PEROXYNITRITE DECOMPOSITION CATALYSTS - THERAPEUTICS FOR PEROXYNITRITE-MEDIATED PATHOLOGY

Inflamed tissue is often characterized by the production of NO and sup eroxide, These radicals react at diffusion-limited rates to form the p owerful oxidant peroxynitrite (PN), When protonated, PN decomposes int o either nitrate or reactive intermediates capable of mediating tissue damage by oxidation of protein, lipid, and nucleic acid, We recently have identified porphyrin derivatives capable of catalyzing an increas e in nitrate formation with a concomitant decrease in the HO .-like an d NO2.-like reactivity of PN, Here, we present evidence for the effica cy of these PN decomposition catalysts both in vitro and in vivo, Cell s in culture were protected from exogenously added PN by the catalyst 5,10,15,20-tetrakis ,4,6-trimethyl-3,5-disulfonatophenyl)-porphyrinato iron (III), whereas free iron and the structurally related compound w ithout iron 5,10,15,20-tetrakis 2,4,6-trimethyl-3,5-disulfonatophenyl) porphyrinato did not protect, Cytoprotection correlated well with a re duction in the nitrotyrosine content of released cytosolic proteins, a biochemical marker for PN formation, Carrageenan-induced paw edema is a model of acute inflammation in which PN may play a major role, When tested in this system, both 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5- disulfonatophenyl) porphyrinato iron (III) and 5,10,15,20-tetrakis (N- methyl-4'-pyridyl)porphyrinato iron (III) caused a dose-dependent redu ction in swelling and lactate dehydrogenase release as well as a detec table shift to nitrate formation in paw tissue, In addition, the catal ysts did not elevate mean arterial pressure, suggesting a lack of inte raction with NO, Taken together, our data provide compelling evidence supporting the therapeutic value of manipulating PN pharmacologically. Thus, PN decomposition catalysts may represent a unique class of anti inflammatory agents.