Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.
Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.
复制标题
内皮素受体拮抗作用对体内急性环孢菌素毒性具有保护作用。
DOI：
10.1038/ki.1992.346
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发表时间：
1992
影响因子：
19.6
通讯作者：
Kon,V
中科院分区：
文献类型：
--
作者：
Fogo,A;Hellings,SE;Inagami,T;Kon,V
内皮素受体拮抗剂在体内急性环孢素毒性中具有保护作用。内皮素（Et）与环孢素A（CsA）肾毒性有关。我们以前已经表明，CsA治疗大鼠Et受体的上调，特别是在肾脏内。因此，Et在体内CsA肾毒性中的作用用一种新的竞争性Et受体特异性拮抗剂BQ-123（EtRA）进一步研究。在Munich-Wistar大鼠中，CsA全身给药导致明显的肾小球低灌注和低滤过，左肾和右肾的RPF分别下降约40%至1.60 ± 0.25和1.73 ± 0.38 ml/min，GFR分别下降约20%至0.61 ± 0.05和0.67 ± 0.11 ml/min。全身CsA治疗后选择性向左肾动脉输注EtRA对该血流动力学模式无影响（左肾和右肾的RPF分别为1.58 ± 0.29和1.92 ± 0.34 ml/min，GFR分别为0.60 ± 0.09和0.70 ± 0.08 ml/min，P = NS vs. CsA阶段）。相比之下，在CsA全身给药之前肾内输注EtRA导致了显著不同的肾脏血流动力学模式。因此，左肾中的EtRA预处理可保护CsA后的肾小球功能障碍：RPF维持在3.23 ± 0.28 ml/min vs 2.96 ± 0.31（P = NS EtRA vs EtRA + CsA），GFR为1.04 ± 0.16 ml/min vs 1.12 ± 0.09（P =NS）。而对侧右肾无保护作用，RPF从3.15 ± 0.34ml/min降至2.39 ± 0.19，GFR从1.04 ± 0.10ml/min降至0.85 ± 0.07（P < 0.05）。输注生理盐水而不是EtRA没有保护作用，EtRA本身不改变全身或肾脏血流动力学。与CsA治疗前肾内注射剂量相当的全身性EtRA没有保护作用：RPF从3.36 ± 0.23 ml/min降至1.96 ± 0.33（P < 0.005），GFR从0.94 ± 0.06 ml/min降至0.67 ± 0.12（P < 0.05）。这些研究支持局部Et激活在急性CsA肾毒性中是关键的。局部应用特异性ETA拮抗剂预处理可在很大程度上防止CsA诱导的肾小球低滤过和低灌注。
Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity. Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for EtAreceptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 ± 0.25 and 1.73 ± 0.38 ml/min and GFR decreasing by some 20% to 0.61 ± 0.05 and 0.67 ± 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 ± 0.29 and 1.92 ± 0.34 ml/min and GFR 0.60 ± 0.09 and 0.70 ± 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 ± 0.28 ml/min versus 2.96 ± 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 ± 0.16 ml/min versus 1.12 ± 0.09 (P =NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 ± 0.34 ml/min to 2.39 ± 0.19 and GFR from 1.04 ± 0.10 ml/min to 0.85 ± 0.07 (P < 0.05). Infusion of saline instead of EtRA was without protective effect, and EtRA itself did not alter systemic or renal hemodynamics. Systemic EtRA in a dose comparable to the intrarenal infusion given before CsA treatment was not protective: RPF fell from 3.36 ± 0.23 ml/min to 1.96 ± 0.33 (P < 0.005), and GFR decreased from 0.94 ± 0.06 ml/min to 0.67 ± 0.12 (P < 0.05). These studies support that local Et activation is pivotal in acute CsA nephrotoxicity. Local pretreatment with a specific EtAantagonist can largely prevent this CsA-induced glomerular hypofiltration and hypoperfusion.