Nitric oxide synthase inhibitors have opposite effects on acute inflammation depending on their route of administration.
The bulk of published data has shown that NO is proinflammatory. However, there also exists the conflicting notion that NO may be protective during an inflammatory insult. In an attempt to resolve this issue, we have compared the effects on inflammation of a range of NO synthase (NOS) inhibitors given either directly to the site of the inflammatory lesion or systemically. It was found that in the carrageenin-induced pleurisy, a single intrapleural injection of the selective inducible NO inhibitors S-(2-aminoethyl) isothiourea (AE-ITU; 3 and 10 mg/kg) and N-(3-(aminomethyl)-benzyl) acetamidine (1400W; 10 mg/kg) or the selective endothelial cell NOS inhibitor L-N(5)(1-iminoethyl)-ornithine (10 mg/kg) not only exacerbated inflammation at the very early stages of the lesion (1-6 h), but also prevented inflammatory resolution. By contrast, administering NOS inhibitors systemically ameliorated the severity of inflammation throughout the reaction. To elucidate the mechanisms by which inhibition of NO synthesis locally worsened inflammation, we found an increase in histamine, cytokine-induced neutrophil chemoattractant, superoxide, and leukotriene B(4) levels at the inflammatory site. In conclusion, this work shows that the local production of NO is protective by virtue of its ability to regulate the release of typical proinflammatory mediators and, importantly, that NOS inhibitors have differential anti-inflammatory effects depending on their route of administration.
Paul-Clark
M J
MJ
Department of Experimental Pathology, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom.
Gilroy
D W
DW
Willis
D
D
Willoughby
D A
DA
Tomlinson
A
A
D000208:Acute Disease; D000578:Amidines / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001596:Benzylamines / Q000008:administration & dosage; D002351:Carrageenan / Q000633:toxicity; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004487:Edema / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D016166:Free Radical Scavengers / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007267:Injections; D007274:Injections, Intraperitoneal; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010994:Pleura; D010998:Pleurisy / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D000578:Amidines; D000975:Antioxidants; D001596:Benzylamines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D013481:Superoxides; D019323:omega-N-Methylarginine; C413842:aminoethyl-isothiourea; D009569:Nitric Oxide; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013890:Thiourea