Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation

Expression of the inducible isoform of nitric oxide (NO) synthase, and the formation of peroxynitrite from NO and superoxide are responsible for some of the pathophysiological alterations seen during reperfusion injury and in various inflammatory conditions. Some of the effects of peroxynitrite are related to DNA single-strand breakage, and activation of poly (ADP-ribose) synthetase. Here we investigated the effect of nicaraven (2(R,S)-1,2-bis (n icotinamido)propane), a known hydroxyl radical scavenger compound and neuro protective agent, on several NO- and peroxynitrite related pathways in vitr o, and in shock and inflammation in viva. Nicaraven, at 10 mu M-10 mM, fail ed to inhibit the peroxynitrite-induced oxidation of dihydro-rhodamine 123, indicating that the agent does not act as a scavenger of peroxynitrite, In RAW murine macrophages stimulated with peroxynitrite, nicaraven caused a d ose-dependent, slight inhibition of poly (ADP-ribose) synthetase activation , possibly due to a direct inhibitory effect on the catalytic activity of p oly (ADP-ribose) synthetase. Nicaraven partially protected against the pero xynitrite-induced suppression of mitochondrial respiration in RAW macrophag es and caused a slight, dose-dependent inhibition of nitrite production in RAW macrophages stimulated with bacterial lipopolysaccharide. We next inves tigated the effect of nicaraven treatment in a variety of models of inflamm ation and reperfusion injury. Nicaraven (at 10-100 mu g/paw) exerted signif icant protective effects in the carrageenan-induced paw edema model and (at 100 mg/kg i.v.) reduced neutrophil infiltration and histological damage in splanchnic artery occlusion-reperfusion injury. However, nicaraven failed to alter the course of hemorrhagic and endotoxic shock and arthritis in rod ent models. The current data indicate the limited role of hydroxyl radicals in the pathogenesis of the inflammatory conditions tested.