title: Chronic Inhibition of Renal Outer Medullary Potassium Channel Not Only Prevented but Also Reversed Development of Hypertension and End-Organ Damage in Dahl Salt-Sensitive Rats.
abstract: The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na+/K+/2Cl-cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups-control, high-salt diet alone; ROMKi B 3 mg·kg-1·d-1; ROMKi B 10 mg·kg-1·d-1; and hydrochlorothiazide 25 mg·kg-1·d-1-were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was superior to hydrochlorothiazide at reducing blood pressure. Furthermore, ROMKi B provided beneficial effects on both the plasma lipid profile and bone mineral density. Chronic ROMK inhibition not only prevented but also reversed the development of hypertension and end-organ damage in Dahl salt-sensitive rats. Our findings suggest a potential utility of ROMKi B as a novel antihypertensive agent, particularly for the treatment of the salt-sensitive hypertension patient population.
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ. xiaoyan_zhou@merck.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forrest
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Wanda
authors.initials: W
authors.lastname: Sharif-Rodriguez
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Olga
authors.initials: O
authors.lastname: Urosevic-Price
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Andra S
authors.initials: AS
authors.lastname: Stevenson
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Sloan
authors.initials: S
authors.lastname: Stribling
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Maya
authors.initials: M
authors.lastname: Dajee
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.affiliation: From the Departments of Cardiometabolic Diseases (X.Z., W.S.-R., Y.Z., A.S.S., M.D., K.A.S.), In Vivo Pharmacology (M.J.F., G.F., D.S., O.U.-P., Y.Z., S.S.), and Chemistry (S.P.W., A.P.), Merck & Co, Inc, Kenilworth, NJ.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sullivan
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D001794:Blood Pressure; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006973:Hypertension / Q000378:metabolism / Q000517:prevention & control*; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl
chemical_list: D015415:Biomarkers; C510692:Kcnj1 protein, rat; D024661:Potassium Channels, Inwardly Rectifying
keywords: Dahl salt-sensitive rats; ROMK inhibitor; end-organ protection; hydrochlorothiazide; hypertension