Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ETHACRYNIC ACID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMed1970

The effect of altered sodium concentration in the distal nephron segments on renin release.

Ethacrynic acid, a potent inhibitor of sodium reabsorption in the ascending limb of Henle's loop, produces a sharp rise in renal venous renin activity within 5 min after intravenous administration in anesthetized dogs. This response persists when volume depletion is prevented by returning urinary outflow to the femoral vein. Comparable studies with chlorothiazide, a diuretic with little or no effect on the medullary portion of the ascending limb of the loop of Henle, failed to produce a significant increase in renal venous renin activity.When administered during ureteral occlusion, ethacrynic acid produced no change in renal venous renin activity until ureteral occlusion was released and flow restored. Following release of the ureters, a prompt rise in renal venous renin was again observed within 5 min of release. Control studies of ureteral occlusion yielded a fall in renal venous renin activity following release of the ureter without administration of ethacrynic acid. These studies identify a prompt stimulatory effect of ethacrynic acid on renin release that is unrelated to volume depletion but dependent upon the presence of tubular urine flow. Although further definition of the site and characteristics of the distal tubular mechanism for stimulation of renin release requires more direct study, the data presented here indicate that changes in sodium concentration in distal tubular fluid serve as a stimulus for renin release.

Angiotensin II↗
PubMed1984

Tamm-Horsfall glycoprotein release from rat kidney cortex slices in vitro.

Rat kidney cortex slices were incubated for 30 min at 37 degrees C in unmodified Krebs-Henseleit buffer containing aldosterone, vasopressin, theophylline, ethacrynic acid, frusemide, spironolactone or ouabain. Tamm-Horsfall glycoprotein (THG) released into the media was measured by radioimmunoassay and at the end of each experiment the slices were homogenized and assayed for THG content. Incubation of kidney cortex slices in unmodified buffer resulted in a significant increase in the slice THG content when compared with pre-incubation levels. The increase was prevented by puromycin or cycloheximide. Incubation in ethacrynic acid (1 mmol/l) or frusemide (10 mmol/l) resulted in a significant increase in release of THG when compared with unmodified buffer. Puromycin or cycloheximide failed to prevent the increased release. THG release induced by ethacrynic acid or frusemide is probably the result of an aggregation-disaggregation reaction on the cell membrane. It is suggested that the action of the chloride inhibiting diuretics, ethacrynic acid and frusemide, is mediated in some way via THG.

Animals↗
PubMed1988

Excretory function after renal denervation and administration of diuretics to unanesthetized dogs.

Diuretics were administered intravenously to unanesthetized dogs with exteriorized ureters for separate urine collection from both kidneys: furosemide (0.2 mg/kg), ethacrynic acid (0.22 mg/kg), acetazolamide (3.0 mg/kg), amiloride (1.0 mg/kg b.w.). Diuresis, urine and plasma osmolality, excretion, clearances and excretion fractions of sodium, potassium, chloride and magnesium were determined. After left-side kidney denervation not later than 50 days after operation, the above mentioned diuretics were administered to the same animals. The responses of the denervated and intact kidneys were compared. During some of the experiments after furosemide administration isotonic solution of sodium chloride in a volume, adequate to the volume of the collected urine, was infused. Furosemide or ethacrynic acid administration leads to a higher increase of both diuresis and chloride excretion from denervated kidney as compared to the intact one. After ethacrynic acid administration magnesium excretion from the denervated kidney was registered to be higher than that from the intact one. After chronic renal denervation of unanesthetized dogs, chloride and magnesium reabsorption in the ascending limb of Henle's loop was greater in the denervated than in the intact kidney. Amiloride suppression of potassium secretion in the distal part of the nephron did not lead to differences between the denervated and intact kidneys. The decreased volume of extracellular liquid, resulting from diuretic action, did not change the response of the denervated kidney to furosemide or to ethacrynic acid.

Acetazolamide↗
PubMed2002

A possible effect of sulfhydryl reagents on the contractile activity of the rat detrusor muscle.

We aimed to investigate the effect of sulfhydryl (SH) inactivating agents, ethacrynic acid and N-ethylmaleimide, on the contractile activity of rat detrusor muscle. Wistar Kyoto rats weighing 150-250 g were anaesthetized with ketamine and bled to death. The urinary bladders were surgically removed and detrusor strips were mounted under 0.5 g tension in organ baths. The responses were recorded with isotonic transducers on polygraph paper. After an equilibrium period, the tissues were contracted by electrical field stimulation, acetylcholine, ethacrynic acid or N-ethylmaleimide and the effects of L-cysteine, glutathione, verapamil, Ca(2+)-free solution, sodium nitroprusside or atropine were then examined on these contractions. Verapamil, Ca(2+)-free solution or atropine significantly reduced the contractions elicited by electrical field stimulation and acetylcholine whereas L-cysteine, glutathione or sodium nitroprusside had no effect on the contractions in response to these stimuli. L-Cysteine, glutathione, verapamil or Ca(2+)-free solution significantly inhibited the contractions induced by ethacrynic acid or N-ethylmaleimide. Sodium nitroprusside slightly inhibited only the contraction induced by ethacrynic acid but not that with N-ethylmaleimide. Atropine has no action on the contractions in response to these SH reagents. These findings suggest that SH reagents may play a role in the contractile activity of rat detrusor muscle and this action seems to be related to the gating of Ca(2+) channels. Further experiments are needed to determine the cellular mechanism(s) of action by which these SH reagents act on the detrusor smooth muscle.

Acetylcholine↗
PubMed1991

Effects of various concomitant medications on gastric alcohol dehydrogenase and the first-pass metabolism of ethanol.

Inhibition of gastric alcohol dehydrogenase (ADH) has been shown to enhance alcohol absorption in man under certain circumstances. To determine whether various medications might affect alcohol absorption, we screened 18 compounds for an effect on ADH. Salicylic acid, acetaminophen, propranolol, ethacrynic acid, and three H2-receptor antagonists all inhibited rat gastric ADH in vitro, indicating that several commonly used medications have the potential to enhance alcohol absorption. Of these, cimetidine, ranitidine, and nizatidine were studied further to define their effect on alcohol absorption in man and to assess the clinical relevance of the effect. Both ranitidine and nizatidine enhanced the absorption of small doses of alcohol (0.15 g/kg) in the morning by 63% and 64% and increased Cmax by 48% and 54% respectively (p less than 0.001), effects similar to those reported by others for cimetidine. The effect of ranitidine given before dinner was greatly attenuated with increases in Cmax of 8% (NS) and AUC of 21% (p = 0.02). Cimetidine 800 mg hs did not affect the absorption of 0.15 g/kg alcohol given in the evening, and cimetidine 400 mg bid decreased absorption by 14% (p = 0.11). Cimetidine 300 mg qid had no effect on larger doses of alcohol given at dinner. We conclude that many commonly used medications affect gastric ADH, but that the increase in the actual amount of alcohol absorbed is quite small, and demonstrable only under special conditions.

Acetaminophen↗
PubMed1977

Effects of diuretics on thyroid function of guinea pigs.

Uptake of radioiodide by the isolated thyroid and serum concentrations of thyroxine (T4) and tri-iodothyronine (T3) were determined in guinea pigs pretreated with ethacrynic acid (20 mg/kg), furosemide (40 mg/kg) or hydrochlorothiazide (40 mg/kg). It was found that both ethacrynic acid and furosemide suppressed the 131I uptake by the isolated thyroid tissues. In addition, thyroid weight and serum T3 concentration were lower in ethacrynic acid-treated animals. It seems that some diuretics, particularly ethacrynic acid, depressed the function of thyroidal follicular cells.

Animals↗
PubMedDate not supplied

Reduction of the endocochlear potential by the new "loop" diuretic, bumetanide.

The effect of bumetanide upon the endocochlear potential (EP) was examined in 46 guinea pigs. The EP was reduced with dosages of 5 mg/kg or more. The maximum depression of the EP (reduction to -30 to -40 mV) was obtained at a dosage of 30 mg/kg. The recovery of the potential was incomplete at any dosage within three hours and the response pattern of the EP to bumetanide was similar to that to ethacrynic acid. The present experiments revealed that bumetanide, by weight, has a stronger ototoxic potency than the other "loop" diuretics--furosemide and ethacrynic acid. However, the diuretic effect of 1 mg bumetanide is equivalent to 40 to 60 mg furosemide or ethacrynic acid. Therefore, the relative ototoxic potency of bumetanide is much smaller suggesting that from a clinical standpoint bumetanide is much safer than the other "loop" diuretics.

Action Potentials↗
PubMed1998

Glutathione-dependent biotransformation of the alkylating drug thiotepa and transport of its metabolite monoglutathionylthiotepa in human MCF-7 breast cancer cells.

In this study, the role of glutathione S-transferase (GST) P1-1, the cellular reduced glutathione (GSH) status, and ATP-dependent efflux pumps in the cellular glutathione-dependent biotransformation of thiotepa and transport of the main metabolite monoglutathionylthiotepa in relation to cytotoxicity was studied in control and GST-P1-1-transfected MCF-7 cell lines. It was demonstrated that an enhanced cellular level of GST-P1-1 leads to an enhanced formation of monoglutathionylthiotepa, which is transported out of the cell into the medium. Monoglutathionylthiotepa was able to reversibly inhibit the activity of purified GST-P1-1, but only at nonphysiological concentrations, indicating that feedback inhibition of GST by its metabolites is not a relevant process in vivo. The GST activity, cellular GSH level, and/or ATP-dependent efflux of monoglutathionylthiotepa were modulated using ethacrynic acid, D,L-buthionine-S,R-sulfoximine, probenecid, and verapamil to understand the interplay between GSTs, glutathione conjugation, and efflux of glutathione conjugates in more detail. Inhibition of the GSH biosynthesis by D,L-buthionine-R,S-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, significantly reduced the glutathione conjugation of thiotepa and potentiated the cytotoxicity of thiotepa. Pretreatment of cells with ethacrynic acid resulted in decreased formation of monoglutathionylthiotepa as a result of inhibition of GST in the GST-P1-1 transfectant. In addition, the intracellular amount of monoglutathionylthiotepa increased in both of the cell lines on exposure to ethacrynic acid, indicating that transport of the glutathione conjugate was partially inhibited by the glutathione conjugate of ethacrynic acid. Transport activity of monoglutathionylthiotepa could also be inhibited by probenecid and verapamil, inhibitors of organic anion transport, without influencing the biotransformation capacity of the cells. It was demonstrated that inhibition of glutathione conjugate efflux by probenecid and verapamil leads to enhanced cytotoxicity, which indicates that besides thiotepa, monoglutathionylthiotepa is also cytotoxic for the cells. Only enhanced biotransformation and subsequent transport of the glutathione conjugate into the medium (which occurs with the GST-P1-1 transfectant) results in enhanced viability. Therefore, it was concluded that only enhanced biotransformation of thiotepa represents a real detoxification pathway when the resulting conjugate is transported out of the cells. Altogether, the results indicate that it is not the overexpression of GST per se but the interplay between GSH/GST and glutathione conjugate efflux pumps that results in increased resistance to alkylating anticancer drugs such as thiotepa.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

[Comparative effectiveness of the anti-inflammatory action of diuretics and butadione in an experiment].

Dichlothiazide and butadione were shown to attenuate equally the development of the rat paw inflammatory edema induced by subplantar dextran administration. Ethacrynic acid produced more pronounced antiedematous effect. Also, ethacrynic acid reduced to the highest degree the damp and dry mass of the inflammatory granuloma. Oxadoline and butadione considerably inhibit the formation of granuloma as well. The combined use of diuretics and butadione did not lead to a mutual potentiation of the antiinflammatory effect in exudative and proliferative inflammation.

Animals↗
PubMed1969

Ion movements in human red cells independent of the sodium pump.

1. A study was made of the dependence on external Na of the movements of Na and K in human red cells. Special attention was given to ouabain-insensitive movements. The effect of internal Na on Na influx, and the influence of some sulphydryl inhibitors on ion movements and metabolism was also investigated.2. External Na stimulated ouabain-insensitive Na efflux and K influx. There was also a ouabain-insensitive component of Na influx that was raised on increasing the internal Na concentration. Exchange diffusion of Na appears to occur in the presence of ouabain and external K.3. Net transport of Na and K in the presence of ouabain was independent of external Na, as was also lactate production.4. Ethacrynic acid partially inhibited the Na pump; the Na-dependent components of Na efflux and K influx in the presence of ouabain were completely inhibited by ethacrynic acid. Both ouabain-sensitive and ouabain-insensitive adenosinetriphosphatase activities were inhibited by ethacrynic acid indicating a non-specific effect of this compound. Iodoacetamide decreased only the ouabain-insensitive ATPase activity.5. The results suggest that when the Na pump is blocked by ouabain, part of the residual ion movements can be attributed to exchange diffusion.

Adenosine Triphosphatases↗
PubMed1976

Studies on the nature of a prostaglandin receptor in canine and rabbit vascular smooth muscle.

The contractile response of rabbit renal arteries and canine tibial arteries to prostaglandins A2, B2, F2alpha, E1, E2, D2, and B1 was associated with a reduction in total sulfhydryl group content of smooth muscle. The total sulfhydryl content of rabbit renal and canine tibial arteries and was not affected by norepinephrine or potassium chloride. Reduction of disulfide groups with dithiothreitol (DTT) selectively inhibited contractile responses to angiotensin and prostaglandins; 5,5'-Dithiobisnitrobenzoic acid (DTNB), a sulfhydryl group-oxidizing agent, reversed the inhibitory effect of DTT on the contractile responses to prostaglandins. Alkylation of free sulfhydryl groups with ethacrynic acid did not affect the contractile response of isolated canine tibial or rabbit renal arteries to any agonist studied. Ethacrynic acid added to muscle strips exposed to DTT resulted in alkylation of sulfhydryl groups produced by reduction of disulfide bonds and irreversibly prevented DTNB-induced reversal of DTT inhibition of contractile responses to prostaglandins. However, addition of ethacrynic acid to muscle strips contracted by prostaglandins did not inhibit subsequent responses to these acidic lipids. These findings support the hypothesis that contractile responses of rabbit renal and canine tibial arteries to prostaglandins are dependent on interactions between prostaglandins and disulfide groups located in or on the vascular smooth muscle cell, and the concept that membrane disulfide groups may be integral components of vascular smooth muscle receptors for prostaglandins.

Angiotensin II↗
PubMed1977

Correlated effects of cigarette smoke components on alveolar macrophage adenosine triphosphatase activity and phagocytosis.

An initial examination was made of the hypothesis that one action of cigarette smoke components on pulmonary alveolar macrophage function involves the inhibition of contractile protein adenosine triphosphatase activity. Pulmonary alveolar macrophage calcium-dependent adenosine triphosphatase activity, magnesium-dependent adenosine triphosphatase activity, sodium-potassium-dependent adenosine triphosphatase activity, phagocytosis, and cell adhesiveness were measured in the presence of cigarette smoke, acrolein, ouabain, and ethacrynic acid. Calcium-dependent adenosine triphosphatase activity, magnesium-dependent adenosine triphosphatase activity, phagocytosis, and adhesiveness were inhibited by smoke and ethacrynic acid, but not by ouabain. Acrolein, a component of smoke, inhibited phagocytosis, adhesiveness, and calcium-dependent adenosine triphosphatase activity, indicating that another component of smoke must be effective at inhibiting magnesium-dependent adenosine triphosphatase activity. Sodium-potassium-dependent adenosine triphosphatase activity was inhibited by ouabain and ethacrynic acid, but not by smoke or acrolein. Finally, sulfhydryl reagents at least partially protected the macrophages against the inhibitory actions of each of the agents. The results are in accord with recently obtained experimental evidence that calcium-dependent adenosine triphosphatase and, perhaps, magnesium-dependent adenosine triphosphatase play a role in phagocytosis. The data also suggest that smoke components affect a number of macrophage activities, including adhesion and phagocytosis, by altering the cell's contractile apparatus.

Acrolein↗
PubMed1997

Multifunctional role of Tyr 108 in the catalytic mechanism of human glutathione transferase P1-1. Crystallographic and kinetic studies on the Y108F mutant enzyme.

The possible role of the hydroxyl group of Tyr 108 in the catalytic mechanism of human glutathione transferase P1-1 has been investigated by means of site-directed mutagenesis, steady-state kinetic analysis, and crystallographic studies. Three representative cosubstrates have been used, i.e. ethacrynic acid, 7-chloro-4-nitrobenz-2-oxa-1,3-diazole, and 1-chloro-2,4-dinitrobenzene. In the presence of ethacrynic acid, the enzyme follows a rapid equilibrium random bi-bi mechanism with a rate-limiting step which occurs after the addition of the substrates and before the release of products. The replacement of Tyr 108 with Phe yields a 14-fold decrease of k(cat), while it does not change appreciably the affinity of the H site for the substrate. In this case, it would appear that the role of the hydroxyl function is to stabilize the transition state for the chemical step, i.e. the Michael addition of GSH to the electrophilic substrate. Crystallographic data are compatible with this conclusion showing the hydroxyl group of Y108 in hydrogen bonding distance of the ketone moiety of ethacrynic acid [Oakley, A. J., Rossjohn, J., Lo Bello, M., Caccuri, A. M., Federici, G., & Parker, M. W. (1997) Biochemistry 36, 576-585]. Moreover, no structural differences are observed between the Y108F mutant and the wild type, suggesting that the removal of the hydroxyl group is solely responsible for the loss of activity. A different involvement of Tyr 108 appears in the catalyzed conjugation of 7-chloro-4-nitrobenz-2-oxa-1,3-diazole with GSH in which the rate-limiting step is of a physical nature, probably a structural transition of the ternary complex. The substitution of Tyr 108 yields an approximately 7-fold increase of k(cat) and a constant k(cat)/Km(NBD-Cl) value. Lack of a critical hydrogen bond between 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and Tyr 108 appears to be the basis of the increased k(cat). In the 1-chloro-2,4-dinitrobenzene/GSH system, no appreciable changes of kinetics parameters are found in the Y108F mutant. We conclude that Y108 has a multifunctional role in glutathione transferase P1-1 catalysis, depending on the nature of the electrophilic cosubstrate.

4-Chloro-7-nitrobenzofurazan↗
PubMed2001

3-Methyleneoxindole: an affinity label of glutathione S-transferase pi which targets tryptophan 38.

The compound 3-methyleneoxindole (MOI), a photooxidation product of the plant auxin indole-3-acetic acid, functions as an affinity label of the dimeric pi class glutathione S-transferase (GST) isolated from pig lung. MOI inactivates the enzyme to a limit of 14% activity. The k for inactivation by MOI is decreased 20-fold by S-hexylglutathione but only 2-fold by S-methylglutathione, suggesting that MOI does not react entirely within the glutathione site. The striking protection against inactivation provided by S-(hydroxyethyl)ethacrynic acid indicates that MOI reacts in the active site region involving both the glutathione and the xenobiotic substrate sites. Incorporation of [(3)H]MOI up to approximately 1 mol/mol of enzyme dimer concomitant with maximum inactivation suggests that there are interactions between subunits. Fractionation of the proteolytic digest of [(3)H]MOI-modified GST pi yielded Trp38 as the only labeled amino acid. The crystal structure of the human GST pi-ethacrynic acid complex (2GSS) shows that the indole of Trp38 is less than 4 A from ethacrynic acid. Similarly, MOI may bind in this substrate site. In contrast to its effect on the pi class GST, MOI inactivates much less rapidly and extensively alpha and mu class GSTs isolated from the rat. These results show that MOI reacts preferentially with GST pi. Such a compound may be useful in novel combination chemotherapy to enhance the efficacy of alkylating cancer drugs while minimizing toxic side effects.

2,4-Dinitrophenol↗
PubMed1979

Diuretics, hepatic and thoracic duct lymph flows in the dog.

1. Simultaneous thoracic duct and hepatic lymph flows were measured in 29 mongrel dogs before and after the intravenous administration of mannitol, ethacrynic acid, frusemide and chlorothiazide in separate experiments. 2. Thoracic duct lymph flow increased significantly after each diuretic agent was administered. 3. Hepatic lymph flow increased only after ethacrynic acid and mannitol administration. Frusemide and chlorothiazide did not alter hepatic lymph flow. 4. These data show that increases in thoracic duct lymph flow after ethacrynic acid and mannitol arise partly from the liver, as well as from other organs.

Animals↗
PubMedDate not supplied

[Mechanism of action of diuretics studied by a fluorescent probe method].

The mercuric-xanthine diuretic novurit, ethacrynic acid and furosemide reduced the fluorescence of 1,8-anilinonaphthalene-8-sulfonate (1,8-ANS) in a suspension of phospholipid liposomes and human serum albumin solution. Ethacrynic acid and furosemide eliminated the fluorescence of 1,8-ANS in a suspension of non-energized mitochondria of rat kidney, while novurit provoked fluorescence intensification. The constants of novurit and ethacrynic acid binding with kidney mitochondria determined by the degree of changes in 1,8-ANS fluorescence variation appeared significantly higher than the constants of binding with phospholipids and serum albumin. However furosemide did not show a predominant binding with kidney mitochondria.

Alkylmercury Compounds↗
PubMed1968

Concentration dependence of active potassium transport in the human red blood cell in the presence of inhibitors.

The active potassium influx in the human red blood cell is inhibited by strophanthidin, ethacrynic acid, and MK-870 (a new diuretic), and the degree of inhibition is greater at low concentrations of extracellular potassium than at high. In the case of ethacrynic acid, potassium appears to diminish the rate of combination of the drug with the transport system. The kinetic behavior of the active potassium influx in the presence of the inhibitors strophanthidin and ethacrynic acid is consistent with a model in which the binding of potassium at one of the potassium-sensitive sites in the transport system reduces the affinity of the system for the drug, and binding of a second potassium ion further reduces the affinity. It is not possible to distinguish between the sites on the basis of the studies presented here.

Biological Transport, Active↗