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At least 811 records · Page 45Linked to original sources
PubMed1995

Modulation of detoxification gene expression in human colon HT29 cells by glutathione-S-transferase inhibitors.

We investigated the effects of glutathione-S-transferase (GST) inhibitor treatment on human colon HT29 cell mRNA levels of dihydrodiol dehydrogenase (DDH), glyoxalase I, and gamma-glutamylcysteine synthetase. Time- and concentration-dependent increases in both DDH and gamma-glutamylcysteine synthetase mRNAs resulted from treatment with ethacrynic acid, ethacrynic acid/glutathione conjugate, and T.199 (gamma-glutamyl-S-(benzyl)-cysteinyl-R(-)-phenyl glycine diethyl ester), a selective GST pi inhibitor. In contrast, glutathione analogue GST alpha- and GST mu-selective inhibitors did not induce expression of these genes. Treatment with ethacrynic acid or T.199 had no effect on the mRNA levels of the glutathione-dependent glyoxalase I gene. Pretreatment of cells with buthionine-DL-sulfoximine, a gamma-glutamylcysteine synthetase inhibitor and glutathione depleter, coupled with ethacrynic acid, ethacrynic acid/glutathione conjugate, or T.199 resulted in greater levels of gamma-glutamylcysteine synthetase and DDH induction compared with single treatments. Treatment with buthionine-DL-sulfoximine alone resulted in modest increases in both gamma-glutamylcysteine synthetase and DDH expression. Analyses of DDH induction by both differential Northern hybridization with specific oligonucleotides as probes and reverse transcriptase-polymerase chain reaction amplification of products, followed by diagnostic restriction digestion with endonucleases, showed that ethacrynic acid induced multiple DDH transcripts in HT29 cells and human HepG2 and SKHep1 hepatoma cells. Possible induction mechanisms include the alteration of sulfhydryl status by the electrophilic properties of EA or by elevations of endogenously generated oxidative stress via transient removal of GST pi from the cytosolic GST pool.

Alcohol Oxidoreductases↗
PubMed1976

(Vinylaryloxy)acetic acids. A new class of diuretic agents. 1. (Diacylvinylaryloxy)acetic acids.

A series of (diacylvinylaryloxy)acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. Several compounds exhibit a high order of activity, the most active being [2,3-dichloro-4-(2,2-diacetylvinyl)-phenoxy]acetic acid (3). This compound is about three times as potent as [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]acetic acid (ethacrynic acid) but is qualitatively similar in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Saturation of the double bond of 3 virtually abolishes activity lending support to the hypothesis that the saluresis induced by these compounds, like that of ethacrynic acid, is related at least in part to a chemical reaction with protein-bound sulfhydryl groups. Four mercaptan adducts of 3 were prepared; these probably function as prodrugs in producing saluresis. The adduct with mercaptoacetic acid is as active as 3 itself.

Acetates↗
PubMed1984

On the role of superoxide anion radicals in skin tumour promotion.

The effect of phorbol ester tumour promoters on the release of superoxide anion radicals .O2- by human peripheral leukocytes and the role of such radicals in tumour promotion of mouse skin was studied. No significant difference was found between complete [12-O-tetradecanoylphorbol-13-acetate (TPA)] as compared with incomplete [12-O-retinoylphorbol-13-acetate (RPA), 12-O-(2Z,4E,6,8)tetradecatetraenoylphorbol-13-acetate (Ti8), mezerein] tumour promoters upon induction of .O2- when measured by the reduction of ferricytochrome c. The semisynthetic phorbol esters 12-O-ethacrynylphorbol-13-acetate (EPA) and 4-O-methyl-TPA were less active, and phorbol diacetate, phorbol and ionophore A 23187 were found to be inactive in stimulating superoxide anion radicals. TPA-induced .O2- release from leukocytes was strongly inhibited by Cu(II)-(diisopropylsalicylate)2 (CuDIPS), and, to a lesser extent, by ethacrynic acid, nordihydroguaiaretic acid and quercetin. Retinoic acid exhibited only a moderate inhibitory effect. No .O2- release was observed in epidermal cell cultures upon TPA treatment. When analysed by the alkaline elution technique, TPA-induced .O2- release from leukocytes did not lead to measurable DNA damage in co-cultivated keratinocytes even in the presence of DNA repair inhibitors. In multi-stage-tumourigenesis experiments including two-stage promotion, retinoic acid, ethacrynic acid and CuDIPS were unable to inhibit tumour promotion in mouse skin when applied in combination with TPA in first stage promotion. gamma-Irradiation at a dose level shown to cause DNA damage in vitro could not replace TPA as a stage I-promoting agent. It is concluded that superoxide anion radicals--if related to promotion at all--may play a role in stage II rather than in stage I of mouse skin tumour promotion.

Animals↗
PubMed1986

The significance of the relative effects of loop diuretics and anti-brain edema agents on the Na+,K+,Cl- cotransport system and the Cl-/NaCO3- anion exchanger.

3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on two human erythrocyte ion transport systems--the Na+,K+ cotransport system and the DIDS-sensitive anion carrier. Several classic loop diuretics, including the (aryloxy)alkanoic acid-ethacrynic acid and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide and furosemide, displayed relatively strong inhibitory activity versus the cotransport system with relatively weaker action versus the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency. Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1H-inden-5-yl)oxy]acetic acids, such as indacrinone and MK-473, which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier. Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a sub-class of [(2,3-dihydro-1H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. Most interestingly, the relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.

Bumetanide↗
PubMed2001

Chloride channel antagonists perturb growth and morphology of Neurospora crassa.

The chloride channel antagonists anthracene-9-carboxylic acid, ethacrynic acid and niflumic acid were found to be fungistatic and morphogenic when tested against the ascomycete Neurospora crassa. Potency increased with decreasing pH, suggesting that the protonated forms of the compounds were active. Niflumic acid produced the most pronounced growth aberrations which may reflect an ability to acidify the cytoplasm and block the plasma membrane anion channel of N. crassa.

Agar↗
PubMed1997

ATP-sensitive anion channel from rat brain synaptosomal membranes incorporated into planar lipid bilayers.

An anion channel was incorporated from rat brain synaptic plasma membrane fractions into planar lipid bilayers. The single-channel conductance was found to be 48.5 pS in choline-Cl solution (300 microM cis/100 microM trans). The anion selectivity of the channel was rather low (PCl/Pcholine = 1.7). The gating rate of the channel did not change with membrane potential over the range of -50 mV to 50 mV. Several drugs, which are known as inhibitors of anion channels, were found to be efficient inhibitors for the synaptosomal anion channel. 4-Acetoamino-4'-isothiocyanostilbene-2,2'-disulfonic acid, ethacrynic acid, indanyloxyacetic acid, and 5-nitro-2-(3-phenylpropylamino) benzoic acid inhibited the channel from the cis side of the membrane, corresponding to the cytoplasmic side of the plasma membrane. We found that the channel is regulated by intracellular ATP at millimolar concentrations. Other nucleotides, ADP and GTP, inhibited the channel as well. Glibenclamide, which is known as an inhibitor of an ATP-regulated potassium channel, inhibited the channel at micromolar concentrations from the trans side of the membrane. It is likely that the synaptosomal anion channel is a member of the ATP-binding cassette superfamily.

Adenosine Triphosphate↗
PubMed1984

Influence of serosal hydrostatic pressure on net water and electrolyte transport across the isolated rat colonic mucosa exposed to different secretagogues.

The influence of 2 cm and 7 cm hydrostatic pressure applied upon the serosal side on net water and electrolyte transport and paracellular permeability was investigated in everted sacs of stripped rat colon mucosa exposed to different secretagogues. A 2 cm pressure abolished net fluid absorption in the presence of deoxycholic acid, bisacodyl, ethacrynic acid and rhein and reduced absorption in the tissue pretreated with cholera toxin. The paracellular permeability was increased by deoxycholic acid, bisacodyl and ethacrynic acid and diminished under the influence of rhein and cholera toxin. At a pressure of 7 cm H2O fluid movement was directed toward the mucosal side parallel to the increase of the paracellular permeability. The fluid appearing at the mucosal side was isotonic in the presence of deoxycholic acid, ethacrynic acid and rhein but hypotonic when the tissue was pretreated with cholera toxin. From the pressure-induced net water flow and the composition of the transferred fluid secretagogues acting predominantly on paracellular pathway can be distinguished from secretagogues acting on basis of other mechanisms.

Animals↗
PubMed1984

Renal actions of piretanide and three other "loop" diuretics.

Thirty-nine clearance studies were performed in 17 healthy subjects under conditions of maximal hydration or hydropenia to compare the effects on renal solute and water handling of three sulfamoylbenzoic acid derivatives-piretanide, bumetanide, and furosemide-and the phenoxyacetic acid diuretic ethacrynic acid. Except for furosemide, which caused a 7% fall in effective renal plasma flow (ERPF), and ethacrynic acid, which reduced both the glomerular filtration rate (16%) and ERPF (23%) during maximal hydration, changes in hemodynamics were insignificant. At peak saluresis piretanide induced a mean reduction of -18.3% +/- 4.9% in fractional free-water clearance during hydration and -73.2% +/- 5.9% in fractional free-water reabsorption during hydropenia. The other sulfamoylbenzoates lowered fractional clearance and reabsorption of free water to similar extents, implying a major site of action within the medullary portion of the ascending limb. Ethacrynic acid reduced fractional free-water clearance to a greater degree than did the sulfamoylbenzoates. The mean reduction in fractional free-water reabsorption after ethacrynic acid (71.4% +/- 8.2%) was of the same order as that caused by the sulfamoylbenzoates. Similar excretory maxima for sodium, chloride, potassium, calcium, and magnesium were achieved for all four diuretics. Except for piretanide under hydropenia, sulfamoylbenzoate action did not change urinary pH. Ethacrynic acid consistently lowered urinary pH. During hydration piretanide induced phosphaturia (35.3% +/- 8.8%) and uricosuria (40.9% +/- 9.1%). Both bumetanide and piretanide increased fractional urate clearance during hydropenia (16.7% +/- 5.6% and 34.2% +/- 10.5%). There were no changes in phosphate or urate excretion after ethacrynic acid. Our data support the view that sulfamoylbenzoate diuretics exert additional effects on proximal tubular segments that are not shared by ethacrynic acid. Renal responses to piretanide most closely resemble those to bumetanide.

Absorption↗
PubMed1983

Effect of "high ceiling" diuretics on active salt transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Correlation of chemical structure and inhibitory potency.

The group of "high ceiling" diuretics consists of a variety of chemically different potent diuretic and saluretic substances. Appart from a few exemptions direct evidence for an action of these substances in the thick ascending limb of the loop of Henle (TAL) is still lacking. For furosemide, we have reported recently that it inhibits most likely the Na+-2 Cl--K+ cotransport system present in the lumen membrane of the TAL. The present study tests: 1. whether other "high ceiling" diuretics have a similar site and mode of action, and 2. how modifications of the furosemide molecule alter the inhibitory potency. Isolated cortical TAL (cTAL) segments (n = 185) of rabbit kidneys were perfused in vitro. The equivalent short circuit current (Isc = transepithelial PD/transepithelial resistance), as a measure of active salt transport was correlated to the dose of 64 substances. Several diuretics, such as 2-aminomethyl-4-(1,1-dimethyl-ethyl)-6-iodophenol hydrochloride (MK 447), hydrochlorothiazide, muzolimine, etozoline, tizolimide, amiloride, and triamterene were ineffective both from the lumen and basolateral side at concentrations as high as 10(-4) - 10(-3) mol X 1(-1). The phenoxyacetic acids ethacrynic acid, indacrinone (MK 196), and to less an extend tienilic acid were inhibitory active. They differed from furosemide in one or more of the following criteria: delayed onset, incomplete reversibility, stronger action from the bath, different slope of the dose response curve. Similarly, 1-ozolinone acted stronger from the bath. In contrast, the diuretics of the furosemide type and related compounds (bumetanide and piretanide) showed rapid onset and complete reversibility of inhibition. These substances acted stronger from the lumen. The individual positions in the benzyl ring of the diuretics were differently affected by substitutions, leading to parallel shifts in the dose response curves with halfmaximal inhibition at concentrations ranging between 8 X 10(-8) to greater than 10(-4) mol X 1(-1). For these substances the calculated Hill coefficients were close to unity: 0.96 +/- 0.05. We conclude that the so called "high ceiling" or "loop" diuretics consist of at least 3 groups: 1. drugs that do not interfere with the active salt transport in the cTAL segment, 2. drugs that interfere by so far not characterised mechanisms, and 3. drugs of the furosemide type which inhibit the Na+-2 Cl--K+ cotransport system in the lumen membrane of the cTAL segment.

Animals↗
PubMed1997

Single-channel properties of a rat brain endoplasmic reticulum anion channel.

Many intracellular membranes contain ion channels, although their physiological roles are often poorly understood. In this study we incorporated single anion channels colocalized with rat brain endoplasmic reticulum (ER) ryanodine-sensitive Ca(2+)-release channels into planar lipid bilayers. The channels opened in bursts, with more activity at negative (cytoplasm-ER lumen) membrane potentials, and they occupied four open conductance levels with frequencies well described by the binomial equation. The probability of a protomer being open decreased from approximately 0.7 at -40 mV to approximately 0.2 at +40 mV, and the channels selected between different anions in the order PSCN > PNO3 > PBr > PCl > PF. They were also permeant to cations, including the large cation Tris+ (PTris/PCl = 0.16). Their conductance saturated at 170 pS in choline Cl. The channels were inactivated by 15 microM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and blocked with low affinity (KD of 1-100 microM) by anthracene-9-carboxylic acid, ethacrynic acid, frusemide (furosemide), HEPES, the indanyloxyacetic acid derivative IAA-94, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), and Zn2+. Unlike protein translocation pores, the channels were unaffected by high salt concentrations or puromycin. They may regulate ER Ca2+ release, or be channel components en route to their final cellular destinations. Alternatively, they may contribute to the fusion machinery involved in intracellular membrane trafficking.

Animals↗
PubMed1976

(Vinylaryloxy)acetic acids. A new class of diuretic agents. 3. ((2-Nitro-1-alkenyl)aryloxy)acetic acids.

A series of [(2-nitro-1-alkenyl)aryloxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration; representative of these is (E)-[2,3-dichloro-4-(2-nitropropenyl)phenoxy]acetic acid (5). The most highly active compounds are qualitatively similar in action to [2,3-dichloro-4-(2-methylenebutyryl)phenoxylacetic acid (ethacrynic acid) in causing a prompt increase in the excretion of water and of sodium and chloride ions in approximately equimolar amounts but are three to five times as potent. Potassium ion excretion is increased but less markedly than sodium excretion.

Acetates↗
PubMed2003

A novel Cl- inward-rectifying current in the plasma membrane of the calcifying marine phytoplankton Coccolithus pelagicus.

We investigated the membrane properties and dominant ionic conductances in the plasma membrane of the calcifying marine phytoplankton Coccolithus pelagicus using the patch-clamp technique. Whole-cell recordings obtained from decalcified cells revealed a dominant anion conductance in response to membrane hyperpolarization. Ion substitution showed that the anion channels were selective for Cl(-) and Br(-) over other anions, and the sensitivity to the stilbene derivative 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, ethacrynic acid, and Zn(2+) revealed a pharmacological profile typical of many plant and animal anion channels. Voltage activation and kinetic characteristics of the C. pelagicus Cl(-) channel are consistent with a novel function in plants as the inward rectifier that tightly regulates membrane potential. Membrane depolarization gave rise to nonselective cation currents and in some cases evoked action potential currents. We propose that these major ion conductances play an essential role in membrane voltage regulation that relates to the unique transport physiology of these calcifying phytoplankton.

Biological Transport↗
PubMed1997

Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility.

PURPOSE: The phenoxyacetic acid, ethacrynic acid (ECA), has potential use in glaucoma therapy because it acts to increase aqueous outflow in vivo and in vitro. In human trabecular meshwork (HTM) cell culture, ECA acts to change cell shape and attachment, effects that have been correlated with microtubule (MT) alterations and chemical sulfhydryl (SH) reactivity. To further explore these actions, we evaluated two non-SH reactive phenoxyacetic acids, inadcrinone and ticrynafen, and the MT-disrupting drug vinblastine. METHODS: Excised bovine and porcine eyes were perfused and outflow facility measured. Calf pulmonary artery endothelial and HTM cells were grown in culture and cytoskeletal effects evaluated after drug treatment. RESULTS: Indacrinone, ticrynafen, and vinblastine all caused an increase in outflow facility. In contrast with ECA, the outflow effects of indacrinone and ticrynafen were not blocked by excess cysteine. Although indacrinone and ticrynafen produced changes in cell shape in vitro, the beta-tubulin staining pattern of treated cells was not altered. Vinblastine caused cell shape change and the expected MT disruption. CONCLUSIONS: Phenoxyacetic acids can increase aqueous outflow facility and alter HTM cell shape and attachment in vitro by a non-SH, non-MT mechanism (which is probably shared also by ECA). These findings suggest the possibility of a broader class of glaucoma drugs that may be directed at the HTM. An understanding of the cellular target for these drugs has implications both for potential glaucoma therapy and for the cytoskeletal mechanisms involved in normal outflow function.

Animals↗