Nitric oxide-releasing compounds inhibit neutrophil adhesion to endothelial cells.
In the present work, we demonstrated that chemically different nitric oxide (NO)-releasing compounds inhibit tumor necrosis factor alpha (TNF-alpha)-induced polymorphonuclear leukocyte adhesion to endothelial cells in vitro. Two mesoionic oxatriazole derivatives GEA 3162 (1,2,3,4-oxatriazolium,5-amino-3(3, 4-dichlorophenyl)-chloride) and GEA 3175 (1,2,3,4-oxatriazolium, -3-(3-chloro-2-methylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino]-, hydroxide inner salt) were compared to the earlier-known NO donor SIN-1 (3-morpholino-sydnonimine). GEA 3162 (3-10 microM) and GEA 3175 (10-30 microM) inhibited human polymorphonuclear leukocyte adhesion to B(4) endothelial cells in a dose-dependent manner being more potent than SIN-1. In the present model, leukocytes rather than endothelial cells seemed to be the target of the effect of NO. Flow cytometric analysis showed that NO-releasing compounds did not alter TNF-alpha induced CD11/CD18 surface expression in polymorphonuclear leukocytes. The inhibitory action of NO-releasing compounds on adhesion paralleled with the increased synthesis of cGMP in polymorphonuclear leukocytes. Analogues of cGMP inhibited polymorphonuclear leukocyte adhesion indicating a role for cGMP in the action of NO donors. The results suggest that exogenous NO in the form of NO-releasing compounds inhibits polymorphonuclear leukocyte adhesion to endothelial cells, which may be implicated in the regulation of leukocyte migration and leukocyte-mediated tissue injury.
Kosonen
O
O
Medical School, University of Tampere, P.O. Box 607, FIN-33101, Tampere, Finland.
Kankaanranta
H
H
Malo-Ranta
U
U
Moilanen
E
E
D000818:Animals; D018845:CD11 Antigens / Q000096:biosynthesis; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects*; D018920:Coculture Techniques; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011817:Rabbits; D013873:Thionucleotides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018845:CD11 Antigens; D018821:CD18 Antigens; C093084:GEA 3175; D020030:Nitric Oxide Donors; D013873:Thionucleotides; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C016276:8-bromocyclic GMP; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; C002385:linsidomine; C082874:GEA 3162; D008981:Molsidomine; D006152:Cyclic GMP