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Effect of Nitric Oxide Donors on Oxygen-Dependent Cytotoxic Responses Mediated by Neutrophils¹

G. Andonegui^2,*,, A. S. Trevani^*,, R. Gamberale^*,, M. C. Carreras, J. J. Poderoso, M. Giordano^*, and J. R. Geffner^*,

^* Laboratory of Immunology, Institute of Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina; and Department of Microbiology and Laboratory of Oxygen Metabolism, University Hospital, Buenos Aires University School of Medicine, Buenos Aires, Argentina. The National Academy of Medicine is an organism independent from the Buenos Aires University and both the Department of Microbiology and the Laboratory of Oxygen Metabolism, University Hospital depend on Buenos Aires University School of Medicine.

We analyzed the effect of nitric oxide (NO) on oxygen-dependent cytotoxic responses mediated by neutrophils against unopsonized erythrocytes using three NO donors: S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine (SNAP), and sodium nitroprusside (SNP). Neutrophils were treated with these compounds for 1–2 min at 37°C and cytotoxicity was then triggered in the presence of NO donors by precipitating immune complexes, aggregated IgG, the chemotactic peptide FMLP, or opsonized zymosan. GSNO induced, in all cases, a marked increase in cytotoxic responses, while SNAP moderately increased cytotoxicity triggered by immune complexes, aggregated IgG, or Z, opsonized zymosen, without modifying those responses induced by FMLP. By contrast, SNP dramatically suppressed cytotoxicity triggered by all of the stimuli assessed. The enhancing effects mediated by GSNO and SNAP did not depend on the stimulation of guanylyl cyclase and were prevented by the NO scavengers hemoglobin and PTIO (2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide). The inhibitory activity of SNP, on the other hand, was not prevented by NO scavengers, suggesting that it cannot be ascribed to the release of NO. In another set of experiments, neutrophils were pretreated with GSNO or SNAP for different times. Then cells were washed to remove NO donors from the culture medium, and cytotoxicity was triggered by different stimuli. It was found that neutrophils must be pretreated with NO donors for at least 4 h to increase cytotoxic responses, and pretreatment for longer periods (i.e., 8 or 18 h) further increased cytotoxicity. Not only cytotoxic responses, but also the production of O₂^- and H₂O₂, and the release of myeloperoxidase were increased under these conditions.