Pollock D M, Polakowski J S, Wegner C D, Opgenorth T J
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA.
Ren Fail. 1997 Nov;19(6):753-61. doi: 10.3109/08860229709037215.
Endothelin has been implicated in the pathogenesis of acute renal failure associated with radiocontrast media. The current study was designed to determine the effect of endothelin receptor blockade in a model of radiocontrast-induced nephropathy. Inhibition of prostanoids and nitric oxide with indomethacin and L-nitroarginine methyl ester (L-NAME) predisposes rats to the nephrotoxic effects of radiocontrast media and, therefore, has been proposed as a clinically relevant model. Separate groups of conscious rats were given the ETA receptor antagonist, A-127722 (3, 10, or 30 mg/kg), or water (1 mL/kg) by oral gavage. All rats were then given indomethacin (10 mg/kg), L-NAME (10 mg/kg), and the contrast agent, diatrizoate (6 mL/kg), by intravenous injection at 15-min intervals. Urine was collected for the subsequent 24 h by placing rats in metabolism cages. When indomethacin, L-NAME, and diatrizoate were administered without A-127722, rats displayed typical signs of renal failure; protein excretion was increased from a baseline of 13 +/- 2 to 33 +/- 8 mg/day (p < 0.05) and plasma creatinine increased from 0.52 +/- 0.01 to 0.62 +/- 0.04 mg/dL (p < 0.05). ETA receptor blockade prevented the rise in protein excretion and plasma creatinine in a dose-dependent manner. In separate series of clearance experiments, A-127722 completely inhibited the renal effects of exogenous ET-1. These results suggest that endothelin plays a role in the hemodynamic events in this model and that ETA receptor antagonists should be investigated as potential therapeutic agents for radiocontrast-induced nephropathy.
内皮素与放射性造影剂相关的急性肾衰竭发病机制有关。本研究旨在确定内皮素受体阻断在放射性造影剂诱导的肾病模型中的作用。用吲哚美辛和L-硝基精氨酸甲酯（L-NAME）抑制前列腺素和一氧化氮会使大鼠易受放射性造影剂的肾毒性影响，因此，已被提议作为一种临床相关模型。将清醒的大鼠单独分组，通过口服灌胃给予ETA受体拮抗剂A-127722（3、10或30mg/kg）或水（1mL/kg）。然后所有大鼠每隔15分钟静脉注射吲哚美辛（10mg/kg）、L-NAME（10mg/kg）和造影剂泛影酸盐（6mL/kg）。将大鼠置于代谢笼中，在随后的24小时收集尿液。当在不给予A-127722的情况下给予吲哚美辛、L-NAME和泛影酸盐时，大鼠表现出典型的肾衰竭症状；蛋白质排泄从基线的13±2增加到33±8mg/天（p<0.05），血浆肌酐从0.52±0.01增加到0.62±0.04mg/dL（p<0.05）。ETA受体阻断以剂量依赖的方式阻止了蛋白质排泄和血浆肌酐的升高。在单独的一系列清除实验中，A-127722完全抑制了外源性ET-1的肾脏作用。这些结果表明，内皮素在该模型的血流动力学事件中起作用，并且ETA受体拮抗剂应作为放射性造影剂诱导的肾病的潜在治疗药物进行研究。
