Effects of KB-5492, a new anti-ulcer agent, on ethanol- and acidified aspirin-induced gastric mucosal damage in vivo and in vitro

The effects of KB-5492, a new anti-ulcer agent with selective affinity for the Sigma Receptor, on ethanol- and acidified aspirin-induced gastric mucosal damage were studied in vivo and in vitro and compared with those of 16,16-dimethyl prostaglandin E2 (dmPGE2). In the in vivo study, KB-5492 (200 mg/kg, p.o.) as well as dmPGE2 (0.01 mg/kg, p.o.) significantly prevented the acute macroscopic lesions in rat gastric mucosa induced by oral administration of either absolute ethanol or 80 mM aspirin in 150 mM HCl. The LIGHT microscopic examination revealed that KB-5492 almost completely prevented the deep mucosal lesions induced by these necrotizing agents. KB-5492 also prevented the exfoliation of surface epithelial cells, but its preventive effect was incomplete. In the in vitro study, gastric epithelial cells, isolated from the rat stomach, were cultured for 6 days until they reached confluency. Subsequently, 51Cr was incorporated into the cells. Both 10 mM aspirin (at pH 5.0) and 12.5% ethanol (at pH 7.4) induced damage to the cells and markedly increased 51Cr release from the cells. KB-5492 at 0.3 and 1 mM and dmPGE2 at 0.3 and 1 microM significantly, but not completely, prevented both the aspirin- and ethanol-induced increases in 51Cr release from the cells. These findings indicate that KB-5492 as well as dmPGE2 may exert a direct but limited protective effect on the surface epithelial cells in vivo.