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The interrelationship of stria vascularis and organ of Corti integrity was investigated. Strial morphology was altered by repeated injections of ethacrynic acid in the chinchilla. Although prolonged temporary strial damage was created, neither strial atrophy nor organ of Corti damage resulted.
The absorption of 3H-digitoxin from perfused rat small intestine was inhibited by probenecid (1.0 x 10-2 M), ethacrynic acid (0.5 x 10-3 M), and mersalyl (8.0 x 10-3 M) indicating that digitoxin absorption is at least partly an active process.
When rats were orally administered a daily dose of 300 mg kg-1 body weight of 3,5-di-t-butyl-4-hydroxytoluene (BHT) for 4 days, about 90% increase over basal level in total glutathione (GSH) S-transferase activity towards 1-chloro-2,4-dinitrobenzene (CDNB) was observed in ocular lens. GSH S-transferase activity in the ocular lens was also increased towards other substrates such as p-nitrobenzyl chloride and ethacrynic acid. In the rat lens, two isoenzymes of GSH S-transferase (pI 8.0 and 6.1) are present, and both of these isoenzymes are induced by BHT treatment. The quantification of GSH S-transferase protein in the control and the BHT-treated rat lenses indicates that the increase in GSH S-transferase activity in the ocular lens is due to the increased enzyme protein and not due to the activation of the enzyme. A significant increase in glutathione (acid soluble thiol) levels and glutathione reductase activity was also observed in the lenses of rats treated with BHT. Glutathione peroxidase activity and the enzymes of mercapturic acid pathway except GSH S-transferase remained unaltered by the BHT treatment.
This paper presents the results of an investigation into the possibility that gangliosides (brain cortex glycosphingolipids) are capable of being functionally incorporated into cell membranes and of interfering with enzymatic activity of the ATPase system on the stria vascularis and spiral ligament in the guinea pig. Labelled gangliosides (3H-GM1) were incorporated into the cell membranes of the tissues under examination. (Na+, K+)ATPase activity increased l0 minutes after intravenous injection of gangliosides and prevented the decrease in (Na+, K+)ATPase system produced by ethacrynic acid. The action of gangliosides on the (Na+, K+)ATPase system is discussed.
Teichomycin A2 is a new antibiotic that is similar to vancomycin. Because vancomycin is reported to be ototoxic, teichomycin A2 was tested for ototoxicity. No evidence of ototoxicity was found. Furthermore, ethacrynic acid, a diuretic that augments the ototoxicity of many drugs, did not enhance ototoxicity with teichomycin A2.
The saluretic and uricosuric responses elicited by a novel agent, MK-196, have been studied in a great ape, the chimpanzee. This agent is orally active at very low doses and has a prolonged duration of action. Probenecid does not appear to influence the saluretic and uricosuric properties of MK-196. Net tubular secretion of urate was reduced by MK-196. Urinary pH changes did not compromise the efficacy of this new agent. On a dose basis, MK-196 was more saluretic (and uricosuric) than ethacrynic acid or furosemide and possessed a longer duration of action. Because of the marked natriuresis caused by MK-196, some increase in potassium excretion occurred.
The use of diuretics to treat edema is reviewed. Normal salt and water metabolism is reviewed briefly. The drugs covered are the thiazide diuretics, loop diuretics(ethacrynic acid and furosemide) and distal blocking agents (spironolactone and triamterene). The sites and modes of action, indications, doses, complications and relative costs of these agents are discussed.
Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenic often undergoes methylation, forming compounds such as monomethylarsonic acid (MMAs(V)) and dimethylarsinic acid (DMAs(V)). However, much less information is available on the in vitro toxic potential or mechanisms of these methylated arsenicals, especially MMAs(V). We studied the molecular mechanisms of in vitro cytolethality of MMAs(V) using a rat liver epithelial cell line (TRL 1215). MMAs(V) was not cytotoxic in TRL 1215 cells even at concentrations exceeding 10 mM, but it became weakly cytotoxic and induced both necrotic and apoptotic cell death when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, l-buthionine-[S,R]-sulfoximine (BSO), or the glutathione reductase inhibitor, carmustine. Similar results were observed in the other mammalian cells, such as human skin TIG-112 cells, chimpanzee skin CRT-1609 cells, and mouse metallothionein (MT) positive and MT negative embryonic cells. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase (GST) that catalyses GSH-substrate conjugation, also enhanced the cytolethality of MMAs(V), but aminooxyacetic acid (AOAA), an inhibitor of beta-lyase that catalyses the final breakdown of GSH-substrate conjugates, had no effect. Both the cellular GSH levels and the cellular GST activity were increased by the exposure to MMAs(V) in TRL 1215 cells. On the other hand, the addition of exogenous extracellular GSH enhanced the cytolethality of MMAs(V), although cellular GSH levels actually prevented the cytolethality of combined MMAs(V) and exogenous GSH. These findings indicate that human arsenic metabolite MMAs(V) is not a highly toxic compound in mammalian cells, and the level of cellular GSH is critical to its eventual toxic effects.
The enzyme glutathione-S-transferase, which plays a crucial role in xenobiotic detoxification, was investigated in Drosophila melanogaster. Based upon examination of substrate specificities and pH optima, it was observed that the enzyme in Drosophila is considerably more restricted in its activities than in mammals. The effects of various xenobiotics on activities in third instar larvae were examined. While beta-naphthoflavone and phenobarbital had no effect, pentamethyl benzene (PMB) administration resulted in a 50% increase in enzyme activity. Comparison of lines of known genetic composition indicates that the degree of response to PMB is modulated by genes on chromosome II, and that differences exist with respect to the patterns of response of activities towards the substrates 1-chloro-2, 4-dinitrobenzene and ethacrynic acid. Results obtained suggest the existence of at least two loci on chromosome II that code for glutathione S-transferase isozymes.
Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of the uricosuric properties of some of them. This study was designed to test the utility of the hepatocyte monolayer culture as a model for studying these compounds. In addition, an attempt was made to define the structural components that are common to hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid and A-49816, an investigational compound, were found to be toxic in hepatocyte cultures; thus, with the exception of indacrinone, paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chemical structure. A-56234, an investigational uricosuric, was also found to be toxic in cultures but has not been demonstrated to be hepatotoxic in humans in limited clinical experience. It does not possess the ketodichlorophenoxyacetic acid structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the ketodichlorophenoxyacetic acid structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is ketodichlorophenoxyacetic acid or a closely related compound. The hepatocyte monolayer system appears to be a good model for demonstrating toxicity and, perhaps, for predicting toxicity of new compounds under development.
Incubated slices of young rat cerebellum were used to examine the possible relationship between the neurotoxic effects of excitatory amino acids and their ability to elicit large increases in the levels of cyclic GMP in this tissue. No cell death was detectable following exposure of the slices to the guanylate cyclase activator, nitroprusside (up to 0.3 mM), the phosphodiesterase inhibitor, isobutylmethylxanthine (0.5 mM), or to cyclic GMP (10 mM) and its dibutyryl and 8-bromo derivatives (0.5 mM). However, incubation of the slices with tbe guanylate cyclase inhibitors, N-methylhydroxylamine and hydroxylamine (0.1-1 mM), methylene blue (10-100 microM), ethacrynic acid (300 microM) and retinol (1 mM) caused a progressive destruction of the differentiating cells. The damage induced by N-methylhydroxylamine and hydroxylamine was inhibited by nitroprusside, cyclic GMP and isobutylmethylxanthine. It could also be reduced by lowering the partial pressure of oxygen, by oxygen radical scavenging enzymes and by omitting Ca2+ from the medium. Oxygen radical generating enzyme systems mimicked the pattern of toxicity of the guanylate cyclase inhibitors but their effects were not reduced by nitroprusside or omission of Ca2+. The results indicate that guanylate cyclase/cyclic GMP does not mediate amino acid neurotoxicity but, instead, may be part of a protective mechanism against oxygen free radicals.
A group of [4-(2-bromoalkanoyl)phenoxy]acetic acids was studied to determine if there was an association between the alkylating ability and the diuretic activity of its members. Acute studies in dogs revealed that there is not a consistent correlation in the alkylating potential of these alpha-bromo ketones and their ability to induce a diuretic response. In addition, pretreatment of dogs with the various alpha-bromo ketones did not alter the diuretic activity normally observed with ethacrynic acid (EA). The role of chemical-induced renal tissue alkylation in the initiation of a diuresis or a nephrotoxic response is discussed.
Cellular volume loss or shrinkage is a ubiquitous feature of apoptosis and thus may contribute to this form of degeneration. Chloride (Cl(-)) and potassium (K(+)) efflux has been shown to participate in volume regulation and several recent reports have implicated K(+) efflux in apoptotic neuronal death. Here pharmacological inhibitors of various K(+) and Cl(-) channels and transporters were used to decipher the relationship between cellular volume regulation and apoptosis. Following exposure to a hypotonic media, cells swell but over time gradually recover, returning to their original cell volume in a process known as regulatory volume decrease (RVD). RVD in N1E 115 neuroblastoma cells was monitored using time-lapse videomicroscopy, cell size and DNA degradation were followed using flow cytometry and fragmented apoptotic nuclei were visualized using Hoechst staining. RVD was blocked by high K(+), TEA and 4-AP (K(+) channel blockers), DIDS and niflumic acid but not SITS (Cl(-) channel blockers), ethacrynic acid (Cl(-) pump blocker), bumetanide (Na(+)/K(+)/Cl(-) cotransporter blocker) and furosemide (K(+)/Cl(-) cotransport blocker). In contrast, only DIDS and SITS (blockers of the Cl(-)/HCO(3) exchanger) inhibited apoptosis, suggesting that a common mechanistic link between RVD and apoptosis is the Cl(-)/HCO(3) exchanger. Thus, this study does not support the notion that K(+) channels are universal anti-apoptotic targets. Instead, the Cl(-)/HCO(3) exchanger may prove to be a viable target of therapeutic intervention for treating pathological apoptosis and neurodegeneration.
The rate of eicosanoid synthesis is controlled by the availability of free arachidonic acid. Recently we showed that inhibition of reacylation of liberated fatty acids by the sulfhydryl group-blocking agent thimerosal increased prostaglandin as well as leukotriene synthesis. In order to gain further insight into the basic regulatory mechanisms controlling cellular eicosanoid production, the effects of different sulfhydryl reagents on prostaglandin E2 synthesis in the macrophage-like cell line P388D1 were investigated. As these cells exhibit an enormous acyl turnover of cellular phospholipids even under basal conditions, any interference with their fatty acid deacylation-reacylation cycle should lead to a change in intracellular concentrations of the eicosanoid precursor arachidonic acid. Therefore, arachidonic acid release from prelabelled cells as well as arachidonic acid incorporation into different phospholipid species under the influence of mercuric chloride (HgCl2), ethylmercurithiosalicylate (thimerosal), p-hydroxymercuribenzoic acid (PHMB), 0-(3-hydroxymercuri-3-methoxypropyl)carbamoyl-phenoxyacetic acid (mersalyl), N-ethylmaleimide (NEM), and ethacrynic acid were examined. Additionally, direct effects of those substances on corresponding enzyme activities, i.e. phospholipase A2 (PLA2), acyl-CoA synthetase, and lysophospholipid acyltransferase (LAT), on glutathione levels, and on cell viability were estimated. The results demonstrate that the organic mercury compound thimerosal was the most effective in enhancing free arachidonic acid levels, and concomitantly prostaglandin E2 synthesis in P388D1 cells, as result of a rather selective inhibition of the fatty acid reacylating enzyme LAT.
Preliminary results presented here indicate a simultaneous decrease in endocochlear potential (EP) and in endolymphatic potassium ion concentration (K+e) under noise exposure. Maximum changes were observed after 20 min and 30 min of sound stimulation, respectively for EP and Ke+. EP recovery was faster than that of K+e. Noise-induced K+e alterations varied with the pure-tone frequency, and the locus along the basilar membrane where the measurements were performed. This supports the hypothesis that the noise has a tonotopic effect correlate with the shape of the travelling wave. Results obtained with ethacrynic acid, administered at the end of the recovery period which followed the noise exposure, indicate that the sound stimulation parameters which were used did not irreversibly alter the ionic transport in the cochlea.
Benign adrenocortical adenoma is a major primary cause of Cushing's syndrome. Although numerous studies have been performed, the molecular mechanism of adrenocortical adenoma is yet to be elucidated. In this study we endeavored to identify genes differentially regulated in adrenocortical adenoma by suppression PCR-based complementary DNA (cDNA) subtractive hybridization. The cDNA population in atrophied nontumorous adrenal gland adjacent to the adenoma was subtracted from that in the adenoma. Then adenoma-specific cDNAs were amplified by PCR. We cloned several cDNAs that are selectively up-regulated in the adenoma, one of which was identified to encode glutathione-S-transferase A1 (GSTA1). Northern blot analysis revealed that GSTA1 messenger ribonucleic acid was abundantly expressed in the adenoma compared with that in the adjacent atrophied nontumorous gland. Western blot analysis and immunohistochemistry showed high expression of GSTA1 also at the protein level. In concordance with this finding, GST activity was significantly higher in the adenoma than in the adjacent atrophied nontumorous gland. To clarify the role of GSTA1 in adrenocortical cells, GST activity in the H295R human adrenocortical cell line was inhibited by ethacrynic acid. Inhibition of GSTs interfered with proliferation of the cells. We, therefore, hypothesize that overexpression of GSTA1 in adrenocortical adenomas might be involved in the growth of tumor cells. We also speculate that this overexpression might be an adaptive response to excess cortisol production.
The authors evidence a Mg2+ dependent ATPase activity stimulated by Na+ in absence of K+ in bass gill microsomes. As this stimulated ATPase shows different features from "baseline" activity measured in the absence of both Na+ and K+ ions (Mg2+-ATPase) and from 1mM ouabain sensitive (Na+ + K+)-ATPase, it has been ascribed to a distinct Na+-ATPase. In the present paper the optimal conditions for bass gill Na+-ATPase assay and the temperature dependence of the enzyme are reported. Moreover the Na+-ATPase appears to be insensitive to 1mM ouabain and 100% inhibited by 2,5mM ethacrynic acid. It is suggested a parallel diffusion of Na+- and (Na+ + K+)-ATPase and a possible physiological role of Na+ATPase in osmoregulation.
Effective vascular compliance determined by the delta V/delta P relationship was measured repeatedly in anesthetized open-chest dogs without circulatory arrest utilizing a closed circuit venous bypass system with a constant cardiac output. Production of acute heart failure by gradual aortic constriction was associated with a significant decrease in total effective vascular compliance. The effect of loading and 20-min maintenance doses of different drugs on vascular compliance of animals in acute heart failure was studied. Phenoxybenzamine (total dose 2 mg/kg) produced a rapid and sustained increase in effective vascular compliance and theophylline (12 mg/kg) produced an increase which was more gradual in development than with phenoxybenzamine. Morphine (1 mg/kg) produced a rapid but transient increase in compliance. In contrast, ethacrynic acid (100 mg) or nitroglycerin (0.6 or 1.2 mg) did not alter vascular compliance significantly. These agents differ markedly in the magnitude and time-course of effect on effective vascular compliance.