Kusumoto K, Kubo K, Kandori H, Kitayoshi T, Sato S, Wakimasu M, Watanabe T, Fujino M
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Life Sci. 1994;55(4):301-10. doi: 10.1016/0024-3205(94)00732-2.
Protective effects of a new endothelin (ET) receptor antagonist, TAK-044, were studied in a model of acute renal failure (ARF) in rats. ARF was induced by clamping the left renal pedicle for 45 minutes with contralateral nephrectomy and subsequent reperfusion of the left kidney. Plasma creatinine concentration (Pcr) increased to 2.28 mg/dl 24 hours after reperfusion of the ischemic kidney. Intravenous administration of TAK-044 (1-10mg/kg) prior to renal occlusion dose-dependently but partially attenuated the increase in Pcr and the morphological damages of the kidney. ET-1 and ET-3 increased perfusion pressure in isolated kidney preparations with similar potency, indicating that the renal vasoconstriction evoked by these ET isomers is mainly via ETB receptors, and TAK-044 (10nM) shifted the ET-1 dose-response curve to the right by a factor about 10. In a rat renal membrane fraction, ET-1 showed competitive inhibition of specific [125I]ET-1 binding with an IC50 value of 0.34nM and a Hill slope of 1.10. ET-3 did so with a higher IC50 value (3.3nM) and a lower Hill slope (0.56), suggesting that rat kidney contains both ETA and another receptor subtype, probably ETB. TAK-044 inhibited ET-1 binding with an IC50 value of 6.6nM and a Hill slope of 0.41. Plasma concentrations of immunoreactive TAK-044 were maintained over 7nM for 8 hours following i.v. injection of 10mg/kg TAK-044. These results suggest that endogenous ET is involved in the pathogenesis of post-ischemic ARF, at least, in part and that TAK-044 provided protective effects against ARF by blocking ET receptors, possibly both ETA and ETB receptors in renal vasculature and parenchymal cells.
在大鼠急性肾衰竭（ARF）模型中研究了一种新型内皮素（ET）受体拮抗剂TAK - 044的保护作用。通过夹闭左肾蒂45分钟并对侧肾切除，随后对左肾进行再灌注来诱导ARF。缺血肾再灌注24小时后，血浆肌酐浓度（Pcr）升至2.28mg/dl。在肾闭塞前静脉注射TAK - 044（1 - 10mg/kg）剂量依赖性但部分减轻了Pcr的升高和肾脏的形态学损伤。ET - 1和ET - 3以相似的效力增加离体肾制备物中的灌注压力，表明这些ET异构体引起的肾血管收缩主要通过ETB受体，并且TAK - 044（10nM）使ET - 1剂量反应曲线右移约10倍。在大鼠肾膜部分，ET - 1对特异性[125I]ET - 1结合表现出竞争性抑制，IC50值为0.34nM，希尔斜率为1.10。ET - 3的IC50值较高（3.3nM），希尔斜率较低（0.56），表明大鼠肾脏含有ETA和另一种受体亚型，可能是ETB。TAK - 044以IC50值6.6nM和希尔斜率0.41抑制ET - 1结合。静脉注射10mg/kg TAK - 044后，免疫反应性TAK - 044的血浆浓度在8小时内维持在7nM以上。这些结果表明内源性ET至少部分参与了缺血后ARF的发病机制，并且TAK - 044通过阻断ET受体，可能是肾血管和实质细胞中的ETA和ETB受体，对ARF提供了保护作用。
