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(nicotinamido)propane), a known hydroxyl radical scavenger compound and neuroprotective agent, on several NO- and peroxynitrite related pathways in vitro, and in shock and inflammation in vivo. Nicaraven, at 10 microM-10 mM, failed to inhibit the peroxynitrite-induced oxidation of dihydrorhodamine 123, indicating that the agent does not act as a scavenger of peroxynitrite. In RAW murine macrophages stimulated with peroxynitrite, nicaraven caused a dose-dependent, slight inhibition of poly (ADP-ribose) synthetase activation, possibly due to a direct inhibitory effect on the catalytic activity of poly (ADP-ribose) synthetase. Nicaraven partially protected against the peroxynitrite-induced suppression of mitochondrial respiration in RAW macrophages and caused a slight, dose-dependent inhibition of nitrite production in RAW macrophages stimulated with bacterial lipopolysaccharide. We next investigated the effect of nicaraven treatment in a variety of models of inflammation and reperfusion injury. Nicaraven (at 10-100 microg/paw) exerted significant 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 rodent models. The current data indicate the limited role of hydroxyl radicals in the pathogenesis of the inflammatory conditions tested.
Zingarelli
B
B
Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio 45229, USA.
Scott
G S
GS
Hake
P
P
Salzman
A L
AL
Szabo
C
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D012772:Shock, Septic / Q000378:metabolism*; D013152:Splanchnic Circulation / Q000187:drug effects
D000975:Antioxidants; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D009566:Nitrates; D009536:Niacinamide; C039642:peroxynitric acid; D009569:Nitric Oxide; D007371:Interferon-gamma; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases; C042625:nicaraven