Role of nitric oxide and prostaglandin in the protective effect of pibutidine hydrochloride, a novel histamine H2-receptor antagonist, on the gastric mucosal lesions in rats.
1. The role of endogenous nitric oxide (NO) and prostaglandins (PGs) in the gastric mucosal protective action of pibutidine hydrochloride (IT-066), a novel histamine H2-receptor antagonist, was investigated in a 0.15 N hydrochloride (HCl) + 60% ethanol (EtOH)-induced gastric lesion model. 2. The 0.15 N HCl + 60% EtOH-induced lesion formation was reduced significantly by IT-066 (3 mg/kg, PO), NOR3 (spontaneous NO releaser; 0.03-0.1 mg/kg, SC) or PGE2 (0.01 mg/kg, PO) but was not reduced by famotidine (1-10 mg/kg, PO). 3. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg, IV), an inhibitor of NO synthase, inhibited the protective action of IT-066 (3 mg/kg, PO), and the inhibitory effect of L-NAME was reversed by L-arginine (300 mg/kg, IV). The protective effect of PGE2 (0.01 mg/kg, PO) was not affected by the pretreatment with L-NAME (3 mg/kg, IV). 4. Infusion of carboxy-PTIO (1 mg/kg/min), a direct NO scavenger, inhibited the protective effect of IT-066 (3 mg/kg, SC) or NOR3 (0.1 mg/kg, SC). Pretreatment with indomethacin (5 mg/kg, SC) markedly reduced the protective effect of IT-066 (3 mg/kg, PO) or NOR3 (0.1 mg/kg, SC). 5. These results suggest that endogenous NO and PGs may be implicated in the gastric mucosal protection induced by IT-066 and that the endogenous PGs may contribute to the protective effect of NO.
Department of Pharmacology, Research Center, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan. s14806@ccm.taisho.co.jp
Y
Y
Kiuchi
Y
Y
Isobe
H
H
Kijima
T
T
Saitoh
S
S
Higuchi
D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D015738:Famotidine / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects*; D006635:Histamine H2 Antagonists / Q000627:therapeutic use*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000627:therapeutic use; D011453:Prostaglandins / Q000502:physiology*; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011453:Prostaglandins; D011725:Pyridines; C063924:IT 066; D009569:Nitric Oxide; D000431:Ethanol; D015738:Famotidine; D019001:Nitric Oxide Synthase; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester