Ligands for histamine H(3) receptors modulate cell proliferation and migration in rat oxyntic mucosa.

1. (R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, promotes mucus secretion and increases the number and volume of mucus-secreting cells. The hypothesis that the increased number of mucous cells could reside in an alteration of homeostasis in the gastric epithelium was investigated. 2. (R)-alpha-methylhistamine was administered to rats 1 h (10-100 mg kg(-1) by intragastric and by intraperitoneal route) and 24 h (100 mg kg(-1) by intragastric route) prior to killing. The (S)-isomer of alpha-methylhistamine (55.4 mg kg(-1)), 100 times less potent than the (R)-isomer at H(3) receptors, and the H(3)-receptor agonist FUB 407 (9.14-91.35 mg kg(-1)) were intragrastically administered 1 h prior to killing. The H(1)-receptor antagonist mepyramine (30 mg kg(-1)), the H(2)-receptor antagonist famotidine (3 mg kg(-1)), and the H(3)-receptor antagonists ciproxifan (3 mg kg(-1)) and clobenpropit (30 mg kg(-1)) were intragastrically administered 30 min before (R)-alpha-methylhistamine. Gastric tissue was processed for histology and immunohistochemistry. 3. Within 1 h, (R)-alpha-methylhistamine and FUB 407 dose-dependently increased the number of BrdU-positive cells and of apoptotic cells. (S)-alpha-methylhistamine failed to modify proliferation and apoptosis. The increase in proliferation by (R)-alpha-methylhistamine was reversed by ciproxifan and clobenpropit, but not by mepyramine and famotidine. 4. (R)-alpha-methylhistamine accelerated the differentiation towards pit cells and their outward migration 24 h after its administration. These effects were counteracted by ciproxifan. The apoptosis rate was unaffected at 24 h. 5. These findings reveal a primary role of histamine H(3)-receptor ligands in modulating cell proliferation and migration in rat fundic mucosa.