Intestinal injury resulting from ischemia/reperfusion (I/R) is of fundamental importance in clinical pediatric surgery. I/R injury results from inadequate oxygen delivery as well as a secondary inflammatory response involving neutrophils and oxidants. This study was designed to evaluate a novel use for diclofenac sodium (DS), a nonsteroidal antiinflammatory agent, and to compare it with traditional antioxidants in this setting. Rats were subjected to intestinal ischemia followed by reperfusion. When killed, samples were obtained for measurement of intestinal myeloperoxidase (MPO), a measure of neutrophil sequestration, as well as for adenosine triphosphate (ATP) content, a marker of tissue injury. Animals exposed to I/R injury had significant neutrophil sequestration in the intestine by 120 minutes of ischemia, and this persisted after 60 minutes of reperfusion. DS pretreatment did not prevent neutrophil sequestration in the intestine. Analysis of intestinal ATP content demonstrated a decrease in intestinal ATP after 120 minutes of ischemia, and this did not change with 60 minutes of reperfusion. Pretreatment with DS significantly attenuated this intestinal ATP depletion. Furthermore, with 120 minutes of ischemia and 60 minutes of reperfusion, ATP preservation with DS pretreatment exceeded that obtained using the following conventional antioxidants: a xanthine-oxidase inhibitor (lodoxamide), deferoxamine, dimethysulfoxide, and superoxide dismutase plus catalase. DS has a significant cytoprotective effect for intestine subjected to I/R injury, exceeding that of conventional antioxidants. DS does not attenuate injury by preventing neutrophil influx into injured intestine.(ABSTRACT TRUNCATED AT 250 WORDS)