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Leukocyte-endothelial cell adhesion and an altered metabolism of endothelial cell-derived nitric oxide (NO) have been implicated in the microvascular dysfunction associated with ischemia/reperfusion (I/R). The objective of this study was to determine whether NO donors can attenuate the reperfusion-induced increase in venular albumin leakage via an effect on leukocyte-endothelial cell adhesion. Leukocyte adherence and emigration as well as albumin extravasation were monitored in single postcapillary venules in rat mesentery subjected to 20 minutes of ischemia followed by 30 minutes of reperfusion. This I/R protocol elicits significant leukocyte adherence and emigration as well as a profound albumin leakage response. Superfusion of the mesenteric microcirculation with the NO donors sodium nitroprusside, spermine-NO, and SIN1 significantly reduced the I/R-induced leukocyte adherence/emigration and albumin leakage in post-capillary venules, whereas neither spermine nor the NO synthase inhibitor NG-nitro-L-arginine methyl ester affected the I/R-induced responses. Platelet-leukocyte aggregation and mast cell degranulation were also observed in the postischemic mesentery, and the responses were also attenuated by the NO donors. Plasma nitrate/nitrite levels in the superior mesenteric vein were significantly reduced by I/R. The results of this study indicate that I/R-induced microvascular dysfunction (albumin leakage) is attenuated by NO and that the protective effect of NO donors may be related to their ability to reduce leukocyte-endothelial cell and leukocyte-platelet interactions and/or mast cell degranulation.