钙离子通道阻滞剂在预防他克莫司肾毒性中的作用

Preventive effect of calcium channel blocker in tacrolimus induced nephrotoxicity in rats

目的观察他克莫司（FK506）肾毒性模型中钙离子代谢的变化情况，探讨钙离子通道阻滞剂地尔硫革（DiD对FK506肾毒性的预防作用。方法按公式将肾移植术后FK506、环孢素（CsA）和Dil的首剂治疗剂量换算成大鼠的治疗剂量。雄性SD大鼠24只随机分成对照组、CsA组（25mg·kg^-1·d^-1）、FK506组（0．8mg·kg^-1·d^-1）和FK506加Dil组（0．8mg·kg^-1·d^-1及8mg·kg^-1·d^-1），每组6只，用药4周后建立各组大鼠肾毒性模型，观察各组大鼠SCr、血电解质、肾组织的病理改变（HE染色）、电子显微镜下肾脏细胞内超微结构的改变。结果CsA组和FK506组大鼠SCr值分别为（36．00±2．61）和（34．17±4．54）μmol／L，均高于FK506加Dil组和对照组[（28．50±2．07）和（29．17±3．43）μmol／L，P〈0．05]。CsA组和FK506组大鼠血钙浓度分别为（2．00±0．04）和（2．05±0．04）mmol／L，均低于FK506加Dil组和对照组（P〈0．05）。CsA组和FK506组均可观察到肾小管细胞轻微肿胀及空泡变性、线粒体肿胀及空泡化等病理改变。与FK506组和CsA组相比，FK506加Dil组上述各项指标的变化明显减轻或接近正常。结论钙离子代谢紊乱可能介导了FK506引起的肾毒性，Dil可用于预防FK506的肾毒性。

Objective To study the calcium metabolism in tacrolimus （FK506） induced rats nephrotoxicity and the preventive effect of calcium channel blocker. Methods Twenty-four Sprague- Dawley male rats were randomly divided into 4 groups： control group（n= 6）, CsA group （25 mg·kg^-1·d^-1, n=6）, FK506 group （0.8 mg·kg^-1·d^-1, n=6）, and FK506 ＋diltiazem（Dil） group （0.8 mg·kg^-1·d^-1＋8 mg·kg^-1·d^-1 , n=6）. The rats were treated for 4 weeks to develop CsA-induced or FK506-induced nephropathy model. Blood creatinine, blood electrolytes, renal tissue histo- pathology （HE stain） and the change of ultrastructural organization in renal cells by transmission electron microscope were observed. Results The blood creatinine levels of both CsA and FK506 groups [（36.00±2.61） and （34.17±4.54）μmol/L] were significantly higher than those of the FK506 ＋ Dil group and control group （all P〈0. 05）. The blood calcium levels of both CsA and FK506 groups （2. 00±0.04 and 2.05 ±0.04 mmol/L） were significantly lower than those of the FK506 ＋ Dit group and control group （all P〈0.05）. The blood creatinine and calcium levels of FK506＋Dil group were not significantly different with those of control group（P〈0.05）. Histopathology examination showed cloudy swelling and vacuolization of the renal tubular epithelial cells and intra-cellular mitochondria swelling and vacuolization in the CsA and FK506 groups. However, the pathological changes of the FK506＋Dil group were remarkably milder in comparison with the CsA and FK506 groups. Conclu- sions Disorder of calcium metabolism may be involved in FK506-induced nephrotoxicity in rats. Calcium channel blocker, Dil, could prevent the FK506-induced nephrotoxicity.