Greetings, so today we're going to finish up some of our discussion of how we make acid. And this is going to be the regulation of acid secretion by the stomach. The learning objectives are the, to explain the regulation of the acid secretion. In both the fed and the fasted state. And we want to explain the causes that are underlying gastric ulcers. This is where we have an erosion of the epithelium, of the, of the stomach. And allowing the acid then to dig through into the tissues which are underlining the epithelium. And then thirdly, we'd like to talk about the expression the treatment of these gastric ulcers. So, how do we secrete acid from the stomach? And this, of course, is done in parietal cells. The last time we said that the parietal cell uses the carbonic anhydrase reaction to convert CO2 and water into bicarbonate and a proton. The bicarbonate and the proton are then moved to two opposite sides of the parietal cell. The, the proton is removed from the parietal cell with an ATPase in exchange for potassium. So, this is our potassium proton ATPase, and it's also called the proton pump. At the same time the bicarbonate that we've generated from this reaction, is moved out of the base of the cell. That is, towards the interstitial space, and towards the blood, by a tr, a cotransporter, and this is an anti-porter. So bicarbonate is leaving the cell they extrude it toward the blood and we have, chloride ions which are entering into the cell. The chloride ions then exits the cell through a chloride transporter which is pressing on the luminal surface of the cells and that then allows us to form, hydrochloric acid. The potassium that's needed to gena, to, to to continue the generation of the acid is recycled, and this is recycled at the lumenal surface, through a potassium transporter. So this is how we make the acid and now what we want to talk about is how we regulate the acid, because acid secretion is not constant at the same, at the same level. What we have is that right after, after feeding we will have an increase in the production of acid which will increase to about 90 minutes after feeding. And then subsequent to that after this peak acid output we will then have a fall in the acid production. This rise in acid secretion is in rise to the food which is coming into the stomach. At the same time that we have a rise in acid production, we also have a rise in pH. Going from a luminal pH of two, which is the concentrated hydrochloric acid, to a pH of about five. And then, subsequent to that, the pH will fall. And then we have, again, the basal, the basal level of a pH of two. Now, why does this pH rise rapidly in the first 90 minutes after feeding? In the first 30 minutes after feeding. And the reason that it's rising towards a, a basic, pH. Is that, as the food is arriving in the lumen of the stomach. The free protons are binding to the food. And so, that's removing free protons. As you recall, pH is the logarithmic, to the base ten of the concentration of free protons. So as free protons are being removed by binding to the food, we then have a slight rise in pH. Eventually, as the food is leaving the stomach, then the pH then falls again to a pH of two, which is the free hydrogen ion that we have of concentrated acid. So how is this regulated. This has to be regulated because the acid is very, very caustic and so the cell does not secret acid unless it's really being used, needed. So there's a very small amount of acid being made in the basal state or in the fasting state. And then we increase the production of acid when we need it for feeding, to degrade food, or to digest food. There's two phases for the regulation of the acid's secretion. The first phase is called the "cephalic phase." In this phase, we have a "feed forward." and this phase is triggered by the parasympathetic nervous system. Or it's governed by the parasympathetic nervous system. If you just smell food or you think about food or you see food, if you're going past a bakery and you see all those wonderful cakes in there, then that will trigger a release of acid from the stomach. And that is because the acetylcholine, which is the neurotransmitter of the parasympathetic innervation to the parietal cell and this is the vagus nerve, that that then will stimulate the proton pump. So we increase the activity of the proton pump and make HCl. The cephalic phase with its feed forward phase is also the parasympathetic nervous system is also governing another region of the stomach. That is, this is governing the antrol cells, and the antrol cells we have what are called G cells. These cells secrete gastrin. And gastrin is a hormone. This is an indirect regulation of the g-cell, but when we have parasympathetic activation, the g-cell then will start to secrete gastrin. The gastrin enters into the blood and is delivered to the peridal cell of the stomach by the blood. So the gastrin is coming from the blood and gastrin will bind to the gastrin receptor which is present on the basil surface of the peridal cells. Gastrin also can increase the activity of the proton pump. So gastrin is going to promote the production of acid. Gastrin also works on a neighboring cell within the fundic region, a neighboring cell to the Parietal cell. And this cell is called ECL or eenterochromaffin cell. The enterochromaffin cell, secretes a parachrin, which is called hystamine. A parachrine, as you recall, is a chemical that's going to be secreted into the interstitial. tissue which is surrounding a neighboring cell. And this paracrine is going to bind, histamine is going to bind to the histamine receptor. When histamine binds to the histamine receptor on the Parietal cell, it too will increase the activity of the proton pump. so we have three signals, then. Which are increasing the production of acid. They're driving the proton pump of the parietal cell. The first is acidol colene. Which is the direct parasympathetic input. The second is gastrin, which is a hormone, it's coming from the G-cell of the antrum. And the third is histamine which is a paracrine which is coming from the neighboring ECL cell within the fundic region. This is the cephalic phase. Cephalic phase accounts for about 40% of the acid that's going, that's, that's being made. During feeding. We have a second phase, and that's called the Gastric phase. And in the Gastric phase, we now have the stregna, the food is arriving into the lumen of the stomach, and we have a stretching of the walls of the stomach. The stomach, as you recall, can hold about two liters of food, of. a food. Or liquid. As we stretch the walls of the stomach. Then the antrum will release gastrin. And again gastrin is the hormone so it secreted into the bloodstream. And delivered to the pry of those cells where it will bind to the gastrin receptor. Just as we described in the sephlyx phase. And it increases the activity of the proton pump. Gastrin also is going to bind to the gastrin receptor which is on the ECL cell and it'll cause that cell to secrete histamine and histamine is our paracrin and this paracrin then binds to the histamine receptor of the neighboring cell. Which is the parietal cell and increases the proton pump activity. The gastric phase accounts for about 60% of the acid production that's due to feeding. Whenever we have a positive reflex, we also have to have a negative reflex. So part of the negative reflex in this particular loop is that the proton itself is going to feed back and turn off the secretion of Gastrin. And that's what's diagrammed here. So protons, the free protons, are mediating the negative feedback. Negative feedback is occurring in the antrim of the stomach. There is a proton receptor which is sitting on a cell called the d cell and this d cell secretes somatostatin. Somatostatin is going to act as a[UNKNOWN] And will bind to its neighboring cell, which is the G Cell, which as you know is going to secrete gastrin. So Somatostatin, whenever you see Somatostatin in the body, is always a neg, an inhibitory factor. So Somatostatin, in this case, is an inhibitory factor, which is a paracrine. It binds to the somatostatin receptor, and inhibits the release of gastrin. We have a second signal, which is coming from the beginning of the small intestine, and this, this is called the duodenum, and this signal is, is being secreted from the duodenum. It's a hormone. And the hormone is called secretin. Secretin arrives by the blood to these to the cells within the antrum to the G Cell. And will bind to the secretin receptor which is present on the basal surface of the G Cell. Secretin also inhibits the secretion of gastrin. So we have two signals then that will inhibit the secretion of gastrin from the G cell of the antrum. One is a hormone and that is somatostatin and the second one is the paracrin and that's coming from the D cell which is a neighboring cell. And that is somatostatin. So what are the causes and treatment of ulcers? So ulcers are as I told you at the beginning that we have this mucus, mucus barrier which is lining the entire interior of the stomach. The mucous barrier is resistant to acid, and as long as it's there, the epithelial cells which are sitting beneath this m, this mucous barrier, or mucous blanket, are protected to the, to the low pH of the of the lumen. It's, what's interesting about this, about this particular geometry, is that between the cells and the mucous barrier, there's actually a very small compartment, and that compartment has a pH that's neutral. So the cells are maintaining a neutral compartment immediately around them, and then there's the mucus barrier, and outside of that we have the very low pH, and that's the pH of acid. What happens is that if we have something that disrupts that mucous barrier, then the acid is able to reach the epithelial cells. And they will degrade the epithelial cells. Loss of the mucous barrier can occur, when you take in something called NSAIDs. These are non-steroidal anti inflammatory drugs. These are things such as aspirin or ibuprofen. So,[INAUDIBLE] . I mean, the aspirin or ibuprofen erodes this mucosa barrier. Because it prevents the, the actual, generation of the barrier. Through a, through a second system, which it include, prostaglandins. When we lose that mucosal barrier, now the acid can reach the cells and erode the cells, and this is then called the ulcer. They, and for many, many years it was thought that the people who were developing ulcers were people who were very nervous, highly stressed individuals. They were said to have a type A personality. And then several years ago an individual, it was actually a pathologist from Australia started looking at some of the dissections of his patients after they died. And when he was doing these cadaver dissections he realized that many of them were infected. They had some type of an infection within the stomach in addition to their ulcers. And so he then came up with a theory that perhaps ulcer formation was due to an infection. He isolated the bacterium, and turns out that bacterium was called Heliobacterium pylori. And for many years, he was trying to convince the gastrointestinal field, that this was actually the cause of ulcers and that we'd be able to treat it by giving these individuals an antibiotic that would remove the bacterial infection. This was poo-pooed by the general medical profession, and it was poo-pooed by the scientists, the basic scientists that were working within this field for many years and he was totally discredited. But he persisted in his idea and eventually grew up a batch of these cells. Of these bugs. Of these bacterium and drank it. Trying to give himself an ulcer to prove that these were, in fact, the cause of ulcers. He managed to make himself sick, but he didn't develop an ulcer. And it turns out that, with time it was shown that helio bacterium pri-mori is, in fact, the causal agent. And it is an infective agent, and that the individual is infected, then the bug will go between the mucosal barrier and the epithelium, and will live within that neutral zone between these two compartments. The bug, when it is in that particular area, then does cause erosion of the mucosal barrier, so that's what leads it eventually to ulcers. Although that he never got an NIH grant. He was able to be respected and to be identified as the individual who figured out the, the causation of, of ulcers throughout the world. And and was awarded the nobel peace and the noble prize for his work. The it turns out that there's about fifty% of the population worldwide that actually is infected by the heliobacterium pylori, when only fifteen% of these individuals ever develop any symptoms of ulcers. So there is a resistance to the ultra formation by these particular bacterium. And it turns out that he's one of those individuals that was resistant to the actual, activity of the bacterium. So how do we normally treat ulcers? We normally treat ulcers in one of three manners. The first is, is that individuals will take bicarbonate. When they take bicarbonate, they immediately are titrating or neutralizing the acid that's within thier stomach. This is what essentially what TUMS is. So they, they are taking a base, which is simply titrating the, caustic acid that's within the stomach. The second is, is that you can give a patient a histamine antagonist. This is going to be a drug that binds to the histamine receptor on the parietal cells, and prevents the histamine receptor from activating. The proton pump. An example of this would be Tagamet. So these individuals will make acid, but they don't make as much acid as they would in the absence of the Tagamet. And the third way is to give a proton pump inhibitor. The proton pump inhibitor, or the little purple pills called Nexium or Prilosec, these are drugs which will prevent the synthesis of the proton pump. For these drugs to be effective, it takes about 24 to 48 hours because the proton pump has to undergo a half life. That it has to be replenished on the cell surface. So if you prevent its synthases, eventually the proton pump is lost from the cell surface and there is no new proton pumps to replace it. So the proton pump inhibitor is very effective, it means that you cannot make acid. you've inhibited the entire process by removing the p-the the proton pump, but it t-it's the delayed effect and the individuals then have to wait 24 to 48 hours for it to be effective. So what are our general concepts? So, the general concepts is we have an acid secretion which will increase in the first 90 minutes of feeding, but the pH is going to be buffered by food so that the pH will rise as the acid production is rising. And then eventually, by 90 minutes, we start to see a fall in the production of acid and, concurrent with that, we see a fall in pH. This is as the food is leaving the stomach, then the pH is, falling back to basal levels, which is a pH of two. Secondly, the gastric acid secretion by the parietal cell is stimulated by parasympathetic activity. This is just the smell of food, thinking of food, seeing food, that will activate the proton pump. And that this parasympathetic activity also increases the amount of gastrin which is being secreted into the blood by the antrocell the G cell and the histamine which is paracrine being secreted by the D cell of the fondant region. Third we have low pH decreases gastric acid secretion so as you recall when we after that 90 minutes. The ph then starts to fall within the lumin of the stomach down again to a pH of two, which is our concentrated HCl of pH. So very high amounts of free protons. This pH of two will activate the somatostatin secretion from the D cell of the antrum. That D cell then will secrete the somatostatin, it acts as a paracrine, to inhibit the secretion of gastrin from the G cell. In addition the arrival of acidicon is just the acidic material from the stomach in to the duodenum is will cause the duodenum epithelial cells to secrete secreton. And that's a hormone and secreton feeds back and down regulates the secretion of gastrin from the g cells. Fourth, we said that ulcers can occur when our mucus barrier in the stomach is eroded. And, and this can be lost either due to, absess . That is taking something like aspirin or ibuprofen, which inhibits the synthesis of the, of the mucus. Or by an infection with, heliobacterium pylori. And five, we have treatment of the ulcers, as can occur at one of three sites. The first is the simple pH neutralization. That is by simply adding a buffer, such as bicarbonate to, to the lumen of the stomach. This is our TUMS. Or secondly, adding an inhibitor to the to the histamine receptor which knocks off then the histamine activation of the proton pump. And then, three, we could simply inhibit the, ability of the parietal cell to secrete to synthesis the proton pump and therefore to secrete the proton. And so we then completely abolish the ability to make acid. Now one thing I want you think about is that if we inhibit the production of acid, from these cells, what do you think happens to the secretion of gastrin? Will it go up? Will it go down? Or will it stay unchanged? So think about that and the negative, the, the negative reflex loop. The next time we come in, we're going to talk about absorption and the anti-gestion. See you then.
