only ion that does not “fit” this contact time explanation is HCO₃^-; HCO₃ secretion is selectively stimulated when saliva secretion is stimulated. 4. **Regulation of saliva production (Figure 6.6)** - Saliva production is controlled by the parasympathetic and sympathetic nervous systems (not by GI hormones). - Saliva production is unique in that it is increased by both parasympathetic and sympathetic activity. Parasympathetic activity is more important, however. a. **Parasympathetic stimulation (cranial nerves VII and IX)** - Increases saliva production by increasing transport processes in the acinar and ductal cells and by causing vasodilation. - Cholinergic receptors on acinar and ductal cells are muscarinic. - The second messenger is inositol 1,4,5-triphosphate (IP3) and increased intracellular [Ca2⁺]. - Anticholinergic drugs (e.g., atropine) inhibit the production of saliva and cause dry mouth. b. **Sympathetic stimulation** - Increases the production of saliva and the growth of salivary glands, although the effects are smaller than those of parasympathetic stimulation. - Receptors on acinar and ductal cells are β-adrenergic. - The second messenger is cyclic adenosine monophosphate (cAMP). c. **Saliva production** - Is increased (via activation of the parasympathetic nervous system) by food in the mouth, smells, conditioned reflexes, and nausea. - Is decreased (via inhibition of the parasympathetic nervous system) by sleep, dehydration, fear, and anticholinergic drugs. # B. Gastric Secretion 1. **Gastric cell types and their secretions (Table 6.3 and Figure 6.7)** - Parietal cells, located in the body, secrete HCl and intrinsic factor. - Chief cells, located in the body, secrete pepsinogen. - G cells, located in the antrum, secrete gastrin. 2. **Mechanism of gastric H⁺ secretion (Figure 6.8)** - Parietal cells secrete HCl into the lumen of the stomach and, concurrently, absorb HCO₃^- into the bloodstream as follows: - In the parietal cells, CO₂ and H₂O are converted to H⁺ and HCO₃^-, catalyzed by carbonic anhydrase. - H⁺ is secreted into the lumen of the stomach by the H⁺-K⁺ pump (H⁺, K⁺-ATPase). Cl^- is secreted along with H⁺; thus, the secretion product of the parietal cells is HCl. - The drug omeprazole (a “proton pump inhibitor") inhibits the H⁺, K⁺-ATPase and blocks H⁺ secretion. - The HCO₃^- produced in the cells is absorbed into the bloodstream in exchange for Cl^- (Cl^--HCO₃^- exchange). As HCO₃^- is added to the venous blood, the pH of the blood increases (“alkaline tide"). (Eventually, this HCO₃^- will be secreted in pancreatic secretions to neutralize H⁺ in the small intestine.) - If vomiting occurs, gastric H⁺ never arrives in the small intestine, there is no stimulus for pancreatic HCO₃^-secretion, and the arterial blood becomes alkaline (metabolic alkalosis). 3. **Stimulation of gastric H⁺ secretion (Figure 6.9)** a. **Vagal stimulation** - Increases H⁺ secretion by a direct pathway and an indirect pathway. - In the direct path, the vagus nerve innervates parietal cells and stimulates H⁺ secretion directly. The neurotransmitter at these synapses is ACh, the receptor on the parietal cells is muscarinic (M₃), and the second messengers for CCK are IP₃ and increased intracellular [Ca²⁺]. - In the indirect path, the vagus nerve innervates G cells and stimulates gastrin secretion, which then stimulates H⁺ secretion by an endocrine action. The neurotransmitter at these synapses is GRP (not ACh). - Atropine, a cholinergic muscarinic antagonist, inhibits H⁺ secretion by blocking the direct pathway, which uses ACh as a neurotransmitter. However, atropine does not block H⁺ secretion completely because it does not inhibit the indirect pathway, which uses GRP as a neurotransmitter. - Vagotomy eliminates both direct and indirect pathways. b. **Gastrin** - Is released in response to eating a meal (small peptides, distention of the stomach, vagal stimulation). - Stimulates H⁺ secretion by interacting with the cholecystokinin (CCK_B) receptor on the parietal cells. - The second messenger for gastrin on the parietal cell is IP₃/Ca²⁺. - Gastrin also stimulates enterochromaffin-like (ECL) cells and histamine secretion, which stimulates H⁺ secretion (not shown in figure). c. **Histamine** - Is released from ECL cells in the gastric mucosa and diffuses to the nearby parietal cells. - Stimulates H⁺ secretion by activating H₂ receptors on the parietal cell membrane. - The H₂ receptor is coupled to adenylyl cyclase via a G_s protein. - The second messenger for histamine is cAMP. - H₂ receptor-blocking drugs, such as cimetidine, inhibit H⁺ secretion by blocking the stimulatory effect of histamine. d. **Potentiation effects of ACh, histamine, and gastrin on H⁺ secretion** - Potentiation occurs when the response to simultaneous administration of two stimulants is greater than the sum of responses to either agent given alone. As a result, low concentrations of stimulants given together can produce maximal effects. - Potentiation of gastric H⁺ secretion can be explained, in part, because each agent has a different mechanism of action on the parietal cell. 4. **Inhibition of gastric H⁺ secretion** - Negative feedback mechanisms inhibit the secretion of H⁺ by the parietal cells.. a. **Low pH (<3.0) in the stomach** - Inhibits gastrin secretion and thereby inhibits H ⁺ secretion. - After a meal is ingested, H⁺ secretion is stimulated by the mechanisms discussed previously (see IV B 2). After the meal is digested and the stomach emptied, further H⁺ secretion decreases the pH of the stomach contents. When the pH of the stomach contents is less than 3.0, gastrin secretion is inhibited and, by negative feedback, inhibits further H ⁺ secretion. b. **Somatostatin (see Figure 6.9)** - Inhibits gastric H⁺ secretion by a direct pathway and an indirect pathway. - In the direct pathway, somatostatin binds to receptors on the parietal cell that are coupled to adenylyl cyclase via a G_i protein, thus inhibiting adenylyl cyclase and decreasing cAMP levels. In this pathway, somatostatin antagonizes the stimulatory action of histamine on H⁺ secretion. - In the indirect pathways (not shown in Figure 6.9), somatostatin inhibits release of histamine and gastrin, thus decreasing H ⁺ secretion indirectly. c. **Prostaglandins (see Figure 6.9)** - Inhibit gastric H⁺ secretion by activating a G_i protein, inhibiting adenylyl cyclase and decreasing cAMP levels. - Maintain the mucosal barrier and stimulate HCO₃^-secretion, thus protecting the gastric mucosa from the damaging effects of H⁺. 5. **Peptic ulcer disease** - Is an ulcerative lesion of the gastric or duodenal mucosa. - Can occur when there is loss of the protective mucous barrier (of mucus and HCO₃^-) and/or excessive secretion of H⁺ and pepsin. - Protective factors are mucus, HCO₃^-, prostaglandins, mucosal blood flow, and growth factors.. - Damaging factors are H ⁺, pepsin, Helicobacter pylori (H. pylori), nonsteroidal anti-inflammatory drugs (NSAIDs), stress, smoking, and alcohol. a. **Gastric ulcers** - The gastric mucosa is damaged. - Gastric H⁺ secretion is decreased because secreted H⁺ leaks back through the damaged gastric mucosa. - Gastrin levels are increased because decreased H⁺ secretion stimulates gastrin secretion. - A major cause of gastric ulcer is the gram-negative bacterium Helicobacter pylori (H. pylori). - H. pylori colonizes the gastric mucus and releases cytotoxins that damage the gastric mucosa. - H. pylori contains urease, which converts urea to NH₃, thus alkalinizing the local environment and permitting H. pylori to survive in the otherwise acidic gastric lumen. - The diagnostic test for H. pylori involves drinking a solution of ¹³C-urea, which is converted to ¹³CO₂ by urease and measured in the expired air. b. **Duodenal ulcers** - The duodenal mucosa is damaged. - Gastric H⁺ secretion is increased. Excess H⁺ is delivered to the duodenum, damaging the duodenal mucosa. - Gastrin secretion in response to a meal is increased (although baseline gastrin may be normal). - H. pylori is also a major cause of duodenal ulcer. H. pylori inhibits somatostatin secretion (thus stimulating gastric H ⁺ secretion) and inhibits intestinal HCO₃^- secretion (so there is insufficient HCO₃^- to neutralize the H ⁺ load from the stomach). c. **Zollinger-Ellison syndrome** - Occurs when a gastrin-secreting tumor of the pancreas causes increased H⁺ secretion. - H⁺ secretion continues unabated because the gastrin secreted by pancreatic tumor cells is not subject to negative feedback inhibition by H⁺. 6. **Drugs that block gastric H⁺ secretion (see Figure 6.9)** - Atropine - Blocks H⁺ secretion by inhibiting cholinergic muscarinic receptors on parietal cells, thereby inhibiting ACh stimulation of H⁺ secretion. - Cimetidine - Blocks H₂ receptors and thereby inhibits histamine stimulation of H⁺ secretion. - Is particularly effective in reducing H⁺ secretion because it not only blocks the histamine stimulation of H⁺ secretion but also blocks histamine’s potentiation of ACh effects. - Omeprazole - Is a proton pump inhibitor. - Directly inhibits H⁺, K⁺-ATPase, and H⁺ secretion. ## Table 6.3 Gastric Cell Types and Their Secretions | Cell Type | Part of Stomach | Secretion Products | Stimulus for Secretion | |---|---|---|---| | Parietal cells | Body (fundus) | HCl, Intrinsic factor (essential) | Gastrin, Vagal stimulation (ACh), Histamine | | Chief cells | Body (fundus) | Pepsinogen (converted to pepsin at low pH) | Vagal stimulation (ACh) | | G cells | Antrum | Gastrin | Vagal stimulation (via GRP), Small peptides, Inhibited by somatostatin, Inhibited by H⁺ in stomach (via stimulation of somatostatin release) | | Mucous cells | Antrum | Mucus, Pepsinogen | Vagal stimulation (ACh) | ACh = acetylcholine; GRP = gastrin-releasing peptide. # C . Pancreatic Secretion - Contains a high concentration of HCO₃^-, whose purpose is to neutralize the acidic chyme that reaches the duodenum. - Contains enzymes essential for the digestion of protein, carbohydrate, and fat. 1. **Composition of pancreatic secretion** a. Pancreatic juice is characterized by: - High volume. - Virtually the same Na⁺ and K⁺ concentrations as plasma. - Much higher HCO₃^- concentration than plasma. - Much lower Cl^- concentration than plasma. - Isotonicity. - Pancreatic lipase, amylase, and proteases. b. The composition of the aqueous component of pancreatic secretion varies with the flow rate (**Figure 6.10**). - At low flow rates, the pancreas secretes an isotonic fluid that is composed mainly of Na⁺ and Cl^-. - At high flow rates, the pancreas secretes an isotonic fluid that is composed mainly of Na⁺ and HCO₃^-. - Regardless of the flow rate, pancreatic secretions are isotonic. 2. **Formation of pancreatic secretion (Figure 6.11)** - Like the salivary glands, the exocrine pancreas resembles a bunch of grapes. - The acinar cells of the exocrine pancreas make up most of its weight.. a. **Acinar cells** - Produce a small volume of initial pancreatic secretion, which is mainly Na⁺ and Cl^-. b. **Ductal cells** - Modify the initial pancreatic secretion by secreting HCO₃^- and absorbing Cl^- via a Cl^--HCO₃^- exchange mechanism in the luminal membrane.. - Because the pancreatic ducts are permeable to water, H₂O moves into the lumen to make the pancreatic secretion isosmotic. 3. **Stimulation of pancreatic secretion** a. **Secretin** - Is secreted by the S cells of the duodenum in response to H⁺ in the duodenal lumen. - Acts on the pancreatic ductal cells to increase HCO₃^- secretion. - Thus, when H⁺ is delivered from the stomach to the duodenum, secretin is released. As a result, HCO₃^- is secreted from the pancreas into the duodenal lumen to neutralize the H⁺. - The second messenger for secretin is cAMP. b. **CCK** - Is secreted by the I cells of the duodenum in response to small peptides, amino acids, and fatty acids in the duodenal lumen. - Acts on the pancreatic acinar cells to increase enzyme secretion (amylase, lipases, proteases).. - Potentiates the effect of secretin on ductal cells to stimulate HCO₃^- secretion. - The second messengers for CCK are IP₃ and increased intracellular [Ca²⁺]. The potentiating effects of CCK on secretin are explained by the different mechanisms of action for the two GI hormones (i.e., cAMP for secretin and IP₃/Ca₂⁺ for CCK). c. **ACh (via vagovagal reflexes)** - Is released in response to H⁺, small peptides, amino acids, and fatty acids in the duodenal lumen. - Stimulates enzyme secretion by the acinar cells and, like CCK, potentiates the effect of secretin on HCO₃^- secretion. 4. **Cystic fibrosis** - Is a disorder of pancreatic secretion.. - Results from a defect in Cl^- channels that is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. - Is associated with a deficiency of pancreatic enzymes resulting in malabsorption and steatorrhea. # D. Bile secretion and gallbladder function (Figure 6.12) 1. **Composition and function of bile** - Bile contains bile salts, phospholipids, cholesterol, and bile pigments (bilirubin). a. **Bile salts** - Are amphipathic molecules because they have both hydrophilic and hydrophobic portions. In aqueous solution, bile salts orient themselves around droplets of lipid and keep the lipid droplets dispersed (emulsification). - Aid in the intestinal digestion and absorption of lipids by emulsifying and solubilizing them in micelles. b. **Micelles** - Above a critical micellar concentration, bile salts form micelles. - Bile salts are positioned on the outside of the micelle, with their hydrophilic portions dissolved in the aqueous solution of the intestinal lumen and their hydrophobic portions dissolved in the micelle interior. - Free fatty acids and monoglycerides are present in the inside of the micelle, essentially “solubilized” for subsequent absorption. 2. **Formation of bile** - Bile is produced continuously by hepatocytes. - Bile drains into the hepatic ducts and is stored in the gallbladder for subsequent release. - Choleretic agents increase the formation of bile. - Bile is formed by the following process: - Primary bile acids (cholic acid and chenodeoxycholic acid) are synthesized from cholesterol by hepatocytes. - In the intestine, bacteria convert a portion of each of the primary bile acids to secondary bile acids (deoxycholic acid and lithocholic acid).. - Synthesis of new bile acids occurs, as needed, to replace bile acids that are excreted in the feces. - The bile acids are conjugated with glycine or taurine to form their respective bile salts, which are named for the parent bile acid (e.g., taurocholic acid is cholic acid conjugated with taurine).. - Electrolytes and H₂O are added to the bile. - During the interdigestive period, the gallbladder is relaxed, the sphincter of Oddi is closed, and the gallbladder fills with bile. - Bile is concentrated in the gallbladder as a result of isosmotic absorption of solutes and H₂O. 3. **Contraction of the gallbladder** a. **CCK** - Is released in response to small peptides and fatty acids in the duodenum. - Tells the gallbladder that bile is needed to emulsify and absorb lipids in the duodenum. - Causes contraction of the gallbladder and relaxation of the sphincter of Oddi. b. **ACh** - Causes contraction of the gallbladder. 4. **Recirculation of bile acids to the liver** - The terminal ileum contains a Na⁺–bile acid cotransporter, which is a secondary active transporter that recirculates bile acids to the liver. - Because bile acids are not recirculated until they reach the terminal ileum, bile acids are present for maximal absorption of lipids throughout the upper small intestine. - After ileal resection, bile acids are not recirculated to the liver but are excreted in feces. The bile acid pool is thereby depleted, and fat absorption is impaired, resulting in steatorrhea. # V DIGESTION AND ABSORPTION (TABLE 6.4) ## Table 6.4 Summary of Digestion and Absorption | | | |---|---| | | |