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PubMed1971

Effect of Na, metabolic inhibitors and ATP on Ca movements in L cells.

1. The Ca movements in normal and ;ghost' L cells have been examined; all measurements were made using (45)Ca.2. Normal cells have a Ca concentration of about 1 m-mole/l. of cell volume, and exchange Ca in a complex way but with great rapidity; the time taken for the initial Ca(*) content to fall to half was less than 2 min.3. Poisoning normal cells with DNP 10(-3)M + IAA 10(-4)M causes a marked reduction in the Ca efflux, no change in Ca influx and an increase in total Ca.4. Variation in internal or external Na concentration does not alter the Ca fluxes or concentrations. Application of cyanide or ouabain and alteration of external K concentration had no effect on the Ca fluxes.5. The sulphydryl reagents, ethacrynic acid and N-ethylmaleimide (NEM), have a rapid and marked effect on reducing the Ca efflux.6. L cell ghosts previously poisoned with DNP+IAA have a low Ca efflux. When ATP or CTP is incorporated into such cells the Ca efflux becomes normal.7. An extra amount of phosphate is produced by L cell ghosts when pumping Ca. This is equivalent to the splitting of 1.8 moles of ATP per mole of Ca pumped.8. It is concluded that L cells have a Ca pump driven by ATP, and that Na has no effect on Ca movements in these cells.

Adenosine Triphosphate↗
PubMed1986

Morphological changes in the renal macula densa during natriuresis and diuresis.

Morphological changes in the macula densa have been studied during the infusion of diuretic agents into the renal artery of anesthetized dogs. The kidneys were fixed by rapid high pressure perfusion with glutaraldehyde. Large basolateral intercellular spaces were seen between macula densa cells in control kidneys, but the number and extent of these spaces were strikingly reduced during the natriuresis and diuresis induced by the infusion of frusemide, ethacrynic acid or mannitol. Natriuresis and diuresis produced by the intravenous infusion of large volumes of 0.9% NaCl solution also resulted in closure of these spaces. No simple relationship existed between changes in plasma renin activity and closure of the spaces between macula densa cells during these procedures. A distinctive, membrane-bound, vesicle-containing structure was identified between the basolateral processes of the cells of each macula densa; the function of this structure awaits elucidation. We suggest that changes in the size of the basolateral intercellular spaces of the macula densa reflect changes in fluid flux between the distal tubule and the interstitium of the juxtaglomerular apparatus.

Animals↗
PubMed1985

Modulation of substrate-specific glutathione S-transferase activity in Daphnia magna with concomitant effects on toxicity tolerance.

Glutathione S-transferase (GST) activity was measured in Daphnia magna and Ceriodaphnia reticulata using 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid (EA) as conjugation substrates. Levels of GST activity were comparable between species with CDNB; however, D. magna had nearly twice the GST activity with EA as compared to C. reticulata. GST activity with CDNB was elevated from exposure of daphnids to either CDNB or sodium pentachlorophenate (PCP), but not from exposure to EA. GST activity with EA could not be modulated from exposure to CDNB or EA. GST activity towards CDNB and EA was biochemically separated into different protein fractions suggesting the existence of two distinct isozymes. Preexposure of daphnids to CDNB or PCP increased the organisms' tolerance to the toxic effects of PCP, but not CDNB.

Animals↗
PubMed1992

Depletion of ATP but not of GSH affects viability of rat hepatocytes.

The purpose of this study was to examine the role of glutathione depletion and alterations in the energy status in the induction of acute cytotoxicity to freshly isolated rat hepatocytes. Depletion of intracellular glutathione by diethyl maleate and phorone to levels below 5% of control did not induce loss of viability nor loss of intracellular ATP. Ethacrynic acid, a compound known to deplete mitochondrial GSH in addition to cytosolic GSH, induced cell killing after a depletion of ATP, next to GSH depletion. The results confirmed that depletion of intracellular glutathione alone does not necessarily result in cell killing. Only when glutathione depletion is succeeded by reduction in ATP levels, loss of cell viability is observed. The relationship between alterations in the energy status and the induction of cell death was further substantiated by inhibition of glycolytic and mitochondrial ATP generation. Treatment of hepatocytes either with iodoacetic acid to inhibit glycolysis (in hepatocytes from fed rats) or with potassium cyanide to inhibit mitochondrial respiration (in hepatocytes from both fed and fasted rats) revealed that depletion of intracellular ATP could lead to lethal cell injury. The susceptibility of cells to metabolic inhibition was better reflected by the rate of reduction in the energy charge than by the reduction of ATP alone. In conclusion, our results suggest that alterations of the energy status may be a critical event in the induction of irreversible cell injury. Depletion of cellular GSH is only cytotoxic when followed by a reduction of the energy charge.

Adenosine Triphosphate↗
PubMed1976

Properties of the calcium-activated adenosine tri-phosphatase from L-cell membranes.

Preparation of surface membranes from mouse L-cells using a technique previously described in the literature [Perdue & Sneider, 1970] allowed characterization of a Ca-activated ATPase apparently separate from the mitochondrial ATPase also dependent on calcium. This enzyme is associated with the Na-K-ATPase, a marker for surface membranes, and not wilth alkaline phosphatase, a mitochondrial enzyme. In temperature sensitivity, pH dependence and inhibition by ethacrynic acid, the partially purified enzyme has properties similar to those previously described for active calcium efflux from these cells. For maximal activity of the enzyme system magnesium and sodium are required, although the calcium transport from whole cells was apparently independent of both. Adenosine triphosphate only was metabolized by the enzyme system, whereas CTP could be utilized for calcium transport from 'ghost' cells, probably as a result of intracellular conversion to ATP. It is suggested that the active calcium transport from cultured L-cells is closely linked to the calcium dependent ATPase, and that the method of calcium extrusion is similar to that described for red blood cells.

Adenosine Triphosphatases↗
PubMed1982

Enrichment and partial enzyme characterization of ATPase activity associated with the outward-facing membrane complex and inward-facing membrane of the surface epithelial syncytium of Schistosoma mansoni.

The outward-facing (OFM) and inward-facing (IFM) membranes of the surface epithelial syncytium of Schistosoma mansoni were separated by sequential exposure to saponin solutions. The OFM, containing both inner and outer bilayers, contained ATPase activity that was stimulated by Mg2+ and Ma+, but not K+ or HCO-3, and was inhibited by Ca2+ and ethacrynic acid. The OFM enzyme was unaffected by ouabain, oligomycin, SCN- and azide and had a pH optimum of 7.5. The OFM ATPase therefore has properties similar to ATPases characterized from the apical membrane of a variety of epithelial cells where it is thought to augment the regulatory cell volume decreasing function of (Na++K+)Mg2+- ATPase. The IFM contained ATPase activity that was stimulated by Mg2+, Na+ and K+, and was inhibited by ouabain indicating the IFM enzyme was the Na+-pump ATPase. The results are discussed in terms of the transepithelial transport function of the surface epithelial syncytium and a Ca2+-ATPase reported previously from the OFM of S. mansoni.

Adenosine Triphosphatases↗
PubMedDate not supplied

Ultrastructural histopathology in a case of human ototoxicity due to loop diuretics.

The temporal bones of a patient who suffered sudden deafness and ataxia after administration of both furosemide and ethacrynic acid, were prepared for light and electron microscopy. There was no loss of hair or supporting cells. However, some hair cells, in both the vestibular neuroepithelium and the organ of Corti, particularly in the basal turn, were more densely staining and more granular than normal. Membrane whorls also were common within mitochondria of such cells. The endoplasmic reticulum of some spiral ganglion cells was dilated. The major cytologic changes were found in the stria vascularis of the cochlea and dark cell areas of the vestibular system. There was marked dilatation of the intercellular fluid spaces, consistent with the biochemical observation that loop diuretics interfere first with enzyme systems responsible for fluid transport within the inner ear.

Cochlea↗
PubMed1977

The glutathione S-transferases of the small intestine in the rat.

Glutathione S-transferase activities have been identified in the small intestine of the rat. Thrree activities obtained with p-nitrobenzyl chloride (aralkyl), 1,2-epoxy-3(p-nitrophenoxy)propane (epoxide), and ethacrynic acid (alkene) as substrates were present in significant amounts. Gel filtration indicated an elution volume for the intestinal transferase activities that was similar to those activities in the liver and kidney. The induction of the intestinal transferases by polycyclic aromatic hydrocarbons and phenobarbital is similar to those effects observed previously for the hepatic and renal enzymes. The highest concentration of transferase activities occurs in the proximal small intestine; these activities are reduced upon fasting. Parallel observations have been reported for aryl hydrocarbon hydroxylases. Because only low or negligible levels of epoxide hydrases have been reported in the small intestine, the glutathione S-transferases may be the primary epoxide-detoxifying system in that organ.

Animals↗
PubMed1976

Experimental pathogenesis of hydrops.

1. The best method for inducing hydrops in guinea pigs is obliteration of the endolymphatic duct. 2. The location of hydrops produced in the guinea pig is comparable to that of Menière's disease. 3. The major histopathological finding in the guinea pig is atrophy of sensorineural elements in the apical turns of the cochlea. 4. The vestibular sensory cell population is rarely decreased, though ultrastructural changes are noted. 5. Attempts to prevent or minimize development of hydrops by surgical fistulization of the vestibular endolymphatic walls or by administration of a diuretic drug, ethacrynic acid, failed in the guinea pig. Treatment of Menière's disease by these means is questionable. 6. Electron microscopy of the organ of Corti in cochleas taken from a patient with bilateral Menière's disease revealed that only a small percentage of te sensorineural elements was abnormal at the apical turns. Thus, it is questionable whether these small ultrastructural changes in the organ of Corti are a major cause of severe hearing loss. 7. In Menière's disease biochemical changes in cochlear fluid and/or changes in motion mechanics of the cochlear duct are probably important factors producing the hearing loss. 8. The present ultrastructural study did not resolve the question of the etiology of Menière's disease.

Animals↗
PubMed1995

Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells.

The cellular and regional distribution of glutathione (GSH) and GSH-related enzyme systems involved in cellular defense against reactive oxygen species and electrophilic xenobiotics in the nervous system has been extensively studied. However, little is known about the subcellular distribution of GSH systems in brain tissue and cultured neural cells. The present study investigates the distribution of mitochondrial and cytosolic GSH and GSH-related enzymes in cultured cerebellar astrocytes and granule cells, and compares them with levels in the adult rat cerebellum. Cytosolic GSH levels and cytosolic activities of glutathione reductase (GR), glutathione peroxidase (GPX) and glutathione-S-transferase (GST) in astrocytes were 57, 153, 245, and 92% higher than those found in granule cells, respectively. In contrast, granule cells contained significantly higher mitochondrial GSH levels than astrocytes. Granule cells also demonstrated comparable mitochondria/cytosolic concentrations of GSH and GR, GPX and GST activities to those observed in the cerebellar tissue, whereas ratios in astrocytes were markedly lower. Although in vitro treatments with 100 microM ethacrynic acid depleted both cytosolic and mitochondrial GSH in cultured astrocytes and granule cells in a time-dependent fashion, cellular GSH in granule cells was more resistant to the GSH-depleting agent than astrocytes. These results suggest that although GSH and GSH-related enzymes are abundant in cytosolic compartments of astrocytes, mitochondrial pools are relatively small. Since brain mitochondria are sites of significant hydrogen peroxide generation, the mitochondrial localization of GSH and its associated enzymes in neural cells provide important defenses against toxic oxygen species in the nervous system. Differences in subcellular distribution of GSH systems in individual neural cell types may provide a basis for selective cellular and/or subcellular expression of neurotoxicity.

Animals↗
PubMed1975

Renal autoregulation: evidence for the transmural pressure hypothesis.

Autoregulation of glomerular filtration rate (GFR) was examined during uteral orarterial constriction in anesthetized dogs after renal denervation. GFR was sustaineduntil ureteral pressure greater than 80 mmHg, provided renal arterial pressure exceeded 180 mmHg, but fell at ureteral pressure less than 54 mmHg when arterial pressure averaged 127 plus or minus 5 mmHg; renal blood rose as GFR declined. Ethacrynic acid, saline, or mannitol infusion increased tubular pressure without reducing GFR,but during subsequent ureteral constriction GFR fell at uteral pressure less than 40mmHg. During arterial constriction GFR was maintained at lower arterial pressures in hydropenic than in diuretic dogs. Because of thisdifference in the range of autoregulation, saline infusion increased GFR more in hydropenic than in diuretic dogs except at high arterial pressure. This response to reduced plasma oncotic pressure and the constancy of GFR over a wide range of proximal tubular and arterial pressure indicate constancy of thehydrostatic transmural pressure of glomerular capillaries. Afferent arteriolar resistance is, in addition to a regulation by transmural pressure, perhaps controlled by vascular stretch receptors in the glomeruli.

Animals↗
PubMedDate not supplied

Xenobiotic metabolizing and antioxidant enzymes in normal and neoplastic human breast tissue.

An investigation was made of ethoxyresorufin O-deethylase (EROD) activity, a cytochrome P450 (CYP) dependent enzyme mainly catalyzed by CYP1A1, glutathione S-transferase (GST) activity toward the substrates 1-chloro-2,4- dinitrobenzene (CDNB) and ethacrynic acid (EAA), reduced glutathione (GSH) levels, and antioxidant enzyme (AOE) activity namely catalase (CAT) and selenium- dependent glutathione peroxidase (Se-GPx) in tumor and surrounding tumor-free (normal) tissues in female breast cancer patients. Wide interindividual variations were found in the enzyme activities in both tumor and normal breast tissues. No significant differences were noted between mean EROD and CAT activities in tumor and normal breast tissues. The mean activities of CDNB GST, EAA GST and Se-GPx and GSH levels in tumor tissue were significantly higher than those in normal breast tissue. These results show that CYP, GST and AOE behave differentially in breast tumors.

Antioxidants↗
PubMed1976

Diuretic agents. Mechanisms of action and clinical uses.

Diuretics act primarily by blocking reabsorption of sodium at four major sites in the nephron. Clinically useful agents that block sodium reabsorption effectively in the proximal tubule are lacking. Furosemide (Lasix), ethacrynic acid (Edecrin), and possibly organomercurial agents are effective in the ascending limb of Henle's loop. Thiazides are the major agents acting in the early distal tubule. In the late distal tubule and collecting duct, spironolactone (Aldactone) and triamterene (Dyrenium) are useful, especially in combination with diuretics which act more proximally. In treating edematous states, initial therapy with thiazides is effective in most patients who do not exhibit moderate or severe renal insufficiency, severe hyperaldosteronism with excessive distal reabsorption of sodium in exchange for potassium, or excessive sodium reabsorption in the proximal tubule or ascending limb. Nonedematous states in which diuretic therapy is useful include hypertension, hypercalcemia, hypercalciuria, diabetes insipidus, and acute renal failure.

Acute Kidney Injury↗
PubMed1970

Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine.

1. Administration of frusemide or ethacrynic acid to cephaloridine-treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine-treated control mice.2. Administration of frusemide to cephaloridine-treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.3. Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.4. It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.

Acute Kidney Injury↗
PubMed1994

Inter-individual variability of human hepatic glutathione S-transferase isozymes assessed by inhibitory capacity.

Glutathione S-transferases (GSTs) are important as drug metabolizing enzymes mainly in the detoxication process. To assess individual differences in susceptibility to different chemicals, it would be useful to know the activity of specific GST isozymes in individuals. In order to study individual variability, typical substrates specific for the three major classes of GSTs were used not only as substrates but also as inhibitors using 17 organ-donor livers. Out of 17, 4 livers were low in the mu-form isozyme, judging from the depressed GST activity for trans-4-phenyl-3-buten-2-one (tPBO), a mu-class substrate. The range of tPBO activity exhibited more than 20-fold variation, while less than 2-fold variation was observed in the activities for 1-chloro-2,4-dinitrobenzene (CDNB), a non-specific substrate for alpha-, mu-, and pi-class GSTs. In addition to the conventional approach to assessing individual variability, well known substrates for GSTs, cumene hydroperoxide (CHP, alpha-class), tPBO (mu) and ethacrynic acid (EA, pi) were used as inhibitors against CDNB-GSH conjugation. CHP inhibited the CDNB-GSH conjugation in mu-depressed livers more potently than in the non-depressed livers, probably because CHP is a specific inhibitor for alpha-class GST. Inhibition by CHP may therefore be used to detect livers which are low in mu-form. The inhibition by tPBO was found to be weak and the variability was small (CV of 9% in 17 livers). EA potently inhibited GST activity with its inhibition constant (Ki) 2,000-fold lower than that of CHP. The small individual variation in inhibition by EA (CV of 6%) supported that EA is a universal but potent inhibitor against major GSTs contained in human liver.

Benzene Derivatives↗
PubMed1998

Involvement of nitrosothiols, nitric oxide and voltage-gated K+ channels in photorelaxation of vascular smooth muscle.

The effects of nitrosothiol depleting compounds (p-hydroxymercuribenzoate, iodacetamide and ethacrynic acid), a guanylyl cyclase inhibitor (1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and nitric oxide (NO) scavenger agents (xanthine/xanthine oxidase and 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; carboxy-PTIO) on light-induced photorelaxation in rat thoracic aorta were investigated. Photorelaxation responses were decreased in the presence of nitrosothiol depleting compounds suggesting S-nitrosothiols as the tissue source of the NO, whereas reduction in photorelaxation by the guanylyl cyclase inhibitor and NO scavenger agents indicates involvement of both NO and cGMP in photorelaxation. In addition the sensitivity of photorelaxation to the voltage-gated potassium channel (KV) inhibitor, 4-aminopyridine, indicates that photorelaxation is mediated via a NO/cGMP-dependent, and, perhaps, direct light, activation of KV channels.

Benzoates↗
PubMed1996

Neuroprotective effect of insulin-like growth factor I in immortalized hypothalamic cells.

The neuroprotective action of insulin-like growth factor I (IGF-I) was tested in immortalized hypothalamic GT1-7 cells exposed to reduced glutathione depleting agents, which cause oxidative stress and cell death. The extent of cell survival was assessed by either using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide cytotoxicity assay or counting at the fluorescence microscope GT1-7 cells prelabeled with fluorescent dyes selective for viable and dead cells. Treatments with buthionine sulfoximine (500 microns), diethylmaleate (1 mM), and ethacrynic acid (200 microns) caused diffuse GT1-7 cell death (40-60%). Exposure of the same cells to IGF-I (either before or concomitant to the toxic agent, depending on the drug used) significantly prevented neuronal death. This effect was rapid, concentration-dependent, maximal at concentrations of 25-50 ng/ml, and mimicked by IGF-II, fibroblast growth factor, and the potent antioxidant idebenone. In contrast, IGF-I, as well as idebenone, were completely ineffective in antagonizing the toxic effect produced by different concentrations of menadione. In conclusion, the present data demonstrate a protective role for IGF-I against glutathione depleting agents-induced damage in GT1-7 cells suggesting an antioxidant action of this growth factor in hypothalamic neurons.

Animals↗
PubMed1977

Potassium release from submandibular salivary gland in vitro.

Rat submandibular gland slices, incubated in continuously-gassed Krebs-Ringer bicarbonate buffer, were shown to release K+ in response to alpha-adrenergic and muscarinic cholinergic stimulation. The system employed the specific alpha-, beta-adrenergic and cholinergic receptor-blocking agents phentolamine, propranolol and atropine, respectively, in combination with the agonists L-epinephrine and carbamylcholine both of which required the presence of Ca2+ for their effect. The introduction of Ca2+ into the cell via the ionophore A23187, with all neurotransmitter receptors blocked, resulted in K+ release. Ouabain also allowed extensive K+ release which was in addition to, and hence independent of, that elicited by epinephrine and carbamylcholine. Ethacrynic acid, a potent inhibitor of salivary secretion in vivo, had no influence on K+ movement. K+ was released by both physalaemin and an eledoisin-related peptide independently of normal neurotransmitter receptors. The activity of the eledoisin-related peptide did not require the presence of extracellular Ca2+. The implication of cyclic GMP at some stage of K+ release was suggested by experiments with a phosphodiesterase inhibitor. The results support an hypothesis where the initial stimulus at either alpha-adrenergic or muscarinic cholinergic receptors causes an immediate permeability change such that Ca2+ enters the cells resulting in K+ release. The loss of K+ is quickly countered by the ouabain-sensitive (Na+ + K+) ATPase which would be activated by the lowered intracellular K+ levels.

Animals↗