Acute Hyperkalemia Associated with Inhalation of a Potent ENaC Antagonist: Phase 1 Trial of GS-9411

O’Riordan, Thomas G.; Donn, Karl H.; Hodsman, Peter; Ansede, John H.; Newcomb, Terry; Lewis, Sandra A; Flitter, William D.; White, Vicki Shigekane; Johnson, Melissa; Montgomery, A. Bruce; Warnock, David G.; Boucher, Richard C.

doi:10.1089/jamp.2013.1037

Cited by 50 publications

(36 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These efforts include: 1) the design of more potent and long-acting ENaC blockers [100,101]; 2) inhibition of ENaCactivating proteases [44,102]; 3) ENaC silencing with specific short interfering RNAs [103]; and 4) highcontent screens to identify novel ENaC regulators that may be druggable in CF lung disease [104]. Since ENaC is also expressed in the kidney, where it plays an important role in electrolyte balance, strategies are warranted that reduce systemic absorption of ENaC inhibitors effectively to prevent renal exposure and electrolyte imbalance including hyperkalaemia [105]. Several promising compounds are currently in active preclinical to early clinical development and may become available for clinical testing in patients with CF in the near future.…”

Section: Alternative Targets To Counteract the Basic Ion Transport Dementioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

View full text Add to dashboard Cite

Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

show abstract

Section: Alternative Targets To Counteract the Basic Ion Transport Dementioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

View full text Add to dashboard Cite

show abstract

“…The search for novel generations of MRA with the ultimate goal of a more tissue-selective mode of action may require novel compounds that are differentiated with respect to the binding mode to the MR [54]. With respect to the vasoprotective potential of ENaC blockade [125,134] besides the already used potassium-sparing amiloride, amiloride analogues are currently under investigation for clinical use [82].…”

Section: Beneficial Effects Of Mineralocorticoid Receptor Antagonistsmentioning

confidence: 99%

Salt controls endothelial and vascular phenotype

Kusche-Vihrog

Schmitz

Brand

2014

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

High salt (NaCl) intake promotes the development of vascular diseases independent of a rise in blood pressure, whereas reduction of salt consumption has beneficial effects for the arterial system. This article summarizes our current understanding of the molecular mechanisms of high salt-induced alterations of the endothelial phenotype, the impact of the individual endothelial genotype, and the overall vascular phenotype. We focus on the endothelial Na(+) channel (EnNaC)-controlled nanomechanical properties of the endothelium, since high Na(+) leads to an EnNaC-induced Na(+)-influx and subsequent stiffening of endothelial cells. The mechanical stiffness of the endothelial cell (i.e., the endothelial phenotype) plays a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. This endothelium-born process is followed by the development of arterial stiffness (i.e., the vascular phenotype), predicting the development of vascular end-organ damage such as myocardial infarction, stroke, and renal impairment. In this context, we outline the potential clinical implication of direct (amiloride) and indirect (spironolactone) EnNaC inhibition on vascular function. However, interindividual differences exist in the response to high salt intake which involves different endothelial genotypes. Thus, selected genes and genetic variants contributing to the development of salt-induced endothelial dysfunction and hypertension are discussed. In this review, we focus on the role of salt in endothelial and vascular (dys)function and the link between salt-induced changes of the endothelial and vascular phenotype and its clinical implications.

show abstract

“…56,57 Similar to amiloride, however, the clinical development of inhalation therapy with some of these novel ENaC blockers has been hampered by their systemic absorption, leading to hyperkalemia resulting from inhibition of ENaC in the kidney. 58 Despite challenging, it is nonetheless tempting to speculate that the development of strategies to modulate the activity of one or more of these Rab proteins may prove relevant to CF therapy, particularly in combination with current and future ENaC blockers and smallmolecule modulators of mutant CFTR trafficking and function. In fact, the latest evidence with this latter class of molecules agrees with the concept that the treatment of a pathology as complex as CF will require the combination several therapeutic approaches directed at the several biochemical and physiologic processes that are compromised in CF disease.…”

Section: Rab Proteins As Putative Therapeutic Targetsmentioning

confidence: 99%

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

View full text Add to dashboard Cite

The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

show abstract

Acute Hyperkalemia Associated with Inhalation of a Potent ENaC Antagonist: Phase 1 Trial of GS-9411

Cited by 50 publications

References 20 publications

CFTR: cystic fibrosis and beyond

CFTR: cystic fibrosis and beyond

Salt controls endothelial and vascular phenotype

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Contact Info

Product

Resources

About