Ketotifen, a histamine H1-receptor antagonist and mast cell stabilizer, significantly pro tected the rat gastric mucosa against lesions induced by necrotizing agents, histamine or compound 48/80. The agent significantly inhibited the basal gastric acid secretion, but had little or no effect on the histamine-stimulated secretion. The mucosal protective effect was observed even at a dose that had lit tle or no effect on gastric acid secretion, suggesting that ketotifen exhibits so-called cytoprotective activ ity.
Keywords:Ketotifen, Acute gastric lesions, CytoprotectionKetotifen is an antianaphylactic drug used for the prevention of asthma or various allergic diseases, most probably due to its histamine H,-receptor antagonistic and mast cell stabilizing activities (1-3). Interestingly, Karmeli et al. (4) recently found that it could prevent the development of ethanol-induced gastric lesions in rats. We thus examined whether or not ketotifen pro tects the gastric mucosa against acute gastric lesions in duced by several necrotizing agents including ethanol, histamine or compound 48/80. The effects of ketotifen on gastric basal and histamine-stimulated acid secretion were also studied to elucidate the mechanism of action of the drug.Male Sprague-Dawley rats (240-260g) were de prived of food for 24 hr before the induction of gastric lesions, except for in the case of compound 48/80-in duced lesions (no fasting before or during the experi ment) and gastric secretory studies. Tap water was given freely during fasting, but withheld during the last 2 hr. Necrotizing agent-induced gastric lesions were produced by administering p.o. 1 ml/200 g body wt. of either 100% ethanol (v/v) (5), 60% ethanol (v/v) in 150 mM HCl (HCl -ethanol) (6), or aspirin (150 mg/kg, Nacalai Tesque) in 150 mM HCl (HCl -aspirin) (7). The animals were killed 1 hr later, and their stomachs were removed and then inflated with 8 ml of 2% formalin for 10 min. Subsequently, the length (mm) of each lesion in the glandular portion was determined under a dissecting microscope (X 10) and summed per stomach. Ketotifen (Sandoz), dissolved in saline, or the vehicle alone was administered p.o. 0.5 hr before the administration of each necrotizing agent in a volume of 1 ml/animal. Histamine-induced gastric lesions were produced as pre viously described (8). Briefly, the abdomen was incised under ether anesthesia, and both the gastric artery and vein were ligated. The gastro-epiploic artery and vein remained intact. Immediately after the ligation of blood vessels, the pylorus were ligated. After the abdomen had been closed, histamine • 2HC1, dissolved in saline, was administered s.c. at 40 mg/kg (as the salt). The animals were killed 3 hr later. The area (mm2) of each lesion in the glandular portion was determined and summed per stomach. Ketotifen or the vehicle alone was administered p.o. 0.5 hr before the ligation of ves sels. Compound 48/80 (Sigma), dissolved in saline, was administered i.p. at 0.75 mg/kg in a volume of 0.4 ml/rat once daily (9:30 AM) fo...