Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation.
OBJECTIVE
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.
Davenpeck
K L
KL
Department of Physiology, Jefferson Medical College, Philadelphia, Pennsylvania.
Gauthier
T W
TW
Lefer
A M
AM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001808:Blood Vessels / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D007082:Ileum / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation
D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester