title: Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.
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.
authors.affiliation: Departments of Ion Channels (M.L.G., B.T.P., J.P.F., R.M.B., T.B., B.T.-F., J.L., A.S., G.J.K.), Hypertension (M.A.-G., X.Z., L.-Y.P., J.X., M.H., S.R.), Drug Metabolism (K.O.), and Medicinal Chemistry (H.T., R. K.J., A.P.), Merck Research Laboratories, Rahway, New Jersey; and Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, Pennsylvania (K.H.).
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brochu
authors.forename: Timothy
authors.initials: T
authors.lastname: Bailey
authors.forename: Brande
authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.forename: Andrew
authors.initials: A
authors.lastname: Swensen
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hoagland
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.forename: Reynalda K
authors.initials: RK
authors.lastname: de Jesus
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004231:Diuresis / Q000187:drug effects* / Q000502:physiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C086989:KCNJ1 protein, human; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying