Subclinical intestinal ischemia-reperfusion injury (IRI) causes an increase in mucosal permeability and may represent an early event in the pathogenesis of necrotizing enterocolitis. The present study was undertaken to determine whether these changes are mediated by local or systemic factors. In 6-week-old weanling rats, the ileum was divided into two isolated loops with separate vascular supplies. The mesentery of the proximal loop was occluded for 30 minutes, following which the bowel was reperfused; permeability to 51Cr EDTA was then assessed in the distal loop 30 minutes after reperfusion. In control groups, the distal loop was subjected to 30-minute IRI ("positive" control) or 30-minute sham operation ("negative" control). Permeability in the distal loop was increased only with IRI to the distal bowel (15.4 +/- 3 counts/min/standard), and not with IRI to the proximal bowel (5.1 +/- 1) or with sham operation (8.5 +/- 2). To determine whether a mild "priming" injury might be necessary for systemic factors to have an effect, the distal loop was subjected to 2-minute IRI and the proximal to 30-minute IRI or sham. Permeability was not increased in the distal loop in either of these groups (5.7 +/- 1 and 7.8 +/- 2, respectively). Thirty-minute IRI in the proximal loop did not increase permeability in the distal loop, with or without a priming injury. Only direct IRI in the distal loop resulted in a significant increase in permeability. We conclude that the permeability changes in this model are mediated through local tissue effects, rather than by systemic factors.