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

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-tetramethylimidazole-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 N omega-monomethyl-L-arginine. This indicates that carboxy-PTIO exhibits a potent therapeutic value in endotoxin shock through the direct scavenging action against NO.

• Authors: M Yoshida, T Akaike, Y Wada, K Sato, K Ikeda, S Ueda, H Maeda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 202 Issue 2 Pg. 923-30 (Jul 29 1994) ISSN: 0006-291X [Print] United States
• PMID: 8048966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Cyclic N-Oxides
• Free Radical Scavengers
• Imidazoles
• Lipopolysaccharides
• 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole
• Nitric Oxide

Topics

• Animals
• Benzoates
• Blood Pressure
• Cyclic N-Oxides (therapeutic use)
• Escherichia coli
• Free Radical Scavengers
• Heart Rate
• Imidazoles (therapeutic use)
• Kidney (physiopathology)
• Lipopolysaccharides
• Male
• Nitric Oxide (metabolism)
• Rats
• Rats, Wistar
• Shock, Septic (chemically induced, drug therapy, physiopathology)
• Urine