TY - JOUR. T1 - Modulation of cardiac performance by amiloride and several selected derivatives of amiloride. AU - Pierce, G. N.. AU - Cole, W. C.. AU - Liu, K.. AU - Massaeli, Hamid. AU - Maddaford, T. G.. AU - Yi Jing Chen, Jing Chen. AU - McPherson, C. D.. AU - Jain, S.. AU - Sontag, D.. PY - 1993/1/1. Y1 - 1993/1/1. N2 - Amiloride and its derivatives (benzamil, dichlorobenzamil, 5-(N,N- dimethyl)-amiloride, 5-(N-ethyl-N-isopropyl)-amiloride, (N,N-hexamethylene)- amiloride and 5-(N-methyl-N-isobutyl)-amiloride) are commonly used as selective blockers of Na+/Ca++ exchange or Na+/H+ exchange. Very little information is currently available regarding their effects on cardiac performance. It was observed that addition of amiloride or any of the selected derivatives to the coronary perfusate of the right ventricular wall produced a potent depressive effect on peak developed tension and the rates of tension generation and dissipation. The concentrations at which this occurred are those that are ...
Expression of the α-subunit of the amiloride-sensitive sodium channel (αENaC) is regulated by a number of factors in the lung, including oxygen partial pressure (Po2). As transcriptional activation is a mechanism for raising cellular mRNA levels, we investigated the effect of physiological changes in Po2 on the activity of the redox-sensitive transcription factor nuclear factor κB (NF-κB) and transcriptional activity of 5′-flanking regions of the human αENaC gene using luciferase reporter-gene vectors transiently transfected into human adult alveolar carcinoma A549 cells. By Western blotting we confirmed the presence of NF-κB p65 but not p50 in these cells. Transiently increasing Po2 from 23 to 42mmHg for 24h evoked a significant increase in NF-κB DNA-binding activity and transactivation of a NF-κB-driven luciferase construct (pGLNF-κBpro), which was blocked by the NF-κB activation inhibitor sulphasalazine (5mM). Transcriptional activity of αENaC-luciferase constructs containing ...
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Read "Effects of Purinergic Stimulation, CFTR and Osmotic Stress on Amiloride-sensitive Na+ Transport in Epithelia and Xenopus Oocytes, The Journal of Membrane Biology" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Using pharmacological screening of a wide spectrum of ion channel antagonists, we found that low concentrations of amiloride inhibited the spiking of water gustatory receptor neurons in Drosophila. Interestingly, several previous studies also demonstrated the effect of amiloride on the spiking of these receptor neurons in the flesh fly and blowfly (Liscia et al., 1997; Sadakata et al., 2002). Using physiological recordings, behavioral assays, and mutational analyses, we identified PPK28 as the putative amiloride-sensitive receptor for gustatory water reception. Further gain-of-function studies showed that PPK28 is sufficient to confer hypoosmotic activity. These results suggest that PPK28 is a good candidate for the Drosophila gustatory water receptor.. The IC50 of amiloride necessary to inhibit the gustatory water response (∼20 μm) was about two orders of magnitude higher than that observed for mammalian ENaC; however, it was comparable to that used for the Drosophila RPK channel (Adams et ...
The steady-state transport kinetics of the interaction between external sodium and the diuretic drug, amiloride, was studied in isolated anuran skin epithelia. We also investigated the effect of calcium on the amiloride-induced inhibition of short-circuit current (Isc) in these epithelial preparations. The major conclusions of this study are: (a) amiloride is a noncompetitive inhibitor of Na entry in bullfrog and grassfrog skin, but displays mixed inhibition in R. temporaria and the toad. A hypothesis which states that the interaction sites for amiloride and Na on the putative entry protein are spatially distinct in all of these species is proposed. (b) The stoichiometry of interaction between amiloride and the Na entry mechanism is not necessarily one-to-one. (c) The external Ca requirement for the inhibitory effect of amiloride is not absolute. Amiloride, at all concentrations, is equally effective in inhibiting Isc of bullfrog skin independently from the presence or absence of external Ca. ...
γ- amino butyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate brain, and targets the ionotropic GABAA receptors. GABAC, or GABAA rho, is a subclass of GABAA receptors composed entirely of rho (ρ) subunits and are located on the axonal terminal of retinal bipolar cells, where it not only exhibits a tonic inhibitory current, but also regulates the GABAA and other GABAA rho synaptic currents (Jones et al 2011). GABAA-rho exhibits unique properties, such as insensitivity to select antagonists of the heteromeric GABAA receptors (Korpi et al., 2002). A group of ligands, which possess a guanidine group, have been shown to influence GABAA receptors. This includes the acid sensing ion channel (ASIC) ligand, amiloride. Our previous work elucidated the intrinsic activity of the guanidine compound amiloride as having an allosteric modulatory effect on the human GABAA rho1 receptor, but the exact mechanism, or site of interaction, remains unknown. Homology modeling of amiloride
Combination therapy using nebulized amiloride hydrochloride and uridine-5-triphosphate (UTP) trisodium salt aerosols has been investigated for the treatment of cystic fibrosis (CF). Amiloride in aqueous solution precipitates in the presence of UTP, reducing drug concentrations. Interactions between these drugs and NaCl in solution were studied using phase-solubility techniques monitored by UV spectrophotometry. Elemental analyses were employed for precipitate characterization. Amiloride solubility was reduced by more than 85% in saline.
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Vomiting, low blood pressure, and fever may be signs of an amiloride overdose. This eMedTV selection discusses in greater detail the symptoms a person may experience after taking too much amiloride, as well as treatment options that are available.
Kleyman, T.R., Cragoe, E.J. Amiloride and its analogs as tools in the study of ion transport. J. Membrain Biol. 105, 1-21 (1988). https://doi.org/10.1007/BF01871102. Download ...
The diuretic agent amiloride is used for the treatment of high blood pressure. Ludwig Maximilian University of Munich researchers have now synthesized a photosensitive version, which allows regulating the function of sodium-specific ...
Amiloride official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more.
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Lithium therapy frequently induces nephrogenic diabetes insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site for lithium and the beneficial effect of amiloride may be through inhibiting lithium entry. Using a mouse collecting duct cell line, we found that vasopressin caused an increase in Aquaporin 2 (AQP2) expression which was reduced by clinically relevant lithium concentrations similar to what is seen with in vivo models of this disease. Further amiloride or benzamil administration prevented this lithium-induced downregulation of AQP2. Amiloride reduced transcellular lithium transport, intracellular lithium concentration, and lithium-induced inactivation of glycogen synthase kinase 3beta. Treatment of rats with lithium downregulated AQP2 expression, reduced the principal-to-intercalated cell ratio, and ...
In the present study, we confirmed ENaC expression in SDMAs, and we found that ENaC blockers reduced the contractile response to phenylephrine and serotonin. The EC50 values obtained in dose-response experiments with pharmacological ENaC inhibitors are similar to the published inhibition constant and IC50 values for ENaC in mammalian distal nephron segments and Xenopus oocytes expressing α, β, and γ ENaC (amiloride: 10 to 100 nmol/L; benzamil: 10 nmol/L).1,2 In addition, an amiloride derivative (ethyl isopropyl amiloride) did not affect the contractile response to phenylephrine. In situ hybridization and immunohistochemistry studies showed α, β, and γ ENaC expression in the tunica media and endothelial cells of SDMAs. In addition, amiloride-sensitive sodium currents were detected in primary cultures of mesenteric artery endothelial cells. These data indicate expression of all 3 of the ENaC subunits in SDMAs that would form trimeric channels with biophysical properties similar to the ...
Epithelial Na+ channels historically have been classified according to their kinetics, pharmacology, and single channel conductance (see Palmer, 1992; Smith and Benos, 1991). The molecular identity of these channels was unknown until the cloning of the Na(5) channel (classification of Palmer, 1992) independently by Canessa et al. (1993, 1994), by Lingueglia et al. (1993), and Voilley et al. (1994). This channel is also referred to as the epithelial Na+ channel (ENaC)1 and is characterized by a 5-pS single channel conductance, long open and close times, high amiloride sensitivity (Ki , 100 nM), and high Na+ to K+ selectivity. ENaC is composed of three subunits, α, β, and γ, that are necessary to reconstitute the in vivo single channel properties and maximal amiloride-sensitive currents in Xenopus oocytes (Canessa et al., 1994).. The epithelial Na+ channel shares little molecular homology with other known ion channels (for review see Garty and Palmer, 1997). However, this channel belongs to a ...
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Lists the various brand names available for medicines containing amiloride. Find information on amiloride use, treatment, drug class and molecular formula.
G.I. Sandle, S.A. Lewis, J.P. Hayslett, H.J. Binder; Dexamethasone Induces Amiloride Sensitive Na Transport in Rat Distal Colon. Clin Sci (Lond) 1 February 1982; 62 (2): 30P. doi: https://doi.org/10.1042/cs062030Pa. Download citation file:. ...
Enhanced Na+/H+ exchange, measured as amiloride derivative-sensitive Na+ and H+ fluxes in cells with a preliminary acidified cytoplasm (Δμ H+-induced Na+/H+ exchange), is one of the most prominent intermediate phenotypes of altered vascular smooth muscle cell (VSMC) function in spontaneously hypertensive rats (SHR). Analysis of Na+/H+ exchange in F2 hybrids of SHR and normotensive rats seems to be the most appropriate approach in the search for the genetic determinants of abnormal activity of this carrier. However, the measurement of Δμ H+-induced Na+/H+ exchange is hardly appropriate for precise analysis of the carriers activity in VSMC derived from several hundred F2 hybrids. To overcome this problem, we compared the rate of 22Na influx under baseline conditions and in Na+-loaded (ouabain-treated) VSMC. The dose-dependency of the rate of Δμ H+-induced H+ efflux as well as of 22Na influx in control and ouabain-treated cells on ethylisopropylamiloride (EIPA) concentration were not ...
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This article from the eMedTV library presents some basic information on amiloride HCl, a drug used to treat certain conditions related to heart disease. This segment looks at when and how to take this medicine and factors that affect your dose.
BOSTON and DURHAM, NC - Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Parion Sciences today announced that the companies will collaborate to develop investigational epithelial sodium channel (ENaC) inhibitors for the potential treatment of cystic fibrosis (CF) and other pulmonary diseases. Under the agreement, Vertex gains worldwide development and commercial rights to Parions investigational ENaC inhibitors, including P-1037 and P-1055, for CF and other pulmonary diseases. P-1037 is currently being evaluated in an exploratory Phase 2a study in people with CF, regardless of genotype, and Vertex and Parion plan to begin an additional Phase 2a study that adds P-1037 to treatment with the investigational combination of lumacaftor and ivacaftor for people with CF who have two copies of the F508del mutation. Parion will receive an $80 million up-front payment from Vertex with the potential to receive additional development and regulatory milestone payments and tiered royalties related to ...
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Change in other NPD measures from baseline and Days 4, 7, and 14 to include baseline PD, change in amiloride, low chloride, and low chloride plus isoproterenol ...
We investigated in a physiological salt solution (PSS) containing HCO3- the intracellular pH (pHi) regulating mechanisms in smooth muscle cells cultured from human internal mammary arteries, using the pH-sensitive dye 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and 22Na+ influx rates. The recovery of pHi from an equivalent intracellular acidosis was more rapid when the cells were incubated in CO2/HCO3(-)-buffered PSS than in HEPES-buffered PSS. Recovery of pHi was dependent on extracellular Na+ (Km, 13.1 mM); however, it was not attenuated by 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS), indicating the absence of SITS-sensitive HCO3(-)-dependent mechanisms. Recovery instead appeared mostly dependent on processes sensitive to 5-(N-ethyl-N-isopropyl)amiloride (EIPA), indicating the involvement of Na+/H+ exchange and a previously undescribed EIPA-sensitive Na(+)- and HCO3(-)-dependent mechanism. Differentiation between this HCO3(-)-dependent mechanism and Na+/H+ ...
The epithelial sodium channel (short: ENaC, also: amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to Na+ ions and that is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. It is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidneys nephrons. The apical membranes of many tight epithelia contain sodium channels that are characterized primarily by their high affinity for the diuretic blocker amiloride. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis. In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception. ENaC is located in the apical membrane of polarized epithelial cells in particular in the kidney (primarily in the ...
The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPxY, motif which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddles syndrome, where mutations delete or alter the PPxY motif of either the beta or gamma subunits, has been proposed to result in increased ENaC activity. Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC. We demonstrate that KIAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na(+)-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC ...
BACKGROUND: In the airway of subjects with cystic fibrosis (CF) the combination of defective cAMP mediated chloride secretion and enhanced sodium absorption leads to dehydration of mucosal mucus and is reflected in an increased trans-epithelial potential difference (PD). The airway secretions may be less viscid and easier to expectorate if sodium (and water) reabsorption is inhibited. METHODS: To evaluate the response to sodium blocking agents, changes in the nasal PD in 20 transgenic CF mice were compared with 14 control mice (MF1 strain) before and after administration of nebulised amiloride and loperamide (both in a concentration of 1 mmol/l). The duration of action for both drugs was also determined after a single inhaled dose of 1 mmol/l for two minutes. RESULTS: The median basal PD was -24 mV in controls and -28 mV in CF mice (p , 0.01). This fell in CF mice after amiloride and loperamide administration by 15 mV and 14 mV, respectively, compared with a decrease of 7 mV and 5.5 mV in ...
Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is an antihypertensive, potassium-sparing diuretic that was first approved for use in 1967 and helps to treat hypertension and congestive heart failure. The drug is often used in conjunction with thiazide or loop diuretics. Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements ...
p,,strong,BACKGROUND: ,/strong,Early life adversities are risk factors for anxiety disorders and for pain syndromes, which are, in turn, highly comorbid with anxiety disorders. Repeated cross-fostering mouse pups to adoptive lactating females induces epigenetic modification and heightened mRNA-expression of the acid-sensing-ion-channel-1 gene, altered nociception, and hypersensitivity to 6% carbon dioxide air mixtures, a trait marker of specific human anxiety disorders such as, most clearly and prominently, panic disorder.,/p,. ,p,,strong,AIMS: ,/strong,We hypothesized that the acid-sensing ion channel inhibitor amiloride can modulate repeated cross-fostering animals exaggerated responses to carbon dioxide and nociceptive thermal stimulation.,/p,. ,p,,strong,METHODS: ,/strong,Respiratory carbon dioxide sensitivity was assessed by plethysmography during 6% carbon dioxide air mixture challenges, and nociception was assessed by latency of paw withdrawal to thermal stimulation, in repeated ...
... : Amiloride inhibition of basolateral membrane depolarization in response to increased bath osmolality correlates with afferent neural activity and behavior ...
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