Kurata Hayato, Takaoka Masanori, Kubo Yasuhiro, Katayama Tomoaki, Tsutsui Hidenobu, Takayama Junji, Ohkita Mamoru, Matsumura Yasuo
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Eur J Pharmacol. 2005 Jul 11;517(3):232-9. doi: 10.1016/j.ejphar.2005.05.026.
To elucidate the role of nitric oxide (NO) in the pathogenesis of ischemic acute renal failure, we examined the effects of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N(G)-nitro-L-arginine methyl ester (L-NAME) as a NO donor and a non-selective NO synthase inhibitor on ischemia/reperfusion-induced renal injury and renal endothelin-1 content. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage. In addition, increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2, 6, and 24 h after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, i.v.) attenuated ischemia/reperfusion-induced renal dysfunction, histological damage, and endothelin-1 overproduction after reperfusion. In contrast, pretreatment with L-NAME (1 or 10 mg/kg, i.v.) aggravated renal injuries of acute renal failure rats at 24 h after reperfusion, and the effect is accompanied by further increases in the renal endothelin-1 content at 2 and 6 h, but not at 24 h, after reperfusion. These results suggest that suppressive effects of NO on the renal endothelin-1 overproduction induced by ischemia/reperfusion in an early phase are probably responsible for the protective effect of NO against ischemic acute renal failure.
为阐明一氧化氮（NO）在缺血性急性肾衰竭发病机制中的作用，我们研究了作为NO供体的（±）-（E）-4-乙基-2-[(E)-羟基亚氨基]-5-硝基-3-己烯酰胺（FK409）和作为非选择性NO合酶抑制剂的N（G）-硝基-L-精氨酸甲酯（L-NAME）对缺血/再灌注诱导的肾损伤及肾内皮素-1含量的影响。在对侧肾切除术后2周，通过阻断左肾动脉和静脉45分钟后再灌注诱导缺血性急性肾衰竭。再灌注后24小时，未治疗的急性肾衰竭大鼠的肾功能显著下降，组织学检查显示严重的肾损伤。此外，急性肾衰竭大鼠在再灌注后2、6和24小时肾内皮素-1含量分别明显增加。FK409（1或3mg/kg，静脉注射）预处理减轻了再灌注后缺血/再灌注诱导的肾功能障碍、组织学损伤和内皮素-1过量产生。相反，L-NAME（1或10mg/kg，静脉注射）预处理加重了急性肾衰竭大鼠再灌注后24小时的肾损伤，且该作用伴随着再灌注后2和6小时肾内皮素-1含量的进一步增加，但在24小时时没有增加。这些结果表明，NO在早期对缺血/再灌注诱导的肾内皮素-1过量产生的抑制作用可能是NO对缺血性急性肾衰竭具有保护作用的原因。
