Nitric oxide: an endogenous modulator of leukocyte adhesion.
The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), and observing single (30-microns diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAME-induced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-arginine but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation.
Department of Physiology, Louisiana State University Medical Center, Shreveport 71130.
P
P
Kubes
M
M
Suzuki
D N
DN
Granger
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018845:CD11 Antigens; D018821:CD18 Antigens; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D013152:Splanchnic Circulation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014699:Venules / Q000502:physiology; D019323:omega-N-Methylarginine
D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester