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 dissolve struvite stones because it inhibits the urease produced by Proteus mirabilis. To be effective, the concentration of AHA must be high in the collecting duct system and final urine. Because AHA is structurally similar to urea, we investigated whether AHA is transported by the urea carrier found in the terminal inner medullary collecting duct (IMCD) and the erythrocyte. We examined AHA transport under four conditions known to affect urea movement across the terminal IMCD, i.e., stimulation by vasopressin (AVP) and hyperosmolality, and inhibition by phloretin and urea analogues. The AHA permeability was determined with a 10 mM bath-to-lumen AHA gradient. AHA was measured by ultramicrocolorimetry. Addition of 1 nM AVP to the bath increased the AHA permeability of the perfused terminal IMCD. Increasing perfusate and bath osmolality from 290 to 690 mosmol/kgH2O (by adding NaCl) also increased tubule permeability to AHA. Addition of either 0.25 mM phloretin to the bath or 200 mM thiourea to the lumen reversibly inhibited the AVP-stimulated AHA permeability. AHA-induced osmotic lysis of erythrocytes was inhibited by phloretin or thionicotinamide; AHA inhibited the osmotic lysis induced by the urea analogue acetamide. Thus, in the rat terminal IMCD, both urea and AHA transport are stimulated by AVP and hyperosmolality, and both are inhibited by phloretin and thiourea. In erythrocytes, both urea and AHA transport are inhibited by phloretin or thionicotinamide. Thus AHA is transported by the urea carrier in the terminal IMCD and erythrocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8856.
Gillin
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Parikh
V J
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Sands
J M
JM
D000081:Acetamides / Q000097:blood; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001692:Biological Transport; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006877:Hydroxamic Acids / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007679:Kidney Medulla; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D009994:Osmolar Concentration; D010539:Permeability; D010693:Phloretin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000494:pharmacology; D014508:Urea / Q000378:metabolism*; D014510:Urease / Q000037:antagonists & inhibitors*
D000081:Acetamides; D006877:Hydroxamic Acids; D001127:Arginine Vasopressin; C006358:acetohydroxamic acid; D014508:Urea; C030686:acetamide; D014510:Urease; D013890:Thiourea; D010693:Phloretin