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PubMed1975

Ethacrynic acid induced inotropism.

Ethacrynic acid (ECA), a sulfhydryl group inhibiting diuretic was examined for positive inotropic effects. These were found to be present in isolated guinea pig left atria studied in 0.9 and 1.8 mM Ca bathing solutions and were partially dependent upon adrenergic mechanisms (presumably secondary to norepinephrine release from sympathetic nerve endings) and partly independent of such mechanisms as demonstrated by propranolol induced beta-blockade and reserpine-induced catecholamine depletion. The mechanism of the non-beta adrenergic inotropism is unclear but may relate to the ability of ECA to inhibit the sarcolemmal Na-K-Mg-dependent ATPase. ECA-induced premature contractile failure occurred in all atria as well as a late increase in diastolic tension, the latter being comparable to that described for toxic doses of cardiac glycosides in similar preparations.

Animals↗
PubMed1985

[Morphologic findings of the secretory epithelium of the ampulla following ethacrynic acid].

The effect of ethacrynic acid (dose 60 mg./kg. and 100 mg./kg.) on the secretory epithelium of guinea pig ampulla and semicircular epithelium was investigated. With high doses of ethacrynic acid and after long periods (3-4 hours) only, discrete electron microscopic alterations were seen. These consisted mainly in swelling of mitochondria, increase of vesicles, and movement or destruction of melanocytes. Interstitial oedema, well-documented in stria vascularis, was not observed.

Animals↗
PubMed1975

Influence of ethacrynic acid on intrarenal renin release mechanisms.

Ethacrynic acid infused i.v. in anesthetized dogs after inhibiting sympathetic mechanisms of renin release increased renal blood flow rate (RBF) by 54% and practically abolished autoregulation of RBF; renin release increased from 0.8 +/- 0.9 (mean +/- SEM) to 16.4 +/- 3.7 mug/min (P less than 0.05). Without infusion of ethacrynic acid; constriction of the renal artery to a pressure below the range of autoregulation reduced renovascular resistance markedly and renin release rose to 27.2 +/- 5.5 mug/min (P less than 0.05). During arterial constriction, ethacrynic acid had no additional effect on renovascular resistance or renin release averaging 28.4 +/- 6.7 mug/min. Infusion of ethacrynic acid and saline at control pressure increased sodium excretion to about one-half of the filtrate and reduced rein release which did not, however, return to control. Infusion of hypertonic saline during autoregulated vasodilatation induced by arterial constriction had a similar effect, but again renin release continued to exceed control. We propose that ethacrynic acid increases renin release through a hemodynamic mechanism triggered by afferent arteriolar dilation and inhibits renin release by greatly increasing the delivery of sodium to the distal convoluted tubules.

Animals↗
PubMed1978

Formation of a cyclic derivative of ethacrynic acid with diazomethane.

Samples of ethacrynic acid were treated with methanol-hydrochloric acid or with diazomethane. GLC and mass spectrometric analysis indicated that the methanol-hydrochloric acid reaction gave the expected methyl ester, whereas diazomethane treatment gave a compound containing an additional 14 mass units. Accurate mass measurement and PMR and IR spectra showed that this product was a cyclic derivative of the methyl ester of ethacrynic acid, methyl 4-(2,3-dihydro-4-ethyl-5-furyl)-2,3-dichlorophenoxyacetate. Either derivatization method can be used for development of an assay for ethacrynic acid.

Chromatography, Gas↗
PubMed2005

Ethacrynic acid inhibits multiple steps in the NF-kappaB signaling pathway.

Ethacrynic acid has been used as a safe and effective diuretic for more than 30 years. In this study, we tested the hypothesis that ethacrynic acid is also an anti-inflammatory agent that inhibits signaling by the proinflammatory transcription factor NF-kappaB. We showed that ethacrynic acid inhibited luciferase expression in lipopolysaccharide-stimulated macrophage-like RAW 264.7 cells transfected with an NF-kappaB-dependent luciferase reporter vector and also inhibited NF-kappaB DNA binding in lipopolysaccharide-stimulated RAW 264.7 cells (electrophoretic mobility shift assay). Ethacrynic acid inhibited degradation of IkappaBalpha and IkappaBbeta in lipopolysaccharide-stimulated RAW 264.7 cells. Ethacrynic acid impaired DNA binding of wild-type p65 subunits of NF-kappaB in cells. However, DNA binding of a Cys--> Ser p65 mutant was not inhibited by ethacrynic acid, suggesting that ethacrynic acid inhibits DNA binding by alkylating p65 at Cys. In a cell-free system, binding of p50 homodimers to an NF-kappaB consensus sequence was inhibited by ethacrynic acid at concentrations from 10 to 100 microM, indicating that ethacrynic acid probably also covalently modifies the p50 subunit. These data indicate that ethacrynic acid inhibits activation of the NF-kappaB pathway at multiple points and suggest that this well-studied drug warrants further investigation as a potential therapeutic for various conditions that are associated with excessive inflammation.

Animals↗
PubMed1990

Enhancement of anthracycline and alkylator cytotoxicity by ethacrynic acid in primary cultures of human tissues.

Ethacrynic acid [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxyl] acetic acid, is a water-soluble diuretic agent that has been shown to potentiate the in vitro cytotoxicity of chemotherapeutic agents in established cell lines. We used the differential staining cytotoxicity (DiSC) assay to determine whether ethacrynic acid at 1 and 3.3 microM would potentiate the cytotoxicity of nitrogen mustard and/or doxorubicin in primary cultures of hematologic neoplasms from heavily pretreated patients and in normal peripheral blood lymphocytes. At 3.3 microM, ethacrynic acid was toxic to 8 of 24 (33%) tumor specimens studied. In subsequent studies, ethacrynic acid at 1 microM was toxic to only 2 of 54 (4%) tumor specimens. Significant enhancement for doxorubicin or nitrogen mustard was confined to lymphatic malignancies and to normal peripheral blood lymphocytes. Interspecimen variability was observed, with no enhancement in most individual specimens, 2-fold enhancement in some specimens, and 4-fold enhancement in occasional specimens. Clinical trials will be required to determine whether the observed in vitro activity for ethacrynic acid is associated with clinical benefit in unselected or assay-selected patients.

Cell Survival↗
PubMed1997

The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.

The potent diuretic drug ethacrynic acid has been tested in clinical trials as an adjuvant in chemotherapy. Its target is the detoxifying enzyme glutathione transferase which is often found overexpressed in cancer tissues. We have solved the crystal structures of human pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Ethacrynic acid is found to bind in a nonproductive mode to one of the ligand binding sites of the enzyme (the H site) while the glutathione binding site (G site) is occupied by solvent molecules. There are no structural rearrangements of the G site in the absence of ligand. The structure indicates that bound glutathione is required for ethacrynic acid to dock into the H site in a productive binding mode. The binding of the ethacrynic acid-glutathione conjugate shows that the contacts of the glutathione moiety with the protein are identical to those observed in crystal structures of the enzyme with other glutathione-based substrates and inhibitors. The ethacrynic acid moiety of the conjugate binds in the H site in a fashion that has not been observed in crystal structures of other glutathione-based inhibitor complexes. The crystal structures implicate Tyr 108 as an electrophilic participant in the Michael addition of glutathione to ethacrynic acid.

Crystallography, X-Ray↗
PubMed2001

Ethacrynic acid inhibits pancreatic exocrine secretion.

AIM: The effect of ethacrynic acid on pancreatic exocrine secretion function and potential mechanisms of interference with the secretory process in pancreatic acinar cells were investigated. METHODS: After incubation with ethacrynic acid for 30 min, caerulein-stimulated amylase release and cholecystokinin (CCK) receptor binding characteristics were assessed in isolated rat pancreatic acini. The level of thiol groups (glutathione and protein thiols) and cytosolic free calcium were measured in pancreatic acinar cells. RESULTS: Ethacrynic acid decreased caerulein (0.1 nmol/L)-stimulated amylase release and the level of pancreatic acinar glutathione in a concentration-dependent fashion without a marked increase in cell damage. Ethacrynic acid also inhibited the caerulein (1 nmol/L)-induced Ca2+ mobilization in pancreatic acinar cells. But neither protein thiol nor CCK-receptor binding characteristics was altered by ethacrynic acid. CONCLUSION: Ethacrynic acid inhibit pancreatic exocrine secretion by depletion of glutathione and down-regulation of caerulein-induced Ca2+ mobilization. Glutathione might play a potential role in the secretory process in pancreatic acinar cells and in the secretory blockade observed in acute pancreatitis.

Amylases↗
PubMed1979

Effect of ethacrynic acid on guinea pig ileum.

The effect of ethacrynic acid on the motor function of guinea pig ileum was studied in vitro. Ethacrynic acid produced dose-related (5-160 microgram/ml) contractions in this tissue. Morphine, tetrodotoxin and sodium-free medium prevented the contractions while hexamethonium, diphenhydramine, methysergide or indomethacin did not. Atropine in a high concentration (0.1 microgram/ml) only inhibited the contractions. Ethacrynic acid inhibited the contraction of ileum induced by electrical stimulation of intramural nerves. This was not prevented by pretreatment with reserpine. Repeated exposure to ethyacrynic acid developed tachyphylaxis in contractile response. Inhibition of electrically elicited contraction of guinea pig ileum also diminished with repeated treatment. Ethacrynic acid (80-160 micrograms/ml) inhibited the peristaltic reflex of the guinea pig ileum. It is concluded that the excitatory effect of ethacrynic acid is most probably mediated by the release of neurotransmitter, however, the mechanism of the inhibitory effect remains to be elucidated.

Animals↗
PubMed1974

Effects of ethacrynic acid on the isolated collecting tubule.

Effects of the diuretic ethacrynic acid on osmotic water permeability were investigated in the isolated perfused collecting tubule of the rabbit kidney. The base-line water permeability of the collecting tubule was not affected when the drug (10(-4)M) alone was added to the bathing medium. Vasopressin alone in the bathing medium (2, 5 muU/ml) elicited a significant increase in osmotic water absorption. With vasopressin kept in the bathing medium, the addition of 10(-5)M ethacrynic acid depressed the hydro-osmotic effect of vasopressin by 50%. This inhibitory effect of low concentrations of ethacrynic acid could be surmounted by high, supramaximal dosage levels of vasopressin. When 10(-4)M ethacrynic acid was added to the bathing medium before vasopressin, the hydro-osmotic effect of vasopressin and the diuretic in combination was insignificant.Dibutyryl adenosine 3'5'-monophosphate (10(-4)-10(-2)M) alone in the bathing medium significantly increased baseline osmotic water flow, mimicing the effect of antidiuretic hormone. When ethacrynic acid was added together with the nucleotide, the permeability remained at the same high level. Theophylline, like the nucleotide and vasopressin, produced a significant hydro-osmotic effect. The magnitude of this response was not affected by further addition of ethacrynic acid (10(-4)M). It was concluded that ethacrynic acid is an antagonist of antidiuretic hormone. The antagonism probably occurs at the level of the receptor site of the hormone on the peritubular membrane. Antagonism to circulating antidiuretic hormone may therefore be one of the factors involved in the loss of renal concentrating ability brought about by ethacrynic acid diuresis.

Animals↗
PubMed1992

Effects of topical ethacrynic acid adducts on intraocular pressure in rabbits and monkeys.

We evaluated the effect of topical ethacrynic acid on rabbit and monkey intraocular pressure. In a preliminary experiment, 100-mmol/L ethacrynic acid applied topically to Dutch-Belted rabbit eyes was associated with an 8-mm Hg lowering of intraocular pressure. However, corneal edema was severe, and the corneal epithelium sloughed off. To try to maintain the pressure-lowering effect but reduce the corneal side effects, we attempted to create an adduct of ethacrynic acid by utilizing ethacrynic acid's sulfhydryl reactivity. Ethacrynic acid was mixed with equimolar cysteine to bind the sulfhydryl-reactive sites on ethacrynic acid. The goal was to expose the cornea to adducted ethacrynic acid, which might then dissociate in the anterior chamber via a retro-Michael reaction. Intraocular pressure decreased 8.9 mm Hg (n = 40) with this treatment, and corneal edema was lessened (32 of 40 eyes had mild to no edema). However, we observed that when the eye was treated before ethacrynic acid-cysteine administration with topical acetylcysteine, the corneal side effects were reduced further and the intraocular pressure effect remained. In living cynomolgus monkeys receiving a single pretreatment drop of 75-mmol/L acetylcysteine followed by two drops of 130-mmol/L ethacrynic acid and 130-mmol/L cysteine, an intraocular pressure lowering of 9.9 mm Hg was observed (n = 7). However, in three of seven eyes corneal edema developed. Pretreatment with two drops of acetylcysteine eliminated the pressure-lowering effect but did not confer any added corneal protection. Our results indicate that topical ethacrynic acid-cysteine is effective in lowering the intraocular pressure of rabbits and cynomolgus monkeys and, when combined with acetylcysteine pretreatment, may offer the potential for a new topical therapeutic regimen for use in glaucoma.

Acetylcysteine↗
PubMed1982

Energetics of tubular sodium reabsorption sensitive to ethacrynic acid and ouabain.

Ouabain reduces renal oxygen consumption more extensively than ethacrynic acid despite similar natriuretic effects. Therefore, ethacrynic acid, which does not inhibit Na-K-ATPase, might stimulate energy metabolism unrelated to net sodium reabsorption. Experiments were performed on anesthetized dogs that had received isotonic saline intravenously corresponding to 10% of body wt and acetazolamide (100 mg.kg-1 i.v.). Subsequent infusion of ouabain in nine dogs (120 nmol.kg-1 intrarenally) reduced sodium reabsorption and oxygen consumption in parallel, giving a delta Na/delta O2 ratio of 18.0 +/- 1.1. With ethacrynic acid (3 mg.kg-1 i.v.) in six other dogs the delta Na/delta O2 ratio averaged 24.5 +/- 1.4. In a third group of five dogs, ouabain administered after ethacrynic acid reduced sodium reabsorption and oxygen consumption to the same levels as when ouabain was given alone. Thus, the high oxygen consumption remaining after ethacrynic acid can be inhibited by ouabain. We propose that ethacrynic acid generates a futile cycling of sodium by Na-K-ATPase across the basolateral cell membrane that is not apparent as net sodium reabsorption and is stopped by ouabain.U

Absorption↗
PubMed1976

Specificity of ethacrynic acid as a sulfhydryl reagent.

Ethacrynic acid is not an absolutely specific SH-reagent. It reacts rapidly and reversibly with cysteine, imidazole, histidine, and lysine. The reaction products increase with increasing pH. LDH is rapidly and reversibly inhibited by ethacrynic acid.

Cysteine↗
PubMed1992

Ethacrynic acid increases facility of outflow in the human eye in vitro.

Anterior segments of human donor eyes were perfused with culture medium at a perfusion pressure of 15 mm Hg in a 5% carbon dioxide environment at 37 degrees C. After determination of a baseline facility of outflow, the perfusion chamber contents were exchanged with either drug vehicle or ethacrynic acid, at concentrations ranging from 0.01 to 0.25 mmol/L, after which postdrug facility was measured in the continuous presence of drug vehicle or ethacrynic acid. Ethacrynic acid increased facility of outflow from 28% to 105% at ethacrynic acid concentrations of 0.01 to 0.25 mmol/L, respectively. No morphologic correlate of the facility increase was observed with 0.01-mmol/L ethacrynic acid, nor were there any signs of cellular toxic effects. At 0.1 mmol/L, separations between trabecular meshwork cells and breaks between inner-wall cells were observed. At 0.25 mmol/L, focal areas of cell swelling and necrosis were noted. This study demonstrated that ethacrynic acid increases outflow facility in the aged human eye at concentrations that produce no apparent toxic effects. Therefore, ethacrynic acid may potentially prove useful in the treatment of glaucoma.

Adult↗
PubMed1989

Intracerebroventricular injection of ethacrynic acid induces status epilepticus.

The intracerebroventricular (i.c.v.) injection of ethacrynic acid to mice at a dose of more than 25 micrograms induced repeated tonic-clonic convulsions with subsequent death. Ethacrynic acid was more potent than other loop diuretics such as furosemide and bumetanide. Diazepam and 2-amino-5-phosphonovaleric acid notably reduced both the incidence of convulsion and the lethality seen after ethacrynic acid administration. Both phenobarbital and ketamine suppressed the incidence of convulsions but not the lethality. Without effects on the incidence of convulsions or lethality, dextromethorphan prolonged, while phenytoin or atropine shortened, the time to the onset of convulsion. Neither ethosuximide, carbamazepine, nor muscimol had a significant effect on the responses to ethacrynic acid. The present findings indicate that i.c.v. injected ethacrynic acid shows strong convulsive activity, probably due to impairment of Cl- transport processes, concomitant with enhancement of excitatory amino acid activity in the brain.

Animals↗
PubMed1984

Effects of ethacrynic acid in the newborn infant.

The effects of ethacrynic acid on electrolyte and water excretion were examined in 10 neonates with fluid overload states. Ethacrynic acid (1 mg/kg IV) produced a 10-fold increase in FENa+ and FECl - and a sixfold increase in urine volume and osmolar clearance. These effects peaked within 1 hour of ethacrynic acid administration, and progressively decreased to the baseline value by 5 hours after drug administration. The mean excretion of potassium increased by 280% in 1 hour, and returned to baseline value after 5 hours. The mean Ca++ excretion increased fourfold after 1 hour, and the effect lasted for 4 hours. Two infants developed mild hyponatremia. Our data emphasize the prolonged diuretic and saluretic effect of ethacrynic acid in neonates.

Chlorides↗
PubMed1993

Inactivation of mouse liver glutathione S-transferase YfYf (Pi class) by ethacrynic acid and 5,5'-dithiobis-(2-nitrobenzoic acid).

Mouse liver glutathione S-transferase YfYf (Pi class) reacts with [14C]ethacrynic acid to form a covalent adduct with a stoichiometry of 1 mol per mol of subunit. Proteolytic digestion of the enzyme-[14C]ethacrynic acid adduct with V8 protease produced an 11 kDa fragment containing radioactivity. Sequencing revealed this to be an N-terminal peptide (minus the first 15 residues, terminating at Glu-112) which contains only one cysteine residue (Cys-47). This is tentatively identified as the site of ethacrynic attachment. Kinetic studies reveal that glutathione S-conjugates protect against inactivation by ethacrynic acid, but the level of protection is not consistent with their potency as product inhibitors. A model is proposed in which glutathione S-conjugates and ethacrynic acid compete for the free enzyme, and a second molecule of ethacrynic acid reacts covalently with the enzyme-ethacrynic acid complex. The native protein contains one thiol reactive with 5,5'-dithiobis-(2-nitrobenzoic acid) at neutral pH. The resultant mixed disulphide, like the ethacrynic acid adduct, is inactive, but treatment with cyanide (which incorporates on a mol for mol basis) restores activity to 35% of that of the native enzyme.

Amino Acid Sequence↗
PubMed1998

GSTP1-1 stereospecifically catalyzes glutathione conjugation of ethacrynic acid.

Using 1H NMR two diastereoisomers of the ethacrynic acid glutathione conjugate (EASG) as well as ethacrynic acid (EA) could be distinguished and quantified individually. Chemically prepared EASG consists of equal amounts of both diastereoisomers. GSTP1-1 stereospecifically catalyzes formation of one of the diastereoisomers (A). The GSTP1-1 mutant C47S and GSTA1-1 preferentially form the same diastereoisomer of EASG as GSTP1-1. Glutathione conjugation of EA by GSTA1-2 and GSTA2-2 is not stereoselective. When human melanoma cells, expressing GSTP1-1, were exposed to ethacrynic acid, diastereoisomer A was the principal conjugate formed, indicating that even at physiological pH the enzyme catalyzed reaction dominates over the chemical conjugation.

Amino Acid Substitution↗