Gastric and intestinal secretion Today lecture Gastric and intestinal secretion **Types **Functions **Mechanisms **Regulation special consideration will be on gastric secretion

Types of gastric glands and cells Gastric cells 1. mucous neck cells (secrete mucus) 2. surface epithelial cells (secrete mucus) 3. chief cells (secrete pepsinogen) 4. G cells (secrete gastrin - in antrum) 5. parietal (oxyntic) cells (secrete HCl and intrinsic factor) 6. enterochromaffin-like-cells (ECL) secrete histamine. Gastric glands 1. The oxyntic glands (80% of gastric glands)-body and fundus 2. Pyloric glands (20% of gastric glands)- antrum region

Structure of a gastric exocrine secretory gland The oxyntic glands

GASTRIC SECRETION • approx. 2 L gastric juice per day • secretion is isotonic, pH 2-3 (in stomach lumen) Functions of gastric secretion Intrinsic Factor: - from parietal cells, for vitamin B12 uptake in lower small intestine (ileum). - It is indispensable substance in gastric juice. It’s absence leads to pernicious anemia 2. Mucus: protects gastric epithelium. It adheres to gastric surface and prevents H+ and pepsin eroding the mucosa; failure of this process leads to gastric ulceration

GASTRIC SECRETION (cont.) 3. HCl - from parietal (oxyntic) cells Function of Gastric acid -to kill micro-organisms but H. pylori survives by making ammonia (alkaline) from urea using urease enzyme. -to activate pepsinogen (cleaved to form pepsin) - pepsin: initiates protein digestion -breaks down connective tissue in food -denatures protein 4. Pepsinogen - from chief (peptic) cells - conversion to pepsin (active enzyme) requires low pH - pepsin initiates protein digestion; optimum pH 1-2

Mucosal Protection of gastric epithelium mucus layer on gastric surface forms a mucosal barrier against damage to gastric epithelium a gel about 1 mm thick secreted by neck cells, surface epithelium release is stimulated by acetylcholine from nerve endings also rich in bicarbonate HCO3- content creates a "micro-environment" around surface cells to prevent acid damage HCO3- secretion is inhibited by adrenergic input (prominent in stress!) prostaglandins are protective agent (increase mucus production and blood flow) inhibition of enzymes involved in prostaglandin production (cyclo-oxygenases =COX) by NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, etc. results in gastric damage

Gastric Mucous layer ***The surface epithelial cells of the stomach secrete thick insoluble, unstirred mucus that lines the surface of the stomach. This mucus contains glycoproteins that form an almost gelatinous coating which contains relatively high concentrations of bicarbonate ion. This coating protects the stomach epithelium from gastric acid and pepsin. Glycosylation of mucin makes it relatively resistant to proteolysis by pepsin.

Mucus layer lining the gastric mucosa is for protection

A second type of mucus (soluble) is secreted along with the gastric juice from the gastric pits to lubricate the food bolus and facilitate mixing. Soluble mucus restricts the access of gastric juice to the gastric pit epithelial cells. Viscid mucus Soluble mucus

Parietal cells secret HCl and intrinsic factor

Parietal cells and it’s receptors

HCl secretion Three chemicals stimulate production of HCl from parietal cells: Acetylecholine: released from cholinergic nerve fibres (parasympathetic) - acts on muscarinic receptors (M3 ) 2. Gastrin: released from G cells of pyloric glands acts on G receptors 3. Histamine: released from enterochromaffin-like-cells (ECL) and mast cells. It acts on H2 receptors (activates adenyl cyclase enzyme). inhibited by H2 receptor antagonists (eg. cimetidine) -ECL are stimulated by gastrin and acetylcholine ** each one of the three stimulants potentiates the effects of the others EFFECT of parietal stimulation by the three stimulants are: **more H+/K+-ATPase insertion in membrane **more Cl- channels insertion

PARACRINE HORMONES AND HCl RELEASE IN THE GASTRIC PHASE OF SECRETION Histamine: Released from mast cells in mucosa by Ach (from nerves) and gastrin (G-cells) ***Acts directly on parietal cells to stimulate HCl production. H2-receptor antagonists block action of histamine Somatostatin: Released from D-cells in gastric epithelium by direct action of H+ (at lumen pH < 2). Reduces gastrin release → reduced HCl secretion

Inhibitory effect of somatostatin is indirect (through inhibition of G cells) One inhibitory and three stimulatory signals that alter acid secretion by parietal cells in the stomach.

inhibition of acid secretion through somatostatin

Interaction between different factors that Regulate HCl secretion histamine ECL cell Gastrin secretion is stimulated by: Peptides Gastrin-releasing peptides released from intrinsic nerve Histamine release is stimulated by Ach 2. gastrin

Mechanism of HCl formation 1. H+ ions are formed inside parietal cells from dissociation of carbonic acid which is formed from combination of CO2 and water under the influence of carbonic anhydrase enzyme (HCO3 conc. Increases inside parietal cell). 2. Cl- is pumped inside parietal cell in exchange of HCO3 (antiporter). 3. H+ ions are pumped into gastric lumen by K+/H+ pump. 4. Cl- moves out (by diffusion) of parietal cell into lumen through electrical gradients. ****H+/K+-ATPase (i.e. proton pump), located in the luminal membrane of parietal cells

Another version (Guyton) for Hydrochloric acid formation: Hydrogen ions are formed from the dissociation of water molecules. The enzyme carbonic anhydrase facilitates the reaction of carbon dioxide and water forming carbonic acid which dissociates into a bicarbonate ion (HCO3-) and a hydrogen ion (H+). The bicarbonate ion (HCO3-) diffuses out in exchange with chloride ion (Cl-) which diffuses inside. Potassium (K+ ions diffuse into the canaliculi. Hydrogen ions are pumped out of the cell into the canaliculi in exchange for potassium ions, via the H+/K+ ATPase.

Extra points regarding HCL formation During active secretion of HCl after a meal, the pH of the blood drained from the stomach is elevated (due to secretion of HCO3 ions). this increase in pH of the venous blood leaving the stomach is referred to as the alkaline tide. It raises the pH of systemic blood and make urine alkaline (postprandial alkaline tide). * The K+/H+ pump is very powerful and requires appreciable amount of energy because H+ is pumped against more than 1000000 concentration gradient (pH 7 to pH 1) ) It can concentrate H+ 3 million times. Inhibition of this pump by drugs called proton pump inhibitor (Omeprazole ) helps in reducing the amount of HCl secretion. The pH of parietal cell secretion into canaliculi is very low (about 0.8).

Regulation of pepsinogen secretion Stimulation of chief cells by acetylcholine released from Vagus nerve endings Gastric enteric nervous plexus 2. Presence of acid in the stomach: through eliciting enteric reflexes. Absence or less acid secretion will cause less pepsinogen formation

Phases of gastric secretion Cephalic phase: Occurs before food enters stomach ~30% of total secretion Direct vagal stimulation + gastrin release Gastric phase: Occurs while food is in stomach >60% of total secretion Involvement of: vagal and enteric nerves paracrine (local) hormones (histamine) endocrine hormones (gastrin) Gastrin secretion is inhibited at lumen pH <2 Intestinal phase: Occurs after food enters small intestine Largely hormonal: - stimulatory effects (gastrin) - inhibitory effects (secretin, GIP, cholycystokinin)

Cephalic Phase of gastric secretion 1. The taste or smell of food, tactile sensations of food in the mouth, or even thoughts of food stimulate the medulla oblongata (green arrow) via stimulation of appetite center of hypothalamus and amygdala. 2. Parasympathetic action potentials are carried by the vagus nerves to the stomach (pink arrow). 3. Parasympathetic vagus nerve fibers stimulate enteric plexus of the stomach. 4. Postganglionic neurons stimulate secretion by parietal and chief cells and stimulate gastrin secretion by endocrine cells. 5. Gastrin is carried through the circulation back to the stomach (purple arrow), where it stimulates secretion by parietal and chief cells. Taste or smell of food Tactile sensation in mouth Medulla oblongata 1 5 Secretions stimulated Vagus nerves 3 2 4 Gastrin Circulation Stomach

Gastric Phase **Peptides in stomach cause also secretion of gastrin ***Inhibition of HCl secretion by low luminal pH. A local effect to prevent gastric damage by very acidic gastric contents Medulla oblongata Vagus nerves (long vago-vagal reflex Gastric Phase 1 1. Distention of the stomach activates a parasympathetic reflex. Action potentials are carried by the vagus nerves to the medulla oblongata (green arrow). 2. The medulla oblongata stimulates stomach secretions (pink arrow). 3. Distention of the stomach also activates local reflexes that increase stomach secretions (purple arrow). 4. Peptides in stomach cause secretion of gastrin Secretions stimulated 2 Distention 3 Local reflexes stimulated by stomach distention Stomach

Phases of gastric secretion 3. INTESTINAL phase - occurs when chyme enters small intestine - largely hormonal: 1. Initial stimulatory effects on gastric secretion (via enteric gastrin) 2. Feedback inhibitory effects (secretin, gastric-inhibitory-polypeptide)

Inhibition of gastric secretion by intestinal factors **Chyme in the duodenum with a pH less than 2 or containing fat digestion products (lipids) inhibits gastric secretions by three mechanisms. 1. Sensory vagal action potentials to the medulla oblongata (green arrow) inhibit motor action potentials from the medulla oblongata (pink arrow). 2. Local reflexes inhibit gastric secretion (orange arrows) this called reverse entrogastric reflex . 3. Acid, fat, protein breakdown products, hyperosmotic or hypo-osmotic or any irritating factor in duodenum and upper small intestine cause secretion of Secretin and gastric inhibitory polypeptide produced by the duodenum (brown arrows) inhibit gastric secretions in the stomach. Secretion has more powerful inhibitory effect than other factors Vagus nerves Medulla oblongata Decreased gastric secretions Vagus nerves 2 Local reflexes 1 pH<2 or lipids 3 4 Circulation

Secretion from other parts of GIT Esophygeal secretion: entirely mucus and it’s function is; to prevent mucosal excoriation by newly entering food. To protect the lower esophagus from the effect of refluxed gastric juice. Duodenal secretion: alkaline (containing large amount of HCO3 ions) mucus secretion from compound mucous glands called Brunner’s glands which are found in large no. in duodenal wall in area between pylorus and papilla of Vater. Brunner’s glands secretion (about 200 ml/day) is stimulated by: 1. Tactile or irritating stimuli on duodenal mucosa 2. Vagal stimulation 3. Secretin hormone Their secretion is inhibited by sympathetic stimulation Function of Brunner’s gland secretion is to protect duodenal mucosa against the destructive effects of acidic chyme coming from the stomach.

Secretion from other parts of GIT (cont.) Secretion of small intestine about 1.8 liter/day (pure small intestine secretion contains no digestive enzymes). Intestinal epithelium (crypts of Lieberkuhn) has two types of cells Goblet cells- secrete mucus (mucin) for lubrication and protection and also bind some bacteria and Immunoglobulins. Secretion of mucus is increased by parasympathetic stimulation and by chemical and physical irritation. Entrocytes- secrete alkaline (pH 7.5-8) watery fluid similar to extracellular fluid. This helps in absorption of different substances by intestinal villi. ***The mechanism of intestinal watery secretion: Cl- and HCO3- ions are actively secreted. Sodium diffuse because of electrical gradient. Water will follow ions by osmosis. Regulation of intestinal secretion: ** mainly by local enteric nervous reflexes initiated by tactile and irritative stimuli ** Hormonal : secretin and CCK (endocrine cell secrete defensins(

Secretion from other parts of GIT (cont.) Secretion of the large intestine (200 ml/day) ***The epithelium of large intestine consists mainly mucous cells that secret mucus * this mucus contains HCO3- ions (CHO3- ions are secreted by non-mucus secreting epithelial cells). * mucus secretion is increased by: tactile stimulation of epithelium lining the intestine. Local nervous reflexes Stimulation of parasympathetic nerve fibers Functions of Mucus Protection Neutralization of acids formed in large intestine