Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats.
FRG-8813 ((+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2- pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions 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 gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection. Furthermore, prior administration of tetrodotoxin, the calcitonin gene-related peptide (CGRP) antagonist hCGRP or NG-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813.
Onodera
S
S
Pharmaceuticals Research Laboratories, Fujirebio, Inc., Tokyo, Japan.
Shibata
M
M
Tanaka
M
M
Inaba
N
N
Yamaura
T
T
Ohnishi
H
H
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000473:pathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control
D000081:Acetamides; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D009853:Omeprazole