Nitric Oxide Synthase Inhibitors Have Opposite Effects on Acute Inflammation Depending on Their Route of Administration

Abstract

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-N5(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 B4 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.

Involvement of NO in the failure of neutrophil migration in sepsis induced by Staphylococcus aureus

“…Similar to our observations, there is evidence that the treatment of animals with selective inhibitors of iNOS or cNOS enhances the neutrophil migration to in¯ammatory sites (Ialenti et al, 2000;Paul-Clark et al, 2001;McCartney-Francis et al, 2001); on the other hand, other studies contradict our ®ndings, i.e. animals treated with NOS inhibitors, or iNOS7/7 mice, presented a reduction in neutrophil migration to in¯ammatory sites (Ajuebor et al, 1998;Ialenti et al, 2000;Cuzzocrea et al, 2000;Paul-Clark et al, 2001;Franco-Penteado et al, 2001;McCartney-Francis et al, 2001). It is suggested that the suppressor eect of NOS inhibitors upon neutrophil migration could be a consequence Figure 7 Quanti®cation of neutrophil migration into the peritoneal cavity (A), CFU in the peritoneal exudate (B) and survival of iNOS Knockout mice (C) injected with sub-lethal or lethal inoculums of S. aureus.…”

“…However, there is controversy regarding the in vivo eects of NOS inhibitors on neutrophil migration to in¯ammatory sites and also concerning neutrophil migration in iNOS7/7 animals. Similar to our observations, there is evidence that the treatment of animals with selective inhibitors of iNOS or cNOS enhances the neutrophil migration to in¯ammatory sites (Ialenti et al, 2000;Paul-Clark et al, 2001;McCartney-Francis et al, 2001); on the other hand, other studies contradict our ®ndings, i.e. animals treated with NOS inhibitors, or iNOS7/7 mice, presented a reduction in neutrophil migration to in¯ammatory sites (Ajuebor et al, 1998;Ialenti et al, 2000;Cuzzocrea et al, 2000;Paul-Clark et al, 2001;Franco-Penteado et al, 2001;McCartney-Francis et al, 2001).…”

“…In (D) survival of the animals is expressed as per cent survival and was determined daily for 7 days. of vasoconstriction, leading to a reduction in local blood ow, due to the use of high doses and/or systemic administration of the drugs (Ialenti et al, 2000;Paul-Clark et al, 2001;Franco-Penteado et al, 2001). However, a decrease in blood¯ow in the microcirculation cannot alone explain the reduction in neutrophil migration induced by zymosan and carrageenan observed in iNOS7/7 mice (Ajuebor et al, 1998;Cuzzocrea et al, 2000).…”

Nitric Oxide Mediates Apoptosis Through Formation of Peroxynitrite and Fas/Fas-Ligand Interactions in Experimental Autoimmune Uveitis

“…In particular, dose rate and route of administration seems to be crucial. 19,41 Access of inhibitors to peripheral tissues may be incomplete, but in some models a 60% reduction in inflammation despite only 15% reduction in NOS2 activity has been reported 31 suggesting that comparatively small reductions in NOS are physiologically relevant. Alternatively, other, as yet unappreciated effects of the treatment may influence inflammation.…”

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

“…Nitric oxide (NO) in portal plasma was determined as its metabolites (NO 2 Ϫ ϩNO 3 Ϫ ) by the Griess reaction with some modification. 25) Data Analysis BSP concentration-time data (C p (t)) obtained from the individual experiments were fitted to the following Eq. 1 using a nonlinear least squares program, MULTI edited by Yamaoka et al, 26) and the parameters for a typical 2-compartment model were calculated.…”