Peroxynitrite decomposition catalysts: therapeutics for peroxynitrite-mediated pathology.
Inflamed tissue is often characterized by the production of NO and superoxide. These radicals react at diffusion-limited rates to form the powerful oxidant peroxynitrite (PN). When protonated, PN decomposes into 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 increase in nitrate formation with a concomitant decrease in the HO.-like and NO2.-like reactivity of PN. Here, we present evidence for the efficacy of these PN decomposition catalysts both in vitro and in vivo. Cells in culture were protected from exogenously added PN by the catalyst 5,10,15,20-tetrakis(2,4, 6-trimethyl-3,5-disulfonatophenyl)porphyrinato iron (III), whereas free iron and the structurally related compound without iron 5,10,15, 20-tetrakis(2,4,6-trimethyl-3,5-disulfonatophenyl)porphyrin did not protect. Cytoprotection correlated well with a reduction 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 reduction in swelling and lactate dehydrogenase release as well as a detectable shift to nitrate formation in paw tissue. In addition, the catalysts did not elevate mean arterial pressure, suggesting a lack of interaction 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.
Salvemini
D
D
Discovery Pharmacology, G. D. Searle Co., St. Louis, MO 63167, USA. DDSALV@ccmail.monsanto.com
Wang
Z Q
ZQ
Stern
M K
MK
Currie
M G
MG
Misko
T P
TP
D000818:Animals; D002351:Carrageenan; D002384:Catalysis; D016923:Cell Death; D002460:Cell Line; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages; D008297:Male; D008956:Models, Chemical; D009566:Nitrates / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D009573:Nitrites / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011166:Porphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D009566:Nitrates; D009573:Nitrites; D016877:Oxidants; D011166:Porphyrins; C039642:peroxynitric acid; D002351:Carrageenan; D007770:L-Lactate Dehydrogenase