Shibata Yujiro, Takaoka Masanori, Maekawa Daisuke, Kuwahara Chika, Matsumura Yasuo
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S459-61. doi: 10.1097/01.fjc.0000166315.38258.e1.
It is known that 17beta-estradiol (E2-beta) increases the production of nitric oxide. We have demonstrated that E2-beta prevents renal injury and suppresses renal endothelin-1 overproduction in ischemic acute renal failure in rats. In the present study, we investigated whether N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, can reverse the effect of E2-beta in ischemic acute renal failure. Ischemic acute renal failure was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. Pre-ischemic treatment with E2-beta (100 microg/kg, intravenously) attenuated the ischemia/ reperfusion-induced renal dysfunction and suppressed the increment of renal endothelin-1 content 24 hours after reperfusion. The effects of E2-beta on renal dysfunction and increased endothelin-1 content in acute renal failure rats were reversed by pretreatment with N(G)-nitro-L-arginine methyl ester (0.3 mg/kg, intravenously). An in vivo microdialysis study revealed that the concentration of nitric oxide metabolites in the kidney was reduced during ischemia, and quickly recovered after reperfusion in E2-beta-treated acute renal failure rats, compared with cases in untreated acute renal failure rats. This recovery of renal nitric oxide metabolite concentration with E2-beta was abolished by the pretreatment with N(G)-nitro-Larginine methyl ester. These findings suggest that nitric oxide is closely related to suppressive effect of E2-beta on renal endothelin-1 overproduction in acute renal failure rats and this suppression is probably involved in the beneficial effect of E2-beta on ischemia/reperfusion-induced renal injury.
已知17β-雌二醇（E2-β）可增加一氧化氮的生成。我们已经证明，E2-β可预防大鼠缺血性急性肾衰竭中的肾损伤，并抑制肾内皮素-1的过度生成。在本研究中，我们调查了一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸甲酯是否能逆转E2-β在缺血性急性肾衰竭中的作用。在对侧肾切除术后2周，通过夹闭左肾动脉和静脉45分钟然后再灌注来诱导缺血性急性肾衰竭。缺血前用E2-β（100微克/千克，静脉注射）治疗可减轻缺血/再灌注诱导的肾功能障碍，并抑制再灌注后24小时肾内皮素-1含量的增加。N（G）-硝基-L-精氨酸甲酯（0.3毫克/千克，静脉注射）预处理可逆转E2-β对急性肾衰竭大鼠肾功能障碍和内皮素-1含量增加的影响。一项体内微透析研究显示，与未治疗的急性肾衰竭大鼠相比，E2-β治疗的急性肾衰竭大鼠在缺血期间肾脏中一氧化氮代谢物的浓度降低，再灌注后迅速恢复。用N（G）-硝基-L-精氨酸甲酯预处理可消除E2-β使肾一氧化氮代谢物浓度恢复的作用。这些发现表明，一氧化氮与E2-β对急性肾衰竭大鼠肾内皮素-1过度生成的抑制作用密切相关，这种抑制作用可能参与了E2-β对缺血/再灌注诱导的肾损伤的有益作用。
