Gastric secretion and its control Flashcards
Glands in the stomach
Cardiac glands:
Mucus from the cardiac glands to protect the stomach from these unhostile environments.
Oxyntic glands:
The pepsinogens are inactive form before releasing preventing self-digestion. Pepsinogen are active to become pepsins by the low pH in the stomach.
Chymosin (rennin) is used to clot milk, it is released in the baby calf. Humans don’t secret even with gene present but inactivated.
Intrinsic factors secreted also by the oxyntic glands, binds to the vitamin B12, which may have taken in meals.
It protects B12 to later be absorbed in the ileum. So intrinsic factors are essential for life. If stomach removed, supplementary for B12 needed.
-anaemia (inequality of blood, reduce oxygen capacity of blood, ion deficiency anaemia-bleeding, gut internal bleeding, ulcers, cancers also cause bleeding-light dizziness, fatigue, pallet being pale- red blood cells size,(macrocytic, etc.) and iron screening )
Nutritional deficiency might leads to also cancer may leads to anaemia, B12 deficiency might lead to macrocytic.
Acid secreted by the parietal cells, chief cells with a lot of vesicles to release pepsinogen.
Pyloric glands: gastrin released into the blood and act on oxyntic gland to release acid.
Roles of gastric acid: (by the parietal cells in an oxyntic gland)
-Delays gastric emptying
-Solubilizes and improves absorption of ions and vitamin B12
-Activates pepsinogen
-Destroys many ingested microbes
Thousands of gastric glands drain into the anus lumen, generating a daily secretion of up to 2 litres. The glands of the stomach mucosa include:
- The cardiac glands, near the entrance of the oesophagus, mainly secrete mucus.
- The oxyntic glands in the fundus and body contain parietal cells (= oxyntic cells) which secrete hydrochloric acid and intrinsic factor. Chief cells (= peptic cells) secrete pepsinogens and prochymosin. Mucus-secreting cells line the necks.
- The pyloric glands in the antrum contain mucus-secreting cells and G-cells, which secrete the hormone gastrin into the blood.
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Oxyntic gland
The secretion of pepsinogens from chief cells is promoted by vagal ACh and a cholinergic reflex in response to acidity.
Acidity catalyzes the cleavage of inactive pepsinogens to form pepsins, enzymes which digest proteins and peptides, and HCl also provides the low pH environment (pH<3) that pepsins require to work properly. Pepsins can also cleave pepsinogens.
Acidity also catalyzes the cleavage of prochymosin to form the active enzyme chymosin (= rennin). Chymosin curdles milk in neonatal mammals, converting the soluble protein caseinogen into the insoluble casein. This allows the milk protein to remain in the stomach long enough to be acted upon by pepsins. The prochymosin gene is inactive in human neonates, in which pepsins take over the role of milk curdling. Gastric lipase is also secreted by the stomach.
Vitamin B12 binds to haptocorrin, secreted in saliva, which protects it from stomach acidity. Released in the small intestine, B12 binds now to intrinsic factor, a glycoprotein secreted by the stomach. This complex resists digestion by proteases, and is taken up into the epithelial cells of the ileum by receptor-mediated endocytosis. Secretion of intrinsic factor by the parietal cells is the only gastric function essential to human life. In dogs and cats, most intrinsic factor comes from the pancreas.
Gastric acid
Gastric acid:
- Delays gastric emptying;
- Solubilizes and thereby improves absorption of calcium and iron, and helps to release vitamin B12 from food;
- Activates pepsinogens;
- Destroys many ingested microbes.
Between meals, gastric juice contains more NaCl: HCl is secreted at a low, basal rate. Within minutes of stimulation, many tubules and vesicles, the membranes of which contain transport proteins, fuse with the luminal membrane of the parietal cell. When the parietal cells are maximally stimulated, the juice becomes largely an isotonic solution of HCl. The intracellular pH is 7, whereas the pH within the gastric gland may be 0.8 during maximum secretion, requiring the pumps to work against a million-fold concentration gradient.
Gastric acid
Gastric acid:
- Delays gastric emptying;
- Solubilizes and thereby improves absorption of calcium and iron, and helps to release vitamin B12 from food;
- Activates pepsinogens;
- Destroys many ingested microbes.
Between meals, gastric juice contains more NaCl: HCl is secreted at a low, basal rate. Within minutes of stimulation, many tubules and vesicles, the membranes of which contain transport proteins, fuse with the luminal membrane of the parietal cell. When the parietal cells are maximally stimulated, the juice becomes largely an isotonic solution of HCl. The intracellular pH is 7, whereas the pH within the gastric gland may be 0.8 during maximum secretion, requiring the pumps to work against a million-fold concentration gradient.
Acid pumping mechanism
The protons secreted by the H+,K+-ATPase pumps (‘proton pumps’) on the luminal membranes of the parietal cells are generated from the intracellular reaction of CO2 with water, under the influence of carbonic anhydrase (CA). This also forms HCO3-, which is exchanged for Cl- by a secondary active transporter on the basolateral membrane, the energy for which comes from the electrochemical gradient for HCO3-. The Cl- that builds up in the cell leaves down its electrochemical gradient, through channels in the luminal membrane.
Proton potassium ATPase (proton pump), potassium is allowed to be cycled out. The protons comes from water and CO2. To transport out bicarbonate, chloride is pumped in then lumen.
As acid secretion proceeds, CO2 is removed from the plasma and bicarbonate is added. The gastric venous blood becomes more alkaline: this so-called ‘alkaline tide’ can be detected as a rise in urinary pH.
Control of acid secretion
One endocrine, one paracrine and one neurocrine transmitter work on parietal cells to increase acid secretion:
Promoting secretion: (gastrin, histamine, acetylcholine)
Inhibit secretion: (secretin, somatostatin, prostaglandins)
1) Gastrin travels in the blood from G cells in antrum and duodenum to the parietal cells.
Gastrin release is promoted by:
- Local stretch reflexes, via ACh.
- Vagal stimulation, via gastrin-releasing peptide (GRP).
- Peptides, amino acids and Ca2+ in the stomach lumen.
Gastrin’s most important role is to promote histamine production and release from ECL cells.
Histamine is the most powerful for acid secretion (Histamine type 2 receptors H2 receptor) H1 on blood vessels is different so not drug development won’t influence that. H1 is also present in the brain, anti-histamine cream instead of antacid for H1 receptor.
+ stimulate parietal cells
2) Histamine is the strongest agonist of HCl secretion. It is released from enterochromaffin-like cells (ECL cells) within the gastric glands themselves, so it is a paracrine transmitter.
3) Acetylcholine, released from nerve terminals, promotes release of acid, histamine and gastrin, and inhibits somatostatin release.
ACh and gastrin both increase free Ca2+ within the parietal cell; histamine acts on H2 receptors to increase cAMP. These second messengers increase numbers and activity of the various transporters. Maximum secretion of HCl requires the activation of both Ca2+ and cAMP pathways,which results in potentiation.
Coincidence response
-CNS leads to the release of acetylcholine
-Gastrin-peptide and amino acids-there’s food
- It isn’t too acidic in the stomach -histamine and somatostatin
Where do we find H1 receptors?
On the blood vessels and bronchial system.
What else promotes gastrin release?
Something in beer and wine, not alcohol but something
Why acid release should be tightly regulated?
Stress?
Alcohol?
Smoking?
Tipping towards the ulcer.
Zollinger-Ellison syndrome oversecreting acid (gastrin-secreting tumour)
NSAIDS (e.g. aspirin- may cause stomach bleeding) promote acid secretion, inhibit prostaglandin thus inhibit HCO3- secretion
Helicobacter lives in the mucus with pH level of 7 which induce low inflammation without knowing it, but it increases the risk of stomach ulcer.
How to reduce pH secretion
Proton-pumping inhibitors
H2 receptor antagonist
Plus antibiotics, if there’s an underlying Helicobacter infection.
Inhibition of acid secretion is mediated by:
1) Somatostatin, a paracrine released from D cells in response to luminal acidity which inhibits parietal cells. This forms an important, negative feedback ‘brake’ mechanism to prevent excessive acid secretion.
Reduce cAMP through its own receptor
2) Secretin, released from S cells in response to acid in the duodenum.This hormone inhibits acid secretion indirectly by stimulating vagal afferent fibres. Among other things, the reflexes elicited reduce gastrin release from G cells.
3) Prostaglandins, paracrines which also promote bicarbonate and mucus production.
Acid secretion in the three phases of digestion
1) The cephalic phase is in response to the sight, smell and taste of food, and is largely mediated by feedforward ACh release. Acid secretion increases, but negative feedback through somatostatin release and neural reflexes limits any pH change. The cephalic phase accounts for around 30% of the total secretion.
2) The gastric phase results from the presence of food in the stomach. Protons are buffered by proteins in the food and luminal pH rises up to around 6. This releases secretory mechanisms from inhibition, so there is a dramatic rise. Contributing to this, stretch of the stomach wall results in vagovagal and local reflexes which increase both gastrin and acid release; peptides and amino acids stimulate G cells to increase gastrin secretion further. (60%)
3) The intestinal phase occurs when chyme enters the duodenum. Initially, duodenal stretch triggers vagovagal reflexes, increasing acid secretion by the stomach, and products of protein digestion result in gastrin release from duodenal G cells. However, as the duodenal contents become increasingly acidic, different vagovagal reflexes, local enteric reflexes and the production of secretin all decrease acid secretion by the stomach. (10% being turned off partly by the secretin)
Stomach volume goes up to 1.5 L
Acid secretion rate increases when there is food in the stomach (gastric phase)
However, the luminal pH actually rises when food comes in which is the buffering role of the food which takes off the gastric juice, the pH drops as buffering effect stops, then somatostatin inhibits the secretion.
Protection from acid and ulcer formation
The stomach mucosa is protected by the secretion of mucus and bicarbonate by the mucous cells forming the epithelial lining of the stomach and in the necks of the gastric glands. This alkaline lining, referred to as the gastric mucosal barrier, helps to maintain the luminal surface of the stomach at around pH 6-7, although the pH of the stomach contents may be as low as 1-2. The barrier protects the lining from mechanical and chemical damage.
The mucus trap the bicarbonate to maintain the pH of the mucus which protect the gastric epithelial cells.
Epithelial mucous cells are continually lost from the stomach surface and are replaced by mucous cells from the necks of the gastric glands, which migrate upwards and over the surface. The neck mucous cells are themselves replaced as stem cells deeper within the glands divide and differentiate.
If the gastric mucosal barrier is compromised, the surface of the stomach can be attacked by acid and pepsins, giving rise to a gastric ulcer. Ulcers can be treated with drugs which suppress acid secretion, including H2-receptor antagonists (e.g. ranitidine, cimetidine) and H+,K+-ATPase proton pump inhibitors (PPIs, e.g. omeprazole).
-During hernia, apply antibiotics, coz ulcer also leads to heartburn.
One of the most important predisposing factors for ulcer formation is overuse of NSAID drugs such as aspirin. Another is the presence of the Gram-negative bacterium Helicobacter pylori, which inflames the stomach wall. Successful ulcer treatment in this case requires the use of antibiotics to eliminate the underlying Helicobacter infection, in addition to acid-suppressing drugs (see Blaser, 1996).
Pancreatic secretion
At the abdominal cavity, which release the juice into the pancreatic duct and delivered to the duodenum. This is the exocrine secretion as the lumen of the duct. It also contains endocrine function islet of Langerhans. (insulin and glucagon)
Pancreas also have acini which store the contents like the salivary glands which also have similar effect. Water following, both release amylase and bicarbonate.
Difference: The salivary gland has myoepithelial cells while pancreases not.
In the pancreases, water is secreted by the duct and has a wider range of enzymes than the salivary gland including some really powerful protease.
The proteases zymogens as inactivated in the vesicle accompanied by the pancreatic secretory trypsin inhibitor. Trypsin is one of the proteases, if activated, PSTI acts on it to inhibit trypsin.
Pancreas is vulnerable, if activated at the wrong time-life-threatening the P-bomb
Composition of pancreatic juice is produced at a high flow rate with sodium bicarbonate solution which protect the duodenum.
Secretion by pancreatic acinar cells with sodium chloride with water following.
Worth looking at the duct cells which secret the bicarbonate using sodium proton antiporter (2nd transporter) Using the H+-Na+ antiporter, the H+ goes out to meet bicarbonate in the ECF while bicarbonate forming carbonic acid flows in then H+ is then moved out through the antiporter.
This is similar to the kidney wanting to reabsorb the HCO3-.
Then the bicarbonate is transported out using bicarbonate-Cl- antiporter. So now the bicarbonate is out in the lumen, chloride comes in. We can’t allow chloride to be stored so facilitated diffused out. This electrochemical gradient will allow the sodium to move out followed by water through the paracellular route.
Control of pancreatic secretion
Phases of pancratic secretion
-Cephalic phase (vagal Ach)
-Gastric phase (vagovagal & local reflexes)
-Intestinal phase (secretin & CCK) most of it occurs in this phase
Parasympathetic nerves stimulate pancreatic secretion; sympathetic stimulation results in vasoconstriction, reducing secretion. Enteric neurons also pass from stomach and duodenum to the pancreas.
- Cephalic phase release is under feedforward control;
- Gastric phase release occurs in response to vagovagal and local neural reflexes;
- The intestinal phase results in much higher levels of secretion, mainly due to secretin, released from S cells in the mucosa of the duodenum and jejunum in response to a pH of under 4.5. Secretin is a potent stimulator of bicarbonate and water secretion from pancreatic duct cells
Phases of acid secretion
1) The cephalic phase is in response to the sight, smell and taste of food, and is largely mediated by feedforward ACh release. Acid secretion increases, but negative feedback through somatostatin release and neural reflexes limits any pH change. The cephalic phase accounts for around 30% of the total secretion.
2) The gastric phase results from the presence of food in the stomach. Protons are buffered by proteins in the food and luminal pH rises up to around 6. This releases secretory mechanisms from inhibition, so there is a dramatic rise. Contributing to this, stretch of the stomach wall results in vagovagal and local reflexes which increase both gastrin and acid release; peptides and amino acids stimulate G cells to increase gastrin secretion further. (60%)
3) The intestinal phase occurs when chyme enters the duodenum. Initially, duodenal stretch triggers vagovagal reflexes, increasing acid secretion by the stomach, and products of protein digestion result in gastrin release from duodenal G cells. However, as the duodenal contents become increasingly acidic, different vagovagal reflexes, local enteric reflexes and the production of secretin all decrease acid secretion by the stomach. (10% being turned off partly by the secretin)
Pancreatic acinar cells
The pancreas produces both an endocrine secretion (insulin and glucagon) and an exocrine secretion which enters the duodenum. The exocrine secretion is bicarbonate rich, but includes enzymes such as amylase, lipases, proteases, ribonucleases and deoxyribonucleases.
Pancreatic acinar cells secrete enzymes by exocytosis, the proteases as inactive zymogens. Pancreatic secretory trypsin inhibitor (PSTI), packaged in the same zymogen granules as trypsinogen, helps to protect the acinar cells from inappropriate activation of trypsin. Acinar cells secrete a small amount of NaCl-rich solution into the lumen of the acinus, through a mechanism resembling acinar salivary secretion. The pancreatic duct cells secrete the bulk of the aqueous component of the pancreatic juice in the form of a bicarbonate-rich solution: the basic process is shown below.
Stimulation of pancreatic release
When acid is drained into the duodenum from the stomach which is released by the oxyntic gland. It will stimulate the secretin release from the upper intestine S cell, it acts on the pancreas to increase secretion of the bicarbonate to increase the pH, also acts on the stomach to reduce acid secretion
“Natures’ antacid ”
Parasympathetic nerves stimulate pancreatic secretion; sympathetic stimulation results in vasoconstriction, reducing secretion. Enteric neurons also pass from stomach and duodenum to the pancreas.
- Cephalic phase release is under feedforward control;
- Gastric phase release occurs in response to vagovagal and local neural reflexes;
- The intestinal phase results in much higher levels of secretion, mainly due to secretin, released from S cells in the mucosa of the duodenum and jejunum in response to a pH of under 4.5. Secretin is a potent stimulator of bicarbonate and water secretion from pancreatic duct cells.
Fat digestion products in the duodenum are the main stimuli for CCK release: CCK stimulates enzyme secretion from acinar cells and potentiates the effects of secretin on duct cells. At least some of its effects may be indirect, via vagovagal reflexes.
Stimulation of pancreatic cells
Compare with acid or saliva
In pancreatic cells, ACh and CCK increase intracellular [Ca2+],(basal K+ channel), whereas secretin and VIP increase intracellular [cAMP],(The Apical chloride channels). Since both of these pathways augment secretion, potentiation is possible.
The Apical chloride channels are activated by the secretin and VIP, while basal K+ channel is activated by the CCK and Ach. Potential is going to be possible, with full on bicarbonate secretion.
In both the acinar cells and the duct cells, cAMP opens the luminal chloride channels, increasing secretion. The luminal chloride channel in duct cells is the CFTR (cystic fibrosis transmembrane conductance regulator). The most common form of cystic fibrosis results in impaired electrolyte and water secretion into the duct system. Clogged ducts lead to severe maldigestion and nutrient deficiency, while the blockage combined with premature activation of proteolytic enzymes can result in pancreatic damage.
Digestion and absorption of carbohydrates
50% of the carbohydrate in most human diets is starch, which consists of branched or unbranched chains of glucose. Salivary and pancreatic amylase cleave the internal α-1,4 bonds in starch but cannot touch the α-1,6 branching links or the α-1,4 bonds next to them. The result is smaller chains of glucose molecules (oligosaccharides), mostly two (maltose) or three units long, plus α-limit dextrins which contain the branch points.
Enzymes on the brush border of the duodenum and jejunum complete carbohydrate digestion. Glucoamylase and α-dextrinase break down the α-1,4 and α-1,6 bonds respectively within glucose oligosaccharides, while lactase, sucrase and trehalase digest lactose (glucose + galactose), sucrose (glucose + fructose) and trehalose respectively.
Glucose and galactose are taken up by SGLT1 (sodium-glucose transport protein 1) on the apical membranes of epithelial cells in the duodenal and jejunal villi. Fructose is taken up by GLUT5, a facilitated diffusion transporter?????; some is converted to glucose within the cell. Export is typically via GLUT2, on the basolateral membrane.
Digestion and absorption of proteins
Acid in the stomach helps to denature protein, rendering it vulnerable to attack. Pepsins contribute up to 15% of protein digestion: they are useful in digesting collagen, which is relatively immune to attack by other proteases.
Pancreatic proteases are much more important in protein digestion. The inactive zymogen trypsinogen is converted to trypsin by enteropeptidase on the brush border of the upper small intestine. Trypsin itself will activate trypsinogen, as well as the other pancreatic proteases such as chymotrypsin, elastase and the carboxypeptidases. These enzymes digest proteins to peptides, which are digested further by brush border peptidases located on the apical membranes of epithelial cells in the upper small intestine.
The products are taken up into the cells by facilitated diffusion or secondary active transport. Within the cell, peptides are further digested into amino acids, which are released from the cell by facilitated diffusion or secondary active transport. Some amino acids, notably glutamine, are oxidised for energy within the rapidly-dividing intestinal cells themselves.
Glutamine is used as a source of nitrogen, used to make nucleic acids to support rapid cell division in the epithelial lining of the gut.
Absorption of calcium and iron
Calcium and iron availability is reduced by their binding to other dietary constituents (e.g. phytate anions) to yield insoluble salts. Gastric acid improves solubility, while vitamin C in the stomach helps to reduce insoluble Fe3+ to Fe2+.
The main mechanisms for calcium absorption are illustrated. Paracellular uptake of calcium is important if calcium intake is high, but if not the active form of vitamin D3, 1,25(OH)2D, can upregulate the expression of several of the proteins involved in transcellular uptake, including the transport protein calbindin.
**Iron reductase **on duodenal brush border reduces Fe3+ to Fe2+, which is taken up via the proton-Fe2+ cotransporter DMT1. Iron may also be taken up as haem. The iron is ferried across the duodenal cell and then transported out via ferroportin. It travels in the blood bound to the protein transferrin. In the presence of the peptide hormone hepcidin from the liver, efflux is reduced and excess iron is trapped in the cell, bound to the protein ferritin: this will be lost when the epithelial cell is shed.
Bacteria need iron to grow, so reducing iron availability can be used by the body to fight infection. Hepcidin production is increased in response to inflammatory mediators, reducing circulating levels of iron.
What salivary constituent reduces iron availability in the mouth, to combat bacterial growth there?
lactoferrin
Absorption of the major electrolytes
Sodium absorption is highest in the small intestine, where its movement into cells down its electrochemical gradient is coupled to the movement of monosaccharides (SGLT1) and some amino acids. Other sodium transporters include Na+/H+ antiporters and (in the colon) epithelial sodium channels (ENaC).
Potassium becomes concentrated as water is absorbed, and this provides the driving force for paracellular uptake by the small intestine. There is usually net potassium secretion from the colon, via apical potassium channels.
Chloride is absorbed throughout the digestive tract both via the paracellular pathway and by exchange with bicarbonate.
Similar to the kidney with application of aldosterone-Compare and contrast with the digestive tract and kidney in retention of water.
Oral rehydration therapy: Glucose with sodium can allow salt to be more easily absorbed which allows water to be retained in the body.
Absorption of water
Water enters the digestive tract both through the ingesta (~2 litres day-1) and through gastrointestinal secretions (~7 litres day-1, from saliva, stomach, pancreas, bile and crypts). Of this, the small intestine (especially the ileum) absorbs ~7.5 litres, and the colon ~1400 ml, leaving ~100 ml to be lost in the faeces. There is a considerable reserve capacity: the gut can take up two or three times more water than this, if necessary.
The standing gradient model of water uptake across an epithelium holds that sodium is pumped into the intercellular clefts by the sodium pumps, which are concentrated around the edges of these spaces on the basolateral membranes. Anions follow. A solute concentration gradient is set up, highest near the tight junctions, decreasing towards the open ends where it becomes equal to the concentration in the bulk phase. Because of the high solute concentration within the intercellular clefts, water enters from the adjacent cells and from the lumen via ‘leaky’ tight junctions. A rise in pressure drives flow across the basement membrane, whereupon the water and salts are taken up and removed by capillaries.
Because the small intestinal epithelium is ‘leaky’, absorption is isosmotic. Much less water is absorbed in the colon but this can be against a larger osmotic gradient since the tight junctions between cells are tighter, limiting back-diffusion of ions.
