Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome

Abstract

One of the hallmarks of the mammalian stomach is its ability to secrete large quantities of concentrated (0.16 mol/L) hydrochloric acid (HCl).1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Although it is generally assumed that gastric acid and the proteolytic enzyme pepsin are required to initiate digestion, achlorhydric individuals generally do not develop malabsorption unless small bowel bacterial overgrowth is present. It is thus likely that the ability of the stomach to secrete acid evolved primarily from a need to sustain a sterile intragastric milieu. Organisms that possessed the capacity to kill ingested bacteria and other microbes were able to avoid the development of enteric colonization, and thereby ensure both efficient absorption of nutrients and prevention of systemic infections.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar Nevertheless, when present, gastric acid does play a significant role in protein hydrolysis and other aspects of the digestive process, and under various conditions, acid may play an etiologic role in producing various forms of discomfort and inciting esophageal and gastroduodenal mucosal injury. The normal human stomach contains approximately 1 billion parietal cells that secrete hydrogen ions into the gastric lumen in response to various physiological stimuli. The generation of H+ ions is mediated by 3 pathways: neurocrine, paracrine, and endocrine (Figure 1). The principal neurocrine transmitter is acetylcholine, which is released by vagal postganglionic neurons and appears to stimulate H+ ion generation directly via a parietal cell muscarinic M3 receptor. Histamine is the primary paracrine transmitter that binds to H2-specific receptors on parietal cells. Adenylate cyclase is then activated, leading to an increase in adenosine 3′,5′-cyclic monophosphate (cAMP) levels and subsequent generation of H+ ions. The secretion of gastrin from antral G cells comprises the endocrine pathway and stimulates H+ ion generation both directly and indirectly, the latter by stimulating histamine secretion from enterochromaffin-like (ECL) cells of the corpus and fundus. Interactions among neurocrine, paracrine, and endocrine pathways are coordinated to promote or inhibit H+ ion generation. Histamine appears to represent the dominant route, because gastrin stimulates acid secretion principally by promoting histamine release from ECL cells.2Waldum HL Sandvik AK. The enterochromaffin-like (ECL) cells.Acta Oncol. 1993; 32: 141-147Crossref PubMed Google Scholar, 3Prinz C Scott DR Hurwitz D Helander HF Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary culture.Am J Physiol. 1994; 267: G663-G675PubMed Google Scholar Thus, ECL cells are often referred to as "controller" cells in the process of gastric acid secretion. A negative feedback loop governs both gastrin release and the return of acid secretion to basal level.1Wolfe MM Soll AH. The physiology of gastric acid secretion.N Engl J Med. 1988; 319: 1707-1715Crossref PubMed Google Scholar, 4Van Dam J Wolfe MM. Gastrin and other peptide hormones. In Pharmacology of peptic ulcer disease.in: eds Collen MJ Benjamin SB Springer-Verlag,, Berlin1991: 55-58Google Scholar, 5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 6Schubert ML Saffouri B Makhlouf GM. Identical patterns of somatostatin secretion from isolated antrum and fundus of rat stomach.Am J Physiol. 1988; 254: G20-G24PubMed Google Scholar This autoregulatory mechanism prevents postprandial acid hypersecretion. After ingestion of a meal, gastrin release stimulates secretion of gastric acid. The intraluminal pH begins to decrease, which stimulates release of somatostatin from antral D cells, possibly through the activation of calcitonin gene-related peptide (CGRP) neurons.5Brand SJ Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.J Clin Invest. 1988; 82: 1059-1066Crossref PubMed Google Scholar, 7Ren J Dunn ST Tang Y Wang Y Gao J Brewer K Harty RF. Effects of calcitonin gene-related peptide on somatostatin and gastrin gene expression in rat antrum.Regul Pep. 1998; 73: 75-82Crossref PubMed Scopus (9) Google Scholar Somatostatin then appears to act via a paracrine mechanism to inhibit further release of gastrin from G cells.8Wolfe MM Jain DK Reel GM McGuigan JE. Effects of carbachol on gastrin and somatostatin release in rat antral tissue culture.Gastroenterology. 1984; 87: 86-93Abstract Full Text PDF PubMed Google Scholar Somatostatin produced by D cells in the gastric corpus and fundus may also directly inhibit acid secretion from parietal cells and may suppress histamine release from ECL cells (Figure 1).6