TY - JOUR T1 - Pharmacologic Inhibition of the Renal Outer Medullary Potassium Channel Causes Diuresis and Natriuresis in the Absence of Kaliuresis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 153 LP - 164 DO - 10.1124/jpet.113.208603 VL - 348 IS - 1 AU - Maria L. Garcia AU - Birgit T. Priest AU - Magdalena Alonso-Galicia AU - Xiaoyan Zhou AU - John P. Felix AU - Richard M. Brochu AU - Timothy Bailey AU - Brande Thomas-Fowlkes AU - Jessica Liu AU - Andrew Swensen AU - Lee-Yuh Pai AU - Jianying Xiao AU - Melba Hernandez AU - Kimberly Hoagland AU - Karen Owens AU - Haifeng Tang AU - Reynalda K. de Jesus AU - Sophie Roy AU - Gregory J. Kaczorowski AU - Alexander Pasternak Y1 - 2014/01/01 UR - http://jpet.aspetjournals.org/content/348/1/153.abstract N2 - 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. ER -