Mechanisms underlying gastric antiulcerative activity of nitroxides in rats

Reactive oxygen-derived species and redox-active metals are implicated in m ediation of the pathogenesis of gastric mucosal damage and ulceration. Ther efore, common strategies of intervention employ metal chelators, antioxidat ive enzymes, and low-molecular-weight antioxidants (LMWA). The aim of the p resent study was to elaborate the mechanism(s) responsible for the protecti on provided by nitroxide radicals in the experimental model of gastric ulce ration Fasted male rats were treated ig with 1 ml 96% ethanol, with or without ig pretreatment with nitroxide or hydroxylamine. In several experiments, rats were injected ip or iv with iron(III) or iron(II) prior to ethanol administ ration. Rats were sacrificed 10 min after ethanol administration, the stoma ch was removed, washed and lesion area measured. Pretreatment with iron(III ) complexed to nitrilotriacetate or citrate, aggravated the extent of the g astric injury. Conversely, iron(II) inhibited the formation of lesions. The nitroxides were rapidly reduced to their respective hydroxylamines and dem onstrated antiulcerative activity for rats treated with iron. However, inje cting the hydroxylamine resulted in a similar tissue distribution of nitrox ide/ hydroxylamine but did not provide protection. The results show that: (ai the nitroxide radicals, rather than their respec tive non-radical reduced form, are the active species responsible for prote ction; (b) nitroxides protect by dismutating O-2(.-) and possibly indirectl y increasing the NO level; (c) unlike classical LMWA which are reducing age nts, nitroxides inhibit gastric damage by acting as mild oxidants, oxidizin g reduced metals and pre-empting the Fenton reaction; and (d) the nitroxide s act catalytically as recycling antioxidants.