Antiinflammatory effects of mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, in carrageenan-induced models of inflammation.
In vitro studies have demonstrated that mercaptoethylguanidine (MEG), a selective inhibitor of the inducible NO synthase (iNOS), is also effective as a scavenger of peroxynitrite (a potent cytotoxic oxidant produced by the reaction of NO and superoxide). In the present study, we evaluated the antiinflammatory potential of MEG treatment in two models of acute inflammation (carrageenan-induced paw edema and pleurisy), where oxyradicals, NO, and peroxynitrite play a crucial role in the inflammatory process. Our data show that MEG (given at 25 microg/paw in the paw edema model or 10 mg/kg in the pleurisy model) inhibits the inflammatory response (paw swelling, pleural exudate formation, mononuclear cell infiltration, histological injury) in both models. Furthermore, MEG reduced nitrite/nitrate concentrations in the exudate and reduced the activity of the inducible isoform of NO synthase in the lung ex vivo. MEG also reduced the appearance of nitrotyrosine immunoreactivity in the inflamed tissues. Taken together, the present results demonstrate that MEG exerts potent antiinflammatory effects. Part of these antiinflammatory effects may be related to an inhibition of the expression/activity of the inducible NO synthase, another part may be related to oxyradical and peroxynitrite scavenging.
Cuzzocrea
S
S
Division of Critical Care, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Zingarelli
B
B
Hake
P
P
Salzman
A L
AL
Szabó
C
C
D000818:Animals; D002351:Carrageenan; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016166:Free Radical Scavengers; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000473:pathology; D009566:Nitrates / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D016877:Oxidants; C039642:peroxynitric acid; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C100078:2-mercaptoethylguanidine