Physio #5 - Function of the Stomach and Pancreas

What happens to the composition of gastric secretions as the secretion/flow rate changes? What happens when eating and not eating

-The basal secretion of gastric juices (baseline level when you are not secreting much because not eating) is mostly Na and Cl --> so the conc of Na+ is les than plasma, the conc of Cl is greater than plasma, the conc of K+ is greater than plasma When you eat, the gastric glands are stimulated to produce secretions --> so teh production of gastric juices increases from about 5 - 8 times -so the the volume of gastric secretions increases and the luminal composition of things in the secretions changes from NaCl at low flow rate to HCL at high flow rate (because nee HCl to digest food and don't need HCL when not eating)

What are the general regions of the stomach?

-most distal part is the antrum -body of the stomach is called the fundus -the top part is the cardiac region or corpus region (closest part to the heart hence cardiac)

What is pepsinogen secreted by? How is it formed? Highest activity?

-secreted by chief cells/peptic cells -At, pH less than 5, pepsinogen is converted to the active enzyme pepsin and pepsin catalyzes its own conversion (meaning pepsin will digest pepsinogen to create more pepsin). --> Pepsin hydrolyzes interior peptide bonds of dietary protein Pepsin highest activity is between pH 1 - 3

What are the functions of the stomach? 6

-stomach relaxes when food is present within reason --> if you are already full, it can't expand

What doProton pump inhibitors do? Given how often?

Omeprazole is a H+ pump inhibitor (proton pump inhibitor) and it is prescribed for people with ulcers or gerd because the have reflux of acid from the stomach into the mouth. This drug attacks the areas on teh alpha subunit of teh H+/K+ ATPase and forms covalent disulfide bridges with cysteine residues on the lumen side --> so the alpha subunit can't extrude protons in exchange for K+ anymore so no more H+ in the lumen so no more acid secretion and no more reflux The inhibition is irreversible so the drug is only given once a day!

So is is prescribed to prevent aspirin from harming? Specific drug

Prescribe COX-2 inhibitors like Celecoxib to prevent reduction of prostaglandins and thromboxanes to prevent erosion of stomach lining and suppress inflammation

What are the functions of the pancreas? Cells here?

Produces secretions that neutralize the gastric secretions Endocrine function: to make insulin and glucogaon (and somatostatin secreted by D-cells) --> secreted at the islet of langerhans Exocrine function: makes bicarbonate to neutralize the stomach acid ALSO makes enzymes (secreted by the acinar cells) required for digestion of fats, proteins and carbohydrates

What specific cells secrete secretin? CCK? Where are these cells found?

S cells make secretin I cells make CCK The cells are found in the duodenum

What makes up the organic component of the gastric secretions?

pepsinogen intrinsic factor Mucous

What are the 2 components of the pancreatic secretions? Enzymes, function, secretion?

1.) Aqueous component: bicarbonate 2.) Organic component: • amylases - breaks up starch (carbohydrates) into smaller units. Synthesized & secreted in active form. • lipases - break down fats. Synthesized & secreted in inactive (like have to be activated by cleaving or something) & active (ready to work) forms. • proteases - digest proteins. Secreted in inactive form called zymogens, to prevent autodigestion of the pancreas. Trypsin inhibitors in pancreas prevent premature activation of these proteases. If there is premature activation, the trypsins can digest the pancreas very easily and that is bad. • ribonucleases digest DNA and RNA from food

The following are made the body to naturally block the receptors to turn off H+ secretion: 1.) What can block the M3 receptor for ACh at the bacolateral side of the parietal cell? 2.) What can block the CCK-beta receptor? 3.)What is teh antagonist for the H2 receptors

1.) atropine 2.) proglumide 3.) cimetidine whihc is an H2 receptor blocker also called Tagamet in pharmacy

How is potentiation possible? Different tracks? What is the most potent track for acid stimulation?

ACh stimulates the ECL cell, the G cell, the parietal cell and then it inhibits the D cell from making somatostatin which is another inhibitory pathway for secretion of acid. Gastrin stimulates the ECL cell more so than it stimulation of the parietal cell (on pic there are more + on the ECl cell) Histamin is the MAIN stimulator of acid production (has the most +) that's why when histamine blockers are used like Zantac and Tagamet, most of the acid production is blocked Ultimately meaning that there are many ways to stimulate acid production and inhibition and the interactions together have big implications in acid secretion or inhibition = potentiation

At the chief cells, what happens?

Ach binds at teh chief cell on teh muscarinic receptors, gastrin/CCK also binding and somatostatin being the major negative regulator on the cheif cell of pepsinogen secretion. THe point is that the regulatory factors that release HCL also link the release of pepsinogen/pepsin to the release of HCL. Thereby increasing the efficiency of protein digestion. AcH is also regulating the surface mucus cells and mucus neck cells to secrete mucus.

What kind of glands are in the distal antral region? What cells are there?

Antral glands 1.) Surface mucus cells 2.) Mucus neck cells 3.) D cells - secrete somatostatin 4.) G cells - secrete gastrin hormone 5.) Prostaglandin-2 secreted from the bottom of the gland from the submucosa but the exact cell type is not known

Again, what are the 2 major causes of gastric ulcers?

Aspirin drugs used to control inflammation and pain ---> so aspirin and its family of anti inflammatory drugs. and the H pylori bacteria that causes inflammation leading to ulcers

Describe how the components of the aqueous pancreatic secretions change with flow rate/secretion rate? ***

At normal, basal rates the composition of pancreatis aqueous sections is primarily NaCl and HCO3. The HCO3 concentration levels are higher than plasma concentration and the Cl- concentration is equal to plasma concentration. Between meals , your pancreas is secreting a small amount of secretions full of NaCl. Then if you have a snack, your pancreas is stimulated, the volume of secretions increase up to 10 fold, the Cl- concentration decreases with flow rate, the HCO3- concentration increases with flow rate so at high flow rates when eating meals, the pancreas converts its secretions from primarily NaCl to virtually mostly Na & HCO3. The sum of Cl- concentration plus HCO3- concentration equals the sum of Na+ and K+ concentrations. Na+ and K+ are always secreted independent of teh pancreas secretion rate! So since HCO3- changes in an equimolar way with Cl-, basically the osmolality of pancreatic secretions will not change with the flow rate so it will stay similar to plasma (on graph the plateau during stimulated periods)

What happens to the bicarbonate that is made in the cell? (from previous card) What happens to the blood? What is it called?

At the basolateral membrane, the bicarbonate is extruded from the cytosol by the HCO3-/Cl exchanger --> so the bicarb goes through the exchanger in exchange for Cl coming into the cell and that is actually the Cl- that goes through the channel on the apical side into the lumen to combine with H+ to make HCL! *****The high basolateral bicarbonate secretion rate makes the blood pH leaving the stomach elevated aka more alkaline called "alkaline tide"

Describe the H+/K+ ATPase that pumps the H+ ions out of the apical side of the parietal cell to get H+ ions into the stomach lumen Phosphorylation site?

Consists of 2 subunits: a.) the alpha subunit which has 8 transmembrane domains with extracellular and intracellular loops. it also posses catalytic activity which means it expends ATP to extrude the H+ ions to the food side and absorbs K+ back into the cell. The phosphorylation site for the ATP on the alpha subunit is on Asp in position 385.

What else can cause gastric ulcers? What is the mechanism here? Specific things!

Drugs that are used to control inflammation and pain --> Aspirin!! Aspirin irreversibly inhibits COX including COX 1 which is required for prostaglandin synthesis and remember prostaglandins inhibit acid secretion so if there are no more prostaglandins then not much protection against acid! And COX1 is required for synthesis of thromboxane synthesis in the gastric mucosa which is required for blood clots. So it reduces levels of prostaglandins PGE2, PGI2 (causing inhibition of acid secretion and making mucus) and also of thromboxanes that are required for blood clotting.

Describe the chemical gradient between the stomach lumen and the blood outside the stomach?

H+ secretion is very expensive to secrete so need to spend much ATP --> so to keep the stomach lumen pH so low, much H+ has to be secreted which creates a strong chemical gradient for teh blood outside the stomach to go against because the it is 1 million fold difference in H+ concentration in the stomach compared to the blood outside. So when the stomach is making HCL, it adds the H+ concentration uphill from low concentration to high concentration and this is what takes so much energy ATP.

What makes up the aqueous component of the gastric secretions?

HCL

So as all of this exchange and transport is happening, what is happening to concentrations?

HCO3- concentrations in teh cell increase rapidly and so it passes via downhill gradient through the exchanger, in exchange for Cl- to enter the cell against its chemical gradient and then recycled back out by the CFTR. The lumen is negative so Na+ and K+ diffuse to the lumen through paracellular pathway (between cells) and water osmotically follows the transport of the HCO3-, Na+ and K+ into the lumen through aquaporin channels.

Explain the composition of the gastric juices at high secretion rates when eating pH? pH at peak gastric secretion? How does teh pH in the lumen of the stomach compare to in teh blood vessels outside the stomach lining it?

In the lumen of the stomach, at high HCL secretion rates, the gastric juice is about isotonic to plasma --> so the aqueous component has little HCO3- so not enough to buffer the HCL so the lumen of the stomach becomes about pH 1 and lower so the concentration of the H+ ions in the stomach becomes 140nM! This is lethal acid concentration! The pH in the blood vessels lining the stomach is 7.4 and the H+ concentration is 0.000050mM which is 1 million fold lower than in the stomach!

What is the pathophysiology of the bleeding ulcers? How do they occur?

Normally, there are damaging forces like acid and defensive forces against them like the mucus, bicarb etc. When an ulcer develops due to increased damaged to stomach lining, or you have an H. pylori infection. The H.pylori bacteria plays a large role --> CDC says that 90% of duodenal ulcers and 70% gastric ulcers are caused by that bacteria! On the pic it says delayed gastric emptying which means stomach contents not released and erode teh walls to create ulcer.

AS you know at the parietal cell, there is an enormous gradient of H+ ions going from teh cytosol of the parietal cell into the lumen of the stomach --> the million to one gradient ...explain again - how is the parietal cell able to make this gradient very high?

THe huge chemical gradient --> between meals teh parietal cell in is a resting state. THe other is the stimulated state. During the resting state, you see that theere are tubulovesicles with the H+/K+ ATPases and K+ channels inside of them in the cytosol of the cell. When you decide to eat, the Ach, gastrin and histamine not only stimulates all of thsoe pumps, but also changes teh parietal cell in terms of structures. So when all of the things that stimulate acid secretion come into play, they also stimulate the fusion of teh tubulovesicles with the plasma membrane creating cannaliculi in the surface making a sort fo serrated look to the parietal cell and teh active parietal cell is even more serrated. THis creates more surface area of the cell so that the parietal cell can increase the density of the H+/K+ ATPases and K+ channels in the apical membrane. So larger surface area, and more pumps per unit area so that results in the huge chemical gradient and very very lo pH in the lumen of the stomach.

So explain the path of secretions from the acinar cells in the pancreas and the components at different points Secretion stimulated by? Be aware of the location of things happening and the particular cells! (HE stresses cells a lot)

THe pancreatic gland resembles the salivary gland in that there are acinar cells with the acinar end and duct lined with duct cells and those cells change the composition of teh pancreatic secretions along the duct. First, secretion by the acinar cells is stimulated by Ach and CCK (Cholecystokinin) and the fluid is first isotonic with NaCl resembling plasma. Then as the fluid passes down the duct, the interlobular duct cells contribute HCO3- making the secretions have higher HCO3- concentration than plasma (but he said other than that the fluid is mostly isotonic to plasma) Then when the pancreas is stimulated by hormone secretin, this causes high secretion rates and much pancreatic juices made, then the extralobular duct cells add Na+, K+ and HCO3- to the fluid but NOT Cl-. SO the secretions pH increase a lot do to the high amount of HCO3- which will then be used to neutralize the acidic going into SI from the stomach.

What regulates the organic component of pancreatic secretions? 3 things second messenger?

THis enzyme secretion is controlled mainly by vagus nerve releasing Ach act on muscarinic receptors on the baserolateral membrane of the acinar cells. CCK is a minor control of enzyme secretion. In humans it is a minor but still significant Somatostatin inhibits adenyl cyclase **Note the pathways here and receptor names and second messengers associated with what receptors

Describe the cells of the gastric glands that make up the gastric pits in the stomach? In what regions of the stomach are gastric glands found?

The amount of gastric glands depends on the region of the stomach --> most found in the proximal regions of the stomach which are the cardiac / fundus body region 1.) Surface Mucus cells (top) - secrete mucus, trefoil peptide and bicarbonate 2.) Mucus neck cells - give rise to all of the other cells of the gastric glands so if they divide going up they give rise to the surface mucus cells and if the divide going down they give rise to the others 3.) Parietal cells - look like sharks with serrated teeth - secrete acid and intrinsic factor 4.) ECl cell - histamine secretion 5.) Chief cells - pepsinogen secretion

Explain the molecular mechanisms of the extralobular duct cells secreting HCO3-?

The duct cells in the extralobular portion of the pancreatic ducts. The lumen/apical side of the cell is where the things are being secreted into and the basolateral side is the blood side. In the cell cytosol, CO2 (diffuses into cell from blood) combines with H20 with help of carbonic anhydrase to yield carbonic acid and that is quickly dissociated into H+ and HCO3_ (bicarb). The HCO3- is moved out of the cell through the Cl-/HCO3- exchanger on the apical/lumen side. So HCO3- goes out into the lumen secretions and Cl- comes into the cell. Also the H+ that was made with the HCO3- after dissociation of teh carbonic anhydrase is pumped out to the blood via that Na+/H+ exchanger. Also the CFTR (cystic fibrosis transmembrane regulator) is a channel on the apical side of the cell. SO people with CF have faulty pancreas as well as lungs because no CFTR channel in pancreas because the CFTR works to recycle the Cl- to be used in the Cl-/HCO3- exchanger. In the basolateral memebrane, the Na+/H+ exchanger functions to extrude the protons out of the cell. Along with other transporters listed in the picture.

Describe what regulates the secretions in the pancreas? Hormone? What happens to amylase?

The hormone that controls pancreatic secretions is secretin. In response to secretin, the bicarb secretion increases ten fold. Stimulus for secretion release is HCL and fatty acids in the duodenum. Because secretin is releaser of the body's own natural antacid, HC03, it is adaptive that luminal HCl releases secretin.

Describe mucous What is it? What secretes mucous? What does a mucous gel look like? What parts are resistant to what? Where does pepsin attack the mucous to break it down? What happens

The mucous intact and not degraded has high viscosity, but when pepsin breaks it down, the viscosity decreases Functions to protect stomach lining

Describe the molecular mechanism of secreting HCL in the stomach by the parietal cells

The point is to secrete out of the lumen/apical side of the cell to make the lumen very acidic... First in the cytosol is the reaction of water with CO2 with carbonic anhydrase enzyme to make carbonic acid which is converted to HCO3-(bicarb) and H+ ions. The the H+ ions are extruded from the cytosol by the H+/K+ ATPase into the lumen. The K+ dosen't build up in teh cell because it is basically being reused over and over. Then the Cl- is also secretd out of teh cell ---> that makes HCL!

How does the stomach protect itself from the huge amount of HCL in its lumen?

The protective components are very robust in the stomach --> The gastric mucosal barrier prevents harm. There are several layers in the stomach. In the picture you see the blood vessels with the mucus neck cells and surface neck cells that secrete a gel over the mucosa creating a protective lubricating coat. Those same cells are very productive in making HCO3- bicarbonate at the same time as they are making mucus. So right at the surface of the epithelial cells the pH is higher because of the thick mucus and abundant of bicarb secreted from those cells. Also the cells have tight junctions and the phospholipid bilayer which helps them to have low permeability to the H+ ions so they don't get through at the apical membrane back into lumen of the GI. If a monlayer is created in the lab of these cells, they can survive a pH of 2 due to teh tight junctions and apical membrane structures. So if the stomach lining is compromised, the blood vessels are compromised and bleeding ulcers occurs.

So what stimulates the HCL secretion in the stomach? How is it regulated?

There are 3 factors that bind to the basolateral side of the parietal cell to stimulate HCL secretion 1.) Neuroendocrine signal coming from the parasympathetic vagus nerve to release ACh and act on M3 receptor which stimulates Ca2+ as second messenger to increase H+/K+ ATPase activity 2.) Endocrine path - G cells make gastrin which binds to CCK-beta/ CCK-2 receptor to then act on Ca2+ to increase H+/K ATPase activity 3.) Paracrine path - ECL cells make histamine which binds to H2 receptors to act on cAMP to increase H+/K+ ATPase activity

Describe how CCK is released from duodenal I cells What has to be present? 2 "pathways"? Negative feedback?

When you eat proteins and they are broken up by trypsin, there are free amino acids and fatty acids floating in the intestinal lumen. These amino acids and fatty acids act at the I cell at teh apical membrane. The CCK-releasing peptide (CCK-RP) alone will not cause release of CCK. It needs a partner peptide and that is called monitor peptide. Monitor peptide is contributed by the pancreas. SO when both the CCK-RP and monitor peptide are present on teh apical membrane of the I cells, only then will CCK be released. THis tight control over release of CCK may be evolutionarily due to the fact that CCK main role is release all of teh enxymes and once the enxymes are present, their functions are very one sided so they have one job and will do it no matter what so they have potential to harm the pancreas wall. Once CCK is released by the I cells it goes into the blood stream, but on its way to the blood stream there are sensory nerves that have CCK receptors and these sensory nerves detect the CCK and signal through the nervous system to release Ach to go to pancreas and cause pancreas to release trypsin. CCK also will independentlytravel through blood as a hormone to pancreas anddirectly stimulate pancreatic cells to release trypsin and all the other proteases. THe negatives on the picture show that when you are eating, the trypsin is busy digesting the proteins into AAs. Once you have digested most of the food eaten, the trypsin will then digest the CC-RP and the monitor peptide. So when they are no longer present, then the I cells stop making CCK and this stimulatory pathway to release trypsin via the hormonal pathway and the sensory CNS pathway, will then stop. So this regulates when you are eating and when not eating

So do each of those factors above stimulate H+ secretion by the H+/K+ ATPase alone? What about when they are all acting to stimulate the secretion of H+ by eh H+/K+ ATPase together? What is their simultaneous interaction called?

Yes - each "secretagogue" meaning the 3 factors can stimulate H+ by themselves Basically means that when all three are working together its a greater effect == potentiation

Do we have H. pylori in or stomachs normally? What happens with worsening infections?

Yes, about 40% of Americans have it in their stomach. That doesn't mean they have ulcers, it just means that the bacteria is in their gut. THere is a greater prevalence of the bacteria in people living in third world countries. It is though that the bacteria secrete proteins that results in mucosal inflammation and superficial gastritis (inflamed stomach lining). In some people for unknown reasons, the infection progresses to ulcers and in other people the infection can progress to atrophic gastritis which is atrophy of the stomach lining folds with the epithelial cells have reduced acid secretion. IN rare cases, those symptoms can lead to gastric cancer.

Do the extralobular ducts cells require a lot of HCO3- ?

Yes, the cell requiresnso much HCO3- that the pathway of CO2 entering the cell from the blood side is not sufficient enough to give anout HCO3- required inside of the cell to be pumped out into the secretions. So at this stage, there is a Na+HCO3- co-transporter that basically brings in more HCO3- from the blood side to the cytosol to add to the amount of HCO3- to be extruded by the Cl-/HCO3- exchanger into the lumen secretions.

What are the 2 components of gastric secretions from the stomach>?

aqueous component organic component

What is the beta subunit of the H+/K+ ATPase like?

involved in recycling of H+/K+ ATPase to stop the production of HCL at the appropriate time so don't burn hole in your stomach