ROMK inhibitor actions in the nephron probed with diuretics

Kharade, Sujay V.; Flores, Daniel; Lindsley, Craig W.; Satlin, Lisa M.; Denton, Jerod S.

doi:10.1152/ajprenal.00423.2015

Cited by 16 publications

(13 citation statements)

References 10 publications

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“…In addition, the inhibition of ROMK at the CCD, where it participates in potassium secretion, may ameliorate the hypokalemia resulting from the use of loop and thiazide diuretics. These assumptions are consistent with recent data showing that the major diuretic target site of compound A is the TALH, and that the compound prevents the kaliuretic response caused by either bumetanide or HCTZ as a consequence of its inhibitory actions at both TALH and CCD (Kharade et al, 2015). The results presented in this study with MK-7145 also support these expectations of a ROMK inhibitor, and further illustrate constant diuretic and blood pressure effects in SHRs, without evidence for the development of diuretic resistance during the course of the experiments.…”

Section: Discussionsupporting

confidence: 92%

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

Hampton

Zhou

Priest

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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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 Bartter's 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'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-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.

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Section: Discussionsupporting

confidence: 92%

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

Hampton

Zhou

Priest

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…These responses are different from those induced by inhibitors of the renal outer medullary K 1 channel [ROMK (or Kir1.1)], another emerging diuretic target in the Kir channel family (Denton et al, 2013). We and others have shown that ROMK inhibition evokes diuresis and natriuresis without causing K 1 wasting (Garcia et al, 2014;Kharade et al, 2016;Zhou et al, 2017). The K 1 -sparing effect appears to result predominantly from the inhibition of K 1 secretion in the TAL with a relatively minor effect on distal K 1 secretion (Kharade et al, 2016).…”

Section: Discussionmentioning

confidence: 82%

“…All studies involving animals were approved by Institutional Animal Care and Use Committee. Metabolic cage studies were performed as described previously (Kharade et al, 2016). Briefly, male Sprague-Dawley rats (250-300 g) were allowed to acclimatize to single housing in metabolic cages for 2 hours before an experiment.…”

Section: Metabolic Cage Studiesmentioning

confidence: 99%

Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992

et al. 2018

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The inward rectifier potassium (Kir) channel Kir4.1 () carries out important physiologic roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness. Although genetic approaches have been indispensable for establishing the importance of Kir4.1 in the normal function of these tissues, the availability of pharmacological tools for acutely manipulating the activity of Kir4.1 in genetically normal animals has been lacking. We therefore carried out a high-throughput screen of 76,575 compounds from the Vanderbilt Institute of Chemical Biology library for small-molecule modulators of Kir4.1. The most potent inhibitor identified was 2-(2-bromo-4-isopropylphenoxy)--(2,2,6,6-tetramethylpiperidin-4-yl)acetamide (VU0134992). In whole-cell patch-clamp electrophysiology experiments, VU0134992 inhibits Kir4.1 with an IC value of 0.97 M and is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC = 9 M) at -120 mV. In thallium (Tl) flux assays, VU0134992 is greater than 30-fold selective for Kir4.1 over Kir1.1, Kir2.1, and Kir2.2; is weakly active toward Kir2.3, Kir6.2/SUR1, and Kir7.1; and is equally active toward Kir3.1/3.2, Kir3.1/3.4, and Kir4.2. This potency and selectivity profile is superior to Kir4.1 inhibitors amitriptyline, nortriptyline, and fluoxetine. Medicinal chemistry identified components of VU0134992 that are critical for inhibiting Kir4.1. Patch-clamp electrophysiology, molecular modeling, and site-directed mutagenesis identified pore-lining glutamate 158 and isoleucine 159 as critical residues for block of the channel. VU0134992 displayed a large free unbound fraction () in rat plasma ( = 0.213). Consistent with the known role of Kir4.1 in renal function, oral dosing of VU0134992 led to a dose-dependent diuresis, natriuresis, and kaliuresis in rats. Thus, VU0134992 represents the first in vivo active tool compound for probing the therapeutic potential of Kir4.1 as a novel diuretic target for the treatment of hypertension.

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“…Specifically, ROMK variant 2 (ROMK2) contains an N-terminal mitochondrial localization sequence, and although its endogenous expression could only be detected by reverse-transcriptase polymerase chain reaction (RT-PCR), overexpression of recombinant ROMK2 fused to an epitope tag allowed immunodetection of its co-localization with mitochondrial markers. Recently, specific ROMK2 activators have been reported [168–170], but it is yet to be determined if these molecules can elicit protection against IR injury or activate a mitochondrial K + flux. In addition, although a whole-body ROMK knockout exists [171,172], renal insufficiency and hypertension render this model unsuitable for cardiovascular studies such as IR injury, and as of the submission of the present study, a cardiac-specific ROMK knockout mouse has not been reported.…”

Section: Mitochondrial Katp Channel: Composition Pharmacology Regulmentioning

confidence: 99%

The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection

Smith

Nehrke

Brookes

2017

Biochemical Journal

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Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K+ channel opening. In the case of IPC, research has focused on a mitochondrial ATP-sensitive K+ channel (mitoKATP), but, despite recent progress, the molecular identity of this channel remains a subject of contention. In the case of APC, early research suggested the existence of a mitochondrial large-conductance K+ (BK, big conductance of potassium) channel encoded by the Kcnma1 gene, although more recent work has shown that the channel that underlies APC is in fact encoded by Kcnt2. In this review, we discuss both the pharmacologic and genetic evidence for the existence and identity of mitochondrial K+ channels, and the role of these channels both in IR protection and in regulating normal mitochondrial function.

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ROMK inhibitor actions in the nephron probed with diuretics

Abstract: Kharade SV, Flores D, Lindsley CW, Satlin LM, Denton JS. ROMK inhibitor actions in the nephron probed with diuretics.

Cited by 16 publications

References 10 publications

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

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

Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992

The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection

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