Sensitive isotope dilution liquid chromatography/tandem mass spectrometry method for quantitative analysis of bumetanide in serum and brain tissue

Li, Yijun; Cleary, Ryan T.; Kellogg, Mark D.; Soul, Janet S.; Berry, Gerard T.; Jensen, Frances E.

doi:10.1016/j.jchromb.2011.02.018

Cited by 49 publications

(64 citation statements)

References 14 publications

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“…This approach would likely yield more specificity and a more favorable side effect profile than existing GABAergic agents. Although drugs exist to inhibit the N[K]CCs, these drugs generally have poor penetration into the central nervous system (100). However, prodrug forms of bumetanide that have improved blood-brain barrier permeability show therapeutic potential (101).…”

Section: Inhibition Of Mo25 a Key Spak/osr1 Regulatormentioning

confidence: 99%

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

et al. 2014

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The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.

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Section: Inhibition Of Mo25 a Key Spak/osr1 Regulatormentioning

confidence: 99%

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

et al. 2014

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“…Therefore, bumetanide is currently being studied in an ongoing clinical trial on newborn seizures (http://clinicaltrials.gov). However, because of its chemical structure, bumetanide is highly ionized at physiological pH and highly bound to plasma proteins so that it poorly penetrates into most organs, including the brain [66, 67]. Scientists started to seek bumetanide prodrugs with enhanced BBB penetration and prolonged maintenance in the brain.…”

Section: Nkcc-1 In Gliomamentioning

confidence: 99%

Ion Transporters in Brain Tumors

Cong

Zhu

Kuo³

et al. 2015

CMC

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Ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions. They have recently emerged as important players in cancer progression. In this review, we discussed two important ion transporter proteins, sodium-potassium-chloride cotransporter isoform 1 (NKCC-1) and sodium-hydrogen exchanger isoform 1 (NHE-1) in Glioblastoma multiforme (GBM) and other malignant tumors. NKCC-1 is a Na+-dependent Cl− transporter that mediates the movement of Na+, K+, and Cl− ions across the plasma membrane and maintains cell volume and intracellular K+ and Cl− homeostasis. NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pHi) and extracellular microdomain pH (pHe) homeostasis and cell volume. Here, we summarized recent pre-clinical experimental studies on NKCC-1 and NHE-1 in GBM and other malignant tumors, such as breast cancer, hepatocellular carcinoma, and lung cancer. These studies illustrated that pharmacological inhibition or down-regulation of these ion transporter proteins reduces proliferation, increases apoptosis, and suppresses migration and invasion of cancer cells. These new findings reveal the potentials of these ion transporters as new targets for cancer diagnosis and/or treatment.

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“…As both furosemide (Javaheri et al, 1994) and bumetanide (Li et al, 2011) are able to cross the blood-brain barrier, the possible effects of these drugs on HNS function should now be considered, particularly in patients with insufficient hydration.…”

Section: Discussionmentioning

confidence: 99%

Osmoregulation Requires Brain Expression of the Renal Na-K-2Cl Cotransporter NKCC2

et al. 2015

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TheNa-K-2Clcotransporter2(NKCC2)wasthoughttobekidneyspecific.Hereweshowexpressioninthebrainhypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABAmediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.

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Sensitive isotope dilution liquid chromatography/tandem mass spectrometry method for quantitative analysis of bumetanide in serum and brain tissue

Cited by 49 publications

References 14 publications

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

Ion Transporters in Brain Tumors

Osmoregulation Requires Brain Expression of the Renal Na-K-2Cl Cotransporter NKCC2

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