The regulation of acid secretion has been divided into cephalic and peripheral (gastric and intestinal) phases (1). The cephalic phase of gastric acid secretion originates in the central nervous system and impacts the hypothalamus; signals travel via the vagus nerve to the myenteric plexuses of the gastric mucosa. In the succeeding neural network, a variety of secondary neurons signal the gastric fundic and antral epithelia to influence gastric acid secretion by either primary or secondary action, namely, direct effects on parietal cells or gastric epithelial endocrine cells. The peripheral phase of acid secretion regulation involves local signaling within a variety of endocrine cells, transmitting regulatory information to the secretory cells of the gastric mucosa; the peripheral phase is more limited than the cephalic phase in terms of the possible mediators involved (2). Studies of isolated gastric endocrine cells have proved useful in defining the interactions of various signals in the regulation of gastric acid secretion, but such studies must be placed in context when considering their physiological implications. The isolated rabbit gastric gland is a more integrated model than that provided by isolated cells.With the isolation and purification (to between 85% and 95%) of functional enterochromaffin-like (ECL) cells from the rat gastric mucosa, a variety of receptors has been defined on this cell type. This has been done by measurement of calcium signals under superfusion conditions using video microscopy, and by histamine or pancreostatin release by radioimmunoassay under static conditions (3-5). When histamine release is measured in a static system, cross-talk is a problem. Superfusion of isolated, enriched ECL cells while measuring responses of intracellular calcium [Ca 2+ ] i eliminates cross-talk between possible contaminating gastric endocrine cells. Nevertheless, few (if any) inconsistencies have been found between the results of video-imaging and release measurements in this particular preparation. In this preparation, there are less than 2% D cells, and the addition of somatostatin antibody has not affected either calcium signaling or histamine release in response to a variety of agonists (3, 4).Histamine, released from ECL cells, is the most important direct stimulant of acid secretion, as shown by the broad efficacy of histamine-2 receptor antagonists as full inhibitors of gastrin and partial inhibitors of vagally stimulated acid secretion (6). The involvement of ECL cells in mediation of the cephalic (neural) phase of gastric acid secretion has been less clear. The atropine sensitivity of cephalic stimulation of acid secretion pointed

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SUMMARY BackgroundTo date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years.

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The ligands interacting with enterochromaffin-like (ECL) and parietal cells and the signaling interactions between these cells were investigated in rabbit gastric glands using confocal microscopy. Intracellular calcium concentration ([Ca(2+)](i)) changes were used to monitor cellular responses. Histamine and carbachol increased [Ca(2+)](i) in parietal cells. Gastrin (1 nM) increased [Ca(2+)](i) in ECL cells and adjacent parietal cells. Only the increase of [Ca(2+)](i) in parietal cells was inhibited by H(2) receptor antagonists (H(2)RA). Gastrin (10 nM) evoked an H(2)RA-insensitive [Ca(2+)](i) increase in parietal cells. Carbachol produced large H(2)RA- and somatostatin-insensitive signals in parietal cells. Pituitary adenylate cyclase-activating peptide (PACAP, 100 nM) elevated [Ca(2+)](i) in ECL cells and adjacent parietal cells. H(2)RAs abolished the PACAP-stimulated [Ca(2+)](i) increase in adjacent parietal cells. Somatostatin did not inhibit the increase of [Ca(2+)](i) in parietal cells stimulated with histamine, high gastrin concentrations, or carbachol but abolished ECL cell calcium responses to gastrin or PACAP. Hence, rabbit parietal cells express histaminergic, muscarinic, and CCK-B receptors coupled to calcium signaling but insensitive to somatostatin, whereas rabbit and rat ECL cells express PACAP and CCK-B calcium coupled receptors sensitive to somatostatin.