Three different stable lipoxin A4 (LXA4) analogs (i.e., 16-phenoxy-LXA4-Me, 15-cyclohexyl-LXA4-Me, and 15-R/S-methyl-LXA4-Me) were studied for their ability to modulate leukocyte-endothelial cell interactions in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 micromol/liter NG-nitro-L-arginine methyl ester (L-NAME) caused a significant, time-dependent increase in leukocyte rolling (56 +/- 8 cells/min; P < 0.01 vs. control) and leukocyte adherence (12.5 +/- 1. 2 cells/100 micron length of venule; P < 0.01 vs. control) after 120 min of superfusion. Concomitant superfusion of the rat mesentery with 10 nmol/liter of each of three lipoxin analogs consistently and markedly attenuated L-NAME-induced leukocyte rolling to 10 +/- 4 (P < 0.01), 4 +/- 1 (P < 0.01), and 32 +/- 7 (P < 0.05) cells/min, and adherence to 4 +/- 0.8 (P < 0.01), 1.1 +/- 0.4 (P < 0.01), and 7 +/- 0.7 (P < 0.05) cells/100 micron length of venule (16-phenoxy-LXA4-Me, 15-cyclohexyl-LXA4-Me, and 15-R/S- methyl-LXA4-Me, respectively). No alterations of systemic blood pressure or mesenteric venular shear rates were observed in any group. Immunohistochemical up-regulation of P-selectin expression on intestinal venular endothelium was significantly increased (P < 0.01) after exposure to L-NAME, and this was significantly attenuated by these lipoxin analogs (P < 0.01). Thus, in vivo superfusion of the rat mesentery with stable lipoxin analogs at 10 nmol/liter reduces L-NAME-induced leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. This anti-inflammatory mechanism may represent a novel and potent regulatory action of lipoxins on the immune system.