Yoshida M, Akaike T, Wada Y, Sato K, Ikeda K, Ueda S, Maeda H
Department of Urology, Kumamoto University School of Medicine, Japan.
Biochem Biophys Res Commun. 1994 Jul 29;202(2):923-30. doi: 10.1006/bbrc.1994.2018.
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.
我们最近发现了一类新型一氧化氮（NO）解毒剂，即2-苯基-4,4,5,5-四甲基咪唑啉-1-氧基-3-氧化物衍生物（PTIOs）。它对内皮源性舒张因子具有强大的抑制作用。在此，我们报告了PTIO的水溶性羧基衍生物（羧基-PTIO）对内毒素休克的影响。将内毒素[脂多糖（LPS）]（10mg/kg）注射到Wistar大鼠体内，并连续测量平均动脉血压（MABP）、心率和尿液参数。LPS注射后1小时内，MABP和尿量逐渐下降，4小时内，这两个值均下降至50%-70%。当在LPS注射后90分钟开始以0.056-1.70mg/kg/min的剂量输注羧基-PTIO 1小时时，低血压、肾功能障碍和存活率得到显著改善，避免了休克状态。给正常大鼠施用羧基-PTIO不影响各项参数。对羧基-PTIO和羧基-2-苯基-4,4,5,5-四甲基咪唑-1-氧基（羧基-PTI，羧基-PTIO与NO的反应产物）的尿量测量表明，由于NO生成增加，LPS处理可增强羧基-PTIO向羧基-PTI的转化，而施用Nω-单甲基-L-精氨酸可显著抑制这种增强的转化（PTIO→PTI）。这表明羧基-PTIO通过对NO的直接清除作用在内毒素休克中具有强大的治疗价值。
