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 indu ced by indomethacin in rats. Indomethacin (25 mg/kg) was given subcuta neously, and gastric acid secretion, motility, lipid peroxidation, vas cular permeability, and myeloperoxidase as well as gastric lesions wer e measured. Indomethacin produced high-amplitude contractions of the s tomach and caused hemorrhagic lesions in the corpus mucosa with signif icant 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 admi nistration of atropine (3 mg/kg s.c.). Pretreatment of the animals wit h DDC (75-1,000 mg/kg s.c.) prevented these lesions induced by indomet hacin in the corpus mucosa in a dose-dependent manner (> 100 mg/kg), t hough at high doses (>750 mg/kg) some damage was found in both the ant rum and duodenum. DDC showed a significant inhibition against the gast ric mucosal SOD activity (>400 mg/kg), yet potently suppressed the inc rease of lipid peroxidation, vascular permeability, and myeloperoxidas e activity caused by indomethacin. DDC dose-dependently (>75 mg/kg) in hibited 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 b y 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 event s including the neutrophil-related processes may be secondary to gastr ic hypercontraction caused by indomethacin.