Therapeutic effects of imidazolineoxyl N-oxide against endotoxin shock through its direct nitric oxide-scavenging activity.
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.
Yoshida
M
M
Department of Urology, Kumamoto University School of Medicine, Japan.
Akaike
T
T
Wada
Y
Y
Sato
K
K
Ikeda
K
K
Ueda
S
S
Maeda
H
H
D000818:Animals; D001565:Benzoates; D001794:Blood Pressure; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D004926:Escherichia coli; D016166:Free Radical Scavengers; D006339:Heart Rate; D007093:Imidazoles / Q000627:therapeutic use*; D007668:Kidney / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D014556:Urine
D001565:Benzoates; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D008070:Lipopolysaccharides; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide