Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.

Abstract

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.