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We found indomethacin aggravates healed gastric ulcers (ulcer relapse) in rats. In the present study, we examined the effects of human basic fibroblast growth factor (bFGF) mutein CS23 (TGP-580) and histamine H2-receptor antagonists (H2-RAs) on ulcer relapse in this model. In male SD rats, gastric ulcers were induced in the antrum by injection of acetic acid. Indomethacin (1 mg/kg/day) given s.c. for 2 weeks starting 4 weeks after the operation aggravated the healed ulcer; the areas with and without indomethacin were 4.8 +/- 1.4 and 0.4 +/- 0.3 mm2, respectively. Drugs were given orally once daily for 4 weeks starting 2 days after the operation or for the 2-week indomethacin administration period. Treatment with ranitidine (100 mg/kg), cimetidine (100 mg/kg) and TGP-580 (0.1 mg/kg) for 4 weeks accelerated the healing. The aggravation by indomethacin was significantly inhibited by pretreatment with TGP-580 and mildly inhibited by cimetidine but not ranitidine. When the drugs were co-administered with indomethacin for 2 weeks, the aggravation was significantly prevented by ranitidine and mildly inhibited by cimetidine and TGP-580. Both TGP-580 and H2-RAs can prevent the ulcer relapse induced by indomethacin but via different modes of action: TGP-580 inhibits relapse mainly by acting on the process of healing, while H2-RAs act mainly on the process of aggravation.

Indomethacin produces gastric corpus erosions in the fasted rat and small intestinal ulcers in the conventionally fed rat. We found that in rats fed chow pellets for 1 h after a 24-h fast, indomethacin given within 2 h after refeeding produced lesions in the gastric antrum, primarily along the lesser curvature, and also in the small intestine. The antral lesions reached a maximum size in 6–10 h, penetrated the muscularis mucosae within 3 days, and did not diminish for at least 7 days. The formation of the antral ulcer was prevented by prostaglandins or adrenalectomy, but was not affected by cimetidine, atropine, and/or vagotomy. In contrast, the gastric corpus erosions produced by indomethacin in the fasted rat were prevented by antisecretory drugs or vagotomy, and were aggravated by adrenalectomy. It is concluded that: (a) the chronic antral ulcers produced by indomethacin in the refed rat mimic human gastric ulcer with regard to location and histology; and (b) the mechanism of antral ulcer formation is different from corpus erosion formation, in that it was resistant to antisecretory drugs and vagotomy and was prevented by adrenalectomy. This experimental ulcer model could prove useful for studies of the etiology and therapy of gastric ulcer disease.

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED 50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25–200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E 2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H + and Na + caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E 2 , exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E 2 . The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog proximal duodenal mucosa mounted in an Ussing chamber. Spizofurone (10−4-10−3 M) as well as prostaglandin E2 (PGE2, 10−8-10−5 M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.