Histamine H-3-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat

1 (R)-alpha-methylhistamine, a selective agonist of hist amine H-3 receptor s, is capable of protecting the gastric mucosa against differently acting d amaging agents. The objective of the present study was to determine whether H-3 receptors mediate its protective action in the rat. 2 Gastric mucosal lesions were induced intragastrically (i.g.) by 0.6 N HCl , 1 mi rat(-1). (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., substantiall y reduced the severity of macroscopically and histologically assessed damag e caused by concentrated acid. Prior treatment with highly selective H-3- r eceptor antagonists, ciproxifan (0.3, 1 and 3 mg kg(-1) i.g.) and clobenpro pit (3, 10 and 30 mg kg(-1) i.g.), dose-dependently inhibited the protectio n exerted by (R)-alpha-methylhistamine up to a complete reversal. When give n alone at high doses, both antagonists tended to worsen the HCl-induced hi stologic damage. 3 During basal conditions, (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., c aused a significant increase in titratable acidity of the gastric juice. Pr ior treatment with ciproxifan (3 mg kg(-1) i.g.) and clobenpropit (30 mg kg (-1) i.g.) did not alter the secretory response to (R)-alpha-methylhistamin e. Clobenpropit alone, but not ciproxifan, increased the volume of gastric juice, and both compounds alone had no effect on titratable acid. 4 Present findings support evidence that H-3 receptors an actively involved in the maintenance of gastric mucosal integrity, with no apparent role in the regulation of basal gastric acid secretion.