Regulation of Acid Secretion

Regulation of acid secretion How does low pH in upper gut switch off acid secretion? • Low pH is sensed by somatostatin D cells in the antral glands → secrete somatostatin (short peptide hormone) in a paracrine manner → inhibits gastrin secretion by nearby G cells → gastrin plasma levels fall → acid secretion falls • When acid enters the duodenum secretin is secreted into the circulation and inhibits gastrin stimulated acid secretion • Summary: acid in lumen of stomach or duodenum inhibits its own secretion via endocrine feedback loops • Clinician’s corner: Zollinger Ellison (ZE) syndrome o Rare disease due to tumours (benign or malignant) composed of gastrin secreting cells o Although there is normally virtually no gastrin in the pancreas, these most often occur in pancreas o Sustained very high plasma levels of gastrin lead to marked and sustained oversecretion of gastric acid o Patients get severe peptic ulcer disease (often multiple ulcers, including in unusual sites such as 3rd or 4th part of duodenum) even without H. pylori or NSAIDs as a precipitating factor Cholecystokinin (CCK) • Peptide hormone produced by the I cell in the crypts of the intestine • Most numerous in the duodenum and proximal jejunum • Stimuli for secretion: food (lipids are the most potent stimulator, also aa) • Action: o Enzyme rich secretions by pancreas o Contraction of gall bladder and relaxation of the sphincter of Oddi (at bottom of bile duct) → allows release of bile into small bowel o Inhibition of gastric emptying o Increases motility of small intestine and colon o Augments the contraction of the pyloric sphincter o Increases glucagon secretion o Induces satiety by working through the hypothalamus • Mechanism of action o Through CCK receptors: ▪ CCK-A: located in periphery and brain ▪ CCK-B: located in brain (virtually identical to gastrin receptor) o CCK binds to receptor to activate phospholipase C → IP3, DAG → increased intracellular calcium → activates protein kinase → release of granule (pancreatic enzyme) o CCK also stimulates vagus nerve to pancreas to release pancreatic enzymes • Control of CCK secretion = positive feedback loop: CCK → enzyme release → more digestive products → more CCK (stops when digestive products move to next part of small intestine) Secretin family • Secretin, GIP, glucagon, vasoactive intestinal polypeptide • Secretin is a peptide hormone produced by S cells in crypts of intestine – most numerous in duodenum o Stimuli for secretion is low pH (<4) in duodenum o Secretin causes: ▪ Bicarbonate-rich secretion by pancreas ▪ Bicarbonate-rich secretion in bile ▪ Inhibition of gastric emptying • Actions of secretin: o Most potent humoral stimulator of fluid and bicarbonate secretion by pancreas o Acts in concert with CCK and acetylcholine to stimulate bicarbonate secretion o ↑ HCO3− secretion by duct cells of pancreas and biliary tract → ↑secretion of a watery, alkaline pancreatic juice o Acts via cAMP o ↑pancreatic enzyme secretion (augments CCK) o ↓ gastric acid secretion o Pyloric sphincter contraction o Stimulates growth of the exocrine pancreas • Control of secretin secretion o Cannot be released if duodenal pH rises above 4.5 o Release is inhibited by somatostatin • Effects of secretin and CCK on bile acid secretion • Effects of secretin and CCK on pancreatic secretion • Effects of secretin and CCK on motility Gastric inhibitory peptide (GIP) • Produced by K cell in duodenal and jejunal mucosa • Stimulated by glucose and fat in duodenum, acid in stomach • Stimulates insulin release from pancreatic islet in response to duodenal glucose and fat • Mild effect in decreasing gastric motility • Inhibit gastric acid secretion by directly inhibiting parietal cells or indirectly inhibiting release of gastrin via somatostatin Glucagon • Produced by alpha cell of pancreatic islet • Action: increase glycogenolysis, increase gluconeogenesis Vasoactive intestinal peptide (VIP) • Found in enteric nervous systems (both myenteric and submucosal plexus), brain, autonomic nerves • Released in response to oesophageal and gastric distension, vagal stimulation, fatty acid and ethanol in duodenum • Amino acid and glucose do not affect VIP release • Action: o ↑ secretion of electrolyte and water from small bowel o Intestinal circular smooth muscle relaxation o Longitudinal smooth muscle contraction o ↑ pancreatic secretion o Inhibit gastric acid secretion and motility Motilin • Secreted by enterochromaffin cell and M cell in duodenum, jejunum • Acts on G‐protein coupled receptor on enteric neurons in stomach, duodenum → GI tract smooth muscle contraction • Circulatinglevelincreasedatintervalof90‐100 minutes in the inter-digestive state • Major regulator of MMC (migrating motor complex) that move through the stomach and small intestine every 90 minutes in fasted person Somatostatin • Growth hormone inhibitory hormone (GH‐IH) • First found in hypothalamus • Secreted by D cell in stomach, duodenum, pancreatic islet • Secreted in larger amount into gastric lumen > circulation • Released in response to acid in stomach • Action: o Inhibit secretion of gastrin, VIP, GIP, secretin, motilin, insulin, glucagon o ↑fluid absorption and ↓ secretion from intestine o ↓ endocrine and exocrine pancreatic secretion o ↓bile flow and gall bladder secretion o ↓gastric acid secretion and motility o ↓absorption of glucose and amino acids