Nitric oxide ((NO)-N-.) plays a central role in the pathogenesis of diverse inflammatory and infectious disorders(1,2). The toxicity of (NO)-N-. is thought to be engendered, in part, by its reaction with superoxide (O-2(.-)), yielding the potent oxidant peroxynitrite (ONOO-)(3). However, evidence for a role of ONOO- in vivo is based largely upon detection of 3-nitrotyrosine in injured tissues(4-8). We have recently demonstrated that nitrite (NO2-), a major end-product of (NO)-N-. metabolism, readily promotes tyrosine nitration through formation of nitryl chloride (NO2Cl) and nitrogen dioxide ((NO2)-N-.) by reaction with the inflammatory mediators hypochlorous acid (HOCl) or myeloperoxidase(9,10). We now show that activated human polymorphonuclear neutrophils convert NO2- into NO2Cl and (NO2)-N-. through myeloperoxidase-dependent pathways. Polymorphonuclear neutrophil-mediated nitration and chlorination of tyrosine residues or 4-hydroxyphenylacetic acid is enhanced by addition of NO2- or by fluxes of (NO)-N-.. Addition of (NO2-)-N-15 led to N-15 enrichment of nitrated phenolic substrates, confirming its role in polymorphonuclear neutrophil-mediated nitration reactions. Polymorphonuclear neutrophil-mediated inactivation of endothelial cell angiotensin-converting enzyme was exacerbated by NO2-, illustrating the physiological significance of these reaction pathways to cellular dysfunction. Our data reveal that NO2- may regulate inflammatory processes through oxidative mechanisms, perhaps by contributing to the tyrosine nitration and chlorination observed in vivo.