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 now known whether this effect can al so be shown in vivo. Inhibition of osmolyte efflux by KC would impair osmotic adaptation and result in stress to the cells of the renal medu lla when extracellular osmolality falls. Stress-inducible heat shock p roteins (HSPs) may also participate in this response to osmotic stress . The aim of the present study was thus to establish whether KC inhibi ts organic osmolyte efflux from the cells of the renal medulla in vivo in response to a furosemide diuresis, and to establish whether HSPs a re involved. A 20-minute furosemide infusion reduced urine osmolality and medullary urea content in control and KC-treated rats similarly. H owever, the efflux of methylamines (glycerophosphorylcholine, betaine) and polyols (myo-inositol, sorbitol) was attenuated in KC-treated rat s while the efflux of amino acids was not significantly affected. Phos phorylation of HSP25 after the 20-minute furosemide diuresis was incre ased in KC rats. With continuing diuresis this returned to control lev els 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 amount s of HSP25 and HSP72 in KC-treated rats compared with control. These r esults suggest the KC inhibits the efflux of methylamines and polyols, thus impeding osmoadaptation of renal modullary cells during the onse t of diuresis. This situation apparently increases the osmotic stress experienced by the cells of the renal medulla and provokes expression of HSP25 and HSP72.