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At least 19 recordsLinked to original sources
PubMed1977

[Experimental cholestasis by dibucaine and harmaline: effects on bile flow and hepatic transport of bile acids, ethacrynic acid and ouabain (author's transl)].

For further confirmation of the hypothesis that bile-salts independent bile flow depends on transepithelial Na+ fluxes, the effect of dibucaine (0.5 to 1.6 mM) and of harmaline (1.7 to 4.0 mM) on bile formation was studied in the isolated rat liver. Both compounds, which are known to inhibit passive Na+ entry into tissues other than liver, inhibit bile secretion in a dose-dependent fashion. Measurements of oxygen consumption and examination of liver tissue by electronmicroscopy exclude unspecific damage to liver cells as the cause for secretory failure. Cholestasis induced by dibucaine and harmaline is reversible upon wash-out of the drugs from the perfusion system. Simultaneously added choleretics, such as taurocholate, cholate, ethacrynic acid or ouabain, fail to elicit a secretory response. Since harmaline is an inhibitor of Na+-dependent transport processes, its effect and that of dibucaine on Na+-linked uptake of these choleretics by the isolated liver was determined. Harmaline and dibucaine reduce taurocholate transfer to the extent of the Na+-independent fraction only, but completely inhibit active entry of cholate, ethacrynic acid and ouabain. It is concluded that drug-membrane interactions primarily on the sinusoidal surface but possibly also at the canalicular pole of the hepatocytes are responsible for the impairment of basal and stimulated bile secretion.

Alkaloids↗
PubMed1982

Inhibition of some polymorphonuclear leukocyte functions by ethacrynic acid.

Ethacrynic acid (10(-4) M) inhibits exocytosis, phagocytosis and superoxide release in rabbit polymorphonuclear leukocytes (PMN's). Dihydroethacrynic acid is a much weaker inhibitor of these PMN functions. Though ethacrynic acid inhibits ATPase activity in the PMN, this occur at much higher concentrations than required for inhibition of exocytosis and superoxide release, thus a causal relationship seems unlikely. The same applies to inhibition of ATP generation by ethacrynic acid: the concentration required to decrease ATP level in PMN's is much higher than required for the inhibitory effect on exocytosis. Inhibition of exocytosis by ethacrynic acid can be prevented by dithiothreitol. It is concluded that vulnerable sulfhydryl groups are involved in the inhibition by ethacrynic acid.

Adenosine Triphosphatases↗
PubMed1977

Blocking of histamine release from human basophils in vitro by the ATPase inhibitor, ethacrynic acid.

Ethacrynic acid, a known inhibitor of both Na+--K+ and Mg2+-activated ATPases, effectively inhibits histamine release from antigen-challenged human basophils in vitro. Ouabain, an inhibitor specific for Na+--K+-activated ATPases, shows no effect upon the quantity of histamine released from the antigen-challenged basophils. Ethacrynic acid also effectively inhibits Ca2+--ionophore A23187-induced release, implying it inhibits the Ca2+-dependent secretory stage of the histamine-release process. Inhibition of ATPases and histamine release by ethacrynic acid both require the presence of the olefinic bond in the ethacrynic-acid molecule. Possible utilization of analogues of ethacrynic acid as anti-allergic drugs and as a device to investigate the ATPase system of histamine-releasing cells is suggested.

Adenosine Triphosphatases↗
PubMed1984

Antimicrotubular effects of ethacrynic acid.

Ethacrynic acid is a well known diuretic drug. We present here evidence that this compound is also an antimicrotubular agent which inhibits the brain tubulin polymerization and can displace 3H colchicine from its binding site. Since 2-mercaptoethanol reversibly inhibits the anti-microtubular properties, we conclude that ethacrynic acid binds covalently to brain tubulin through a cysteine near the colchicine site.

Animals↗
PubMed1994

HPLC determination of glutathione and L-cysteine in pharmaceuticals after derivatization with ethacrynic acid.

Ethacrynic acid and its methyl ester are proposed as useful pre-chromatographic derivatization reagents for the HPLC analysis (UV detection) of reduced glutathione (GSH) and L-cysteine. The optimum experimental conditions for the thiol derivatization, the removal of the excess reagent by liquid-liquid or solid-phase extraction and the reversed-phase chromatographic separations of the thiol adducts were investigated. The method was applied to the HPLC determination of GSH and L-cysteine in commercial formulations and proved to be suitable for the HPLC determination of oxidized glutathione (GSSG) after reduction to GSH using dithiothreitol (DTT).

Calibration↗
PubMed1997

A novel mechanism of glutathione conjugate formation by lipoxygenase: a study with ethacrynic acid.

Ethacrynic acid (EA), a diuretic drug, is known to interact with glutathione transferases in the presence of reduced glutathione (GSH) to yield an EA-SG conjugate. Here we present evidence for a new mechanism for the formation of EA-SG conjugate by a soybean lipoxygenase (SLO)-mediated reaction involving oxidation of GSH to a GS.. Similar to the glutathione transferase-mediated reaction, EA-SG conjugate generated by SLO exhibited an absorbance maximum at 270 nm. The conjugate formation was dependent on the concentration of linoleic acid, EA, GSH, and SLO. The optimal assay conditions to observe a maximal rate of EA-SG formation required the presence of 0.4 mM linoleic acid, 1 mM GSH, 50 nM SLO, and 0.2 mM EA at pH 9.0. Classical inhibitors of lipoxygenase, e.g., nordihydroguaiaretic acid, gossypol, and 5,8,11-eicosatriynoic acid, significantly inhibited EA-SG conjugation. The SLO-generated EA-SG was isolated as a single peak by HPLC. Quantitation of EA-SG by HPLC-coupled radiometry using [3H]GSH yielded a rate of 16.5 mumol/min/mg SLO protein. This rate is up to 1650-fold greater than that reported for different purified isozymes of mammalian glutathione transferase. The structure of EA-SG isolated from HPLC column was confirmed by matrix-assisted laser desorption mass spectroscopy. These results suggest that lipoxygenase, which is primarily known for xenobiotic oxidation, may represent yet another important pathway for GSH conjugate formation that could lead to detoxification of certain chemicals.

Animals↗
PubMed1974

Reversal of cyclic AMP-mediated intestinal secretion by ethacrynic acid.

Ethacrynic acid (EA) has been reported to reduce cholera toxin-induced intestinal fluid secretion in the intact animal. We explored the nature of this inhibition in vitro by measuring unidirectional, transmural fluxes of (22)Na and (36)Cl across isolated rabbit ileal mucosa. Under control conditions (short-circuited mucosa bathed in bicarbonate-Ringer), there was net absorption of Na and Cl. Theophylline (10 mM), cyclic AMP (5 mM), and cholera toxin (added in vivo) abolished net Na flux and produced net Cl secretion. In the presence of either theophylline or cAMP, addition of 0.1 mM EA to the serosal bathing solution abolished net Cl secretion and restored net Na absorption. Cholera toxin-treated mucosa was exposed to 0.05 and 1.0 mM EA. The lower concentration restored net Na absorption but did not significantly reduce Cl secretion. The higher concentration abolished net transport of both Na and Cl. Short-circuit current and Na flux measurements in the presence and absence of glucose indicated that 0.1 mM EA does not inhibit glucose-coupled Na transport. Short-circuit current measurements in the presence of 1.0 mM EA suggested that even this concentration of EA does not inhibit glucose-coupled Na transport. Thus EA appears to specifically inhibit Cl (or NaCl) secretion without inhibiting the absorptive Na "pump." The anti-secretory effect of 0.1 mM EA does not appear to result from inhibition of adenylate cyclase since secretion stimulated by addition of 5 mM cAMP was abolished. Furthermore, 0.1 mM EA did not significantly reduce theophylline-augmented and cholera toxin-augmented cAMP levels in ileal mucosa. We conclude that EA interacts specifically with the active Cl (or NaCl) secretory mechanism of the small intestine at a step beyond generation of cAMP.

Animals↗
PubMed1982

Interaction of aminooxyacetic acid and ethacrynic acid with intense sound at the level of the cochlea.

Results of previous investigation of the interaction of intense sound and drugs have, in general, failed to show a protective effect mediated by pre-administration with a drug having transient ototoxic effects. The present investigation was designed to further evaluate a protective effect found previously at the anatomical level and explained with an electrochemical theory of noise damage. The alternating current (a.c) potential and compound eighth nerve action potential (CAP) amplitude were monitored in aminooxyacetic acid (AOAA)- or ethacrynic acid (EA)-treated guinea pigs exposed to either moderate or high levels of intense sound and compared to changes observed in the same potentials in animals exposed to the intense sounds alone. Results showed protective effects only in the moderate--intense sound-exposure groups, with changes in sensitivity and voltage on the linear part of the input--output curve of the a.c cochlear potential found to be the only conditions where differences occurred. These results were difficult to interpret in terms of a protective effect and point to the need for obtaining additional data before an electrochemical mechanism is shown to play a role in the effect of intense sound on the cochlea.

Acetates↗
PubMed1978

Diuretic activity of Mannich base derivatives of ethacrynic acid and certain ethacrynic acid analogues.

Various Mannich base derivatives of selected phenoxyacetic acid type diuretics were synthesized and their diuretic potency was evaluated in dogs. It is concluded that the Mannich bases possess little, if any, diuretic activity of their own. Those Mannich bases that do possess diuretic activity undoubtedly do so as a consequence of an elimination reaction (a retro-Michael type reaction) which yields the corresponding pharmacologically active alpha,beta-unsaturated ketone.

Animals↗
PubMed1975

Thiol adducts of ethacrynic acid: a correlation of the rate of liberation of ethacrynic acid with the onset and magnitude of the diuretic response.

It is thought that a derivative of ethacrynic acid (EA) must possess an intact alpha, beta-unsaturated ketone group in order to be capable of eliciting a diuretic response. The 2,3-dimercapto-1-propanol and the cysteine adducts of ethacrynic acid lack such a functional group and still have diuretic activity, especially the cysteine adduct. An in vitro study showed that various thiol adducts of EA liberate EA and the accompanying thiol at a rate that is primarily dependent on the nature of the functional groups present in the thiol portion of the adduct. When the thiol adducts of EA were injected into dogs, the cysteine and mercaptoethylamine hydrochloride adducts which rapidly release EA under specific in vitro conditions were as effective as EA in producing a diuretic response. The onset of action was also similar to that of EA. The thiosalicylic acid adduct of EA releases the accompanying thiol at an intermediate rate in vitro and was less effective than EA in a small dose (3.3 mumol/kg) and the peak response to it was slower to develop. Other adducts that release EA and the accompanying thiol slowly in vitro either produce a very weak response which takes considerable time to develop or are completely devoid of diuretic activity. Thus, the onset and magnitude of the diuretic response produced by various thiol adducts of EA (with the possible exception of the cysteine adduct) are governed primarily by the rate of in vivo release of EA.

Analysis of Variance↗