Roles of prostaglandins, nitric oxide and the capsaicin-sensitive sensory nerves in gastroprotection produced by ecabet sodium.
We determined the mechanism of the gastroprotective effects of ecabet sodium (ecabet), a new antiulcer drug. Ecabet (12.5-100 mg/kg p.o.) dose-dependently protected gastric mucosa from ethanol-induced injuries in rats, as determined with the use of both macroscopic and microscopic analyses. Both inhibition of prostaglandin (PG) formation by indomethacin (5 mg/kg s.c.) and functional ablation of capsaicin-sensitive sensory nerves (CPSN) by systemic administration of capsaicin (125 mg/kg s.c.) partly reduced the gastroprotective activity of ecabet (25 and 100 mg/kg p.o.). Ecabet increased rat gastric mucosal PGE2 formation. The treatment with indomethacin but not capsaicin decreased the ecabet-induced increase in PGE2 formation. Inhibition of nitric oxide (NO) formation by NG-monomethyl-L-arginine (L-NMMA; 100 mg/kg i.v.) partly reversed the gastroprotective effect of ecabet and completely reversed that of capsaicin at an oral dose of 0.5 mg/kg, respectively. The effect of L-NMMA was abolished by pretreatment with L-arginine (100 mg/kg i.v.) but not with D-arginine (100 mg/kg i.v.). The gastroprotective activity of ecabet (25 mg/kg p.o.) was fully reversed by pretreatment with indomethacin in combination with L-NMMA or CPSN ablation. On the contrary, a combination of L-NMMA and CPSN ablation did not have additional effect on the suppression by either treatment alone. These findings indicate that the gastroprotection by ecabet is cooperatively mediated by endogenous PGs and CPSN-related endogenous NO.
Kinoshita
M
M
Department of Pharmacology, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Kume
E
E
Tamaki
H
H
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D045784:Abietanes; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D019323:omega-N-Methylarginine
D045784:Abietanes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D004224:Diterpenes; D011453:Prostaglandins; D019323:omega-N-Methylarginine; C061681:ecabet; D009569:Nitric Oxide; D000431:Ethanol; D001120:Arginine; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D002211:Capsaicin; D007213:Indomethacin