Dataset Information


Diuresis and reduced urinary osmolality in rats produced by small-molecule UT-A-selective urea transport inhibitors.

ABSTRACT: Urea transport (UT) proteins of the UT-A class are expressed in epithelial cells in kidney tubules, where they are required for the formation of a concentrated urine by countercurrent multiplication. Here, using a recently developed high-throughput assay to identify UT-A inhibitors, a screen of 50,000 synthetic small molecules identified UT-A inhibitors of aryl-thiazole, ?-sultambenzosulfonamide, aminocarbonitrile butene, and 4-isoxazolamide chemical classes. Structure-activity analysis identified compounds that inhibited UT-A selectively by a noncompetitive mechanism with IC50 down to ?1 ?M. Molecular modeling identified putative inhibitor binding sites on rat UT-A. To test compound efficacy in rats, formulations and administration procedures were established to give therapeutic inhibitor concentrations in blood and urine. We found that intravenous administration of an indole thiazole or a ?-sultambenzosulfonamide at 20 mg/kg increased urine output by 3-5-fold and reduced urine osmolality by ?2-fold compared to vehicle control rats, even under conditions of maximum antidiuresis produced by 1-deamino-8-D-arginine vasopressin (DDAVP). The diuresis was reversible and showed urea > salt excretion. The results provide proof of concept for the diuretic action of UT-A-selective inhibitors. UT-A inhibitors are first in their class salt-sparing diuretics with potential clinical indications in volume-overload edemas and high-vasopressin-associated hyponatremias.

SUBMITTER: Esteva-Font C 

PROVIDER: S-EPMC4139901 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

Similar Datasets

2012-01-01 | S-EPMC3380644 | BioStudies
2010-01-01 | S-EPMC2957250 | BioStudies
2015-01-01 | S-EPMC4523423 | BioStudies
2013-01-01 | S-EPMC3890325 | BioStudies
2019-11-08 | PXD003496 | Pride
2016-01-01 | S-EPMC4933761 | BioStudies
2004-01-01 | S-EPMC409942 | BioStudies
1000-01-01 | S-EPMC2889632 | BioStudies
2015-01-01 | S-EPMC4357013 | BioStudies
2016-01-01 | S-EPMC4996281 | BioStudies