Diethyldithiocarbamate, a superoxide dismutase inhibitor, reduces indomethacin-induced gastric lesions in rats.
We examined the effect of diethyldithiocarbamate (DDC), the superoxide dismutase (SOD) inhibitor, on the development of gastric lesions induced by indomethacin in rats. Indomethacin (25 mg/kg) was given subcutaneously, and gastric acid secretion, motility, lipid peroxidation, vascular permeability, and myeloperoxidase as well as gastric lesions were measured. Indomethacin produced high-amplitude contractions of the stomach and caused hemorrhagic lesions in the corpus mucosa with significant increase in neutrophil-related processes such as myeloperoxidase activity, vascular permeability and lipid peroxidation. These changes caused by indomethacin were all significantly inhibited by prior administration of atropine (3 mg/kg s.c.). Pretreatment of the animals with DDC (75-1,000 mg/kg s.c.) prevented these lesions induced by indomethacin in the corpus mucosa in a dose-dependent manner (> 100 mg/kg), though at high doses (> 750 mg/kg) some damage was found in both the antrum and duodenum. DDC showed a significant inhibition against the gastric mucosal SOD activity (> 400 mg/kg), yet potently suppressed the increase of lipid peroxidation, vascular permeability, and myeloperoxidase activity caused by indomethacin. DDC dose-dependently (> 75 mg/kg) inhibited the enhancement of gastric motility caused by indomethacin and showed a weak antisecretory effect at high doses (> 750 mg/kg). These results showed that DDC reduced indomethacin-induced gastric lesions by suppressing gastric motility, despite inhibiting SOD activity. This study also indicates the prime importance of gastric hypercontraction in the pathogenesis of this lesion model and suggests that other events including the neutrophil-related processes may be secondary to gastric hypercontraction caused by indomethacin.
Takeuchi
K
K
Department of Pharmacology, Kyoto, Japan.
Takehara
K
K
Ohuchi
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002199:Capillary Permeability / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002614:Chelating Agents; D004050:Ditiocarb; D009195:Peroxidase; D013482:Superoxide Dismutase; D007213:Indomethacin