Nitric oxide (NO) is known to be an important endogenous modulator of leukocyte-endothelial cell interactions within the microcirculation. We examined leukocyte rolling and adhesion under baseline conditions and following thrombin (0.25 U/ml) superfusion in the mesentery of wild-type, inducible NOS (iNOS)-deficient (/), neuronal NOS (nNOS) /, and endothelial cell NOS (ecNOS) / mice to further our understanding of NO and leukocyte function. Baseline leukocyte rolling (cells/min) was significantly elevated in both the nNOS / (30.0 ± 4.0) and ecNOS / mice (67.0 ± 12.0) compared with wild-type mice (11.0 ± 1.4). In addition, baseline leukocyte adherence (cells/100 µm of vessel) was also significantly elevated in the nNOS / (5.2 ± 1.0) and ecNOS / (13.0 ± 1.3) compared with wild-type animals (1.3 ± 0.5). Deficiency of iNOS had no effect on baseline leukocyte rolling or adhesion in the mesentery. Baseline surface expression of P-selectin was observed in 68.0 ± 9.0% of intestinal venules in ecNOS / mice compared with 10.0 ± 2.0% in wild-type mice. Additional studies demonstrated that administration of an anti-P-selectin monoclonal antibody (RB40.34) or the soluble P-selectin ligand, PSGL-1, completely inhibited the increased rolling and firm adhesion response in nNOS / and ecNOS / mice. Transmigration of neutrophils into the peritoneum following thioglycollate injection was also significantly augmented in nNOS / and ecNOS / mice. These studies clearly indicate the NO derived from both nNOS and ecNOS is critical in the regulation of leukocyte-endothelial cell interactions.

P-selectin; gene-targeted mice; endothelium; neutrophil; microcirculation

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