Fisch J, Gulmi F A, Chou S Y, Mooppan U M, Kester R R, Kim H
Department of Urology, Brookdale Hospital Medical Center, Brooklyn, New York 11212-3198.
J Urol. 1993 Apr;149(4):878-83. doi: 10.1016/s0022-5347(17)36251-1.
Use of the immunosuppressive agent cyclosporine A (CyA) is limited by its associated nephrotoxicity, characterized by an increase in renal vascular resistance (RVR) and reductions in renal blood flow (RBF) and glomerular filtration rate (GFR). The vascular endothelium produces vasoactive substances including endothelium derived relaxation factor (EDRF) and endothelin (ET), which modulate vascular tone. Since CyA has been shown to damage the endothelium, we examined the renal hemodynamic response to intrarenal ET infusion (4 micrograms./kg./minute) in chronic cyclosporine-treated dogs. Prior to ET infusion, CyA-treated dogs had a lower RBF and a greater RVR than normal dogs. In normal dogs, after ET infusion RVR increased from 30.24 +/- 0.64 to 44.60 +/- 1.66 mmHg./ml./minute (p < 0.001), RBF decreased from 4.26 +/- 0.28 to 2.90 +/- 0.30 ml./min./g. (p < 0.001) and GFR decreased from 50.20 +/- 5.90 to 36.50 +/- 7.90 ml. per minute (p < 0.001). In contrast, there was no change in RBF, GFR and RVR after intrarenal ET infusion in CyA-treated dogs. Prior to ET infusion, arterial plasma ET concentration was 5.0 +/- 1.1 pg./ml. in CyA-treated dogs, similar to 7.5 +/- 1.4 pg./ml. in normal dogs, and was not significantly altered in either group after intrarenal ET infusion. We conclude that ET may not contribute to the increased RVR in chronic cyclosporine nephrotoxicity, and suggest a vascular toxicity of CyA, rendering renal vessels unresponsive to the vasoconstrictive effect of ET.
免疫抑制剂环孢素A（CyA）的使用因相关肾毒性而受到限制，其特征为肾血管阻力（RVR）增加、肾血流量（RBF）和肾小球滤过率（GFR）降低。血管内皮会产生包括内皮衍生舒张因子（EDRF）和内皮素（ET）在内的血管活性物质，这些物质可调节血管张力。由于已证明CyA会损害内皮，我们研究了慢性环孢素治疗犬肾内注射ET（4微克/千克/分钟）后的肾血流动力学反应。在注射ET之前，接受CyA治疗的犬的RBF低于正常犬，RVR高于正常犬。在正常犬中，注射ET后，RVR从30.24±0.64增加至44.60±1.66毫米汞柱/毫升/分钟（p<0.001），RBF从4.26±0.28降至2.90±0.30毫升/分钟/克（p<0.001），GFR从50.20±5.90降至36.50±7.90毫升/分钟（p<0.001）。相比之下，在接受CyA治疗的犬肾内注射ET后，RBF、GFR和RVR没有变化。在注射ET之前，接受CyA治疗的犬的动脉血浆ET浓度为5.0±1.1皮克/毫升，与正常犬的7.5±1.4皮克/毫升相似，且两组在肾内注射ET后均未发生显著变化。我们得出结论，ET可能与慢性环孢素肾毒性中RVR增加无关，并提示CyA具有血管毒性，使肾血管对ET的血管收缩作用无反应。
