Inhibition of Endothelial-derived Nitric Oxide Promotes P-selectin Expression and Actions in the Rat Microcirculation

Background/aims: Inhibition of nitric oxide synthesis increases leukocyte and endothelial interaction in mesenteric venules. In this study, the relationship between inhibition of NO and expression of the adhesion molecule P-selectin was examined.

Methods: The rat mesentery was superfused with the NO inhibitor NG-nitro-L-arginine methyl ester (L-NAME) either alone or in combination with intravenous infusions of L-arginine, D-arginine, a P-selectin-neutralizing monoclonal antibody (PB1.3 [1 mg/kg]), recombinant human superoxide dismutase (hSOD), or 8 bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP). Leukocyte rolling and adherence were monitored in mesenteric venules via intravital microscopy. Ileal tissue superfused with L-NAME was examined immunohistochemically for P-selectin expression.

Results: Superfusion of the rat mesentery with L-NAME resulted in a significant increase in leukocyte rolling and adherence in the mesenteric venule, which was attenuated by administration of L-arginine but not D-arginine. Monoclonal antibody PB1.3 as well as hSOD and 8-br-cGMP administered before initiation of L-NAME superfusion significantly attenuated the increase in leukocyte rolling and adherence. Immunohistochemistry showed a significant increase in P-selectin expression after 60 minutes of superfusion with L-NAME, which was attenuated by L-arginine, hSOD, and 8-br-cGMP.

Conclusions: These data indicate an important functional relationship between endothelial-derived NO production and expression of the endothelial adhesion molecule P-selectin.