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Journal of the... 2020Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and... (Review)
Review
Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and collecting duct. Amiloride is indicated in oedematous states, and for potassium conservation adjunctive to thiazide or loop diuretics for hypertension, congestive heart failure and hepatic cirrhosis with ascites. Historical studies on its use in hypertension were poorly controlled and there is insufficient data on dose-response. It is clearly highly effective in combination with thiazide diuretics where it counteracts the adverse metabolic effects of the thiazides and its use in the Medical Research Council Trial of Older Hypertensive Patients, demonstrated convincing outcome benefits on stroke and coronary events. Recently it has been shown to be as effective as spironolactone in resistant hypertension but there is a real need to establish its potential role in the much larger number of patients with mild to moderate hypertension in whom there is a paucity of information with amiloride particularly across an extended dose range.
Topics: Amiloride; Animals; Clinical Trials as Topic; Diuretics; Humans; Hypertension
PubMed: 33234024
DOI: 10.1177/1470320320975893 -
Acta Physiologica (Oxford, England) May 2022Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in... (Review)
Review
Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in pathogenesis. In this review, we focus on a subclass of membrane-bound and soluble proteases that are defined as channel-activating proteases (CAPs), since they induce Na ion transport through an autocrine mechanism when co-expressed with the highly amiloride-sensitive epithelial sodium channel (ENaC) in Xenopus oocytes. These experiments first identified CAP1 (channel-activating protease 1, prostasin) followed by CAP2 (channel-activating protease 2, TMPRSS4) and CAP3 (channel-activating protease 3, matriptase) as in vitro mediators of ENaC current. Since then, more serine-, cysteine- and metalloproteases were confirmed as in vitro CAPs that potentially cleave and regulate ENaC, and thus this nomenclature was not further followed, but is accepted as functional term or alias. The precise mechanism of ENaC modulation by proteases has not been fully elucidated. Studies in organ-specific protease knockout models revealed evidence for their role in increasing ENaC activity, although the proteases responsible for ENaC activation are yet to be identified. We summarize recent findings in animal models of these CAPs with respect to their implication in ENaC activation. We discuss the consequences of dysregulated CAPs underlying epithelial phenotypes in pathophysiological conditions, and the role of selected protease inhibitors. We believe that these proteases may present interesting therapeutic targets for diseases with aberrant sodium homoeostasis.
Topics: Amiloride; Animals; Epithelial Sodium Channels; Ion Transport; Peptide Hydrolases; Sodium
PubMed: 35276025
DOI: 10.1111/apha.13811 -
Journal of Hypertension Aug 2016
Topics: Amiloride; Diabetes Mellitus; Humans; Kidney; Sodium
PubMed: 27355999
DOI: 10.1097/HJH.0000000000001031 -
Journal of Ayub Medical College,... 2016Hypertension in paediatric age group is commonly secondary to a known cause. It is crucial to identify the cause of hypertension and treat it before development of any...
Hypertension in paediatric age group is commonly secondary to a known cause. It is crucial to identify the cause of hypertension and treat it before development of any associated complications to prevent morbidity and mortality. Paediatric Hypertension is one of the important clinical finding in a child with certain clinical syndrome. We are presenting a case of a 10 month old child presenting with hypertension and hypokalaemia, after excluding all identifiable causes and her positive response to therapy, that is amiloride, along with supportive biochemical data she was diagnosed as a case of monogenic type of hypertension known as Liddle's syndrome.
Topics: Amiloride; Epithelial Sodium Channel Blockers; Female; Humans; Infant; Liddle Syndrome
PubMed: 28586600
DOI: No ID Found -
Frontiers in Cellular and Infection... 2023Fungal infections have become an increasing threat as a result of growing numbers of susceptible hosts and diminishing effectiveness of antifungal drugs due to...
Fungal infections have become an increasing threat as a result of growing numbers of susceptible hosts and diminishing effectiveness of antifungal drugs due to multi-drug resistance. This reality underscores the need to develop novel drugs with unique mechanisms of action. We recently identified 5-(,-hexamethylene)amiloride (HMA), an inhibitor of human Na/H exchanger isoform 1, as a promising scaffold for antifungal drug development. In this work, we carried out susceptibility testing of 45 6-substituted HMA and amiloride analogs against a panel of pathogenic fungi. A series of 6-(2-benzofuran)amiloride and HMA analogs that showed up to a 16-fold increase in activity against were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.
Topics: Humans; Amiloride; Antifungal Agents; Fungi; Mycoses; Microbial Sensitivity Tests; Cryptococcus neoformans
PubMed: 36923593
DOI: 10.3389/fcimb.2023.1101568 -
Medicinal Research Reviews Mar 2020The function of G protein-coupled receptors (GPCRs) can be modulated by compounds that bind to other sites than the endogenous orthosteric binding site, so-called... (Review)
Review
The function of G protein-coupled receptors (GPCRs) can be modulated by compounds that bind to other sites than the endogenous orthosteric binding site, so-called allosteric sites. Structure elucidation of a number of GPCRs has revealed the presence of a sodium ion bound in a conserved allosteric site. The small molecule amiloride and analogs thereof have been proposed to bind in this same sodium ion site. Hence, this review seeks to summarize and reflect on the current knowledge of allosteric effects by amiloride and its analogs on GPCRs. Amiloride is known to modulate adenosine, adrenergic, dopamine, chemokine, muscarinic, serotonin, gonadotropin-releasing hormone, GABA , and taste receptors. Amiloride analogs with lipophilic substituents tend to be more potent modulators than amiloride itself. Adenosine, α-adrenergic and dopamine receptors are most strongly modulated by amiloride analogs. In addition, for a few GPCRs, more than one binding site for amiloride has been postulated. Interestingly, the nature of the allosteric effect of amiloride and derivatives varies considerably between GPCRs, with both negative and positive allosteric modulation occurring. Since the sodium ion binding site is strongly conserved among class A GPCRs it is to be expected that amiloride also binds to class A GPCRs not evaluated yet. Investigating this typical amiloride-GPCR interaction further may yield general insight in the allosteric mechanisms of GPCR ligand binding and function, and possibly provide new opportunities for drug discovery.
Topics: Allosteric Regulation; Amiloride; Animals; Drug Discovery; Humans; Receptors, G-Protein-Coupled
PubMed: 31495942
DOI: 10.1002/med.21633 -
Neuroscience and Biobehavioral Reviews 1998Amiloride at < or = 1 microM may block epithelial Na+ channels without affecting other cellular mechanisms, and attenuates gustatory responses to lingual NaCl from the... (Review)
Review
Amiloride at < or = 1 microM may block epithelial Na+ channels without affecting other cellular mechanisms, and attenuates gustatory responses to lingual NaCl from the chorda tympani nerves (CT) of gerbil, hamster, rhesus monkey, and several strains of laboratory rat and mouse, and from glossopharyngeally innervated frog taste-receptor cells; at 5 microM to 50 microM, also from Wistar rat and mongrel dog CT. Affected units responded more to NaCl than to KCl. Suppression of CT responses to KCl, HCl, NH4Cl, or saccharides also occurred in some mammals, but amiloride did not elicit responses. Taste-dependent behaviors towards NaCl or KCl were altered. DBA and 129/J laboratory mice, and mudpuppy, were unaffected by amiloride. In humans, 10 microM amiloride both produced taste reports and reduced total intensity of NaCl and LiCl by 15-20%. NaCl and LiCl sourness, and KCl and QHCl bitterness declined, but saltiness generally did not change. Effects on sweetness were inconsistent. Amiloride-sensitive gustatory mechanisms were prominent in some mammals, were not necessary for responses to NaCl, and were of minor importance for human taste.
Topics: Administration, Oral; Amiloride; Animals; Humans; Sodium Chloride, Dietary; Taste; Vertebrates
PubMed: 9861611
DOI: 10.1016/s0149-7634(97)00063-8 -
Clinical Endocrinology Apr 2023Human physiology and epidemiology studies have demonstrated complex interactions between the renin-angiotensin-aldosterone system, parathyroid hormone and calcium... (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluating the clinical and mechanistic effects of eplerenone and amiloride monotherapy, and combination therapy with cinacalcet, in primary hyperparathyroidism: A placebo-controlled randomized trial.
OBJECTIVES
Human physiology and epidemiology studies have demonstrated complex interactions between the renin-angiotensin-aldosterone system, parathyroid hormone and calcium homeostasis. Several of these studies have suggested that aldosterone inhibition may lower parathyroid hormone (PTH) levels. The objective of this study was to assess the effect of 4 weeks of maximally tolerated mineralocorticoid receptor antagonist therapy with eplerenone on PTH levels in patients with primary hyperparathyroidism (P-HPT) when compared to amiloride and placebo. We also investigated the synergistic effect of these interventions when combined with cinacalcet for an additional 2 weeks.
DESIGN
Randomized, double-blinded, three parallel-group, placebo-controlled trial.
PATIENTS
Patients with P-HPT.
RESULTS
Most patients were women (83%) and White (76%). Maximally tolerated doses of eplerenone and amiloride induced significant reductions in blood pressure and increases in renin and aldosterone production; however, despite these physiologic changes, neither intervention induced significant changes in PTH or calcium levels when compared to the placebo. Both eplerenone and amiloride therapy induced significant reductions in procollagen type 1 N-terminal propeptide levels when compared to placebo. When cinacalcet therapy was added, PTH and calcium levels were markedly reduced in all groups; however, there was no significant difference in PTH or serum calcium reductions between groups.
CONCLUSIONS
Although maximally tolerated therapy with eplerenone and amiloride induced expected changes in renin, aldosterone and blood pressure, there were no meaningful changes in PTH or serum calcium levels in P-HPT patients. These results suggest that inhibition of aldosterone action does not have a clinically meaningful role in medical therapy for P-HPT.
Topics: Humans; Female; Male; Eplerenone; Cinacalcet; Amiloride; Aldosterone; Calcium; Renin; Hyperparathyroidism, Primary; Parathyroid Hormone
PubMed: 36316798
DOI: 10.1111/cen.14840 -
Kidney International Jun 1996Amiloride-sensitive Na+ channels play a vital role in many important physiological processes such as delineation of the final urine composition, sensory transduction,... (Review)
Review
Amiloride-sensitive Na+ channels play a vital role in many important physiological processes such as delineation of the final urine composition, sensory transduction, and whole-body Na+ homeostasis. These channels display a wide range of biophysical properties, and are regulated by cAMP-mediated second messenger systems. The first of these channels has recently been cloned. This cloned amiloride-sensitive Na+ channel is termined ENaC (Epithelial Na+ Channel) and, in heterologous cellular expression systems, displays a single channel conductance of 4 to 7 pS, a high PNa/PK (> 10), a high amiloride sensitivity (Ki(amil) = 150 nM), and relatively long open and closed times. ENaC may form the core conduction element of many of these functionally diverse forms of Na+ channel. The kinetic and regulatory differences between these channels may be due, in large measure, to unique polypeptides that associate with the core element, forming a functional channel unit.
Topics: Amiloride; Animals; Diuretics; Humans; Sodium Channels
PubMed: 8743467
DOI: 10.1038/ki.1996.237 -
CNS Neuroscience & Therapeutics Jun 2016ASIC1a, the predominant acid-sensing ion channels (ASICs), is implicated in neurological disorders including stroke, traumatic spinal cord injury, and ALS. Potent ASIC1a...
BACKGROUND
ASIC1a, the predominant acid-sensing ion channels (ASICs), is implicated in neurological disorders including stroke, traumatic spinal cord injury, and ALS. Potent ASIC1a inhibitors should have promising therapeutic potential for ASIC1a-related diseases.
AIMS
We examined the inhibitory effects of a number of amiloride analogs on ASIC1a currents, aimed at understanding the structure-activity relationship and identifying potent ASIC1a inhibitors for stroke intervention.
METHODS
Whole-cell patch-clamp techniques and a mouse model of middle cerebral artery occlusion (MCAO)-induced focal ischemia were used. Surflex-Dock was used to dock the analogs into the pocket with default parameters.
RESULTS
Amiloride and its analogs inhibit ASIC1a currents expressed in Chinese hamster ovary cells with a potency rank order of benzamil > phenamil > 5-(N,N-dimethyl)amiloride (DMA) > amiloride > 5-(N,N-hexamethylene)amiloride (HMA) ≥ 5-(N-methyl-N-isopropyl)amiloride (MIA) > 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In addition, amiloride and its analogs inhibit ASIC currents in cortical neurons with the same potency rank order. In mice, benzamil and EIPA decreased MCAO-induced infarct volume. Similar to its effect on the ASIC current, benzamil showed a much higher potency than EIPA.
CONCLUSION
Addition of a benzyl group to the terminal guanidinyl group resulted in enhanced inhibitory activity on ASIC1a. On the other hand, the bulky groups added to the 5-amino residues slightly decreased the activity. Among the tested amiloride analogs, benzamil is the most potent ASIC1a inhibitor.
Topics: Acid Sensing Ion Channels; Amiloride; Animals; Biophysics; CHO Cells; Cells, Cultured; Cerebral Cortex; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Embryo, Mammalian; Infarction, Middle Cerebral Artery; Inhibitory Concentration 50; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Models, Molecular; Neurons; Patch-Clamp Techniques; Transfection
PubMed: 26890278
DOI: 10.1111/cns.12524