EVIDENCE FOR A REGULATORY ROLE FOR HISTAMINE IN GASTRIC ENTEROCHROMAFFIN-LIKE CELL-PROLIFERATION INDUCED BY HYPERGASTRINEMIA

Background/Aims: Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-l ike (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective H-1-histamine antagonist, terfenadine, on ga stric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation. Methods: The rodent mastomys received th e H-2-antagonist loxtidine (2 g/l drinking water) alone or in combinat ion with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels an d tissue histamine content were assayed by radioimmunoassays, and tiss ue chromogranin levels determined (Western blot analysis). In vivo cel l proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day , 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cel ls quantitated. To evaluate the direct action on ECL cells we then stu died the effect of terfenadine on histamine secretion and DNA synthesi s (BrdU uptake) in an isolated preparation (similar to 90% pure) of EC L cells. Results: Loxtidine increased serum gastrin levels, mucosal th ickness, tissue chromogranin levels, tissue histamine content, BrdU in corporation, ECL cell number, and proliferating ECL cells (all paramet ers p < 0.05). Terfenadine alone, irrespective of dosage, had no signi ficant effect. The high dose in combination with loxtidine significant ly inhibited the increase in tissue chromogranin levels, tissue histam ine content, ECL cell number and proliferating ECL cells (p < 0.05), b ut did not alter other parameters, compared to loxtidine alone. The lo w dose did not alter the loxtidine-induced changes. in pure isolated E CL cells, terfenadine did not alter histamine secretion either alone o r in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC50 10(-10) M). Conclusions: Terfenadine s pecifically inhibited the effect of loxtidine-induced ECL cell prolife ration in vivo and significantly inhibited ECL cell DNA synthesis in v itro. We postulate that histamine, through an H-1 receptor, positively modulates gastric ECL cell proliferation.