THE UREASE INHIBITOR ACETOHYDROXAMIC ACID IS TRANSPORTED BY THE UREA PATHWAY IN RAT TERMINAL IMCD

Acetohydroxamic acid (AHA), a urea analogue, is used clinically to dis solve struvite stones because it inhibits the urease produced by Prote us mirabilis. To be effective, the concentration of AHA must be high i n the collecting duct system and final urine. Because AHA is structura lly similar to urea, we investigated whether AHA is transported by the urea carrier found in the terminal inner medullary collecting duct (I MCD) and the erythrocyte. We examined AHA transport under four conditi ons known to affect urea movement across the terminal IMCD, i.e., stim ulation by vasopressin (AVP) and hyperosmolality, and inhibition by ph loretin and urea analogues. The AHA permeability was determined with a 10 mM bath-to-lumen AHA gradient. AHA was measured by ultramicrocolor imetry. Addition of 1 nM AVP to the bath increased the AHA permeabilit y of the perfused terminal IMCD. Increasing perfusate and bath osmolal ity from 290 to 690 mosmol/kgH2O (by adding NaCl) also increased tubul e permeability to AHA. Addition of either 0.25 mM phloretin to the bat h or 200 mM thiourea to the lumen reversibly inhibited the AVP-stimula ted AHA permeability. AHA-induced osmotic lysis of erythrocytes was in hibited by phloretin or thionicotinamide; AHA inhibited the osmotic ly sis induced by the urea analogue acetamide. Thus, in the rat terminal IMCD, both urea and AHA transport are stimulated by AVP and hyperosmol ality, and both are inhibited by phloretin and thiourea. In erythrocyt es, both urea and AHA transport are inhibited by phloretin or thionico tinamide. Thus AHA is transported by the urea carrier in the terminal IMCD and erythrocyte. Transport across the terminal IMCD may account i n part for its urinary accumulation and its ability to dissolve struvi te stones.