Ketoconazole inhibits organic osmolyte efflux and induces heat shock proteins in rat renal medulla.

Although ketoconazole (KC) is known to inhibit the cellular efflux of organic osmolytes in vitro, it is not known whether this effect can also be shown in vivo. Inhibition of osmolyte efflux by KC would impair osmotic adaptation and result in stress to the cells of the renal medulla when extracellular osmolality falls. Stress-inducible heat shock proteins (HSPs) may also participate in this response to osmotic stress. The aim of the present study was thus to establish whether KC inhibits organic osmolyte efflux from the cells of the renal medulla in vivo in response to a furosemide diuresis, and to establish whether HSPs are involved. A 20-minute furosemide infusion reduced urine osmolality and medullary urea content in control and KC-treated rats similarly. However, the efflux of methylamines (glycerophosphorylcholine, betaine) and polyols (myo-inositol, sorbitol) was attenuated in KC-treated rats while the efflux of amino acids was not significantly affected. Phosphorylation of HSP25 after the 20-minute furosemide diuresis was increased in KC rats. With continuing diuresis this returned to control levels after three hours. While short-term (up to 3 hr) diuresis did not alter the absolute amounts of HSPs in the renal medulla, long-term (24 or 48 hr) diuresis was associated with significantly increased amounts of HSP25 and HSP72 in KC-treated rats compared with control. These results suggest that KC inhibits the efflux of methylamines and polyols, thus impeding osmoadaptation of renal medullary cells during the onset of diuresis. This situation apparently increases the osmotic stress experienced by the cells of the renal medulla and provokes expression of HSP25 and HSP72.