GASTROPROTECTIVE ACTIVITY OF FRG-8813, A NOVEL HISTAMINE H-2-RECEPTORANTAGONIST, IN RATS

FRG-8813 ((+/-)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyr idyl] oxy-(Z)-2-butenyl]acetamide) is a novel histamine H-2-receptor a ntagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastropr otective action. The oral ED(50) values for inhibition of mucosal lesi ons against 1% NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl- and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11. 1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotect ive despite pretreatment with omeprazole, suggesting that the protecti ve effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprot ective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatmen t with indomethacin or N-ethyl-maleimide did not affect the gastroprot ection of FRG-8813, chemical deafferentation induced by capsaicin abol ished the gastroprotection. Furthermore, prior administration of tetro dotoxin, the calcitonin generated peptide (CGRP) antagonist hCGRP(8-37 ) or N-G-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated admin istration of FRG-8813 neither enhanced the susceptibility of the mucos a to damage nor affected the gastroprotective action of short-term tre atment. In conclusion, these results suggest that FRG-8813 has gastrop rotective activity independently of acid antisecretory activity and th at capsaicin-sensitive nerves may be partially or fully involved in th e gastroprotective mechanisms of FRG-8813.