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At least 955 records · Page 53Linked to original sources
PubMed1991

Role of sulfhydryl groups in the stimulatory effect of captopril on vascular prostacyclin synthesis.

The effect of captopril on vascular prostacyclin production was studied, evaluating which of its components--sulfhydryl (SH) group or proline--is responsible for this effect. Rat aortas were incubated with captopril (10-100 microM), 2-mercaptoethanol or proline (10 microM), and captopril plus the SH-binding reagents N-ethylmaleimide or ethacrynic acid (50 microM). Prostacyclin was measured by radioimmunoassay of 6-keto-prostaglandin F1 alpha. Captopril stimulated prostacyclin production. This effect was associated with an enhanced conversion of arachidonate to prostacyclin and was not related to bradykinin. Since 2-mercaptoethanol increased vascular prostacyclin per se and proline did not, the stimulatory effect of captopril appears to be dependent upon the SH group; in addition, both SH blockers, N-ethylmaleimide and ethacrynic acid, antagonized this effect. This study shows that captopril stimulates vascular prostacyclin synthesis directly and that the SH group plays a key role in this action. This stimulation of prostacyclin synthesis may contribute to the antihypertensive action of captopril.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Lactate oxidation and sodium reabsorption by dog kidney in vivo.

Lactate uptake (Qlact) and oxidation (QCO2lact), oxygen consumption (QO2) and net tubular Na+ reabsorption (TNa), were estimated in pentobarbital-anesthetized dogs under control conditions and following unilateral intrarenal injection of ouabain or intravenous infusion of acetazolamide, ethacrynic acid, or furosemide. QCO2lact accounted for approximately half of simultaneous Qlact and for about one-third of QO2 in control periods. Ouabain injection resulted in significant decreases in several functions of the injected kidney: TNa, 46%; TNa/FNa, 36%; QO2, 40%; Qlact, 59%; and QCO2lact, 70%. Acetazolamide infusion decreased TNa, 33%; TNa/FNa, 12%; QO2, 10%; and QCO2lact, 38%; but did not change Qlact. Ethacrynic acid diminished TNa, 60%; TNa/FNa, 36%; QO2, 45%; Qlact, 31%; and QCO2lact, 73%. Furosemide lowered TNa, 37%; TNa/FNa, 28%; QO2, 25%; and Qlact, 48%; but did not change QCO2lact, 2%. Results indicate that decarboxylation is a major pathway of renal lactate metabolism, that lactate oxidation is a substantial source of aerobic energy for the kidney, and that QCO2lact is probably functionally related to sodium reabsorption. This relationship appears to be closer for a fraction of TNa associated with ouabain- and ethacrynic acid-sensitive mechanisms.

Absorption↗
PubMed1990

Loop diuretics reduce lithium reabsorption without affecting bicarbonate and phosphate reabsorption.

The effects of the loop diuretics ethacrynic acid and bumetanide on lithium, bicarbonate and phosphate reabsorption were compared in 16 anaesthetized, normovolaemic dogs. In six dogs, ethacrynic acid (3 mg kg-1 body wt) significantly reduced absolute lithium reabsorption from 29.3 +/- 4.1 to 19.0 +/- 3.4 mumol min-1, fractional lithium reabsorption from 0.65 +/- 0.04 to 0.37 +/- 0.04 and fractional chloride reabsorption from 1.00 +/- 0.00 to 0.65 +/- 0.02. Bicarbonate and phosphate reabsorption did not decrease significantly. In six other dogs, bumetanide (30 micrograms kg-1 body wt) gave similar results. Absolute lithium reabsorption significantly decreased from 34.0 +/- 2.2 to 18.1 +/- 2.6 mumol min-1 and fractional lithium reabsorption decreased from 0.50 +/- 0.03 to 0.25 +/- 0.03. Fractional chloride reabsorption decreased from 0.98 +/- 0.00 to 0.61 +/- 0.05, whereas bicarbonate and phosphate reabsorption were not significantly altered. Thus, both loop diuretics greatly reduced lithium reabsorption. We propose that loop diuretics inhibit passive lithium reabsorption in the thick ascending limb of Henle's loop by reducing the lumen-positive electrical potential that drives passive cation transport.

Absorption↗
PubMed1997

Effect of diuretics, channel modulators and signal interceptors on contractility of the trabecular meshwork.

Measurements of isometric tension were performed on isolated trabecular meshwork (TM) and ciliary muscle (CM) strips of the bovine eye. Anterior segments of bovine eyes with well-preserved TM were perfused to measure outflow rate. (1) Bumetanide (10(-4) mol/l) and hydrochlorothiazide (10(-4) mol/l) did not change the contractility of TM and CM strips in the presence or absence of carbachol. Ethacrynic acid dose-dependently relaxed TM and CM strips precontracted either by carbachol or endothelin. (2) Cytochalasin D totally relaxed TM and CM strips precontracted by carbachol. The outflow rate almost doubled after application of cytochalasin D. (3) The effects of various modulators of K+ and Ca2+ channels are summarized. Carbachol and endothelin are postulated to modify nonselective cation channels. An effective blocker of nonselective cation channels (flufenamic acid) relaxed TM and CM precontracted by carbachol or endothelin. These relaxing effects were independent of the relaxing effects of ethacrynic acid and isosorbide dinitrate. (4) Evidence for the presence of various transporters and receptors in TM cells is summarized. (5) The TM per se is a contractile element which is involved in the regulation of aqueous humor outflow. The contractility of TM and CM cells is differently modulated.

Absorption↗
PubMed2001

Activation of multiple antibiotic resistance in uropathogenic Escherichia coli strains by aryloxoalcanoic acid compounds.

Clofibric and ethacrynic acids are prototypical pharmacological agents administered in the treatment of hypertrigliceridemia and as a diuretic agent, respectively. They share with 2,4-dichlorophenoxyacetic acid (the widely used herbicide known as 2,4-D) a chlorinated phenoxy structural moiety. These aryloxoalcanoic agents (AOAs) are mainly excreted by the renal route as unaltered or conjugated active compounds. The relatedness of these agents at the structural level and their potential effect on therapeutically treated or occupationally exposed individuals who are simultaneously undergoing a bacterial urinary tract infection led us to analyze their action on uropathogenic, clinically isolated Escherichia coli strains. We found that exposure to these compounds increases the bacterial resistance to an ample variety of antibiotics in clinical isolates of both uropathogenic and nonpathogenic E. coli strains. We demonstrate that the AOAs induce an alteration of the bacterial outer membrane permeability properties by the repression of the major porin OmpF in a micF-dependent process. Furthermore, we establish that the antibiotic resistance phenotype is primarily due to the induction of the MarRAB regulatory system by the AOAs, while other regulatory pathways that also converge into micF modulation (OmpR/EnvZ, SoxRS, and Lrp) remained unaltered. The fact that AOAs give rise to uropathogenic strains with a diminished susceptibility to antimicrobials highlights the impact of frequently underestimated or ignored collateral effects of chemical agents.

Anti-Bacterial Agents↗
PubMed1999

The role of tyrosine-9 and the C-terminal helix in the catalytic mechanism of Alpha-class glutathione S-transferases.

Glutathione S-transferases (GSTs) play a key role in the metabolism of drugs and xenobiotics. To investigate the catalytic mechanism, substrate binding and catalysis by the wild-type and two mutants of GST A1-1 have been studied. Substitution of the 'essential' Tyr(9) by phenylalanine leads to a marked decrease in the k(cat) for 1-chloro-2,4-dinitrobenzene (CDNB), but has no affect on k(cat) for ethacrynic acid. Similarly, removal of the C-terminal helix by truncation of the enzyme at residue 209 leads to a decrease in k(cat) for CDNB, but an increase in k(cat) for ethacrynic acid. The binding of a GSH analogue increases the affinity of the wild-type enzyme for CDNB, and increases the rate of the enzyme-catalysed conjugation of this substrate with the small thiols 2-mercaptoethanol and dithiothreitol. This suggests that GSH binding produces a conformational change which is transmitted to the binding site for the hydrophobic substrate, where it alters both the affinity for the substrate and the catalytic-centre activity ('turnover number') for conjugation, perhaps by increasing the proportion of the substrate bound productively. Neither of these two effects of GSH analogues are seen in the C-terminally truncated enzyme, indicating a role for the C-terminal helix in the GSH-induced conformational change.

Amino Acid Substitution↗
PubMed1985

Some actions of sodium nitroprusside and glyceryl trinitrate on guinea-pig isolated trachealis muscle.

The smooth muscle relaxant actions of sodium nitroprusside and glyceryl trinitrate have been compared to those of aminophylline and isoprenaline on isolated guinea pig trachealis muscle. Ethacrynic acid (0.25 X 10(-4) M), an alkylator of sulphydryl groups, interacted differently with the four agents. In the presence of ethacrynic acid the concentration response curve of the muscle preparation to sodium nitroprusside and glyceryl trinitrate was shifted to the higher concentration ranges and the maximum response was severely reduced. The concentration response curve for isoprenaline was shifted to the higher concentration ranges with no change in the maximum response and the response to aminophylline was unchanged. These results argue against common intermediate sites of action involving sulphydryl groups of the four agents in guinea-pig trachealis.

Aminophylline↗
PubMed2005

Filarial glutathione S-transferase: its induction by xenobiotics and potential as drug target.

Glutathione-S-transferase (GST) a Phase-II drug detoxification enzyme, was detected in Setaria cervi, a bovine filarial parasite. In vitro effect of diethylcarbamazine, butylated hydroxyanisole and phenobarbitone on the GST of adult female S. cervi was assayed by the addition of these compounds in the maintenance medium. The specific activity of GST towards 1-chloro-2,4-dinitrobenzene was increased progressively 1.2-1.97, 1.3-2.4 and 1.2-2.7 times at 10-100 microM of diethylcarbamazine, butylated hydroxyanisole and phenobarbitone, respectively, after 5 h at 37 degrees C. Substrate specificity studies showed a higher increase in specific activity with ethacrynic acid and no change with cumene hydroperoxide. Although the intensity of GST activity band was more in extract from diethylcarbamazine or butylated hydroxyanisole treated worms extract, an extra band of activity appeared in those worm extracts compared to control worm extract. SDS/PAGE showed increased thickness of the band corresponding to purified GST in extracts from diethylcarbamazine/butylated hydroxyanisole/phenobarbitone treated worms. Purification and quantification of GST from diethylcarbamazine and butylated hydroxyanisole treated worms indicated an increase in enzyme specific activity. The increase in GST protein by these agents was blocked by prior treatment with actinomycin D, indicative of a transcription dependent response. The role of this enzyme in motility and viability of microfilariae and adult female was tested in vitro using a range of known GST inhibitors. Of those tested, ethacrynic acid, ellagic acid, 1-chloro-2,4-dinitrobenzene, cibacron blue and butylated hydroxyanisole reduced the viability and motility of microfilariae and adult female worms at micromolar concentrations. These results suggest that S. cervi GST is inducible in response to the antifilarial drug diethylcarbamazine and may play an important role in parasite's survival, thus could be a potential drug target.

Animals↗
PubMed1987

Endolymph formation in the inner ear of pigeons.

The endolymphatic space of pigeons was studied by using double-barrelled electrodes with a potassium liquid ion exchanger. The K+ activity of the endolymph was 155 mM in the cochlea and 133 mM in the ampulla, respectively. Positive DC potential in the cochlea (+14.5 mV) was much lower than in guinea pigs (+80 mV) whereas in the ampulla of pigeons the DC potential (+7.4 mV) was 2 times higher than that of guinea pigs (+3.9 mV). General application of ethacrynic acid in pigeons induced a weak change in DC potential and no typical intercellular edema in the cochlea and ampulla. Local application of ethacrynic acid and ouabain in the cochlea and ampulla of pigeons induced a negative DC potential of between -30 and -40 mV. This negative DC potential was higher than the anoxia-induced negative potential. Short hypoxia during a drug-induced DC potential resulted in a decrease in DC potential above the diffusion potential. Below the diffusion potential additional hypoxia increased the DC potential independent of the cause of intoxication.

Animals↗
PubMedDate not supplied

In vitro reversal of glutathione-S-transferase-mediated resistance in canine osteosarcoma (COS31) cells.

BACKGROUND: In this report we describe the establishment, characterization, and research utility of a cell line derived from a dog having a spontaneously occurring osteosarcoma (COS) made resistant to the cytotoxic effects of cisplatin chemotherapy. MATERIALS AND METHODS: Established cells from passage 31 (COS31) were exposed to increasing sublethal concentrations of cisplatin in vitro. RESULTS: A 2.2-fold increase in glutathione-S-transferase (GST) activity was found to be induced in this cell line (COS31/rCDDP) compared to parent cells. Furthermore, these cells were 7.8-fold more resistant to the cytotoxic effects of higher concentrations of cisplatin compared to parent cells. Ethacrynic acid was found to inhibit GST enzymatic activity and increase cisplatin cytotoxicity in resistant COS31 (COS31/rCDDP) cells. CONCLUSIONS: Inhibiting the function of GST with ethacrynic acid pretreatment in humans and dogs with osteosarcoma may result in more tumor cells than normal cells killed in vivo by cisplatin, thus significantly prolonging lifespan without increasing host toxicity.

Animals↗
PubMed2004

Volume-sensitive chloride channels do not mediate activation-induced chloride efflux in human neutrophils.

Many agents that activate neutrophils, enabling them to adhere to venular walls at sites of inflammation, cause a rapid Cl(-) efflux. This Cl(-) efflux and the increase in the number and affinity of beta(2) integrin surface adhesion molecules (up-regulation) are all inhibited by ethacrynic acid and certain aminomethyl phenols. The effectiveness of the latter compounds correlates with their inhibition of swelling-activated Cl(-) channels (I(Clvol)), suggesting that I(Clvol) mediates the activator-induced Cl(-) efflux. To test this hypothesis, we used whole-cell patch clamp in hypotonic media to examine the effects of inhibitors of up-regulation on I(Clvol) in neutrophils and promyelocytic leukemic HL-60 cells. Both the channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid and [3-methyl-1-p-sulfophenyl-5-pyrazolone-(4)]-[1,3-dibutylbarbituric acid]-pentamethine oxonol (WW781), a nonpenetrating oxonol, inhibited I(Clvol) at concentrations similar to those that inhibit beta(2) integrin up-regulation. However, ethacrynic acid, at the same concentration that inhibits activator-induced Cl(-) efflux and up-regulation, had no effect on I(Clvol) and swelling-activated Cl(-) efflux, providing evidence against the involvement of I(Clvol) in the activator-induced Cl(-) efflux.

Benzenesulfonates↗
PubMedDate not supplied

[Effect of diuretics on vascular permeability and proliferative inflammation in rats].

It is shown that ethacrynic acid and dichlothiazide in 50 mg/kg dose reduce the dextran-induced increase of rat skin vascular permeability. Besides, durable administration of furosemide, dichlothiazide and ethacrynic acid in 50-80 mg/kg doses decreases the dry mass of inflammatory granuloma. This fact shows the ability of diuretics to suppress the development of proliferative inflammation.

Animals↗
PubMed1987

Na+, K+ and Cl- transport in isolated small intestinal cells from guinea pig. Evidences for the existence of a second Na+ pump.

Isolated small intestinal epithelial cells, after incubation at 4 degrees C for 30 min, reach ion concentrations (36 mM K+, 113 mM Na+ and 110 mM Cl-) very similar to those of the incubation medium. Upon rewarming to 37 degrees C, cells are able to extrude Na+, Cl- and water and to gain K+. Na+ extrusion is performed by two active mechanisms. The first mechanism, transporting Na+ by exchanging it for K+, is inhibited by ouabain and is insensitive to ethacrynic acid. It is the classical Na+ pump. The second mechanism transports Na+ with Cl- and water, is insensitive to ouabain but is inhibited by ethacrynic acid. Both mechanisms are inhibited by dinitrophenol and anoxia. The second Na+ extruding mechanism could be the Na+/K+/2Cl- cotransport system. However, this possibility can be ruled out because the force driving cotransport would work inwards, and because Na+ extrusion with water loss continues after substitution of Cl- by NO3-. We propose that enterocytes have a second Na+ pump, similar to that proposed in proximal tubular cells.

Animals↗
PubMed1998

Post-translational processing of murine IL-1: evidence that ATP-induced release of IL-1 alpha and IL-1 beta occurs via a similar mechanism.

In response to LPS, peritoneal macrophages produce IL-1, but, for the most part, newly synthesized cytokine molecules remain cell associated. Externalization and proteolytic processing of pro-IL-1 beta can be initiated by extracellular ATP. In this study, kinetics and inhibitor sensitivity of the stimulus-coupled mechanism were investigated with [35S]methionine-labeled macrophages. Optimal ATP concentrations required to promote cytokine post-translational processing suggest the involvement of a P2Z type of receptor. Proteolysis of pro-IL-1 beta initiates within 7.5 min of ATP addition; 17-kDa mature IL-1 beta is observed first intracellularly and subsequently extracellularly. In contrast, ATP-treated cells do not contain 17-kDa IL-1 alpha. Macrophages exposed to ATP continuously or only for a 15-min pulse release IL-1 alpha, IL-1 beta, and lactate dehydrogenase (LDH). Proteolytic maturation of IL-1 beta exceeds that of IL-1 alpha in both formats, but pulsed cells process the externalized cytokines more efficiently. Ethacrynic acid and DIDS (4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid) block ATP-induced proteolysis of pro-IL-1 beta and prevent release of pro-IL-1 alpha/beta and LDH; they do not inhibit ATP-induced K+ (86Rb+) efflux. Ethacrynic acid inhibits release of both forms of IL-1 with a similar concentration dependence; within the arrested cells, procytokines accumulate in a Triton-insoluble fraction. An IL-1 beta-converting enzyme inhibitor blocks proteolysis of IL-1 beta, but it does not prevent release of pro-IL-1 alpha, pro-IL-1 beta, or LDH. These results indicate that ATP stimulates externalization of both IL-1 alpha and IL-1 beta. The ATP-induced cytokine release mechanism is accompanied by cell death and requires activity of an anion transport inhibitor-sensitive component, but this pathway operates independently of cytokine proteolytic processing.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1985

Mg2+-ATP-dependent sodium transport in inside-out basolateral plasma membrane vesicles from guinea-pig small intestinal epithelial cells.

The transport of sodium into inside-out basolateral plasma membrane vesicles from small intestinal epithelial cells has been examined. It was found, under equilibrium conditions, that binding of 22Na represents approx. 55% of the total uptake during an equilibration period of 30 min; 45% of the total uptake correspond to passive sodium entry in the vesicle space. In addition to binding and to passive Na+ entry, two distinct mechanisms capable of accumulating sodium in the intravesicular space can be demonstrated when ATP is added to the incubation medium. One transports sodium actively in the absence of potassium, whereas the other requires the presence of potassium in the interior of the vesicles. The two mechanisms can also be differentiated by their affinities for sodium, their optimal pH and by their behaviour towards different inhibitors. Thus, the mechanism that transports sodium in the absence of potassium is refractory to ouabain, but is inhibited by ethacrynic acid and furosemide, whilst the mechanism that accumulates sodium inside the vesicles in the presence of internal potassium is strongly inhibited by ouabain, is weakly inhibited by ethacrynic acid and is insensitive of furosemide. ATP is a specific stimulator of both processes, and the requirement for magnesium is absolute in both cases.

Adenosine Triphosphate↗
PubMed1988

Drug and fatty acid effects on serum thyroid hormone binding.

We directly compared the competitor potency for serum T4 binding of 11 nonsteroidal antiinflammatory drugs; the diuretics furosemide, ethacrynic acid, and bumetanide; diphenylhydantoin; the cholecystographic contrast agents iopanoate and ipodate; and six long-chain nonesterified fatty acids (NEFA) using equilibrium dialysis. To avoid artefacts that occur in competitor studies with diluted serum or isolated binding proteins, we used undiluted normal serum, with drugs added at concentrations that achieved high therapeutic total and free serum levels at equilibrium. Drug addition was based on the measured free fraction of each drug in serum. The free T4 fraction in normal serum (Tris buffer, pH 7.4; 37 C) was between 1.40 X 10(-4) and 1.53 X 10(-4). Drug-induced increases in T4 free fraction were: fenclofenac, 90%; aspirin, 62%; meclofenamic acid, 39%; diflunisal, 37%; mefenamic acid, 31%; and furosemide, 31%. Significant increases of 7-15% occurred with diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin. Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive at the concentrations studied. Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive. The effect of 5 mmol/L oleic acid in serum could be reproduced by addition of 0.5 mmol/L to serum diluted 1:10, indicating that protein binding of NEFA is the major determinant that limits their competitor potency. These findings provide a basis for anticipating which potential inhibitors may cause important changes in serum thyroid hormone binding. The time course of such effects will be influenced by the pharmacokinetics of the inhibitor itself as well as the equilibrium findings described here.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Identification and modulation of a voltage-dependent anion channel in the plasma membrane of guard cells by high-affinity ligands.

Guard cell anion channels (GCAC1) catalyze the release of anions across the plasma membrane during regulated volume decrease and also seem to be involved in the targeting of the plant growth hormones auxins. We have analyzed the modulation and inhibition of these voltage-dependent anion channels by different anion channel blockers. Ethacrynic acid, a structural correlate of an auxin, caused a shift in activation potential and simultaneously a transient increase in the peak current amplitude, whereas other blockers shifted and blocked the voltage-dependent activity of the channel. Comparison of dose-response curves for shift and block imposed by the inhibitor, indicate two different sites within the channel which interact with the ligand. The capability to inhibit GCAC1 increases in a dose-dependent manner in the sequence: probenecid less than A-9-C less than ethacrynic acid less than niflumic acid less than IAA-94 less than NPPB. All inhibitors reversibly blocked the anion channel from the extracellular side. Channel block on the level of single anion channels is characterized by a reduction of long open transitions into flickering bursts, indicating an interaction with the open mouth of the channel. IAA-23, a structural analog of IAA-94, was used to enrich ligand-binding polypeptides from the plasma membrane of guard cells by IAA-23 affinity chromatography. From this protein fraction a 60 kDa polypeptide crossreacted specifically with polyclonal antibodies raised against anion channels isolated from kidney membranes. In contrast to guard cells, mesophyll plasma membranes were deficient in voltage-dependent anion channels and lacked crossreactivity with the antibody.

Benzoates↗
PubMed1992

[Deafness, induced by sodium ethacrynate in guinea pigs, alleviated by microwave treatment].

Microwave is used to treat temporal hearing loss caused by intravenous injection of the ethacrynic acid in guinea pigs. The recovery of hearing is much faster in the treated groups than in the control group. The article proposes possible mechanism of the effects against the ethacrynic acid induced deafness and assume that the result of this research can provide an experimental basis for treatment of some perceptive deafness due to ischemia of stria vascularis of the cochlea.

Animals↗