Is there a new dawn for selective mineralocorticoid receptor antagonism?

Luther, James M.

doi:10.1097/mnh.0000000000000051

Cited by 20 publications

(15 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, nifedipine decreased and stabilized TEER significantly ( Figure 1A). The most likely explanation for this result is that nifedipine can act as an antagonist to the mineralocorticoid receptor, as previously reported, 36 and inhibit some excitation-triggered responses, such as ion secretion.…”

Section: Camentioning

confidence: 77%

Quantum dots modulate intracellular Ca<sup>2+</sup> level in lung epithelial cells

Yin

Fontana

Solandt

et al. 2017

IJN

View full text Add to dashboard Cite

While adverse effects of nanoparticles on lung health have previously been proposed, few studies have addressed the direct effects of nanoparticle exposure on the airway epithelium. In this work, we examine the response of the pulmonary airway to nanoparticles by measuring intracellular Ca 2+ concentration ([Ca 2+ ] i ) in the Calu-3 epithelial layer stimulated by 3-mercaptopropionic-acid (3MPA) coated CdSe-CdS/ZnS core-multishell quantum dots (QDs). Simultaneous transient transepithelial electrical resistance (TEER) decrease and global [Ca 2+ ] i increase in Calu-3 epithelial layer, accompanied by cell displacements, contraction, and expansion, were observed under QD deposition. This suggests that a QD-induced global [Ca 2+ ] i increase in the Calu-3 epithelial layer caused the transient TEER decrease. The [Ca 2+ ] i increase was marked and rapid in the apical region, while [Ca 2+ ] i decreased in the basolateral region of the epithelial layer. TEER transient response and extracellular Ca 2+ entry induced by QD deposition were completely inhibited in cells treated with stretched-activated (SA) inhibitor GdCl 3 and store-operated calcium entry (SOCE) inhibitor BTP2 and in cells immersed in Ca 2+ -free medium. The voltage-gated calcium channel (VGCC) inhibitor nifedipine decreased, stabilized, and suppressed the TEER response, but did not affect the [Ca 2+ ] i increase, due to QD deposition. This demonstrates that the Ca 2+ influx activated by QDs’ mechanical stretch occurs through activation of both SA and SOCE channels. QD-induced [Ca 2+ ] i increase occurred in the Calu-3 epithelial layer after culturing for 15 days, while significant TEER drop only occurred after 23 days. This work provides a new perspective from which to study direct interactions between airway epithelium and nanoparticles and may help to reveal the pathologies of pulmonary disease.

show abstract

Section: Camentioning

confidence: 77%

Quantum dots modulate intracellular Ca<sup>2+</sup> level in lung epithelial cells

Yin

Fontana

Solandt

et al. 2017

IJN

View full text Add to dashboard Cite

show abstract

“…An effort was made by several laboratories during the 1980’s to develop more selective MR antagonists 59, 75 . Roussel-UCLAF developed highly soluble potent 7-alkyl spironolactone MR antagonists which were used for research but were not marketed for clinical use 76, 77 .…”

Section: The First Generation Antagonistsmentioning

confidence: 99%

“…Spironolactone was a significantly better antihypertensive than eplerenone in two clinical studies, perhaps because of its greater potency and longer half-life 59, 114, 115 . Despite side effects, results of clinical trials continue to show therapeutic benefits of MR antagonists in a growing list of conditions 2, 96, 116, 117 , clearly indicating the need for better MR antagonists 59, 75, 118–120 . The Dialysis Outcomes Heart Failure Aldactone Study and others have been demonstrated their utility in stemming the progression of chronic kidney disease 121–123 .…”

Section: The First Generation Antagonistsmentioning

confidence: 99%

Third-generation Mineralocorticoid Receptor Antagonists

Gómez-Sánchez

2016

Journal of Cardiovascular Pharmacology

View full text Add to dashboard Cite

The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated.

show abstract

“…Their development and early clinical studies have been reviewed previously, and several drugs have advanced into clinical trials [35,36]. As opposed to most diuretic agents, MRAs do not require filtration to reach their renal epithelial target, and therefore would not be anticipated to lose effectiveness in renal insufficiency.…”

Section: Textmentioning

confidence: 99%

“…This potential benefit must be weighed against the increased risk of hyperkalemia, however. Nonsteroidal MRAs, including finerenone, reduce proteinuria in rodents with a lower incidence of hyperkalemia compared to steroidal MRAs [35,36]. Finerenone has advanced the furthest in clinical trials for treatment of diabetic nephropathy and for heart failure with diabetes or chronic kidney disease [37–39].…”

Section: Textmentioning

confidence: 99%

Aldosterone in vascular and metabolic dysfunction

Luther

2016

Current Opinion in Nephrology and Hypertension

Self Cite

View full text Add to dashboard Cite

Purpose of review This review will highlight recent developments in mineralocorticoid receptor research which impact aldosterone-associated vascular and cardio-metabolic dysfunction. Recent findings The mineralocorticoid receptor is also expressed in vascular smooth muscle and vascular endothelium, and contribute to vascular function and remodeling. Adipocyte-derived leptin stimulates aldosterone secretion, which may explain the observed link between obesity and hyperaldosteronism. Adipocyte mineralocorticoid receptor overexpression produces systemic changes consistent with metabolic syndrome. Ongoing studies with novel nonsteroidal mineralocorticoid receptor antagonists may provide a novel treatment for diabetic nephropathy and heart failure in subjects with chronic kidney disease with reduced risk of hyperkalemia. Summary Ongoing research continues to demonstrate novel roles of the vascular and adipocyte mineralocorticoid receptor function, which may explain the beneficial metabolic and vascular benefits of mineralocorticoid receptor antagonists.

show abstract

Is there a new dawn for selective mineralocorticoid receptor antagonism?

Cited by 20 publications

References 41 publications

Quantum dots modulate intracellular Ca<sup>2+</sup> level in lung epithelial cells

Quantum dots modulate intracellular Ca<sup>2+</sup> level in lung epithelial cells

Third-generation Mineralocorticoid Receptor Antagonists

Aldosterone in vascular and metabolic dysfunction

Contact Info

Product

Resources

About