Therapeutic effects of imidazolineoxyl N-oxide against endotoxin shock through its direct nitric oxide-scavenging activity

Masaki Yoshida, Takaaki Akaike, Yoshihiro Wada, Keizo Sato, Kazuyoshi Ikeda, Shoichi Ueda, Hiroshi Maeda

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

We recently found a new class of nitric oxide (NO) antidote, i.e., 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide derivatives (PTIOs). It has a potent inhibitory action against endothelium-derived relaxing factor. Here, we report the effect of a water-soluble carboxy derivative of PTIO (carboxy-PTIO) on endotoxin shock. Endotoxin [lipopolysaccharide (LPS)] (10 mg/kg) was injected into Wistar rats, and the mean arterial blood pressure (MABP), heart rate and urinary parameters were continuously measured. The MABP and urine volume gradually decreased during 1 hr after LPS injection, and within 4 hr, both values decreased to 50-70%. When carboxy-PTIO at 0.056-1.70 mg/kg/min was infused for 1 hr beginning 90 min after the LPS injection, the hypotension, renal dysfunction and survival rate were much improved and the state of shock was avoided. Carboxy-PTIO administered to normal rats did not affect each parameter. Measurement of urinary output of carboxy-PTIO and carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl (carboxy-PTI), which is a reaction product of carboxy-PTIO and NO, showed that conversion of carboxy-PTIO to carboxy-PTI was augmented by LPS treatment due to the increased production of NO, and that the enhanced conversion (PTIO → PTI) was significantly inhibited by administration of Nω-monomethyl-L-arginine. This indicates that carboxy-PTIO exhibits a potent therapeutic value in endotoxin shock through the direct scavenging action against NO.

Original languageEnglish
Pages (from-to)923-930
Number of pages8
JournalBiochemical and biophysical research communications
Volume202
Issue number2
DOIs
Publication statusPublished - 1994 Jul 29
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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