Gastric secretion.
OBJECTIVE
Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, and vitamin B12. It also protects against bacterial overgrowth and enteric infection, including prion disease. When homeostatic mechanisms malfunction, the volume and concentration of acid may overwhelm mucosal defense mechanisms, leading to duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. This article reviews recent knowledge contributing to understanding of the regulation of gastric acid secretion at the central, peripheral, and intracellular levels.


RESULTS
The vagus nerve contains afferent fibers that transmit sensory information from the stomach to the nucleus of the solitary tract. Input from the nucleus of the solitary tract is relayed to vagal efferent neurons that originate from two brain stem nuclei: the nucleus ambiguus and the dorsal motor nucleus of the vagus. The latter is also influenced by thyrotropin-releasing hormone neurons that act centrally to stimulate acid secretion. The main peripheral stimulants of acid secretion are the hormone gastrin and the paracrine amine histamine. Gastrin stimulates acid secretion directly and, more importantly, indirectly by releasing histamine from fundic enterochromaffin-like cells. Gastrin also exerts trophic effects on various tissues, including the gastric and intestinal mucosa. The main inhibitor of acid secretion is somatostatin. Somatostatin, acting via ssTR2 receptors, exerts a tonic paracrine inhibitory influence on the secretion of gastrin, histamine, and acid secretion. Calcitonin gene-related peptide, adrenomedullin, amylin, atrial natriuretic peptide, and pituitary adenylate cyclase-activating polypeptide all stimulate somatostatin secretion and thus inhibit acid secretion. HK-ATPase, the proton pump of the parietal cell, is stored within cytoplasmic tubulovesicles during the resting state, but during stimulation, it is shuttled to the canalicular membrane by a poorly understood mechanism that probably involves soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins. The proton pump inhibitor, pantoprazole, is unique in that it binds cysteine 822, located deep within the membrane domain of the alpha-subunit. The difficulty that reducing agents, such as glutathione, have in reaching cysteine 822 may be responsible for the longer half-time for acid recovery observed with pantoprazole. Hypergastrinemia, induced by proton pump inhibitors, enhances expression of cyclooxygenase-2 and hence prostaglandins within parietal cells, a feedback pathway that may protect the stomach against acid-induced damage.


CONCLUSIONS
In the past year, significant advances have been made in understanding of the regulation of gastric acid secretion. Ultimately, these advances should lead to improved therapies to prevent and treat acid-related disorders. Gastric acid secretion must be precisely controlled at a variety of levels to prevent disease caused by hyperchlorhydria and hypochlorhydria. The mechanisms include neural (central and peripheral), hormonal, paracrine, and intracellular pathways that operate in concert to switch acid secretion on during ingestion of a meal and off during the interdigestive period. A better understanding of the physiology of acid secretion in health and disease should eventually lead to improved therapies to prevent and treat acid-related disorders.
Schubert
Mitchell L
ML
Department of Medicine, Division of Gastroenterology, Medical College of Virginia and McGuire VAMC, Richmond, Virginia, USA. Mitchell.Schubert@med.va.gov