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The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartters Syndrome Type II Phenotype

2016; American Society for Pharmacology and Experimental Therapeutics; Volume: 359; Issue: 1 Linguagem: Inglês

10.1124/jpet.116.235150

1521-0103

Caryn Hampton, Xiaoyan Zhou, Birgit T. Priest, Lee-Yuh Pai, John P. Felix, Brande Thomas-Fowlkes, Jian Liu, Martin Köhler, Jianming Xiao, Alejandra Amador Corona, Owen Price, Christopher Gill, Kirti Shah, Cordelia Rasa, Vincent Tong, Karen Owens, James D. Ormes, Haifeng Tang, Sophie Roy, Kathleen A. Sullivan, Joseph M. Metzger, Magdalena Alonso‐Galicia, Gregory J. Kaczorowski, Alexander Pasternak, María L. García,

Electrolyte and hormonal disorders

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter9s syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5′-((1 R ,1′ R )-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3 H )-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.