Greetings, today we will finish our discussion of how we make acid. In particular, how does the body regulate of acid secretion by the stomach? The learning objectives are to explain the regulation of the acid secretion in both the fed and the fasted states. And we want to explain the causes that underlie gastric ulcers. Ulcers are an erosion of the epithelium of the stomach. The loss of these cells allows acid to dig through into the tissues which underlie the epithelium. Thirdly, we will discuss the various treatments for gastric ulcers. So, how do we secrete acid from the stomach? This, of course, is done by the 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 the opposite sides of the parietal cell. The proton is expelled from the parietal cell with an ATPase in exchange for potassium. This is the potassium-proton ATPase, It is also called the proton pump. At the same time, the bicarbonate that was generated from this reaction, is moved out at the base of the cell. That is, towards the interstitial space and towards the blood. This is accomplished by a co-transporter, an anti-porter. Bicarbonate leaves the cell at the base which faces the blood vessels. The chloride ions enters into the cell. The chloride ions then exit the cell through a chloride transporter which is present on the luminal surface of these cells. This process produces hydrochloric acid in the lumen of the stomach. The potassium that's needed to to continue the generation of this acid is recycled. Potassium is recycled at the lumenal surface, through a potassium transporter. This is how we make the acid, HCl. Now let's consider how we regulate the acid produced. Acid secretion is not constant. It is not secreted at the same level at all times. Right after feeding there is an increase in the production of acid. Which peaks at about 90 minutes after feeding. Subsequent to this peak acid output, there is a fall in the acid production. This rise in acid secretion occurs as food is coming into the stomach. Notice that at the same time that we have a rise in acid production, there is also a rise in pH. At the start, the pH in the lumen is two, which is the concentrated hydrochloric acid. The pH then rises to about five. Then, subsequent to that, the pH falls. We have, again, the basal, the basal level of a pH, pH of two. Why does the pH rise rapidly in the first 90 minutes after feeding? Why in the first 30 minutes after feeding isit rising? The reason that it becomes a more basic pH is that, food is arriving in the lumen of the stomach. The free protons bind to the food. This removes free protons. As you recall, pH is the logarithmic, to the base ten, of the concentration of free protons. So as free protons are removed by binding to the food, there is a slight rise in pH. Eventually, as the food leaves the stomach, then the pH falls again to a pH of two. Now the hydrogen ion is free so we have concentrated acid. How is this regulated and why? This has to be regulated because the acid is very, very caustic. The parietal cell does not secret acid unless it's really being used, needed. There's a very small amount of acid being made in the basal state or in the fasting state. Then the production of acid increases when we need it for feeding, to degrade food, or to digest food. There are two phases for the regulation of the acid secretion. The first phase is called the "cephalic phase." In this phase, we have a "feed forward" control. This phase is triggered by the parasympathetic nervous system. It is governed by the parasympathetic nervous system. If you just smell food, or you think about food, or you see food, as when you pass a bakery and you see all those wonderful cakes in there, then those sensatons trigger a release of acid from the stomach. This occurs because of acetylcholine. This is the neurotransmitter of the parasympathetic innervation to the parietal cell. This is the vagus nerve. It will stimulate the proton pump. So we increase the activity of the proton pump and make HCl. The cephalic phase is a feed forward phase. When activated, the parasympathetic nervous system also governs another region of the stomach. That is, it regulates the antral cells. These antral cells are called G cells. The G cells secrete gastrin. Gastrin is a hormone. This is an indirect regulation of the G-cell. But with parasympathetic activation, the G-cell will start to secrete gastrin. Gastrin enters into the blood. It is delivered to the parietal cell of the stomach by the blood. At the parietal cell, Gastrin binds to the gastrin receptor which is present on the basil surface of these parietal cells. In doing so Gastrin increases the activity of the proton pump. gastrin directly promotes the production of acid. Gastrin also works on a neighboring cell within the fundic region. This is neighbor of the Parietal cell. This cell is called ECL or eenterochromaffin cell. The enterochromaffin cell secretes a paracrine, which is called histamine. A parachrine, as you recall, is a chemical that is secreted into the interstitial space, the tissue surrounding a neighboring cell. This paracrine, histamine, binds to the histamine receptor on the parietal cell. When histamine binds to the histamine receptor on the Parietal cell, it too increases the activity of the proton pump. so we have three signals, then. Which increase the production of acid. They drive the proton pump of the parietal cell. The first is acetylcholine. Which is the direct parasympathetic input. The second is Gastrin, a hormone, coming from the G-cell of the antrum. And the third is histamine which is a paracrine. THis comes 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 to be made. During feeding, There is a second phase, called the Gastric phase. In the Gastric phase, food arrives into the lumen of the stomach. We now have a stretching of the walls of the stomach. The stomach, as you recall, can hold about two liters of food. Food or liquid. As we stretch the walls of the stomach. then the antrum releases Gastrin. Again Gastrin is a hormone secreted into the bloodstream. It is delivered to the parietal cells where it binds to the Gastrin receptor. Just as we described in the cephalic phase. This increases the activity of the proton pump. Gastrin also binds to the Gastrin receptor on the ECL cell. It causes that cell to secrete histamine. Histamine is our paracrine. This paracrine then binds to the histamine receptor of the neighboring cell, the parietal cell. This will increase the proton pump activity. The Gastric phase accounts for about 60% of acid production that's due to feeding. Whenever we have a positive reflex, we also have to have a negative reflex loop. Part of the negative reflex in this particular loop is that the proton itself feeds back to 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 antrum of the stomach. There is also a proton receptor present on a cell called the D cell. This D cell secretes somatostatin. Somatostatin is going to act as a paracrine. It binds to the neighboring cell, which is the G Cell. The G cell secretes Gastrin. Somatostatin, whenever you see Somatostatin in the body, it is always an inhibitory factor. Somatostatin, in this case, is an inhibitory factor, which is a paracrine. It binds to the somatostatin receptor, and inhibits the release of Gastrin. There is a second signal, which comes from the beginning of the small intestine, called the duodenum. This signal is secreted from the duodenum. It's a hormone. The hormone is called Secretin. Secretin arrives by the blood to these G cells within the antrum. Secretin binds 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 Secretin and the second one is a paracrin that comes from the D cells, a neighboring cell. That paracrine is Somatostatin. So what are the causes and treatment of ulcers? Ulcers are as I told you at the beginning of the video are erosions of the mucous barrier which lines the entire interior of the stomach. This mucous barrier is resistant to acid. As long as it's there, the epithelial cells which are sitting beneath this mucous barrier, or mucous blanket, are protected to the low pH (acid) of the of the lumen. What is interesting about this particular geometry, is that between the cells and the mucous barrier, there's actually a very small compartment. That compartment has a pH that is neutral. So the cells are maintaining a neutral compartment immediately around them, and then there's the mucous barrier, and outside of that we have the very low pH, that's the pH of acid. What happens is that if something disrupts that mucous barrier, then the acid is able to reach the epithelial cells. The acid 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. These drugs in excess can lead ti ulcers. The aspirin or ibuprofen erodes this mucous barrier because they prevents its synthesis, its prodcution. This involves a second system, which it uses prostaglandins. Whe we lose that mucous barrier, acid can reach the cells and erode the cells. This is called a gastric ulcer. For many, many years it was thought that the people who developed ulcers were very nervous, highly stressed individuals. They were said to have a type A personality. Then several years ago an individual, a pathologist from Australia, started looking at some dissections of his patients after they died. When he was doing these cadaveric dissections he realized that many were infected. They had some type of an infection within the stomach in addition to their ulcers. He then proposed that perhaps ulcer formation was due to an infection. He isolated the bacterium. That . bacterium was called Helicobacter pylori For many years, he tried to convince the gastrointestinal field, that this was the cause of ulcers and that we'd be able to treat it by giving these individuals an antibiotic to remove the bacterial infection. This was poo-pooed by the general medical profession, and it was poo-pooed by the scientists, the basic scientists who worked in this field. For many years 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. He drank it trying to give himself an ulcer. To prove that these bacteria were, in fact, the cause of ulcers. He managed to make himself sick, but he didn't develop an ulcer. It turns out that, with time it was shown that Heliocobacter pylori is, in fact, the causal agent. It is the infective agent. When the individual is infected, then the bug lives between the mucosal barrier and the epithelium. It lives 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, and that's what leads 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 cause of ulcers throughout the world. He was awarded the Nobel prize for his work. It turns out that there's about fifty per cent of the population worldwide that is infected by the Helicobacter pylori, but only fifteen per cent of these individuals ever develop any symptoms of ulcers. There is resistance to ulcer formation by these particular bacterium. It turns out that he's one of those individuals that is resistant to the activity of the bacterium. So how do we normally treat ulcers? We normally treat ulcers in one of three manners. The first is that individuals take bicarbonate. When they take bicarbonate, they immediately are titrating or neutralizing the acid that's within thier stomach. This is essentially what TUMS is. They are taking a base, which is simply titrating the caustic acid that's within the stomach. The second is that you can give a patient a histamine antagonist. This drug 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. These individuals will make acid, but they don't make as much acid as they would in the absence of the Tagamet. The third way is to give a proton pump inhibitor. The proton pump inhibitor, or the little purple pill called Nexium or Prilosec, are drugs that irreversibly inhibit the proton pump. These drugs are effective for a longer periods of time because proton pump has to be synthesized. It has to be replenished on the cell surface. eventually the proton pump is lost from the cell surface. A new proton pumps replaces it. The proton pump inhibitor is very effective. It means that you cannot make acid. You've inhibited the entire process by removing the proton pump. When appropriate it is given with an antibiotic to remove the H.pylroi. So what are our general concepts? The general concept is that acid secretion will increase in the first 90 minutes of feeding, but the pH is buffered by food. THat means the pH will rise as the acid production is rising. 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 fall in pH occurs as the food leaves The stomach, then the pH falls to basal levels, which is a pH of two. Secondly, gastric acid secretion by the parietal cell is stimulated by parasympathetic activity. Just the smell of food, thinking of food, seeing food, will activate the proton pump. This increase in parasympathetic activity also increases the amount of Gastrin which is secreted into the blood by the antral G cell. Gastrin in turn increases histamine,a paracrine secreted by the D cell of the fundic region. Third, Low pH decreases gastric acid secretion. As you recall, when after 90 minutes, the ph then starts to fall within the lumen of the stomach down again to a pH of two, which concentrated HCl. Now there are very high amounts of free protons. This pH of two activates Somatostatin secretion from the D cell of the antrum. The D cell secretes somatostatin. It acts as a paracrine to inhibit the secretion of Gastrin from the G cell. In addition the arrival of acidic chyme the acidic material from the stomach into the duodenum causes the duodenum epithelial cells to secrete Secretin. That's a hormone. Secretin feeds back and down-regulates the secretion of Gastrin from the G cells. Fourth, we said that ulcers can occur when our mucous barrier in the stomach is eroded. This mucus can be lost either due to NSAIDS. NSAIDS such as
aspirin or ibuprofen, inhibits the synthesis of mucus. Ulcers may occur with an infection with Helicobacter pylori. And five, treatment of gastric ulcers, 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 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. This decreases acid production. And then, three, we could simply inhibit the ability of the parietal cell to produce acid by inhibiting the proton pump and therefore the secretion of free protons. This last treatment completely abolishes 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 feed back, the negative reflex loop. The next time we come in, we're going to talk about absorption and the digestion. See you then.
