Vaziri N D, Ni Z, Zhang Y P, Ruzics E P, Maleki P, Ding Y
Department of Medicine, University of California, Irvine, USA.
Kidney Int. 1998 Aug;54(2):482-91. doi: 10.1046/j.1523-1755.1998.00014.x.
Introduction of cyclosporine (CsA) for clinical use has greatly enhanced the outcome of organ transplantation. However, CsA can cause nephrotoxicity and hypertension (HTN). This study was designed to test the hypothesis that CsA-induced HTN is related to depressed nitric oxide (NO) production.
Urinary excretion of NO metabolites (NOx) and endothelial and inducible NO synthase (eNOS and iNOS) proteins were determined in thoracic aortas and kidneys of CsA-treated (given CsA 18 mg/kg/day for 3 weeks) and placebo-treated rats. In addition, renal tissue eNOS and iNOS mRNA and aorta iNOS activity were measured.
CsA administration resulted ina significant rise in arterial blood pressure (BP) coupled with a steady decline in urinary NOx excretion, suggesting depressed NO production. This was accompanied by a significant reduction in iNOS protein abundance in the kidney and thoracic aorta but no change in eNOS protein abundance. The fall in renal iNOS protein in CsA-treated rats was accompanied by a parallel decline in iNOS mRNA abundance and enzymatic activity.
Administration of CsA for three weeks resulted in a significant rise in BP together with marked reductions in urinary NOx excretion, and renal and vascular iNOS expression. These observations suggest that CsA-induced HTN may be, in part, related to impaired NO production. If true, strategies designed to restore NO availability may mitigate HTN and other vascular complications of CsA therapy.
环孢素（CsA）引入临床应用后极大地改善了器官移植的效果。然而，CsA可导致肾毒性和高血压（HTN）。本研究旨在验证CsA诱导的HTN与一氧化氮（NO）生成减少有关这一假说。
测定经CsA处理（给予CsA 18 mg/kg/天，持续3周）和给予安慰剂处理的大鼠胸主动脉和肾脏中NO代谢产物（NOx）的尿排泄量以及内皮型和诱导型NO合酶（eNOS和iNOS）蛋白水平。此外，检测肾组织eNOS和iNOS mRNA以及主动脉iNOS活性。
给予CsA导致动脉血压（BP）显著升高，同时尿NOx排泄量持续下降，提示NO生成减少。这伴随着肾脏和胸主动脉中iNOS蛋白丰度显著降低，但eNOS蛋白丰度无变化。CsA处理大鼠肾iNOS蛋白的下降伴随着iNOS mRNA丰度和酶活性的平行下降。
给予CsA三周导致BP显著升高，同时尿NOx排泄量、肾和血管iNOS表达显著降低。这些观察结果表明，CsA诱导的HTN可能部分与NO生成受损有关。如果属实，旨在恢复NO可利用性的策略可能减轻CsA治疗的HTN和其他血管并发症。
