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At least 181 records · Page 10Linked to original sources
PubMed1998

Combined expression of multidrug resistance protein (MRP) and glutathione S-transferase P1-1 (GSTP1-1) in MCF7 cells and high level resistance to the cytotoxicities of ethacrynic acid but not oxazaphosphorines or cisplatin.

We tested the hypothesis that combined increased expression of human glutathione S-transferase P1-1 (GSTP1-1), an enzyme that catalyzes the conjugation with glutathione of several toxic electrophiles, and the glutathione-conjugate efflux pump, multidrug resistance protein (MRP), confers high level resistance to the cytotoxicities of anticancer and other drugs. To accomplish this, we developed MCF7 breast carcinoma cell derivatives that express high levels of GSTP1-1 and MRP, alone and in combination. Parental MCF7 cells, which express no GSTP1-1 and negligible MRP, served as control cells. We found that either MRP or GSTP1-1 alone conferred significant resistance to ethacrynic acid cytotoxicity. Moreover, combined expression of GSTP1-1 and MRP conferred a high level of resistance to ethacrynic acid that was greater than resistance conferred by either protein alone. Increased MRP was also associated with modest resistance to the oxazaphosphorine compounds mafosfamide, 4-hydroxycyclophosphamide, and 4-hydroperoxycyclophosphamide. However, coordinated expression of GSTP1-1 with MRP failed to augment this modest resistance. Similarly, GSTP1-1 had no effect on the sensitivities to cisplatin of MCF7 cells regardless of MRP expression. These results establish that coordinated expression of MRP and GSTP1-1 can confer high level resistance to the cytotoxicities of some drugs, including ethacrynic acid, but that such resistance is variable and does not apply to all toxic drugs that can potentially form glutathione conjugates in either spontaneous or GSTP1-1-catalyzed reactions.

Antineoplastic Agents↗
PubMedDate not supplied

A biochemical mechanism of the ototoxic interaction between neomycin and ethacrynic acid.

The effects of neomycin on tissue levels of ethacrynic acid was studied in vivo and in vitro. In vitro, the addition of neomycin to incubations of synaptosomes and inner ear tissues of guinea pigs raised the concentration of bound ethacrynate approximately two-fold. In vivo, radioactive ethacrynate was determined in the inner ear of mice by radioautography after intravenous injection of the drug (50 mg/kg body weight). Treatment of animals with neomycin (100 mg/kg body weight, intramuscularly) 60 min prior to ethacrynate led to a three-to five-fold higher accumulation of ethacrynate in cochlear structures. It is suggested that neomycin breaks down hemolabyrinthine or tissue permeability barriers and allows increased penetration of the other drug into the inner ear.

Animals↗
PubMed1993

Differential effects of extracellular calcium on lipid peroxidation dependent (ethacrynic acid and allyl alcohol) and lipid peroxidation independent (disulfiram)-induced cytotoxicity in normal and vitamin E-deficient rat hepatocytes.

Hepatocytes have been isolated from normal and vitamin E-deficient rats in which the hepatic vitamin E level was less than 6% that of controls. The hypothesis was tested that extracellular calcium ameliorates chemical-induced cell killing because it decreases the extent of vitamin E loss induced by oxidative stress: such a retarding effect of calcium on cytotoxicity should be lost in hepatocytes from vitamin E-deficient rats. In normal hepatocytes, allyl alcohol and ethacrynic acid induced oxidative stress as indicated by GSH depletion, lipid peroxidation and cell death. Extracellular calcium retarded the induction of lipid peroxidation and cell death without affecting the GSH depletion. In vitamin E-deficient cells, extracellular calcium had lost its protective effect on ethacrynic acid- and allyl-alcohol induced cytotoxicity; it did not affect the GSH depletion and subsequent induction of lipid peroxidation and cell death by ethacrynic acid. However, in vitamin E-deficient hepatocytes, extracellular calcium even potentiated the cytotoxicity of allyl alcohol; under those conditions it also increased GSH loss. Neither in normal, nor in vitamin E-deficient hepatocytes, extracellular calcium had an effect on disulfiram-induced cytotoxicity, i.e. cell death in the absence of lipid peroxidation. These results support the hypothesis that the protecting effect of extracellular calcium on cytotoxicity, associated with lipid peroxidation in normal hepatocytes, is mediated by its protection against intracellular vitamin E loss.

1-Propanol↗
PubMed1996

[Studies of changes in filtration angle after experimental administration of ethacrynic acid into the anterior chamber].

The aim of the study is to determine what charges occur in filtration angle after administration of ethacrynic acid solution into anterior chamber. The study was conducted in 9 rabbits. After administration of 0.5 mmol/l and 0.7 mmol/l epsilon. acid solution, oedema of cells, relaxation of structure of trabecular texture and cellular necrobiosis in filtration angle were detected. Intraocular pressure lowered by 6-7 mm Hg. It is possible that ethacrynic acid will be used as an agent inducing changes in filtration angle which reduce intraocular pressure.

Animals↗
PubMed1985

Substrate utilization by the distal nephron in dogs with chronic metabolic acidosis: studies with ethacrynic acid.

Glutamine and lactate oxidations provide the bulk of ATP required for sodium reabsorption in the dog kidney during chronic metabolic acidosis. Indirect evidence has suggested that glutamine is oxidized in the proximal convoluted tubule; if this is true, lactate should be the major fuel of the more distal nephron sites. The purpose of these experiments was to determine which substrates were metabolized by the acidotic dog kidney when a significant proportion of sodium chloride reabsorption was inhibited in the thick ascending limb of the loop of Henle. Ethacrynic acid, a loop diuretic, caused the fractional excretion of sodium to increase from 1 to 34%. The glomerular filtration rate declined somewhat, but there was no significant change in the renal blood flow rate. Renal oxygen consumption declined in conjunction with the natriuresis. However, when the data were examined at a constant filtered load of sodium (a constant rate of ATP turnover), there was no reduction in glutamine uptake or glutamine conversion to ATP in the presence of this natriuretic agent. The major change observed concerned lactate metabolism, in the presence of ethacrynic acid, there was no longer a significant rate of lactate extraction. These data are best explained by assuming that glutamine is the fuel of the proximal convoluted tubule of the acidotic dog kidney, whereas lactate oxidation occurs principally in the nephron sites where sodium reabsorption was inhibited by ethacrynic acid.

Acidosis↗
PubMed1979

Effect of ethacrynic acid upon the peripheral vestibular nystagmus.

The effect of ethacrynic acid (ETA) upon pendular rotation nystagmus and paralytic nystagmus was examined using 61 guinea pigs. 100 mg/kg ETA reduced these nystagmus but 30 mg/kg ETA had on effect. Galvanic nystagmus, Bechterew's compensatory nystagmus, OKN and EEG were not affected by 100 ng/kg ETA. These results are highly suggestive that the inhibition of the peripheral vestibular nystagmus by ETA is mainly due to the reduction of the ampullar endolymphatic potential.

Action Potentials↗
PubMed1993

Inhibition of Na-K-2Cl cotransport and bumetanide binding by ethacrynic acid, its analogues, and adducts.

The inhibitory effect of ethacrynic acid (EA) and a variety of its derivatives on Na-K-2Cl cotransport in avian erythrocytes was investigated. The most potent compound tested was the adduct of EA with L-cysteine, with an IC50 of 7.2 x 10(-7) M. EA itself, dihydro-EA, EA-D-cysteine, and adducts of EA with other sulfhydryl (-SH) compounds were much less potent. The mechanism of action of EA and EA-L-cysteine differed in several respects: 1) EA-L-cysteine acted more rapidly than EA (half times of < 1 and 4 min, respectively, at 37 degrees C); 2) the action of EA-L-cysteine was reversible by washing, whereas that of EA was not; and 3) the degree of inhibition by EA-L-cysteine varied with medium [K], whereas that of EA did not. The inhibitory effects of both EA-L-cysteine and EA were affected by medium [Na] and [Cl]. We conclude that EA-L-cysteine does not "deliver" EA to transport-related -SH residues or act as an alkylating agent but has some stereospecific effect on cotransport that is a property of the entire molecule. EA does appear to inhibit cotransport by alkylating -SH residues, as closely related compounds lacking the ability to covalently react with such groups were reversible, and other -SH reagents (e.g., N-ethylmaleimide) also inhibited cotransport. EA, EA-L-cysteine, and EA-D-cysteine all inhibited [3H]bumetanide binding to membranes from activated avian erythrocytes at concentrations similar to those that inhibited cotransport. It is possible that the EA and bumetanide types of diuretics interact with closely apposed sites on the Na-K-2Cl cotransporter.

Animals↗
PubMed1976

[Nitroglycerin, furosemide and ethacrynic acid effect on hemodynamics in rest and during ergometric load in coronary disease patients].

The haemodynamic effects of intravenous injections of furosemide and ethacrynic acid as well as those of peroral administration of nitroglycerin were studied in 32 patients (4-12 weeks after acute myocardial infarction) during rest and exercise. Cardiac output, heart rate and arterial blood pressure showed no significant changes after administration of nitroglycerin, furosemide and ethacrynic acid (fig 3). A few minutes after application of nitroglycerin or furosemide there were significant falls of pulmonary arteria diastolic pressure and right atrial pressure (fig. 1 and 2), whereas no changes were seen after injection of ehtacrynic acid. This initial effect of furosemide as well as the effect of nitroglycerin is primarily of vascular origin, causing an increased peripheral venous capacitance. Ethacrinic acid failed to exhibit any direct vascular effect. Therefore during pulmonary oedema nitroglycerin together with furosemide should be given.

Blood Pressure↗
PubMedDate not supplied

Quinine reduces noxious cochlear effects of furosemide and ethacrynic acid.

Endocochlear potential (EP) and eighth nerve action potential (AP) were measured in chinchillas. We investigated the interaction of quinine with the loop diuretics furosemide and ethacrynic acid to determine whether the cochlear effects of these agents are attenuated by pretreatment with quinine. Animals were injected with either furosemide, 25 mg/kg intravenously (IV), or ethacrynic acid, 15 mg/kg IV. Control animals injected without pretreatment were found to have a large decrease in EP, with a decrease of compound action potentials (CAP) amplitude and an elevation of CAP threshold. Animals pretreated with quinine, 25 mg/kg, were found to have a significantly smaller reduction of EP and CAP amplitude following injection of either diuretic. No significant differences in urine volumes were noted between experimental and control groups. Quinine is known to cause nonspecific changes in the membranes of epithelial cells, which may cause alterations of the transport of organic anions by such tissues. Such an effect on epithelial cells in the cochlea may cause reduced uptake of loop diuretics in this organ, resulting in reduced toxicity.

Action Potentials↗
PubMed1998

Chemical modification of human albumin at cys34 by ethacrynic acid: structural characterisation and binding properties.

Derivatization of the free cys3,4 in human albumin, which is reported to occur under physiological conditions, has been performed in vitro by reaction of the protein with ethacrynic acid. This modification has been investigated by mass spectrometry and circular dichroism. Ethacrynic acid has been proven to bind human albumin either covalently and non-covalently. This post-translational modification does not determine significant changes in the secondary structure of the protein, as shown by the comparable circular dichroism spectra of the native and the modified proteins. Furthermore, the binding properties of the human albumin samples have been investigated by circular dichroism and equilibrium dialysis. The affinity to the higher affinity binding sites does not change either for drugs binding to site I, like phenylbutazone, or to site II, like diazepam, while a small but significant increase has been observed for bilirubin, known to bind to site III. Nevertheless significant decreases of the affinity at the lower affinity binding sites of the modified protein were observed for both drugs binding to site I or to site II.

Albumins↗
PubMed1982

Effects of ethacrynic acid on the alpha-adrenergic control ov hepatic glycogenolysis.

Ethacrynic acid (ECA) was used to study the relationship between ion transport and alpha-adrenergic activation of glycogenolysis in perfused rat livers. ECA alone enhanced glycogenolysis and produced a massive loss of K+ from the liver. These effects were partially blocked by dithioerythritol. ECA suppressed the metabolic responses to phenylephrine and the alpha-adrenergic redistribution of ions. Ouabain-sensitive and ouabain-insensitive ATPase of isolated liver plasma membranes were inhibited and binding of [3H]epinephrine to alpha-adrenergic sites was decreased by ECA. It is concluded that in liver ECA acts at three different sites by blocking SH groups: active ion transport across the plasma membrane, alpha-adrenoreceptors, and phosphorylase phosphatase.

Animals↗
PubMed1976

Mode of stimulation by aldosterone of the sodium efflux in barnacle muscle fibres: effects of ouabain, ethacrynic acid, diphenylhydantoin, (ATPMg)(2-), adenine translocase inhibitors, pyruvate and oxythiamine.

1. A study has been made of the nature of the delayed stimulation caused by external aldosterone in barnacle fibres pre-exposed to aldosterone. 2. (i) Microinjection of 0-5 M-ATPMg2- caused only a small but prompt rise in the Na efflux. (ii) Microinjection of 0-5 M-ATPMg2- followed by external application of 10(-5)M aldosterone greatly augmented the magnitude of the delayed stimulation. The response was dose-dependent, as well as dependent on the concentration of external K+ and H+, but not Na+, Ca2+ or Mg2+. (iii) External application of 10(-5) M aldosterone for 30 min followed by its withdrawal from the bathing medium failed to bring about delayed stimulation. By contrast, fibres into which ATP had been injected showed delayed stimulation under these conditions. 3. Microinjection of actinomycin-D or spironolactone SC-14266 into fibres into which ATP had been injected followed by external application of aldosterone resulted in complete abolition of the delayed stimulation. 4. Delayed stimulation was reduced whether ATP had been injected or not by prior external application of 10(-4)M ouabain or internal application of 8 x 10(-2)M ethacrynic acid. It was completely abolished by prior application of ouabain externally and ethacrynic acid internally, or only 10(-4)M diphenylhydantoin externally. 5. (i) Microinjection of atractyloside or bongkrekic acid caused a substantial fall in the resting Na efflux. Bonkrekic acid proved more powerful than atractyloside. Microinjection of 0-05 M-ATPMg2- into fibres poisoned with 2-0 x 10(-2)M bongkrekic acid completely restored the Na efflux.

Adenosine Triphosphate↗
PubMed1992

Effects of verapamil, ouabain, and ethacrynic acid on calcium retention in perfused rat kidneys.

A Sprague-Dawley rat kidney perfusion technique was used in situ to study the effect of verapamil, ouabain, and ethacrynic acid on renal calcium retention. The technique involves perfusion of the kidneys via the abdominal aorta and then through the left and right renal arteries and dorsal aorta. Verapamil (1 mM) in Krebs-improved Ringer solution increased calcium retention in the kidneys by approximately 117% compared with controls. With Na-free Krebs-improved Ringer solution, calcium retention increased by only 92%. However, in Krebs-improved Ringer solutions containing 59 and 122 mequivalents of Na, calcium retention in the kidney increased by 46 and 43%, respectively, compared with controls. With Krebs-improved Ringer solution containing 15 mM ouabain, calcium retention in the kidney decreased by 29.5%, whereas with 15 mM ouabain plus 1 mM ethacrynic acid in the perfusate, the effect on calcium retention in the kidney was insignificant compared with controls. These results suggest that two sodium-dependent calcium-transporting systems exist at the peritubular side of the kidney tubules: (1) a Na(+)-Ca+2 countertransport system sensitive to verapamil and (2) a Na(+)-Ca+2 cotransport system sensitive to the intracellular concentration of sodium.

Animals↗
PubMed1985

Dynamics of renal excretory function after furosemide or ethacrynic acid administration to unanaesthetized dogs after mannitol infusion or chronic renal denervation.

To unanesthetized dogs with exteriorized ureter allowing separate collection of urine from both kidneys, furosemide 0.2 mg/kg b.w. or ethacrynic acid 0.22 mg/kg b.w. was given intravenously. The volume of collected urine and the excretion of sodium, chloride, potassium and calcium were studied. The dynamics of diuretic administration was programmed. After unilateral renal denervation furosemide or ethacrynic acid was given and the response of the denervated (left) and intact (right) kidneys was compared. Prior to renal denervation the same dogs were infused with a 15% mannitol solution in a quantity and at a rate causing an increase of diuresis approximately equal to that after renal denervation. The effect of furosemide given with and without mannitol infusion was compared. Description of the dynamics of renal excretory function used by us allowed to demonstrate the modulating role of renal nerves in the regulation of water, chloride and sodium excretion after the administration of diuretics. The principal part of the compensatory reabsorption of chloride after renal denervation occurred in the ascending limb of Henle's loop. Comparison of calcium excretion after renal denervation and administration of furosemide with that after mannitol and furosemide allows to assume that after renal denervation calcium load from the proximal to the distal tubules does not increase.

Animals↗
PubMed1984

Gap junctions in the stria vascularis and effects of ethacrynic acid.

Gap junctions in the stria vascularis of guinea pigs were studied using freeze-fracture. Nearly all junctions were associated with basal cells. They were present between basal cells and spiral ligament cells, adjacent basal cells, basal and marginal cells and basal and intermediate cells. Following administration of ethacrynic acid, gap junction morphology altered. There was a statistically significant decrease in the centre-to-centre spacing of gap junction subunits and the subunits became regularly packed. Such changes were distinct before any other gross morphological change in the stria had occurred. These morphological alterations suggest that physiological uncoupling of stria cells may occur in response to the effects of ethacrynic acid.

Animals↗
PubMed1976

Effects of anoxia and ethacrynic acid upon ampullar endolymphatic potential and upon high energy phosphates in ampullar wall.

The ampullar endolymphatic potential (AEP) was studied in the guinea pig during ischemia and asphyxia and following systemic application of ethacrynic acid. In addition the specialized and nonspecialized portions of the ampullar wall were analyzed for ATP and P-creatine at different conditions of metabolic interference. Under control conditions the AEP amounted to + 4.6 +/- 1.2 mV. In both types of hypoxia the decline of the AEP proceeded on a much slower time scale than that of the cochlear endolymphatic potential (CEP), and the maximum negativity reached was considerably less. Quantitative analysis of both types of ampullar wall tissue indicated a much slower decline in hypoxia of ATP levels than in the stria vascularis. Changes in P-creatine levels were considerably more rapid. The AEP became reduced and changed polarity also by intoxication with ethacrynic acid (EA), but higher dosages (above 70 mg/kg) were necessary than for effects upon the CEP and much longer time periods were required for attainment of maximum negativity. The maximum negativity of the AEP was significantly greater at a dosage of 100 mg/kg of EA than during ischemia. At the point of maximum depression of the AEP P-creatine levels in both types of ampullar tissue were unchanged, but ATP levels were significantly reduced in the specialized portions of ampullar wall.

Action Potentials↗
PubMed2005

Synthesis and structure-activity relationship of ethacrynic acid analogues on glutathione-s-transferase P1-1 activity inhibition.

Ethacrynic acid (EA) is a glutathione-s-transferase pi (GSTP1-1) inhibitor. Fifteen of EA analogues were designed and synthesized and their inhibition on GSTP1-1 activity was tested in lysate of human leukemia HL-60 cells. These compounds were synthesized using substituted phenol as precursors through reacting with 2-chlorocarboxylic acid and acylation. Structure-activity analysis indicates that replacements of chlorides of EA by methyl, bromide, and fluoride at 3' position remain the GSTP1-1 inhibitory effect. The compounds without any substitute at 3' position lose the activity on GSTP1-1 inhibition. These data suggest that the substitution of 3' position of EA is necessary for inhibiting GSTP1-1 activity.

Animals↗
PubMed1983

Ethacrynic acid facilitates gentamicin entry into endolymph of the rat.

Influence of ethacrynic acid (EA) upon gentamicin kinetics in perilymph and endolymph was studied in rats that were given a constant-infusion of gentamicin (150 micrograms/min) and EA (140 micrograms/min). Inner ear fluids and plasma were sampled up to 5 h. The purity of the endolymph was ensured by measurement of sodium and potassium concentrations. Gentamicin assay was done with a modified radioimmunoassay. Results show that EA facilitates the entry of gentamicin into endolymph, while it does not affect the kinetics of the drug in perilymph. Although the mechanism of this facilitation remains unclear, this result may account for the ototoxic potentiation reported between EA and aminoglycoside antibiotics.

Animals↗