Mucosal ulcerogenic action of monochloramine in rat stomachs: effects of polaprezinc and sucralfate.
Effects of a novel zinc compound polaprezinc [N-(3-aminopropionyl)-L-histidinatozinc] and sucralfate on the mucosal ulcerogenic responses induced by monochloramine (NH2Cl) were examined in rat stomachs. Oral administration of NH2Cl (>60 mM) produced severe lesions in unanesthetized rat stomachs, with concomitant increase of lipid peroxidation. These lesions were aggravated by sensory deafferentation but not affected by pretreatment with indomethacin or L-NAME. The mucosal ulcerogenic response to NH2Cl was significantly inhibited by oral pretreatment with either dmPGE2 (10 microg/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastric lesions induced by NH2Cl were also inhibited by prior oral administration of polaprezinc (3-30 mg/kg) as well as sucralfate (30 and 100 mg/kg). The protective effect of polaprezinc was not affected by any pretreatments such as indomethacin, L-NAME, or sensory deafferentation, while that of sucralfate was significantly mitigated in the presence of either indomethacin or L-NAME. On the other hand, mucosal exposure to NH4OH (60 mM) caused a marked PD reduction in ex vivo stomachs made ischemic by bleeding from the carotid artery, followed by severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischemia were also attenuated by prior application of polaprezinc, while dmPGE2 and sucralfate prevented such lesions without affecting the reduced PD response. These results suggest that: (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa, (2) both polaprezinc and sucralfate protect the stomach against injury caused by NH2Cl, and (3) the mechanisms underlying the protective action of sucralfate may be partly mediated by both endogenous PGs and NO but may be different from those of polaprezinc.
Kato
S
S
Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
Nishiwaki
H
H
Konaka
A
A
Takeuchi
K
K
D015064:16,16-Dimethylprostaglandin E2 / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D002336:Carnosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002700:Chloramines; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000187:drug effects*; D008297:Male; D009942:Organometallic Compounds / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000517:prevention & control*; D013392:Sucralfate / Q000627:therapeutic use*; D015032:Zinc / Q000627:therapeutic use*; D017967:Zinc Compounds
D000897:Anti-Ulcer Agents; D002700:Chloramines; D009942:Organometallic Compounds; D017967:Zinc Compounds; C061957:polaprezinc; D013392:Sucralfate; D002336:Carnosine; D015032:Zinc; C030816:chloramine; D015064:16,16-Dimethylprostaglandin E2