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

Basilia Zingarelli, Gwen S. Scott, Paul Hake, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 μM-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 μg/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.

Original languageEnglish (US)
Pages (from-to)126-134
Number of pages9
JournalShock
Volume13
Issue number2
StatePublished - Feb 2000
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Shock
Nitric Oxide
Inflammation
Poly Adenosine Diphosphate Ribose
Ligases
Reperfusion Injury
Macrophages
Hydroxyl Radical
Viscera
Hemorrhagic Shock
Neutrophil Infiltration
nicaraven
Carrageenan
Neuroprotective Agents
Nitric Oxide Synthase Type II
Septic Shock
Nitrites
Superoxides
Arthritis

Keywords

  • Arthritis
  • Edema
  • Encephalomyelitis
  • Endotoxin
  • Hemorrhage
  • Hydroxyl
  • Mitochondrial respiration
  • Nitric oxide
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

Cite this

Zingarelli, B., Scott, G. S., Hake, P., Salzman, A. L., & Szabo, C. (2000). Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. Shock, 13(2), 126-134.

Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. / Zingarelli, Basilia; Scott, Gwen S.; Hake, Paul; Salzman, Andrew L.; Szabo, Csaba.

In: Shock, Vol. 13, No. 2, 02.2000, p. 126-134.

Research output: Contribution to journalArticle

Zingarelli, B, Scott, GS, Hake, P, Salzman, AL & Szabo, C 2000, 'Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation', Shock, vol. 13, no. 2, pp. 126-134.
Zingarelli B, Scott GS, Hake P, Salzman AL, Szabo C. Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. Shock. 2000 Feb;13(2):126-134.
Zingarelli, Basilia ; Scott, Gwen S. ; Hake, Paul ; Salzman, Andrew L. ; Szabo, Csaba. / Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. In: Shock. 2000 ; Vol. 13, No. 2. pp. 126-134.
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