Physiology of gastric acid secretion
- Andrew H Soll, MD
Andrew H Soll, MD
- Emeritus Professor of Medicine
- University of California Los Angeles Center for Health Sciences
- Nimish B Vakil, MD, AGAF, FACP, FACG, FASGE
Nimish B Vakil, MD, AGAF, FACP, FACG, FASGE
- Clinical Professor of Medicine
- University of Wisconsin School of Medicine and Public Health
The regulation of acid and pepsin secretion reflects an intricate balance of chemotransmitters delivered to the gastric mucosa by several pathways that mediate both stimulatory and inhibitory mechanisms . Similarly, several mechanisms contribute to the remarkable ability of normal gastroduodenal mucosa to defend itself against injury from the acid/peptic activity in gastric juice and to rapidly repair injury when it does occur. Secretory, defense, and healing mechanisms are regulated by the same type of overlapping neural, endocrine, paracrine, and autocrine control pathways.
The numerous stimulators and inhibitors of each regulated element suggest redundant control; however, there is limited understanding of the actual physiologic and pathophysiologic importance of most of these pathways and chemotransmitters. The problem is that there remains a limited set of pharmacologic and molecular biologic tools to dissect the significance of each pathway.
Although gastric acid is not essential for life, the universal preservation of gastric acid secretion among vertebrates indicates critical evolutionary advantage. The benefits of gastric acid are to facilitate digestion of proteins and the absorption of calcium, iron, and vitamin B12. It also suppresses growth of bacteria, which can help prevent enteric infections and small intestinal bacterial overgrowth.
PHASES OF ACID SECRETION
The physiologic stimulation of acid secretion has classically been divided into three interrelated phases: cephalic, gastric, and intestinal .
●The cephalic phase is activated by the thought, taste, smell and sight of food, and swallowing. It is mediated mostly by cholinergic/vagal mechanisms.
- Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology 2008; 134:1842.
- Lloyd KCK, Debas HT. Peripheral regulation of gastric acid secretion. In: Physiology of the Gastrointestinal Tract, Johnson LR, Christensen J, Jackson MJ, et al (Eds), Raven Press, New York 1994.
- Soll AH, Berglindh T. Receptors regulating acid secretory function. In: Physiology of the Gastrointestinal Tract, 3rd ed, Johnson LR, Alpers DH, Christensen J, et al (Eds), Raven Press, New York 1994. p.1139.
- Feldman M. Gastrin secretion: Normal and abnormal. In: Gastrointestinal Disease, Feldman M, Scharschmidt BF, Sleisenger MH (Eds), WB Saunders, 1997. p.587.
- Yao X, Forte JG. Cell biology of acid secretion by the parietal cell. Annu Rev Physiol 2003; 65:103.
- Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995; 75:155.
- Roepke TK, Anantharam A, Kirchhoff P, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem 2006; 281:23740.
- Geibel JP. Role of potassium in acid secretion. World J Gastroenterol 2005; 11:5259.
- Heitzmann D, Warth R. No potassium, no acid: K+ channels and gastric acid secretion. Physiology (Bethesda) 2007; 22:335.
- Courtois-Coutry N, Roush D, Rajendran V, et al. A tyrosine-based signal targets H/K-ATPase to a regulated compartment and is required for the cessation of gastric acid secretion. Cell 1997; 90:501.
- Sandvik AK, Waldum HL. Aspects of the regulation of gastric histamine release. Scand J Gastroenterol Suppl 1991; 180:108.
- Kidd M, Modlin IM, Tang LH. Gastrin and the enterochromaffin-like cell: an acid update. Dig Surg 1998; 15:209.
- Chen D, Monstein HJ, Nylander AG, et al. Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation. Gastroenterology 1994; 107:18.
- Waldum HL, Hauso O, Fossmark R. The regulation of gastric acid secretion - clinical perspectives. Acta Physiol (Oxf) 2013.
- Soll AH, Amirian DA, Thomas LP, et al. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984; 73:1434.
- Bitziou E, Patel BA. Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach. Am J Physiol Gastrointest Liver Physiol 2012; 303:G396.
- Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A 1992; 89:3605.
- Langhans N, Rindi G, Chiu M, et al. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 1997; 112:280.
- Samuelson LC, Hinkle KL. Insights into the regulation of gastric acid secretion through analysis of genetically engineered mice. Annu Rev Physiol 2003; 65:383.
- Lindström E, Chen D, Norlén P, et al. Control of gastric acid secretion:the gastrin-ECL cell-parietal cell axis. Comp Biochem Physiol A Mol Integr Physiol 2001; 128:505.
- Koh TJ, Goldenring JR, Ito S, et al. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 1997; 113:1015.
- Soll AH, Amirian DA, Park J, et al. Cholecystokinin potently releases somatostatin from canine fundic mucosal cells in short-term culture. Am J Physiol 1985; 248:G569.
- Schmidt WE, Schmitz F. Cellular localization of cholecystokinin receptors as the molecular basis of the periperal regulation of acid secretion. Pharmacol Toxicol 2002; 91:351.
- Chen D, Friis-Hansen L, Håkanson R, Zhao CM. Genetic dissection of the signaling pathways that control gastric acid secretion. Inflammopharmacology 2005; 13:201.
- Schubert ML, Makhlouf GM. Gastrin secretion induced by distention is mediated by gastric cholinergic and vasoactive intestinal peptide neurons in rats. Gastroenterology 1993; 104:834.
- Schubert ML, Makhlouf GM. Neural, hormonal, and paracrine regulation of gastrin and acid secretion. Yale J Biol Med 1992; 65:553.
- Sugano K, Park J, Soll AH, Yamada T. Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture. J Clin Invest 1987; 79:935.
- Campos RV, Buchan AM, Meloche RM, et al. Gastrin secretion from human antral G cells in culture. Gastroenterology 1990; 99:36.
- Seensalu R, Avedian D, Barbuti R, et al. Bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by protein kinase C, and is enhanced by disruption of rho/cytoskeletal pathways. J Clin Invest 1997; 100:1037.
- Lindström E, Björkqvist M, Boketoft A, et al. Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. Regul Pept 1997; 71:73.
- Zeng N, Athmann C, Kang T, et al. PACAP type I receptor activation regulates ECL cells and gastric acid secretion. J Clin Invest 1999; 104:1383.
- Kinoshita Y, Nakata H, Kishi K, et al. Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells. Gastroenterology 1998; 115:93.
- Soll AH, Toomey M, Culp D, et al. Modulation of histamine release from canine fundic mucosal mast cells. Am J Physiol 1988; 254:G40.
- Chuang CN, Tanner M, Chen MC, et al. Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells. Am J Physiol 1992; 263:G460.
- Black JW, Duncan WA, Durant CJ, et al. Definition and antagonism of histamine H 2 -receptors. Nature 1972; 236:385.
- Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach. Gastroenterology 1997; 113:1545.
- Saffouri B, DuVal JW, Arimura A, Makhlouf GM. Effects of vasoactive intestinal peptide and secretin on gastrin and somatostatin secretion in the perfused rat stomach. Gastroenterology 1984; 86:839.
- Shulkes A, Read M. Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. Endocrinology 1991; 129:2329.
- Martinez V, Curi AP, Torkian B, et al. High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice. Gastroenterology 1998; 114:1125.
- Schubert ML. The effect of vasoactive intestinal polypeptide on gastric acid secretion is predominantly mediated by somatostatin. Gastroenterology 1991; 100:1195.
- Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2005; 21:636.
- Choquet A, Magous R, Bali JP. Gastric mucosal endogenous prostanoids are involved in the cellular regulation of acid secretion from isolated parietal cells. J Pharmacol Exp Ther 1993; 266:1306.
- Lindström E, Håkanson R. Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells. Br J Pharmacol 1998; 124:1307.
- Schepp W, Chan CB, Giraud AS, et al. Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture. Am J Physiol 1994; 266:G194.
- Chen MC, Sanders MJ, Amirian DA, et al. Prostaglandin E2 production by dispersed canine fundic mucosal cells. Contribution of macrophages and endothelial cells as major sources. J Clin Invest 1989; 84:1536.
- Guglietta A, Lesch CA, Romano M, et al. Effect of transforming growth factor-alpha on gastric acid secretion in rats and monkeys. Dig Dis Sci 1994; 39:177.
- Goldenring JR, Tsunoda Y, Stoch SA, et al. Transforming growth factor-alpha (TGF alpha) inhibition of parietal cell secretion: structural requirements for activity. Regul Pept 1993; 43:37.
- Yang H. Central and peripheral regulation of gastric acid secretion by peptide YY. Peptides 2002; 23:349.
- Samloff IM. Peptic ulcer: the many proteinases of aggression. Gastroenterology 1989; 96:586.
- Allen A, Pearson JP, Blackburn A, et al. Pepsins and the mucus barrier in peptic ulcer disease. Scand J Gastroenterol Suppl 1988; 146:50.
- Samloff IM. Pepsins, peptic activity, and peptic inhibitors. J Clin Gastroenterol 1981; 3:91.
- Hersey SJ. Pepsin secretion. In: Physiology of the Gastrointestinal Tract, Johnson LR, Christensen J, Jackson MJ, et al (Eds), Raven Press, 1994. p.1227.
- Sandvik AK, Brenna E, Waldum HL. Review article: the pharmacological inhibition of gastric acid secretion--tolerance and rebound. Aliment Pharmacol Ther 1997; 11:1013.
- Wilder-Smith CH, Ernst T, Gennoni M, et al. Tolerance to oral H2-receptor antagonists. Dig Dis Sci 1990; 35:976.
- Prichard PJ, Jones DB, Yeomans ND, et al. The effectiveness of ranitidine in reducing gastric acid-secretion decreases with continued therapy. Br J Clin Pharmacol 1986; 22:663.
- Fullarton GM, McLauchlan G, Macdonald A, et al. Rebound nocturnal hypersecretion after four weeks treatment with an H2 receptor antagonist. Gut 1989; 30:449.
- Prewett EJ, Hudson M, Nwokolo CU, et al. Nocturnal intragastric acidity during and after a period of dosing with either ranitidine or omeprazole. Gastroenterology 1991; 100:873.
- el-Omar E, Banerjee S, Wirz A, et al. Marked rebound acid hypersecretion after treatment with ranitidine. Am J Gastroenterol 1996; 91:355.
- Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999; 116:239.
- Waldum HL, Arnestad JS, Brenna E, et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996; 39:649.
- Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137:80.
- Kohn A, Annibale B, Prantera C, et al. Reversible sustained increase of gastrin and gastric acid secretion in a subgroup of duodenal ulcer patients on long-term treatment with H2 antagonists. J Clin Gastroenterol 1991; 13:284.
- Gledhill T, Buck M, Hunt RH. Effect of no treatment, cimetidine 1 g/day, cimetidine 2 g/day and cimetidine combined with atropine on nocturnal gastric secretion in cimetidine non-responders. Gut 1984; 25:1211.
- el-Omar EM, Penman ID, Ardill JE, et al. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995; 109:681.
- el-Omar E, Penman I, Dorrian CA, et al. Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer. Gut 1993; 34:1060.
- Peterson WL, Barnett CC, Evans DJ Jr, et al. Acid secretion and serum gastrin in normal subjects and patients with duodenal ulcer: the role of Helicobacter pylori. Am J Gastroenterol 1993; 88:2038.
- Calam J. The somatostatin-gastrin link of Helicobacter pylori infection. Ann Med 1995; 27:569.
- PHASES OF ACID SECRETION
- SECRETION OF ACID AND PEPSIN
- The parietal cell
- - Gastrin receptors
- - Regulation of gastrin secretion
- Neural control
- Other secretory regulators
- ACID SECRETORY REGULATION IN HUMANS
- Tolerance and acid rebound
- - Mechanisms of rebound
- Effect of Helicobacter pylori infection
- GASTRIC ACID HYPERSECRETION