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, t here 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 giv en either directly to the site of the inflammatory lesion or systemically. It was found that in the carrageenin-induced pleurisy, a single intrapleura l injection of the selective inducible NO inhibitors S-(2-aminoethyl) isoth iourea (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-i minoethyl)-omithine (10 mg/kg) not only exacerbated inflammation at the ver y early stages of the lesion (1-6 h), but also prevented inflammatory resol ution. By contrast, administering NOS inhibitors systemically ameliorated t he severity of inflammation throughout the reaction. To elucidate the mecha nisms by which inhibition of NO synthesis locally worsened inflammation, we found an increase in histamine, cytokine-induced neutrophil chemoattractan t, superoxide, and leukotriene B-4 levels at the inflammatory site. In conc lusion, this work shows that the local production of NO is protective by vi rtue of its ability to regulate the release of typical proinflammatory medi ators and, importantly, that NOS inhibitors have differential anti-inflamma tory effects depending on their route of administration.