pancreastatin and alpha-fluoromethylhistidine

Rat stomach ECL cells are rich in histamine and chromogranin A-derived peptides, such as pancreastatin. Gastrin causes the parietal cells to secrete acid by flooding them with histamine from the ECL cells. In the past, gastric histamine release has been studied using anaesthetized, surgically manipulated animals or isolated gastric mucosa, glands or ECL cells. We monitored gastric histamine mobilization in intact conscious rats by subjecting them to gastric submucosal microdialysis. A microdialysis probe was implanted into the submucosa of the acid-producing part of the stomach (day 1). The rats had access to food and water or were deprived of food (48 h), starting on day 2 after implantation of the probe. On day 4, the rats received food or gastrin (intravenous infusion), and sampling of microdialysate commenced. Samples (flow rate 1.2 microl min(-1)) were collected every 20 or 60 min, and the histamine and pancreastatin concentrations were determined. The serum gastrin concentration was determined in tail vein blood. Exogenous gastrin (4-h infusion) raised microdialysate histamine and pancreastatin dose-dependently. This effect was prevented by gastrin receptor blockade (YM022). Depletion of ECL-cell histamine by alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, suppressed the gastrin-evoked release of histamine but not that of pancreastatin. Fasting lowered serum gastrin and microdialysate histamine by 50%, while refeeding raised serum gastrin and microdialysate histamine and pancreastatin 3-fold. We conclude that histamine mobilized by gastrin and food intake derives from ECL cells because: 1) Histamine and pancreastatin were released concomitantly, 2) histamine mobilization following gastrin or food intake was prevented by gastrin receptor blockade, and 3) mobilization of histamine (but not pancreastatin) was abolished by alpha-fluoromethylhistidine. Hence, gastric submucosal microdialysis allows us to monitor the mobilization of ECL-cell histamine in intact conscious rats under various experimental conditions not previously accessible to study. While gastrin receptor blockade lowered post-prandial release of ECL-cell histamine by about 80%, unilateral vagotomy reduced post-prandial mobilization of ECL-cell histamine by about 50%. Hence, both gastrin and vagal excitation contribute to the post-prandial release of ECL-cell histamine.

Topics: Animals; Benzodiazepines; Chromogranin A; Enterochromaffin-like Cells; Enzyme Inhibitors; Fluorescent Antibody Technique; Food; Gastric Mucosa; Gastrins; Histamine; Hormone Antagonists; Male; Methylhistidines; Microdialysis; Pancreatic Hormones; Rats; Rats, Sprague-Dawley; Time Factors; Vagotomy, Proximal Gastric

The ECL cells in the rat stomach release pancreastatin and histamine in response to gastrin stimulation. The present study compares the release of pancreastatin and histamine from the ECL cells and the secretion of acid from the parietal cells in response to gastrin, and examines how a markedly reduced histamine content in the ECL cells will affect the gastrin-evoked release of pancreastatin and the secretion of gastrin acid. Totally isolated, vascularly perfused stomachs were prepared from fasted rats. Some of the rats had been pre-treated for 24 h with (alpha-fluoromethylhistidine (alpha-FMH), resulting in 80% depletion of oxyntic mucosal histamine (mainly ECL-cell histamine). The stomachs were perfused with rat gastrin-17, alpha-FMH, isobutyl methylxanthine (IBMX), or vehicle in various combinations for 8 h. The venous outflow was collected (30-min samples) for determination of histamine and pancreastatin-like immunoreactivity (LI) and the gastric luminal outflow was collected for determination of H+. Gastrin raised the outflow of pancreastatin-LI and histamine but did not raise the acid output unless IBMX was added. The outflow of pancreastatin-LI and histamine was greater after gastrin + IBMX (at least during the first 4-h period) than after gastrin alone. alpha-FMH reduced gastrin-evoked histamine outflow but did not affect gastrin-evoked pancreastatin-LI outflow. Also the acid output in response to gastrin + IBMX was much reduced by alpha-FMH. In conclusion, increased levels of intracellular cAMP enhanced the gastrin-evoked release of pancreastatin-LI and histamine from the ECL cells and made it possible for histamine, released from the ECL cells, to cause acid secretion from the parietal cells. ECL-cell histamine depletion reduced the gastrin-evoked acid secretion; it did not affect the gastrin-evoked release of pancreastatin-LI.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Chromogranin A; Gastric Acid; Gastrins; Histamine Release; Histidine Decarboxylase; Male; Methylhistidines; Pancreatic Hormones; Parietal Cells, Gastric; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley