ROLE OF CALCIUM IN CISPLATIN-INDUCED CELL TOXICITY IN RAT RENAL CORTICAL SLICES

The disruption of intracellular Ca2+ homoeostasis is involved in cispl atin-induced. nephrotoxicity. The role of Ca2+ in cisplatin toxicity w as studied by use of rat renal cortical slices. Cisplatin (2 mM) incre ased the leakage of aspartate aminotransferase (AST) from 1.4 +/- 0.5 units/g wet weight (mean +/- SE) with control slices to 3.4 +/- 0.5 un its/g wet weight. The leakage of lactate dehydrogenase (LDH) was incre ased from 3.8 +/- 1.1 units/g wet weight to 13.7 +/- 1.0 units/g wet w eight. Pretreatment of slices with ethylene ycol-bis(beta-aminoethylet her)N,N,N'N'-tetraacetic acid (1 mM) to buffer intracellular Ca2+ sign ificantly decreased the cisplatin-induced leakage of these two enzymes to 65% and 53%, respectively, of levels with cisplatin alone. An incr ease in extracellular Ca2+, or omission of Ca2+ from the medium, had n o effect on cisplatin-induced slice toxicity. Furthermore, the Ca2+ ch annel blockers nifedipine and diltiazem did not protect against cytoto xicity by cisplatin, although verapamil gave mild protection and decre ased the cisplatin-induced release of AST and LDH to 78% and 75%, resp ectively, of that caused by cisplatin alone. The results suggest that intracellular Ca2+ is important in cisplatin-induced nephrotoxicity bu t that disruption of cytosolic Ca2+ is not caused by opening of Ca2+ c hannels of the plasma membrane or even by leakage through the injured membrane. Copyright (C) 1996 Elsevier Science Ltd.