Role of calcium in cisplatin-induced cell toxicity in rat renal cortical slices

The disruption of intracellular Ca(2+) homoeostasis is involved in cisplatin-induced nephrotoxicity. The role of Ca(2+) in cisplatin toxicity was studied by use of rat renal cortical slices. Cisplatin (2 mm) increased 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 units/g wet weight. The leakage of lactate dehydrogenase (LDH) was increased from 3.8 +/- 1.1 units/g wet weight to 13.7 +/- 1.0 units/g wet weight. Pretreatment of slices with ethylene glycol-bis(beta-aminoethylether)N,N,N'N'-tetraacetic acid (1 mm) to buffer intracellular Ca(2+) significantly decreased the cisplatin-induced leakage of these two enzymes to 65% and 53%, respectively, of levels with cisplatin alone. An increase in extracellular Ca(2+), or omission of Ca(2+) from the medium, had no effect on cisplatin-induced slice toxicity. Furthermore, the Ca(2+) channel blockers nifedipine and diltiazem did not protect against cytotoxicity by cisplatin, although verapamil gave mild protection and decreased the cisplatin-induced release of AST and LDH to 78% and 75%, respectively, of that caused by cisplatin alone. The results suggest that intracellular Ca(2+) is important in cisplatin-induced nephrotoxicity but that disruption of cytosolic Ca(2+) is not caused by opening of Ca(2+) channels of the plasma membrane or even by leakage through the injured membrane.