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PubMed1992

Ethacrynic acid and furosemide alter Cl, K, and Na distribution between blood, choroid plexus, CSF, and brain.

Can loop diuretics like ethacrynic acid and furosemide, when administered intravenously, significantly alter ion transport and fluid dynamics in CNS? To shed light on this unresolved issue, we tested the ability of these agents to effect redistribution of Na, K and Cl in adult rat brain. Cl penetration into various CNS regions was assessed as the volume of distribution, i.e., uptake, of 36Cl from blood. Ethacrynic acid and furosemide (50 mg/kg IV) reduced by 20-30% the rate of permeation of 36Cl across the blood-CSF barrier, and they elevated [K] and [Cl] in choroid plexus (CP) by 15-25%. The loop diuretic-induced buildup of K and Cl in CP (lateral and 4th ventricle) was likely a reflection of decreased movement of these ions across the apical membrane into CSF. 36Cl activity in parietal cortex and pons-medulla decreased in treatment with furosemide and ethacrynic acid, due to slowing of Cl transport across blood-brain and/or blood-CSF barriers. Our inhibitory findings in intact rats are consistent with those from previous in vitro experiments demonstrating diminution by loop diuretics of Na, K and Cl transport across isolated CP membranes.

Acetazolamide↗
PubMed1977

An investigation of the sex difference in the diuretic response to ethacrynic acid in mice.

1. Female mice of the Hough/Porton and Tuck/TO strains were found to be more sensitive than male mice to the diuretic effects of oral and intravenous doses of ethacrynic acid. 2. The sensitivity of Hough/Porton male mice to ethacrynic acid was increased after pretreatment with stilboestrol and the sensitivity of female Hough/Porton mice decreased after pretreatment with testosterone. 3. There were no significant sex differences in the diuretic response to frusemide, acetazolamide, aminophylline, bendrofluazide, and Su 15049A although a small, but significant, increase in the sensitivity of male Tuck/TO mice to triamterene was noted. 4. The sex difference in diuretic response to ethacrynic acid may be related to an effect of sex hormone balance on its metabolism or on the sensitivity of its renal receptor.

Animals↗
PubMed1976

Effects of ethacrynic acid and furosemide on isolated rat kidney mitochondria: inhibition of electron transport in the region of phosphorylation site II.

Previous reports that ethacrynic acid and furosemide inhibit the respiration of isolated mitochondria suggested a direct action of these diuretics on oxidative metabolism. To explore this possibility further, the effects of ethacrynic acid and furosemide on the oxygen consumption of mitochondria isolated from the cortex and outer medulla of rat kidneys were investigated. Both diuretics inhibited state 3 and uncoupled respiration supported by glutamate-malate (which enters the electron transport chain prior to site I) and succinate (which enters prior to site II); respiration supported by tetramethyl phenylene diamine-ascorbate (which enters prior to site III) was relatively unaffected. Biochemical bypass of site II significantly alleviated the respiratory inhibition by both agents. Confirmation of these findings was provided by measurement of the electron transport carriers by dual wavelength spectroscopy, which showed that both diuretics caused a reduction of flavoproteins and an oxidation of the cytochromes. It is concluded that ethacrynic acid and furosemide inhibit oxidative phosphorylation in vitro by inhibiting electron transport through phosphorylation site II.

Animals↗
PubMed1964

ETHACRYNIC ACID: DIURETIC PROPERTY COUPLED TO REACTION WITH SULFHYDRYL GROUPS OF RENAL CELLS.

Ethacrynic acid, injected intravenously after surgical removal of one kidney of anesthetized dogs, lowered the concentration of protein-bound sulfhydryl groups in cells of the remaining kidney. Chloride excretion and urinary output of the kidney exposed to the drug increased. These findings indicate that the diuresis produced by ethacrynic acid may be related to its capacity for binding sulfhydryl groups of renal cellular proteins.

Animals↗
PubMed1992

Physiologic and rheologic effects of the antisickling agent ethacrynic acid and its N-butylated derivative on normal and sickle erythrocytes.

Ethacrynic acid, a loop diuretic, has been shown to inhibit hemoglobin S polymerization. Until now, however, most studies were performed using purified solutions of hemoglobin S. The experiments reported here were designed to examine the effects of ethacrynic acid and its n-butryic acid derivative on the rheological and physiological properties of intact red blood cells. Using net and unidirectional flux measurements, both agents were shown to cause ion and water loss from normal and sickle erythrocytes. Since cell shrinkage adversely influences red cell rheology, it is unlikely that this class of compounds, despite its ability to inhibit hemoglobin S polymerization, will prove useful in the treatment of sickle cell disease.

Anemia, Sickle Cell↗
PubMed2004

Clofibric and ethacrynic acids prevent experimental pyelonephritis by Escherichia coli in mice.

Interfering Escherichia coli attachment to the urinary tract, using P-fimbriation inhibitors, can prevent pyelonephritis. Clofibric and ethacrynic acids are organic compounds structurally related, but with different pharmacological uses. These agents are potentially active in the urinary tract due to its elimination in an unaltered form by the renal route. This study described a pyelonephritogenic E. coli strain, grown in the presence of sub-inhibitory concentrations of clofibric or ethacrynic acids (0.1 and 1 mM, respectively), which exhibits inhibition of P1 erythrocytes agglutination and a drastic decrease in fimbriation, using electron microscopy and quantitative analyses of superficial proteins (decrease to a 17-25% in comparison with the control). In vivo assays were performed using ascending urinary tract infection in mice. The treatment with therapeutic doses of the drugs, administered 2 days before the bacterial challenge and daily until the end of the experiment (22 days), abolished renal infection after 7-10 days of drug exposure. Within this period clofibric acid did not produce adverse effects on the renal parenchyma. However, ethacrynic acid caused pyelitis and tubular cellular desquamation. These results suggested that clofibric acid might be useful in the short-term prophylaxis of urinary tract infection.

Animals↗
PubMed1981

Inhibition of a Cl-/HCO3(-)ATPase in the avian salt gland by furosemide and ethacrynic acid.

An ouabain-insensitive, Mg2+-dependent, chloride- and bicarbonate-stimulated ATPase is present in salt gland homogenates of domestic ducks (Anas platyrhynchos). Furosemide and ethacrynic acid are non-competitive inhibitors of this enzyme in vitro. The inhibitor constant of furosemide is Ki = 2.5 mM and of ethacrynic acid Ki = 1.9 mM. In contrast, under the same conditions the salt gland Na+/K+-ATPase activity is not inhibited by furosemide, whereas ethacrynic acid becomes inhibitory only at higher concentrations (10 mM).

Adenosine Triphosphatases↗
PubMed1993

Reversing of chlorambucil resistance by ethacrynic acid in a B-CLL patient.

We evaluated the reversing activity of ethacrynic acid in a B-CLL patient resistant to chlorambucil. The glutathione S-transferase (GST) activity, measured in peripheral blood lymphocytes, resulted extremely elevated. Ethacrynic acid, at pharmacological concentrations, partially reversed chlorambucil resistance and this result appeared related to the increased GST levels.

Aged↗
PubMed1999

Reversible binding of ethacrynic acid to human serum albumin: difference circular dichroism study.

The reversible binding of ethacrynic acid was characterized by a difference circular dichroism method. A 2/1 stoichiometry was determined for the [drug]/[HSA] (human serum albumin) complex. The reversible binding of ethacrynic acid to HSA determines direct competition with ligands that selectivity bind to site II and to the fatty acid site. Furthermore, indirect competition was shown for ligands for site I (anti-cooperative) and to site III (cooperative).

Anti-Anxiety Agents↗
PubMed1993

Furosemide, bumetanide, and ethacrynic acid.

Furosemide and, less commonly, bumetanide and ethacrynic acid are potent diuretics administered to horses for a variety of reasons, including prophylaxis of exercise-induced pulmonary hemorrhage. These drugs affect urine volume and composition, and furosemide has marked effects on plasma volume and composition and on systemic hemodynamics at rest and during exercise.

Animals↗
PubMed1992

Comparative study of the effects of furosemide, ethacrynic acid and bumetanide on the lithium clearance and diluting segment reabsorption in humans.

The effect of intravenous administration of the loop diuretics bumetanide, furosemide and ethacrynic acid on lithium (Li) clearance (CLi) and diluting segment reabsorption was studied in seven healthy water-loaded men. According to the increments in minimal urine osmolality (Uosm), ethacrynic acid (which increased Uosm from 59 +/- 4 to 233 +/- 3 mOsmol/kg) had the strongest inhibiting effect on diluting segment reabsorption, whereas that of furosemide and especially bumetanide was significantly less pronounced (rise in Uosm from 56 +/- 3 to 222 +/- 4 and 56 +/- 4 to 192 +/- 2 mOsmol/kg, respectively). In contrast, ethacrynic acid induced a significantly smaller rise in CLi (approximately 14% of the filtered load of Li) than furosemide and bumetanide, which increased Li excretion by approximately 23% and approximately 24% of its filtered load. The observation that the loop diuretic with the most pronounced inhibiting effect in the diluting segment had the smallest effect on CLi makes is unlikely that the increase in CLi induced by loop diuretics is predominantly effected in Henle's loop.

Adult↗
PubMed1991

[Effect of ethacrynic acid on the course of cytotoxic glomerulonephritis].

Ethacrynic acid (10 mg/kg subcutaneously 15 days) significantly facilitated the experimental glomerulonephritis in rats. The efficacy of diuretic was confirmed by the improvement of the functional characteristics (the degree of proteinuria, the plasma contents of protein and urea, the creatinine excretion), and by the results of the histological investigation, especially at the second phase of the pathological process.

Animals↗
PubMed1969

The relationship between cell membrane potassium ion transport and glycolysis. The effect of ethacrynic acid.

Cell membrane transport of K(+) stimulates the rate of glycolysis in Ehrlich ascites tumor cells. A study of the characteristics of this relationship indicates that the stimulation occurs under anaerobic as well as under aerobic conditions. The data suggest that glycolysis is stimulated by a K(+) transport mechanism that is coupled to Na(+) transport because the effect is blunted or abolished when the principal intracellular ion is lithium or choline. This stimulus to glycolysis is blocked by ouabain and ethacrynic acid, agents that have been shown to inhibit monovalent cation transport in erythrocytes. In contrast to the action of ouabain, glycolysis is inhibited by ethacrynic acid in Ehrlich ascites tumor cells in the absence of cell membrane K(+) transport. In studies with ghost-free hemolysates of human erythrocytes and with cytosol prepared from Ehrlich ascites tumor cells, ethacrynic acid significantly blocks lactate formation from fructose diphosphate demonstrating the direct inhibitory effect of this agent on one or more enzymes of the Embden-Meyerhof pathway. Since ethacrynic acid has no influence on lactate formation in intact erythrocytes utilizing an endogenous substrate, the presumptive site of inhibition is proximal to the 3-phosphoglycerate level.

Animals↗
PubMedDate not supplied

Reversible and irreversible changes of the stria vascularis. An evaluation of the effects of ethacrynic acid separately and in combination with atoxyl.

The morphological changes in the cochlea following administration of ethacrynic acid occur initially in the stria vascularis of the basal coils as an increased intracellular vesiculation of the marginal cells followed by inter- and intracellular oedema in the intermediate cell layer. The combined administration of ethacrynic acid and atoxyl (individual doses) can cause irreversible damage to the cochlear hair cells and the stria vascularis, while the administration of each of them separately in the same low dose did not cause hair cell degeneration or persistent morphological changes of the stria vascularis. An increased penetration of atoxyl into the cochlea is likely to occur due to the ethacrynic acid-induced changes in the permeability of the endolymphatic partition so that the earlier known penetration of atoxyl into the cochlea is increased.

Aniline Compounds↗
PubMed1976

Immediate short-time effects of ethacrynic acid on frog gastric mucosa in chloride-free solutions.

The presence of ethacrynic acid in the nutrient sulphate solution produces, generally in less than 3 min, a decrease in resistance accompanied by an increase in transmucosal PD. These results strongly suggest that the dominant effect of ethacrynic acid is not on the Na+ pathway of the nutrient membrane, but without further knowledge of the resistance of other ionic pathways, it cannot be inferred whether the effect predominates on the K+ pathway as in Cl- media.

Animals↗
PubMed1999

Effects of ethacrynic acid on intraocular pressure of anesthetized rats.

Ethacrynic acid (ECA) lowers intraocular pressure (i.o.p.) by an effect usually ascribed to increased drainage of aqueous humor by the trabecular meshwork. Here, we describe the effects of a continuous 2-hr intracameral infusion of balanced salt solution (BSS), with or without 2 mM ECA (sodium salt), on IOP of pentobarbital anesthetized rats. The infusion was divided into a constant (0.05 microliter/min) and a periodic (0.25 microliter/min) component that cycled 4 min on then 4 min off. This permitted the calculation of dynamic changes in resistive (trabecular and uveoslceral drainage) and nonresistive (aqueous synthesis, episcleral venous pressure) components of IOP by fitting a second-order transfer function to the responses. ECA markedly blunted the BSS-induced rise in IOP (P < 0.01). The rise in resistive mechanisms (ocular impedance) was transiently blunted by ECA (P < 0.05) during the third and fourth 8-min cycles, and nonresistive mechanisms were reduced by ECA from cycles 3-10 (P < 0.05). Then, at the end of the infusion, the control and ECA dynamic values were similar (P < 0.05), although IOP of ECA-treated rats was still slightly reduced (P < 0.05). The most likely explanation is a summation of small changes in both resistive and nonresistive components of IOP dynamics. Systemic blood pressure was unchanged within either group. The well-known effects of ECA on the trabecular meshwork, alone, are insufficient to explain the dynamic changes in IOP observed in this model.

Anesthesia↗
PubMed1992

Ethacrynic acid inhibition of microtubule assembly in vitro.

Ethacrynic acid (ECA) is a sulfhydryl reactive diuretic drug. Recent studies show that ocular administration of ECA may have potential efficacy for treatment of glaucoma. ECA affects cell shape in cultured cells from the eye outflow pathway and the microtubule system is disrupted. We have studied the effect of ECA on microtubule protein (MTP) (tubulin and microtubule-associated proteins) and purified tubulin assembly. Fifty percent inhibition of MTP (1.8 mg/ml) assembly was found at 70 microM ECA in buffer and 410 microM ECA in 30% glycerol in buffer. If all sulfhydryl groups were attributed to tubulin, then approximately two sulfhydryls were blocked at 50% inhibition. Tubulin (2 mg/ml) assembly showed 50% inhibition at 175 microM ECA and approximately 2 sulfhydryl groups were lost. Increasing ECA preincubation times (0-60 min) with tubulin showed that the longer the preincubation time, the longer the lag time, and the slower the rate of assembly and that the percentage of inhibition was proportional to the ECA preincubation time. The number of blocked sulfhydryls also increased with preincubation time. Approximately two sulfhydryls were blocked at 50% inhibition of assembly. The critical concentration for assembly increased twofold when tubulin was preincubated with 0.1 mM ECA, suggesting a loss of active tubulin. Fifty percent inhibition of taxol-induced MTP and tubulin assembly occurred at 190 and 280 microM ECA, respectively, with 3.6 to 3.8 sulfhydryls blocked, respectively. Taxol protects microtubules from disassembly by ECA, suggesting that the ECA binding key sulfhydryls are blocked in the microtubule. These results suggest that ECA reacts slowly with tubulin and blocks sulfhydryl groups important for assembly. Microtubule-associated proteins and glycerol protect the sulfhydryls and so more ECA is necessary to inhibit assembly. Since the number of blocked sulfhydryls is greater at 50% inhibition for taxol-induced microtubules, sulfhydryl blocked tubulin incompetent to assemble under normal conditions may be induced to do so with taxol.

Alkaloids↗
PubMed1995

A comparison of the effects of inhaled furosemide and ethacrynic acid on sodium-metabisulfite-induced bronchoconstriction in subjects with asthma.

Inhaled furosemide prevents bronchoconstriction induced by a number of challenges in asthma. One approach to determine the mechanism underlying this protection has been to examine the effects of diuretics with different or overlapping pharmacologic effects. We have compared the effects of furosemide on sodium metabisulfite-induced bronchoconstriction with those of equivalent diuretic doses of ethacrynic acid, a loop diuretic that, unlike furosemide, does not interact directly with the membrane Na/K/Cl cotransporter protein or inhibit carbonic anhydrase. Eight subjects with mild asthma were studied on five occasions, receiving nebulized furosemide (20 and 40 mg), ethacrynic acid (25 and 50 mg), or placebo (normal saline) in random order and double-blind 10 min before a cumulative dose challenge with inhaled sodium metabisulfite. After placebo the geometric mean sodium metabisulfite PD20 was 7.9 mumol. Furosemide 20 mg and 40 mg increased the PD20 by a mean 1.1 (95% confidence interval, -0.2-2.4; p > 0.05) and 1.6 (0.4-2.9; p < 0.02) doubling doses to 17.1 and 24.7 mumol, respectively. After inhaled ethacrynic acid 25 mg and 50 mg, the geometric mean PD20 was increased by 0.9 (-0.4-2.2; p > 0.05) and 1.5 (0.2-2.8; p < 0.05) doubling doses to 14.5 and 22.4 mumol, respectively. Thus, equivalent diuretic doses of furosemide and ethacrynic acid have a similar inhibitory effect on sodium metabisulfite-induced bronchoconstriction in asthma. This suggests that interaction with the Na/K/Cl cotransporter protein, or carbonic anhydrase inhibition, is not relevant to the effects of furosemide in asthma.

Administration, Inhalation↗