Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.
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.
Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan. JDK00101@nifty.ne.jp
S
S
Onodera
M
M
Shibata
M
M
Tanaka
N
N
Inaba
Y
Y
Arai
M
M
Aoyama
B
B
Lee
T
T
Yamaura
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000081:Acetamides / Q000627:therapeutic use*; D000641:Ammonia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D002211:Capsaicin / Q000494:pharmacology; D002492:Central Nervous System Depressants; D000431:Ethanol; D005753:Gastric Mucosa / Q000473:pathology; D006635:Histamine H2 Antagonists / Q000627:therapeutic use*; D007213:Indomethacin; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D000081:Acetamides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D002492:Central Nervous System Depressants; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D000431:Ethanol; C076948:lafutidine; D000641:Ammonia; D015064:16,16-Dimethylprostaglandin E2; D002211:Capsaicin; D007213:Indomethacin