Transcription
Hello, how are you? Welcome to the 49th Physiology class on the Medicine channel. My name is Eduardo Paiva, and continuing with our gastrointestinal physiology classes, we are going to talk about gastric secretion. Topics we will cover in this class: We will look at some characteristics of gastric secretions, we will talk about the gastric and pyloric glands, the protection of the gastric barrier, the phases of gastric secretion, and the regulation of gastric secretion. The stomach is located between the esophagus and the duodenum. In the class on propulsion and mixing, we saw the motor functions of the stomach. However, the stomach has very important secretory functions. We saw that the stomach is divided into the fundus, body, antrum, cardia, pylorus, and greater and lesser curvatures. The mucosa of the stomach has two important tubular glands: the gastric glands, which are also called oxyntic glands, but we should not confuse them with oxyntic cells, which are something else and we will see them later. The gastric glands are found in the body and fundus of the stomach and are responsible for secreting hydrochloric acid, pepsinogen, intrinsic factor, and mucus, and they constitute 80 percent of the glands in the stomach. And we have pyloric glands, which are found in the antrum and are responsible for secreting mucus and the gastric hormones gastrin and somatostatin, and they constitute 20 percent of the glands in the stomach. The gastric glands have parietal cells, also called oxyntic cells, which is not the same as oxyntic glands, and they are responsible for secreting hydrochloric acid and intrinsic factor. There are chief cells or principal cells that secrete pepsinogen, mucus-secreting cells, and enterochromaffin-like cells that release histamine. Now, the pyloric glands have G cells that release gastrin and D cells that release somatostatin. We also have mucus cells that secrete mucus. Look here, we have a gastric gland with its different cells. Let's analyze each of the cells, starting with the oxyntic or parietal cells, which we see here in yellow. These cells secrete hydrochloric acid and intrinsic factor. Let's now look at the formation of hydrochloric acid. And here we have the oxyntic cell. This oxyntic cell will secrete hydrochloric acid through its canaliculi. Here we have the canaliculi. Look at the oxyntic cell with the lumen of the canaliculus that exits towards the stomach, meaning from the lumen of the canaliculus, the hydrochloric acid will go towards the stomach. Here we also have interstitial fluid, blood, the basolateral membrane, and the apical membrane. Let's now see how hydrochloric acid is formed. First, the water in the cytoplasm dissociates into hydrogen and hydroxyl ions. The hydrogen ions are actively secreted into the canaliculus thanks to the hydrogen-potassium ATPase pump, also called the proton pump, using energy. The hydrogen ions are exchanged for potassium. Now, the sodium-potassium ATPase pump on the basolateral membrane exchanges sodium for potassium. This potassium, look, goes into the lumen of the canaliculus, but the hydrogen-potassium ATPase pump is responsible for recycling or reabsorbing the potassium. Now, this sodium-potassium ATPase pump, by the fact that it pumps sodium into the interstitium, meaning it creates a low intracellular sodium gradient, causes sodium to be reabsorbed from the lumen of the canaliculus into the intracellular fluid, and that is why most of the sodium and potassium in the canaliculus are exchanged, while the hydrogen ions take their place in the lumen of the canaliculus. Now, how are hydrogen ions pumped into the lumen of the canaliculus? Hydroxide accumulates, and this accumulation of hydroxide causes the enzyme carbonic anhydrase to capture carbon dioxide from cellular metabolism and convert it into bicarbonate through a reaction. Now, chloride ions enter the cytoplasm through chloride channels and are also exchanged for bicarbonate on the basolateral membrane. This bicarbonate goes into the gastric venous blood, and that is why during gastric secretion, the gastric venous pH increases. Well, in short, chloride, think that chloride is secreted into the canaliculus through chloride channels and joins the hydrogen ions to form hydrochloric acid. And along with these ions in the canaliculus, water is transported or dragged by osmosis, and the final concentration that goes to the canaliculi contains water, hydrochloric acid at 150 to 160 milliequivalents per liter, potassium chloride at 15 milliequivalents per liter, and a small but very small amount of sodium chloride. And that is how hydrochloric acid is formed. Now, a curiosity is that proton pump inhibitor drugs, like omeprazole, act on the hydrogen-potassium ATPase pump or proton pump, thus reducing the concentration of hydrochloric acid. Oxyntic cells, in addition to secreting hydrochloric acid, secrete intrinsic factor, which is a glycoprotein. Intrinsic factor, also called Castle's intrinsic factor, is simply essential for the absorption of vitamin B12 in the ileum. Intrinsic factor binds with vitamin B12 and transports it through pinocytosis, which is a type of endocytosis, causing vitamin B12 to be absorbed and go into circulation. The lack of intrinsic factor causes a vitamin B12 deficiency, and as we saw in the erythrocyte class, vitamin B12 is important for the maturation of erythrocytes in the bone marrow. Therefore, the lack of intrinsic factor, as for example in atrophic gastritis, causes us an anemia called pernicious anemia, which is a microcytic anemia. Look here, here we see intrinsic factor and vitamin B12 forming a complex, and when they reach the ileum mucosa, vitamin B12 is absorbed. And in the gastric glands, we also have chief cells. Look at the chief cells that secrete pepsinogen. Pepsinogen is an enzyme that does not have digestive activity. It has a molecular weight of 42,500, but when pepsinogen comes into contact with the hydrochloric acid of the stomach, it is activated and converted into pepsin. Pepsin does have digestive activity; it is a true proteolytic enzyme and has a molecular weight of 35,000. This enzyme is activated in very acidic environments. Its optimal pH varies between 1.8 and 3.5 pH, and as the pH rises, meaning as the environment becomes more alkaline, it loses its activity. In fact, at a pH of 5, it is inactivated in a very short time. The gastric glands also have enterochromaffin-like cells, which synthesize, store, and release histamine. Histamine stimulates the oxyntic cells for the release of hydrochloric acid. Let's talk now about the pyloric glands. The pyloric glands have G cells. Look at these G cells, which are located in the antrum. When stimulated, they release gastrin. Gastrin is a hormone that goes into the blood and stimulates the oxyntic cells for the release of hydrochloric acid. So, gastrin stimulates the secretion of gastric acid, hydrochloric acid, and also stimulates the growth of the mucosa, both gastric and intestinal mucosa. Later, we will talk about the regulation of hydrochloric acid. Let's talk now about mucus cells. There are two types of mucus cells: superficial mucus cells and neck mucus cells. Superficial mucus cells are found throughout the surface of the stomach mucosa and produce large amounts of viscous mucus formed by bicarbonate, which is very important for the gastric mucus barrier. And neck mucus cells secrete a fluid mucus and small amounts of pepsinogen, and they are located mainly in the gastric glands. Now let's talk about the gastric mucus barrier. This barrier is very important for protecting the stomach from hydrochloric acid and also from pepsin. Let's zoom in on the gastric mucus barrier. And here we see the gastric mucus barrier. First, let's see that the pH of the stomach lumen is around 1 to 2. Any solution with a pH of 1 to 2 is a destructive solution for tissues. But for the stomach acid and pepsin not to destroy the stomach, the body creates a defense mechanism, which is the gastric mucus barrier. The superficial mucus cells of the stomach produce bicarbonate through a viscous mucus. This mucus measures approximately 1 millimeter. This mucus layer traps bicarbonate, making the pH of this mucus 7, thus counteracting the pH of the stomach lumen. This is a protective factor. Another protective factor is the regeneration of epithelial cells, as well as adequate microcirculation. A rich vasculature is very important to supply nutrients to the mucus cells so that they can adequately produce mucus and bicarbonate and also regenerate. These are protective factors. All the properties of the gastric mucosa are stimulated by an important mediator, which are prostaglandins. That is why the use of NSAIDs, non-steroidal anti-inflammatory drugs, like aspirin, for example, block prostaglandin synthesis, causing a decrease in mucus and bicarbonate secretion, thus causing damage to the stomach mucosa. Other factors that damage the mucosa are Helicobacter pylori, alcohol, and tobacco. Let's talk now about the stimulation of gastric secretion. The oxyntic or parietal cell is stimulated by gastrin, histamine, and acetylcholine. Acetylcholine comes from parasympathetic stimulation by the vagus nerve, and acetylcholine stimulates all cells to secrete hydrochloric acid, pepsinogen, and mucus. Gastrin and histamine exclusively stimulate the secretion of hydrochloric acid only. Gastrin stimulation occurs when there is gastric distension or when foods containing proteins reach the antrum. This stimulates the G cells found in the antrum. These cells release gastrin. This gastrin directly stimulates the oxyntic or parietal cells through gastrin receptors on their membrane, just as acetylcholine secreted by the vagus nerve stimulates muscarinic receptors 1, 3 on the membrane of the parietal oxyntic cells. Also, histamine released by enterochromaffin-like cells, thanks to a stimulus, is stimulated not by the enteric nervous system but also by acetylcholine, and this histamine also goes to the receptors on the H2 receptors on the membrane of the parietal cell. This is a direct pathway. However, there is an indirect pathway for the stimulation of hydrochloric acid secretion. In the indirect pathway, both gastrin and acetylcholine, in turn, stimulate the enterochromaffin-like cells to also release histamine. This creates synergism, truly stimulating the secretion of hydrochloric acid. Some drugs, like selective H2 antihistamines such as cimetidine, ranitidine, famotidine, act by antagonizing histamine receptors on the oxyntic cells. And here we also see, as we saw before, proton pump inhibitors like omeprazole, lansoprazole, and pantoprazole, which are very important drugs in clinical practice for reducing hydrochloric acid in gastric secretion itself. Let's talk now about the regulation of pepsinogen, which is secreted by the chief cells, and it is regulated by acetylcholine released by the vagus nerves or also by the gastric enteric nervous plexus, and it is also regulated by stomach acid, since when hydrochloric acid is secreted, nervous reflexes are activated that stimulate the secretion of pepsinogen by the chief cells. Therefore, the rate of pepsinogen secretion depends largely on the amount of acid in the stomach. Gastric secretion has three phases, meaning three phases occur: the cephalic, gastric, and intestinal phases. The cephalic phase of gastric secretion occurs before food reaches the stomach and is due to the sight, smell, touch, or taste of food. These signals go to the higher centers of appetite, meaning to the central nervous system, and from there they are transmitted to the vagus nerves, acetylcholine, and stimulate the oxyntic cell to secrete hydrochloric acid. Note, without food in the stomach, this is the phase, that's why it's called the cephalic phase, due to these factors. Now, there are studies that say that hypoglycemia induced by insulin can also stimulate the vagus nerve and therefore gastric secretion. The cephalic phase contributes 30 percent of gastric secretion. Now let's look at the gastric phase. The gastric phase occurs when food enters the stomach and when it distends it, meaning there is gastric distension, which activates local reflexes of the enteric nervous system and long vagovagal reflexes, meaning they go to the brain and return, releasing acetylcholine. This acetylcholine directly stimulates the oxyntic cell for the release of hydrochloric acid. Also, the presence of proteins and gastric distension stimulates the G cells, which, as we know, release gastrin, which in turn directly stimulates gastric secretion. Now, gastrin, as well as acetylcholine, stimulates the enterochromaffin-like cells to also release histamine, which also directly stimulates gastric secretion. Acetylcholine also stimulates the G cells. It may seem difficult, but it's not. The gastric phase contributes 60 percent of gastric secretion. Finally, we have the intestinal phase, which occurs due to the presence of poorly digested protein foods in the duodenum, by the duodenal chyme. This stimulates the G cells, note, duodenal G cells, thus releasing gastrin and stimulating the secretion of hydrochloric acid by the oxyntic cells. But the intestinal phase represents only 10 percent of gastric secretion. And here we have the phases of gastric secretion: cephalic, gastric, intestinal. Now let's talk about the inhibition of gastric secretion. There are two factors that inhibit gastric secretion: nervous factors, which obey the enterogastric reflex, and hormonal factors. The enterogastric reflex depends on the presence of food in the upper part of the small intestine and is transmitted by the enteric nervous system, by the sympathetic nerves, and by the vagus nerves. The reflex is initiated by duodenal distension, irritation of the intestinal mucosa by the presence of acidic chyme in the duodenum, and by protein degradation products. It is practically similar to the enterogastric reflex that inhibits gastric emptying, which we saw in class 45. And we also have hormonal factors. There are hormones that inhibit gastric secretion: the presence of fat degradation products, especially fats, and also proteins, irritation of the mucosa, alterations in chyme osmolarity, and acidity of the chyme in the small intestine and antrum release several hormones that inhibit gastric secretion, such as somatostatin, which is secreted in D cells. When somatostatin is released in response to chyme with a pH less than 3, somatostatin inhibits the gastrin-producing cells. So, somatostatin will inhibit the G cells, which in turn will inhibit gastrin production, thus obviously inhibiting gastric secretion. Somatostatin also inhibits oxyntic cells and enterochromaffin-like cells. In fact, somatostatin is the most potent inhibitor of enterochromaffin-like cells. And also remembering that somatostatin directly inhibits oxyntic cells, and acetylcholine. Remember that acetylcholine was a stimulant, not an inhibitor. It stimulates gastric secretion. Acetylcholine, by stimulating gastric secretion, as we see, also inhibits the D cells. So, in addition to the effect of gastric secretion, it inhibits the D cells that release somatostatin. Another hormone that inhibits gastric secretion is secretin, released by intestinal cells in response to acidic chyme, meaning when there is acidic chyme in the intestine, less than 3, it causes secretin to be released. Secretin is important for pancreatic secretion, as we will see in the pancreatic secretion class. But secretin is also important for inhibiting gastric secretion, and it does so by directly inhibiting the G cells and inhibiting the oxyntic cells and stimulating the somatostatin-producing cells. So, how can we resolve this? Secretin inhibits gastric secretion. Other inhibitory hormones are gastric inhibitory peptide, vasoactive intestinal peptide, and cholecystokinin. These are stimulated by the presence of fatty and protein foods in the small intestine. And to summarize, let's look at this image that shows all the cells and hormones involved in gastric secretion. The most important ones: we have an oxyntic cell. Think of the oxyntic or parietal cell with its receptors: acetylcholine receptor, which stimulates histamine, which stimulates gastrin, which stimulates, and inhibitory somatostatin receptors, which inhibit it. Now, acetylcholine stimulates. Think, here is the vagus nerve. Acetylcholine stimulates enterochromaffin-like cells and G cells. Look how we have a G cell here. Look, acetylcholine stimulates both enterochromaffin-like cells and G cells. Acetylcholine also inhibits the D cells that release somatostatin. Now, gastrin. Here is the G cell releasing gastrin. Gastrin, besides directly stimulating the oxyntic cells, also stimulates the enterochromaffin-like cells, which, as we saw, release somatostatin. Now, look at somatostatin, released by D cells. It inhibits, as we see, directly the oxyntic cell, but it also inhibits enterochromaffin-like cells. G cells are also inhibited, look, by somatostatin. When somatostatin is released, the production of G cells is also inhibited. This is very curious because when G cells are stimulated, gastrin is released, activating D cells. Strange, isn't it? Gastrin activates D cells, and these D cells then release somatostatin, which inhibits secretion. This is to maintain pH balance. This is a true negative feedback, a perfect control by the body to control acid secretion. Hydrogen ions in the lumen of the antrum, look, hydrogen ions stimulate D cells. These D cells release somatostatin, but this somatostatin inhibits G cells that release gastrin. But on the contrary, gastrin stimulates D cells. Gastrin stimulates D cells that release somatostatin. So it doesn't make sense, because D cells inhibit acid secretion, but the same stimulation of acid secretion and subsequent inhibition of acid secretion. And to see how our body always tries to maintain balance, our body always tries to protect us from hyperacidity, to avoid mucosal lesions. And when there are alterations in the acid-base balance, between gastric secretion and the mucus-bicarbonate barrier, when there is an imbalance, the person can develop peptic ulcers. Yes, it's a bit complex, but our body is like that. Our body is complex. And here we have an image from Guyton that summarizes the control of gastric secretion with its phases: cephalic phase, stimulated by the vagus nerve, which releases acetylcholine; gastric phase, which occurs due to local nervous reflexes, distension, long vagal parasympathetic reflexes, stimulation of gastrin, which in turn stimulates histamine by enterochromaffin-like cells, as we saw; and intestinal phase, which depends on practically two factors. The intestinal phase depends on nervous mechanisms, the enterogastric reflexes we saw, and several hormones, as we saw. Perfect. And to finish, let's talk about secretion in the interdigestive period, which is the period of secretion when there is no stimulus, meaning basal secretion. This secretion of the stomach is small. It is small, and above all, mucus is secreted with little pepsin and almost no acid. This basal secretion is lower in the morning and higher in the afternoon and at night, and it can be increased by strong emotional stimuli and is more intense in men than in women. That is why stress is a risk factor for gastritis due to basal gastric hypersecretion. So, you know, don't get stressed. Bibliography used: Guyton and Hall Textbook of Physiology, 13th edition; Boron's Physiology, 3rd edition. Thank you very much. I send you a hug.