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Kidney Int. 2015 Aug;88(2):311-20. doi: 10.1038/ki.2015.138. Epub 2015 May 20.

Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats.

Author information

1
1] Departments of Medicine and Physiology, University of California, San Francisco, CA, USA [2] Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
2
Departments of Medicine and Physiology, University of California, San Francisco, CA, USA.
3
Department of Pharmacology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
4
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA, USA.

Abstract

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.

PMID:
25993324
PMCID:
PMC4523423
DOI:
10.1038/ki.2015.138
[Indexed for MEDLINE]
Free PMC Article

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