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PubMed1985

[Pigment and ion transport in the vestibular organ].

Pigments are found in various parts of the inner ear, especially in the neighbourhood of epithelia, which are supposed to be involved in the secretion and/or absorbtion of the endolymphatic fluid. Microprobe analysis (laser absorption mass micro analyzer "LAMMA" and X-ray) combined with morphological observations were performed in shock frozen, freeze-dried and plastic embedded inner ear tissue from the vestibular organ of pigmented guinea pig. Disturbance of the endolymphatic ionic composition (increased Na+) due to treatment with metabolic inhibitors (ethacrynic acid, ouabain) stimulated the migration of pigment granules and displacement of the dentritic processes of the melanocytes in a close vicinity to the presumably transporting vestibular epithelia (the dark and light cells and capillaries). The melanosomes obtained full range of metal ions that changed characteristically after treatment with metabolic inhibitors. It could be supposed that melanin presents some kind of reservoir for essential trace elements or compounds and may regulate numerous enzymatic and membrane functions by binding and releasing the metal ions.

Animals↗
PubMed1977

Relation of membrane vesicles to volume and Na+ transport in smooth muscle: effect of metabolic and transport inhibition on fresh tissues.

We tested the hypothesis that membrane vesicles of smooth muscle function as organelles controlling cell volume through a mechanochemical mechanism not involving Na+-K+ dependent membrane ATPase. Pieces of rat myometrium were incubated under various conditions at 25 degrees C, and then were analyzed after various times for Na+, K+, ATP and water contents or were prepared and examined in the electron microscope. Metabolic inhibition with iodoacetate (IAA) + dinitrophenol (DNP) rapidly depleted ATP, then decreased membrane vesicle number and increased vesicle size. Thereafter K+ loss, Na+ gain and water gain occurred. Slower depletion of ATP by treatment of tissues with IAA or ethacrynic acid produced similar, but delayed effects. Treatment with DNP alone, DNP in glucose-free Krebs-Ringer or glucose-free solution bubbled with N2 partly depleted the tissues of ATP but did not markedly affect the membrane vesicles or tissue water content. Ouabain affected neither ATP contents of tissues nor the numberof membrane vesicles, but produced large intracellular vesicles. The membrane vesicles were suggested to be sites of a mechanochemical volume control system.

Adenosine Triphosphatases↗
PubMedDate not supplied

Effects of captopril on vascular reactivity of SHR in vivo and in vitro.

The effect of captopril treatment (100 mg/kg by mouth daily for up to 6 months) on pressor responses to norepinephrine (NE) and angiotensin II (AII) was examined in spontaneously hypertensive rats (SHR). Also, helical strips of rat aorta were removed from rats that had been similarly dosed. The aortic strips were suspended for isometric recording in modified Krebs' solution kept at 37 degrees C and bubbled with 95% O2-5% CO2. Pressor responses of both NE and AII in vivo were inhibited by captopril in SHR treated for all treatment periods. Responses to NE were more significantly and consistently inhibited than those for AII. Aortic strips from SHR previously dosed with captopril showed equivalent or greater contractile responses to potassium chloride (KCl) and NE, when compared with strips from untreated age-matched controls. In aortic strips from untreated Sprague-Dawley rats incubated with captopril, 30 micron g/ml for 1 hour ( a concentration 6000 times higher than that needed to inhibit angiotensin-covering enzyme by 50% in vitro), captopril had no effect on nitroglycerin-induced relaxation or NE-induced contractions, whereas ethacrynic acid (25 micron g/ml) reduced both the NE contractile response as well as the nitroglycerin-induced relaxation. These results suggest that captopril has no direct effect on the ability of isolated vascular smooth muscle to contract or relax despite causing a significant inhibition of pressor responses in vivo. It is suggested that this effect is related to an interaction of captopril with blood-borne elements necessary for the full expression of vasoconstriction, but unrelated to angiotensin-converting enzyme inhibition.

Angiotensin II↗
PubMed1982

Effects of nitroprusside on pancreatic juice secretion in the blood-perfused canine pancreas.

The effects of nitroprusside on the secretion of pancreatic juice were investigated in preparations of isolated and blood-perfused canine pancreas. Nitroprusside (10-30 micrograms/kg) injected intravenously elicited a dose-dependent increase in pancreatic secretion accompanied by a decrease in blood pressure. Intra-arterial administration of nitroprusside (3-300 micrograms) into the perfused pancreas also elicited an increased secretion in preparations of both constant pressure and constant flow perfusion system. The results suggest that nitroprusside-induced pancreatic secretion may not result from the peripheral vasodilatation caused by nitroprusside. The effect of 100 micrograms of intra-arterial nitroprusside corresponded roughly to that of 0.1 units of secretin or 0.3 units of pancreozymin. Nitroprusside-induced secretion was inhibited by the infusion of ethacrynic acid (1 mg/min), but was not modified by phentolamine, propranolol, atropine, haloperidol, tetrodotoxin and metiamide. Nitroprusside produced a dose-dependent increase in the bicarbonate and protein concentrations in the juice, but had little effect on chloride concentration. This action was different from that of secretin or pancreozymin. It is concluded that nitroprusside may produce an increase in pancreatic secretion by acting directly on pancreatic cells, and that this action may be mediated at least in part through the increase of intracellular cyclic GMP concentration.

Animals↗
PubMed1998

Multiple-phase model of memory consolidation confirmed by behavioral and pharmacological analyses of operant conditioning in Drosophila.

Previous work on classical olfactory learning and memory in flies has suggested at least four distinct phases of memory consolidation. Similarly, our behavioral and pharmacological analyses also provided clear evidence for at least four pharmacologically distinct memory phases in flies after operant conditioning. Anesthesia-resistant memory (ARM) is present between about 20 and 120 min after training, and susceptible to disruption by the ATPase deactivating chemicals such as ouabain and ethacrynic acid (EA). Long-term memory (LTM) is activated at least 150 min after training, and can be disrupted by protein synthesis inhibitors such as cycloheximide (CXM). In addition, a very short-term memory (pre-STM) is demonstrated by feeding flies with potassium chloride (KCl), which has been shown to disrupt the short-term memory. These observations confirm our previous argument that memory formation in flies involves an intricate, multiple-phase pathway of consolidation.

Animals↗
PubMed1976

Effects of various diuretic agents in the mouse.

Diuretic effects of seven orally-acting diuretic agents have been examined in the mouse. The following compounds, examples of various types of orally active compound available, produced their characteristic diuretic effects: bendrofluazide, frusemide, ethacrynic acid, acetazolamide, triamterene, aminophylline and Su 15049A. The diuretic effects of the various agents were demonstrated under both water and saline-loading conditions. After allowing for differences in baseline sodium excretion, all diuretics except acetazolamide caused a further enhancement of sodium excretion after saline-loading compared with water-loading tests. The mouse possesses several advantages over the more commonly used rat since the range of diuretic responsiveness is greater. These results suggest that the mouse is a suitable species for diuretic testing.

Acetazolamide↗
PubMed1994

Determinants of intrarenal oxygenation. I. Effects of diuretics.

To study renal cortical and medullary oxygen tensions, we used sensitive Clark-type O2 microelectrodes, inserted by micromanipulators into the cortex and medulla of kidneys of anesthetized rats. As previously reported, under basal conditions, medullary PO2 was significantly lower than cortical PO2. Furosemide, which inhibits reabsorptive transport in the medullary thick ascending limb, increased medullary PO2 from 16 +/- 4 to 35 +/- 4 mmHg (P < 0.0005) without altering cortical PO2. This effect, reproduced by ethacrynic acid and bumetanide, was selective for loop diuretics and was directly due to decreased tubular O2 consumption, since medullary blood flow was remarkably reduced by furosemide (-28 +/- 6% from baseline, P < 0.0001, as measured by a laser-Doppler probe). By contrast, acetazolamide, which decreases proximal tubule metabolism, selectively increased cortical PO2. These data are, in general, consistent with tubular metabolism as a major determinant of intrarenal oxygenation and suggest, in particular, that medullary reabsorptive work is at least in part responsible for renal medullary hypoxia.

Absorption↗
PubMedDate not supplied

Altered glutathione S-transferase catalytic activities in female brown bullheads from a contaminated central Florida lake.

Brown bullheads (Ameriurus nebulosus) are a demersal freshwater species that can be found in a number of polluted ecosystems. The purpose of the present study was to determine the overall capacity for in vitro glutathione S-transferase (GST) detoxification by brown bullheads, and to see if bullhead GST catalysis was altered in bullheads from a polluted site. Brown bullhead liver cytosolic GSTs catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) over a large range of substrate concentrations, with apparent Km and Vmax for CDNB at fixed nucleophile (glutathione, GSH) concentrations of 1.8-1.9 mM and 12.1-14.6 mumol CDNB conjugated/min/mg, respectively. Bullhead GSTs were also highly active toward other substrates such as ethacrynic acid (ECA), delta 5-androstene-3,17-dione (ADI), and nitrobutyl chloride (NBC). Initial rate GST catalytic activities toward CDNB, NBC, ECA, and ADI were significantly lower in female bullheads from a contaminated lake (Lake Apopka Marsh) as compared to female bullheads inhabiting a nearby control site (Lake Woodruff). No site differences were observed with respect to male bullhead GST activities. These studies suggest that brown bullheads efficiently carry out GST conjugation of diverse electrophilic substrates. However, bullhead GST catalysis may be compromised in bullheads inhabiting polluted ecosystems.

Androstenedione↗
PubMed1975

Cell electrical potentials during enhanced sodium extrusion in guinea-pig kidney cortex slices.

1. Experiments were performed on outermost slices of the guinea-pig kidney which are mainly made up of proximal tubular cells. 2. Kidney cells loaded with Na+ by chilling at 0.6 degrees C for 2.5 hr, when subsequently rewarmed to 25 degrees C in a medium containing 16 mM-K+ extrude Na+ at enhanced speed for about 10 min. This Na+ movement is accompanied by efflux of Cl and influx of K+. 3. Measurements of cell potential during enhanced Na+ extrusion show that cells hyperpolarize to values about 30 mV more negative than the K+ equilibrium potential. 4. This hyperpolarization is only partly inhibited by 1 mM ouabain or by 2 mM ethacrynic acid but both agents added together suppress it completely. 5. With 16 mM-Rb instead of 16 mM-K the hyperpolarization is smaller. 6. A diminished extracellular K+ concentration outside of the cells, within the slice, can account for only a small part of the hyperpolarization. 7. The hyperpolarization is proportional to the rate of Na+ pumping. 8. Cl- seems to shunt the hyperpolarization to a greater extent than K+. 9. It is concluded that Na+ extrusion is capable of transferring electric charge across the membrane.

Animals↗
PubMed1998

Biochemical markers for differentiation of exposures to nonplanar polychlorinated biphenyls, organochlorine pesticides, or 2,3,7, 8-tetrachlorodibenzo-p-dioxin in trout liver.

The effects of a single intraperitoneal dose of the prototypical contaminant nonplanar 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153, 50 mg/kg), p,p'-DDE (50 mg/kg), or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 200 ng/kg) on the activities of hepatic detoxification enzymes were examined in the liver of immature rainbow trout (Oncorhynchus mykiss). Different modulations of the tested xenobiotics on microsomal cytochrome P450-dependent testosterone hydroxylase activities were found: PCB 153 specifically induced 16beta-hydroxylase activity, whereas p,p'-DDE decreased cytochrome P4503A-dependent 6beta-hydroxylation as well as 16alpha- and 2alpha-hydroxylation. TCDD did not modulate testosterone hydroxylase activities, but a strong induction of cytochrome P4501A activity was observed after TCDD administration; hence, cytochrome P4501A is not involved in the hydroxylation of testosterone. Trout hepatic microsomal glutathione S-transferase (GST) activity, enhanced by all the xenobiotics tested, was found to be a sensitive nonspecific biochemical marker of oxidative stress; cytosolic glutathione reductase was a less sensitive indicator of oxidative stress and was induced significantly only by treatment with p,p'-DDE. Cytosolic GST activity toward ethacrynic acid (GST-ETHA) was induced by PCB 153 or p,p'-DDE, but not by TCDD. Modulations of hepatic microsomal testosterone hydroxylase activities and induction of GST-ETHA appeared to be suitable biochemical markers of acute exposure to nonplanar PCBs and organochlorines that do not induce cytochrome P4501A enzymes in rainbow trout, whereas microsomal GST and cytosolic glutathione reductase may become early biochemical indicators of oxidative stress.

Animals↗
PubMed1992

Role of glutathione and glutathione S-transferase in chlorambucil resistance.

A chlorambucil (CLB)-resistant cell line, N50-4, was developed from the established mouse fibroblast cell line NIH 3T3, by multistep drug selection. The mutant cells exhibited greater than 10-fold resistance to CLB. Alterations in GSH and glutathione S-transferase (GST) were found in CLB-resistant variants. A 7-10-fold increase in cellular GSH content and a 3-fold increase in GST activity were detected in N50-4 cells, compared with parental cells, as determined by enzymatic assays. An increase in steady state levels of the GST-alpha isozyme mRNA was found in the CLB-resistant cells, as analyzed by Northern blotting. No GST gene amplification or rearrangement was shown by Southern blot analysis. To test the relative roles of GSH and GST in CLB resistance, a number of GSH- and GST-blocking agents were used. The CLB toxicity was significantly enhanced in N50-4 cells by administration of either the GSH-depleting agent buthionine sulfoximine or the GST inhibitors ethacrynic acid or indomethacin. The resistance to CLB cytotoxicity in N50-4 cells, however, was still significantly higher than that of parental cells. The resistance of N50-4 cells to CLB was almost completely abolished by combination pretreatment yielding both GSH depletion and GST inhibition. The results indicate that both increased cellular GSH content and increased GST activity play major roles in CLB resistance in N50-4 mutant cells.

3T3 Cells↗
PubMedDate not supplied

Calcium transport in the endolymphatic space of cochlea and vestibular organ.

Ca++ concentrations and d.c. potential within the endolymphatic space of the cochlear duct and the semicircular canal following acute anoxia or ethacrynic acid intoxication (100 mg/kg i.v.) were measured by means of double-barrelled microelectrodes. Ionic calcium content and d.c. potential were found to change in a roughly biphasic fashion after either intervention. The maximal increase in Ca++ concentration coincided with the decline in the d.c. potential, which after a rapid decline finally reached and maintained negative voltages. This phenomenon was more pronounced in the cochlear part than in the semicircular canal. A model of calcium homeostasis is proposed in an attempt to reconcile the data presented with earlier evidence.

Animals↗
PubMed2000

Isoenzymes of glutathione S-transferase from the mosquito Anopheles dirus species B: the purification, partial characterization and interaction with various insecticides.

Previously we have purified and characterized a major glutathione S-transferase (GST) activity, GST-4a, from the Thai mosquito Anopheles dirus B, a model mosquito for study of anopheline malaria vectors [Prapanthadara, L. Koottathep, S., Promtet, N., Hemingway, J. and Ketterman, A.J. (1996) Insect Biochem. Mol. Biol. 26:3, 277-285]. In this report we have purified an isoenzyme, GST-4c, which has the greatest DDT-dehydrochlorinase activity. Three additional isoenzymes, GST-4b, GST-5 and GST-6, were also partially purified and characterized for comparison. All of the Anopheles GST isoenzymes preferred 1-chloro-2,4-dinitrobenzene (CDNB) as an electrophilic substrate. In kinetic studies with CDNB as an electrophilic substrate, the V(max) of GST-4c was 24.38 micromole/min/mg which was seven-fold less than GST-4a. The two isoenzymes also possessed different K(m)s for CDNB and glutathione. Despite being only partially pure GST-4b had nearly a four-fold greater V(max) for CDNB than GST-4c. In contrast, GST-4c possessed the greatest DDT-dehydrochlorinase specific activity among the purified insect GST isoenzymes and no activity was detected for GST-5. Seven putative GST substrates used in this study were not utilized by An. dirus GSTs, although they were capable of inhibiting CDNB conjugating activity to different extents for the different isoenzymes. Bromosulfophthalein and ethacrynic acid were the most potent inhibitors. The inhibition studies demonstrate different degrees of interaction of the An. dirus isoenzymes with various insecticides. The GSTs were inhibited more readily by organochlorines and pyrethroids than by the phosphorothioates and carbamate. In a comparison between An. dirus and previous data from An. gambiae the two anopheline species possess a similar pattern of GST isoenzymes although the individual enzymes differ significantly at the functional level. The available data suggests there may be a minimum of three GST classes in anopheline insects.

Animals↗
PubMed1981

Maintenance of glomerulotubular balance for bicarbonate during carbonic anhydrase inhibition in the dog.

Studies were performed to examine the possible effects of carbonic anhydrase (CA) inhibition on the glomerulotubular balance for bicarbonate in anesthetized dogs. Maximal CA inhibition was achieved by acetazolamide infusion and glomerular filtration rate (GFR) was reduced in a stepwise fashion by progressive clamping of the left renal artery. A close relationship (R equals 0.973) was maintained between the amount of filtered and reabsorbed bicarbonate in normal dogs with CA inhibition. A similar relationship was observed between GFR and bicarbonate reabsorption during CA inhibition in normal dogs (R equals 0.957) as well as in sodium bicarbonate loaded dogs (R equals 0.867). In these two groups, GFR in the clamped kidney was reduced to values ranging respectively from 99 to 5% and from 96 to 3%. Distal tubular blockade with ethacrynic acid and chlorothiazide, performed in normal dogs and in sodium bicarbonate loaded dogs, did not abolish glomerulotubular balance for bicarbonate during CA inhibition. This study demonstrates that the glomerulotubular balance for bicarbonate is maintained during CA inhibition whether or not distal tubular blockade is superimposed. A proportionate decrease in both fractions of bicarbonate reabsorption, either CA dependent or not mediated by CA, or an adaptive increase in the fraction of bicarbonate reabsorption not mediated by CA can explain the maintenance of glomerulotubular balance for bicarbonate.

Acetazolamide↗
PubMed1999

Glutathione S-transferase in human endometrium: quantitation and interindividual variability in isoform content.

OBJECTIVES: The goals of the present study were to determine whether human endometrium contains glutathione S-transferases (GSTs), to identify the isoforms present (if any) and to assess the causes of any intersubject variability which was observed. METHOD: Hysterectomy patients (n = 32, 13 with endometrial carcinoma) were examined in the core study. The ability of cytosol from these endometria to conjugate 1-chloro-2,4-dinitrobenzene was measured. Additional studies with chemical inhibitors and monoclonal antibodies to GSTpi were also performed. RESULTS: The pattern of inhibition caused by ethacrynic acid and cibacron blue strongly suggests substantial interindividual variability in type (alpha and pi dominant) and amount ( approximately 10-fold) of this important group of enzymes. Significantly lower GST activity was seen in cancer patients who were smokers when compared with all other subjects (p < 0.05). CONCLUSION: There are substantial interindividual differences in the GST content of human endometrium. Furthermore, lower GST activity in tissues from endometrial carcinoma patients with a history of smoking may have contributed to the neoplastic transformation of this tissue.

Cytosol↗
PubMed1991

Positive and negative DC potential in the vestibular system of pigeons.

DC potential in the ampulla of pigeons was studied using a glass microelectrode. After the extirpation of the cochlear duct no change in the DC potential was found. A reduction of the negative DC potential due to anoxia (anoxia-sensitive negative potential, ASNP) was found in the ethacrynic acid (EA)-intoxicated ear, while this finding was minimal or absent in the ouabain-intoxicated ear. The perilymphatic perfusion with K(+)-substituted Ringer's solution resulted in a rapid reduction of the negativity due to EA or ouabain. These findings indicate that the positive DC potential in the ampulla seems to be produced by itself and K+ diffusion potential is the main source of negative DC potential. ASNP may be the unique potential in the EA-intoxicated ear in warm-blooded animals.

Animals↗
PubMed1998

Cytotoxicity of xenobiotics and expression of glutathione-S-transferases in immortalised rat hepatocyte cell lines.

1. Immortalised rat hepatocyte cell lines are more sensitive to the cytotoxicity of 1-chloro-2,4-dinitrobenzene and ethacrynic acid than primary cultures of hepatocytes. 2. Class alpha glutathione S-transferases are not expressed in immortalised hepatocyte cell lines. Class pi glutathione S-transferase expression is elevated in the immortalised cell lines compared with freshly isolated hepatocytes, but it is not as high as in the HTC rat hepatoma cell line. 3. Immortalised hepatocyte cell lines may provide a sensitive model system for detecting cytotoxicity associated with xenobiotics which are detoxified by glutathione S-transferases.

Animals↗
PubMed1985

Cholesterol distribution in cells of the stria vascularis of the mammalian cochlea and some effects of ototoxic diuretics.

The distribution of cholesterol in cells of the stria vascularis of guinea pigs and gerbils has been investigated at the ultrastructural level by incubation of tissue in filipin, followed by freeze-fracture. Verification of results has been sought by using tomatin. It is shown that in the cell body region of the marginal cells, the apical and lateral membranes reacted intensely with both agents, but the membranes of the basal processes of the marginal cells did not respond significantly to either filipin or tomatin. On basal cell membranes, filipin-cholesterol complexes were present at a high density, even within the strands of the tight-junctional network of these cells and occasionally within the gap-junctional areas also. Complexes were present on intermediate cell membranes at a lower density than on other plasma membranes that showed a positive response. Tissue from animals that had received an ototoxic diuretic, either ethacrynic acid or furosemide, was characterized by the appearance of membrane regions with closely clustered filipin complexes, suggesting some change in cell membrane structure. At an early stage following diuretic administration, such clusters were particularly noticeable on the membranes of intermediate cells. As intercellular spaces enlarged in response to the effects of diuretics, vesicles released into the extracellular spaces appeared to be cholesterol-enriched. The results are discussed in relation to known features of the structure and function of cells in the normal stria vascularis and of the changes that follow from acute diuretic ototoxicity.

Animals↗