Gastric Secretion: Part 1 PDF

Section 6: Gastric Secretion (Simple stomach) Gastric juice composition: HCl Water Pepsin Intrinsic factor Mucus A. Functional Anatomy of the Gastric Mucosa 1. Surface epithelium and the gastric pit. The glandular gastric mucosa is lined with simple columnar epi...

Section 6: Gastric Secretion (Simple stomach) Gastric juice composition: HCl Water Pepsin Intrinsic factor Mucus A. Functional Anatomy of the Gastric Mucosa 1. Surface epithelium and the gastric pit. The glandular gastric mucosa is lined with simple columnar epithelium that is punctuated with numerous (3 million) gastric pits that serve 1 - 3 gastric glands. 2. The gastric gland. Each gastric gland is composed of several cell types. The mixture of cell types of the gastric gland differs among three different regions of the stomach (see Fig. 1 of Section 1 for species differences in these regions): Regions of Stomach by Species 37 Region Epithelial cell types Secretory products Cardiac Gland Mucous ------------------------------- Mucus and pepsinogen (near esophagus) Enteroendocrine ------------------- Various Region Epithelial cell types Secretory products Oxyntic Gland Parietal------------------------------- HCl and intrinsic factor (proper gastric) Chief ---------------------------------- Pepsinogen Mucous ------------------------------- Mucus and pepsinogen Enteroendocrine ------------------- a) Enterochromaffin-Like Cell (ECL) cell (subepith.)-Histamine ------------------- b) D cell – Somatostatin ------------------- c) X/A cell - Ghrelin Pyloric Gland Mucous ------------------------------- Mucus and pepsinogen (antral) Enteroendocrine ------------------- a) G cell - Gastrin ------------------- b) D cell - Somatostatin Fig. 24 Reprinted from Physiology and Pathophysiology of Digestion, 2018 38 B. Ghrelin (the hunger hormone) Found mainly in oxyntic glands of stomach Released during fasting or stages of negative energy balance Agonists of ghrelin used to stimulate appetite in dogs and cats C. Functions of Gastric HCl 1. Activation of pepsinogen 2. Provides optimal pH (2 - 4) for pepsin action 3. Denatures and some acid hydrolysis of native protein amino acids 4. Bacteriocidal 5. Demineralizes ingested bone (dissolves Ca2+) D. Mechanism of Gastric Acid Secretion (HCl from parietal cells) 1. HCl secretion - Isotonic - Occurs via H+-K+ ATPase (H+ pump) Utilizes energy (ATP) – Thus primary active tranport 2. Mechanism of HCl secretion. Fig. 25 -Alkaline tide: 39 E. Mediators Affecting Parietal Cell HCl Secretion 1. Secretagogue: Histamine a. Action: Paracrine - Binds H2 receptor → Increases cAMP resulting in: 1) Direct stimulation of H-K ATPase 2) Potentiates ACh/gastrin stimulation of H-K ATPase b. Main sources of histamine: ECL cells Minor: Mast cells and histaminergic nerves c. Stimuli of ECL cell: 1) Gastrin - Binds to gastrin (CCK-B) receptor on ECL cells 2) Acetylcholine - Local and central reflex activity d. Inhibitor of ECL cell 1) Somatostatin released locally (paracrine) binds to ECL cell and inhibits histamine release. Fig. 26 Central and Regulation of Parietal Cell HCl Secretion Local Neural Action AA K+ pH pH H+ G cell D cell Also GRP Acetylcholine Gastrin ECL Histamine Somatostatin 40 2. Secretagogue: Acetylcholine a. Action: Neuronal - Binds to muscarinic receptor → Increases intracellular Ca2+→ Stimulates H-K ATPase b. Indirect action: Stimulates gastrin release from G cells and ECL histamine release c. Source: Cholinergic effector neurons d. Stimuli: Parasympathetic outflow and local enteric nervous system Fig. 26 Central and Regulation of Parietal Cell HCl Secretion Local Neural Action AA K+ pH pH H+ G cell D cell Also GRP Acetylcholine Gastrin ECL Histamine Somatostatin 3. Secretagogue: Gastrin a. Direct action: Endocrine - Binds gastrin (CCKB) receptor on parietal cell → Increases intracellular Ca2+ → Stimulates H-K ATPase b. Indirect action: Stimulates histamine release from ECL cells (main effect) c. Sources: Antral G cells d. Stimuli: Neural- 1) ACh acting at muscarinic receptor on G cell 2) Gastrin releasing peptide neurons (release GRP in response to antral filling) Luminal- 1) Amino acids (dietary, acid hydrolysis, pepsin) 2) Decreased luminal [H+] (increased pH) 41 4. Inhibitor: Somatostatin a. Paracrine – Oxyntic stomach: i. Parietal cell: Inhibits H+-K+ ATPase. ii. ECL cell: Inhibits histamine release. Antral stomach: i. G cells: Inhibits gastrin release. b. Source: D cells in oxyntic and antral stomach c. Stimulus: Increased luminal [H+] (decreased pH) Central and Regulation of Parietal Cell HCl Secretion Local Neural Action AA K+ pH pH H+ G cell D cell Also GRP Acetylcholine Gastrin ECL Histamine Somatostatin Parietal Cells are a Dynamic Source of HCl Secretion 1. Cephalic phase (15% of total gastric secretion) - Conditioned reflexes of appetite Appetite via CNS → Vagus (PS) → Cholinergic effectors → a) Gastrin release b) Histamine release c) Parietal cell stimulation 2. Gastric phase (70 - 80% of total gastric secretion)- Presence of food in the stomach is the primary stimulus for gastric secretion. Stimuli include: a) Neural: 1) Mechano-and chemoreceptors activated by digesta in stomach Send afferents locally and centrally 42 Suppl. Fig. 13 Reprinted from Physiology and Pathophysiology of Digestion, 2018 43 F. Three phases of gastric secretion (meal stimulus) 1. Cephalic phase (15% of total gastric secretion) - Conditioned reflexes of appetite Appetite via CNS → Vagus (PS) → Cholinergic effectors → a) Gastrin release b) Histamine release c) Parietal cell stimulation 2. Gastric phase (70 - 80% of total gastric secretion)- Presence of food in the stomach is the primary stimulus for gastric secretion. Stimuli include: a) Neural: 1) Mechano-and chemoreceptors activated by digesta in stomach Send afferents locally and centrally Local and parasympathetic reflexes activate cholinergic neurons i) Direct muscarinic activation of parietal cell ii) Stimulation of gastrin release iii) Stimulation of histamine release 2) Stretch of antrum activates gastrin releasing peptide neurons GRP acts at G cell to stimulate gastrin release b) Hormonal: Increased gastrin release due to: 1) ACh 2) GRP 3) Amino acids in lumen 4) “Food buffering” effect Food buffering effect = Decreased gastric proton concentration by neutralization with food constituents (i.e., food buffering): a. Removes acid inhibition of G cell gastrin release b. Decreases D cell release of somatostatin. 44  Fig. 27 3. Intestinal phase (5% of gastric secretion) Partial agonist of gastrin receptor CCK - Stimulated by lipid and amino acids G. Physiological Inhibitors of Acid Secretion a. Local feedback control by gastric luminal acidity (low pH) i) Releases somatostatin from D cells b. Feedback control by duodenum i) Enterogastric reflex ii) CCK (partial agonist at gastrin receptor) and GLP-1 Clinical Relevance: Gastroduodenal ulcers Therapies: 1. Pharmacological Main treatment: Antibacterial: Helicobacter pylori H+-K+ ATPase inhibitors (omeprazole) H2 receptor antagonists (ranitidine) 45  Muscarinic antagonists (pirenzipine) Antacids, Sulcrafate 2. Surgical - Antrectomy Vagotomy H. Other gastric juice constituents 1. Pepsin a. Pepsinogen (inactive state) synthesized in chief and mucous cells -Release is mediated by neural reflexes responding to luminal acid b. Activated by HCl and pepsin c. Action as a protease Optimal pH = 2 - 4. 2. Intrinsic factor a. Glycoprotein synthesized and secreted by: Humans: Parietal cells Pig: Glandular cells in pyloric region Dogs/Cats: Pancreatic acinar cells Ruminants: Microbial production in rumen Horses: Microbial production in large intestine (ingested by coprophagy) b. Vitamin B12 (cobalamin - containing cobalt) is ingested in foods except for adult strict herbivores (require cobalt) c. Vitamin B12 binds to intrinsic factor in stomach and duodenum d. Complex dissociates in ileum and B12 is actively transported to blood e. Vitamin B12 needed for hemoglobin formation in RBC production, myelin synthesis and indirectly for mucin formation Clinical: Atrophic gastritis and pernicious anemia in humans 46  3. Rennin a. Milk clotting enzyme of neonatal ruminants b. Pepsin in other species Objectives: 1. Know the site and cell types of the gastric mucosa that secrete: HCl, pepsinogen, histamine, gastrin releasing peptide and gastrin. 2. Describe the general anatomical regions of the gastric pit. 3. Know how HCl is secreted by the H-K ATPase. 4. Know the stimulatory mediators of HCl secretion from the parietal cell, including cellular action, source and main stimuli. 5. Know the physiological inhibitors of acid secretion and their site of action. 6. List the functions of gastric HCl. 7. Describe the phases of gastric secretion and the relative contribution to secretion after a meal. 8. Describe the secretion and action of pepsin. 9. Describe the secretion and action of intrinsic factor. 47