Grieve E M, Hawksworth G M, Simpson J G, Whiting P H
Department of Medicine & Therapeutics, University of Aberdeen, U.K.
Biochem Pharmacol. 1990 Nov 15;40(10):2323-9. doi: 10.1016/0006-2952(90)90729-5.
One component of cyclosporin A (CsA) nephrotoxicity is thromboxane (Tx) A2 induced renal vasoconstriction. This study was designed to investigate whether coadministration of angiotensin converting enzyme inhibitors (ACEI) and thromboxane synthetase inhibition (TSI) could act synergistically to improve the glomerular filtration rate in CsA treated animals. CsA administration (50 mg/kg/day p.o.) to Sprague-Dawley rats for 14 days caused a significant decline in creatinine clearance (CCR), an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage. These changes were associated with a ten-fold increase in urinary TxB2 excretion (from pretreatment values of 17.2 +/- 6.0 ng/day to 174.9 +/- 65.4 ng/day on day 14). Treatment with TSI normalized TxB2 excretion; this was associated with partial protection against CsA induced changes in CCR and NAG enzymuria and the complete prevention of acute proximal tubular vacuolation. However, the coadministration of both TSI and ACEI removed the protective effects exerted by TSI alone and resulted in elevated urinary TxB2 levels similar to those observed in other CsA treated groups. Treatment with ACEI alone did not affect CsA nephrotoxicity. We suggest that elevated TxB2 synthesis is in part responsible for some aspects of renal functional and morphological damage, but that CsA nephrotoxicity is multifactorial and may result from direct cellular toxicity in addition to vascular changes.
环孢素A（CsA）肾毒性的一个组成部分是血栓素（Tx）A2诱导的肾血管收缩。本研究旨在调查血管紧张素转换酶抑制剂（ACEI）与血栓素合成酶抑制（TSI）联合应用是否能协同作用，改善CsA处理动物的肾小球滤过率。给Sprague-Dawley大鼠口服CsA（50 mg/kg/天），持续14天，导致肌酐清除率（CCR）显著下降，N-乙酰-β-D-氨基葡萄糖苷酶（NAG）尿酶增加以及肾小管间质损伤。这些变化与尿TxB2排泄增加10倍相关（从预处理时的17.2±6.0 ng/天增加到第14天的174.9±65.4 ng/天）。TSI治疗使TxB2排泄恢复正常；这与对CsA诱导的CCR和NAG尿酶变化的部分保护以及急性近端肾小管空泡化的完全预防有关。然而，TSI与ACEI联合应用消除了TSI单独应用所产生的保护作用，并导致尿TxB2水平升高，类似于其他CsA处理组观察到的水平。单独使用ACEI治疗不影响CsA肾毒性。我们认为，TxB2合成增加部分导致了肾功能和形态学损伤的某些方面，但CsA肾毒性是多因素的，除血管变化外，可能还源于直接的细胞毒性。
