BACKGROUND Nephrotoxicity induced by contrast media (CM) is well recognized. Nonionic CM with lower osmolality than that of conventional ionic CM have been developed in an effort to reduce toxicity. However, the nephrotoxic effects of nonionic CM have not been well evaluated. Although our previous experiments using rat renal cortical slices indicated that the direct cellular toxicity of nonionic CM is less than that of ionic CM, it was suggested that the less toxic effects of nonionic CM on the metabolic function of renal epithelial cells were in part attributable to the lower osmolality of nonionic CM. In the present experiment, the direct toxicity of nonionic CM on renal epithelial cells was compared with that of ionic CM under equiosmolar conditions, where the effects of osmotic pressure were excluded. METHODS Rat renal cortical slices were incubated with several kinds of CM at 37 degrees C for 120 min. Diatrizoate and iothalamate were employed as ionic CM. Iopamidol and iohexol were employed as nonionic CM. The activities of N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyltransferase (GGTP), and lactate dehydrogenase (LDH) released from the renal slices into the incubation buffer were determined in order to evaluate renal epithelial damage caused by CM. Gluconeogenesis, p-aminohippuric (PAH) acid accumulation and ATP content in rat renal slices were determined with a view to examine the inhibitory effects of CM on the metabolic function of renal epithelial cells. The toxic effects of nonionic CM were compared with those of ionic CM under equiosmolar conditions, where mannitol was added to the experimental groups containing nonionic CM in order to exclude the effects of osmotic pressure. RESULTS A significant difference was generally not found with regard to enzyme release between ionic CM and nonionic CM plus mannitol. The inhibition of gluconeogenesis and PAH accumulation in rat renal slices by nonionic CM with mannitol was less than that by ionic CM. Although the ATP content was reduced by both ionic CM and nonionic CM plus mannitol, there was no significant difference between these two groups. CONCLUSIONS The present experiments demonstrated that nonionic CM were less nephrotoxic than ionic CM with regard to the function of renal epithelial cells, including gluconeogenesis and PAH accumulation, under equiosmolar conditions. These differences in nephrotoxicity between ionic and nonionic CM cannot be fully attributable to differences in osmotic pressure.