Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresiss

Garcia, Maria L., Priest, Birgit, T., Alonso-Galicia, Magdalena, Zhou, Xiaoyan, Felix, John P., Brochu, Richard M., Bailey, Timothy, Thomas-Fowlkes, Brande, Liu, Jessica, Swensen, Andrew, Pai, Lee-Yuh, Xiao, Jianying, Hernandez, Melba, Hoagland, Kimberley, Owens, Karen, Tang, Haifeng, de Jesus, Reynalda K., Roy, Sophie, Kaczorowski, Gregory J. and Pasternak, Alexander (2014) Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresiss. Journal of Pharmacology and Experimental Therapeutics, 348 1: 153-164. doi:10.1124/jpet.113.208603

Author Garcia, Maria L.
Priest, Birgit, T.
Alonso-Galicia, Magdalena
Zhou, Xiaoyan
Felix, John P.
Brochu, Richard M.
Bailey, Timothy
Thomas-Fowlkes, Brande
Liu, Jessica
Swensen, Andrew
Pai, Lee-Yuh
Xiao, Jianying
Hernandez, Melba
Hoagland, Kimberley
Owens, Karen
Tang, Haifeng
de Jesus, Reynalda K.
Roy, Sophie
Kaczorowski, Gregory J.
Pasternak, Alexander
Title Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresiss
Journal name Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2014-01
Year available 2013
Sub-type Article (original research)
DOI 10.1124/jpet.113.208603
Open Access Status
Volume 348
Issue 1
Start page 153
End page 164
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2014
Language eng
Formatted abstract
The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter’s syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter’s syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 12 times in Scopus Article | Citations
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Created: Mon, 16 Dec 2013, 15:35:52 EST by Susan Allen on behalf of Institute for Molecular Bioscience