Rankin G O, Valentovic M A, Teets V J, Nicoll D W, Sutherland C H, Brown P I
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Toxicology. 1991 Feb 11;66(1):19-34. doi: 10.1016/0300-483x(91)90175-z.
The nephrotoxicity induced by a wide variety of chemical compounds can be attenuated by agents which modify calcium ion (Ca2+) movement across membranes or calcium-dependent processes. The purpose of this study was to examine the ability of nifedipine, a calcium channel blocking drug, and chlorpromazine (CPZ), an antagonist of many calcium-dependent processes, to attenuate the nephrotoxicity induced by the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) or its metabolite N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS). Male Fischer 344 rats (4 rats per group) were pretreated intraperitoneally (i.p.) with nifedipine (0.25 or 0.50 mg/kg), CPZ (1.0 or 5.0 mg/kg) or vehicle 1 h before NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). In separate experiments, rats were pretreated with nifedipine (0.25 or 0.50 mg/kg/day, i.p.) starting 2 days before NDPS or NDPS vehicle and continuing throughout the experiment. Renal function was monitored at 24 and 48 h. Nifedipine (single or multiple treatments) and CPZ (1.0 mg/kg) were ineffective in substantially altering NDPS (0.4 mmol/kg)-induced nephrotoxicity. However, CPZ (5.0 mg/kg) markedly attenuated all aspects of NDPS-induced nephropathy. Also, CPZ (5.0 mg/kg) partially protected against NDHS (0.1 mmol/kg)-induced renal effects. These results demonstrate the inability of the calcium channel blocker nifedipine to attenuate NDPS nephrotoxicity. Attenuation of NDPS nephrotoxicity by CPZ could suggest that CPZ is antagonizing calcium influx into renal tissue and/or renal intracellular calcium-dependent processes to modify the renal response to NDPS. However, the inability of CPZ to markedly attenuate NDHS nephrotoxicity could indicate that CPZ protected against NDPS nephrotoxicity by inhibiting biotransformation of the parent compound to its toxic chemical species.
多种化合物诱导的肾毒性可被改变钙离子（Ca2+）跨膜转运或钙依赖性过程的药物所减轻。本研究的目的是检测钙通道阻滞剂硝苯地平以及许多钙依赖性过程的拮抗剂氯丙嗪（CPZ）减轻农用杀菌剂N-（3,5-二氯苯基）琥珀酰亚胺（NDPS）或其代谢产物N-（3,5-二氯苯基）-2-羟基琥珀酰亚胺（NDHS）诱导的肾毒性的能力。雄性Fischer 344大鼠（每组4只）在腹腔注射NDPS（0.4 mmol/kg）、NDHS（0.1 mmol/kg）或溶剂（芝麻油，2.5 ml/kg）前1小时，腹腔注射硝苯地平（0.25或0.50 mg/kg）、CPZ（1.0或5.0 mg/kg）或溶剂。在单独的实验中，大鼠在NDPS或NDPS溶剂注射前2天开始腹腔注射硝苯地平（0.25或0.50 mg/kg/天），并持续整个实验过程。在24小时和48小时监测肾功能。硝苯地平（单次或多次给药）和CPZ（1.0 mg/kg）对显著改变NDPS（0.4 mmol/kg）诱导的肾毒性无效。然而，CPZ（5.0 mg/kg）显著减轻了NDPS诱导的肾病的各个方面。此外，CPZ（5.0 mg/kg）部分保护了大鼠免受NDHS（0.1 mmol/kg）诱导的肾脏效应。这些结果表明钙通道阻滞剂硝苯地平无法减轻NDPS肾毒性。CPZ减轻NDPS肾毒性可能表明CPZ正在拮抗钙流入肾组织和/或肾细胞内钙依赖性过程，以改变肾脏对NDPS的反应。然而，CPZ无法显著减轻NDHS肾毒性可能表明CPZ通过抑制母体化合物向其有毒化学物质的生物转化来预防NDPS肾毒性。
