Therapy with foscarnet is associated with acute renal failure. Prior studies have emphasized foscarnet's proximal tubular toxicity, but there have been isolated reports of foscarnet-induced nephrogenic diabetes insipidus. As a phosphate analog, foscarnet is a competitive inhibitor of NaPO 4 cotransport. However, foscarnet's effect on antidiuretic hormone (ADH)-induced transport has not been previously investigated. We studied foscarnet's modulation of transport in the toad urinary bladder. Foscarnet at 10 M to 10 mM did not alter basal water or urea flux. Urea transport induced by a maximal dose of ADH (24 mIU/ml) was inhibited by 0.1 to 5.0 mM foscarnet. In tissues challenged with 0.5 to 1.0 mIU of ADH per ml, 1.0 to 10 mM foscarnet increased water flow but did not alter urea flux. Foscarnet also increased water flow induced by 1.0 to 10 M forskolin. In tissues pretreated with 10 M naproxen, foscarnet did not alter water flow induced by 0.5 to 1.0 mIU of ADH per ml or forskolin. These results indicate that foscarnet stimulates water flow induced by 0.5 to 1.0 mIU of ADH per ml at a site proximal to that of the generation of cyclic AMP and inhibits urea flux induced by a maximal dose of ADH at a separate site. In humans, foscarnet nephrotoxicity is likely not limited to the proximal nephron, but extends to the collecting duct. Patients receiving foscarnet should be closely monitored for disorders of urinary concentration.
We previously reported that HgCl2 inhibits water and urea flux in tissues fixed with glutaraldehyde after antidiuretic hormone (ADH) stimulation and suggested that the ADH-induced water channel may share characteristics of the red blood cell and proximal tubule water transport pathway. To determine the specificity of mercury's action, we examined the effect of numerous other metals. In tissues fixed after ADH stimulation, water flow and urea and sucrose permeabilities are maintained from mucosal bath pH 2.5 through pH 12. Several metals including Ba, Co, Fe, Sr and Zn did not alter flux. Al, Cd, La, Li, Pb and U inhibited urea permeability but not water flow. At pH 2.8, Cu inhibited water flow by 30% and urea permeability by 50%. At pH 4.9-7.4, Cu inhibited urea permeability but not water flow. At pH less than or equal to 3.0, Pt inhibited flow in ADH-pretreated tissues. The inhibitory effect was not present at pH greater than 3.0. At pH less than 3.0, Au inhibited flow by 90% in tissues fixed after pretreatment with ADH but increased the permeability of tissues fixed in the absence of ADH. Ag inhibited flow by 70% but also increased sucrose, urea, and basal permeabilities. This suggests that Ag and Au disrupt epithelial integrity. These results indicate that at physiologic pH, the ADH-induced water channel is specifically blocked by Hg but not by other metals. This specificity may reflect the presence of a large number of sulfhydryl groups in the water channel.
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