CCK 2 receptor antagonists: pharmacological tools to study the gastrin–ECL cell-parietal cell axis

Abstract

Gastrin-recognizing CCK 2 receptors are expressed in parietal cells and in so-called ECL cells in the acid-producing part of the stomach. ECL cells are endocrine/paracrine cells that produce and store histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. The ECL cells are the principal cellular transducer of the gastrin-acid signal. Activation of the CCK 2 receptor results in mobilization of histamine (and pancreastatin) from the ECL cells with consequent activation of the parietal cell histamine H 2 receptor. Thus, release of ECL-cell histamine is a key event in the process of gastrin-stimulated acid secretion. The oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration are useful markers for the activity of the gastrin-ECL cell axis. Powerful and selective CCK 2 receptor antagonits have been developed from a series of benzodiazepine compounds. These agents are useful tools to study how gastrin controls the ECL cells. Conversely, the close control of ECL cells by gastrin makes the gastrin-ECL cell axis well suited for evaluating the antagonistic potential of CCK 2 receptor antagonists with the ECL-cell HDC activity as a notably sensitive and reliable parameter. The CCK 2 receptor antagonists YF476, YM022, RP73870, JB93182 and AG041R were found to cause prompt inhibition of ECL-cell histamine and pancreastatin secretion and synthesis. The circulating pancreastatin concentration is raised, was lowered when the action of gastrin on the ECL cells was blocked by the CCK 2 receptor antagonists. These effects were associated with inhition of gastrin-stimulated acid secretion. In addition, sustained receptor blockade was manifested in permanently decreased oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and CGA mRNA concentrations. CCK 2 receptor blockade also induced hypergastrinemia, which probably reflects the impaired gastric acid secretion (no acid feedback inhibition of gastrin release). Upon withdrawal of the CCK 2 receptor antagonists, their effects on the ECL cells were readily reversible. In conclusion, gastrin mobilizes histamine from the ECL cells, thereby provoking the parietal cells to secrete acid. While CCK 2 receptor blockade prevents gastrin from evoking acid secretion, it is without effect on basal and vagally stimulated acid secretion. We conclude that specific and potent CCK 2 receptor antagonists represent powerful tools to explore the functional significance of the ECL cells.