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At least 1,567 records · Page 87Linked to original sources
PubMed1986

Mechanism of S-(1,2-dichlorovinyl)glutathione-induced nephrotoxicity.

S-(1,2-Dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-DL-cysteine are potent nephrotoxins. Agents that inhibit gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and renal organic anion transport systems, namely L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), aminooxyacetic acid, and probenecid, respectively, protected against S-conjugate-induced nephrotoxicity. Furthermore, S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine, which cannot be cleaved by cysteine conjugate beta-lyase, was not nephrotoxic. These results strongly support a role for renal gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and organic anion transport systems in S-(1,2-dichlorovinyl)glutathione- and S-(1,2-dichlorovinyl)cysteine-induced nephrotoxicity.

Aminooxyacetic Acid↗
PubMed1986

Protection against paraquat-induced injury by exogenous GSH in pulmonary alveolar type II cells.

Exogenous GSH provided rat alveolar type II cells with significant protection against injury induced by paraquat. This protection was also observed in cells treated with acivicin to inhibit GSH degradation and buthionine sulfoximine to inhibit GSH synthesis. Exogenous GSH was transported into cells by a Na+-dependent system. Addition of inhibitors of this transport system, gamma-glutamyl-glutamate and probenecid, prevented the protection against injury afforded by GSH. Thus, the results indicate that alveolar type II cells can supplement endogenous synthesis of GSH with uptake of exogenous GSH to protect against paraquat-induced injury.

Animals↗
PubMed1989

Toxicity of the cysteine-S-conjugates and mercapturic acids of four structurally related difluoroethylenes in isolated proximal tubular cells from rat kidney. Uptake of the conjugates and activation to toxic metabolites.

Isolated proximal tubular cells from rat kidney were incubated with the cysteine-S-conjugates and corresponding mercapturates of the potent nephrotoxicants tetrafluoroethylene (TFE), chlorotrifluoroethylene (CTFE), 1,1-dichloro-2,2-difluoroethylene (DCDFE) and 1,1-dibromo-2,2-difluoroethylene (DBDFE). Toxicity of these S-conjugates was determined by their ability to inhibit alpha-methylglucose uptake by the cells. The cytotoxicity of the cysteine-S-conjugates and mercapturates of TFE and CTFE was similar, but the cysteine-S-conjugates of DCDFE and DBDFE were more toxic than their mercapturates. The cytotoxicity of the conjugates decreased in the following order TFE approximately CTFE greater than DCDFE greater than DBDFE, which is the same as observed in vivo. Inhibition of renal cysteine-S-conjugate beta-lyase by aminooxyacetic acid alleviated the cytotoxicity of both the cysteine-S-conjugates and the mercapturic acids of the four haloethylenes. The cytotoxicity of the mercapturates, but not of the cysteine-S-conjugates, could be reduced by probenecid, suggesting that the cysteine-S-conjugates are transported by a different carrier system than the mercapturates. The deacetylation of the mercapturates of TFE and CTFE in the cells was much higher than that of the mercapturates of DCDFE and DBDFE. The cysteine-S-conjugates of DCDFE and DBDFE were N-acetylated by the cells whereas the other cysteine-S-conjugates were not (TFE) or only marginally (CTFE) N-acetylated. The observed differences in cytotoxicity may be explained by differences in (1) the balance between acetylation/deacetylation by the cells, (2) the conversion rate of the S-conjugates to toxic metabolites by renal beta-lyase and (3) the transport into the proximal tubular cells.

Acetylation↗
PubMed1991

Desensitization of atriopeptin stimulated accumulation and extrusion of cyclic GMP from a kidney epithelial cell line (MDCK).

Atriopeptin caused dose- (EC50 ca. 2 x 10(-8) M) and time-dependent increases in the intracellular concentration of cyclic GMP in the MDCK kidney epithelial cell line; an effect potentiated by the phosphodiesterase inhibitor, IBMX. The atriopeptin-catalysed increase in cyclic GMP was transient and reached a maximum some 10-20 min after challenge of cells with atriopeptin. The basis for the transience of this increase was shown to be due to the desensitization of guanylate cyclase coupled with extrusion of cyclic GMP from the cells and the degradation of cyclic GMP by phosphodiesterase activity. Atriopeptin-catalysed extrusion of cyclic GMP was time- and dose-(EC50 ca. 1.5 x 10(-8) M) dependent and was inhibited by probenecid but not by high external cyclic GMP concentrations. The extrusion process underwent apparent desensitization as did guanylate cyclase with similar half lives (T1/2 of ca. 20 min). Desensitization was dose-dependent upon atriopeptin and did not appear to be mediated by elevated cyclic GMP concentrations as pre-incubation with 8-bromo cyclic GMP did not cause desensitization and the half-times for desensitization were similar whether or not IBMX was present. The majority of the cyclic nucleotide phosphodiesterase activity was found in the cytosol fraction of the cells and could be separated into two cyclic AMP specific forms and two cyclic GMP preferring forms.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1995

Comparison of transport properties of the reduced folate carrier and folate receptor in murine L1210 leukemia cells.

This laboratory previously described an L1210 murine leukemia cell line with a functional defect in the reduced folate carrier and increased expression of folate receptor-beta (F2-MTXrA). This cell line was used to characterize methotrexate (MTX) influx mediated by folate receptor-beta and to compare this with influx mediated by the reduced folate carrier in L1210 parental cells. Influx of 0.2 microM MTX in F2-MTXrA cells was one-third that of L1210 cells and was abolished by very low concentrations of folic acid. Kinetic analysis revealed that MTX transport mediated by folate receptor-beta exhibited an influx kappa t one-third, and an influx Vmax one-fourth, that of the reduced folate carrier. Metabolic inhibitors markedly suppressed influx in F2-MTXrA cells but had no effect on MTX influx in L1210 cells. MTX influx in both cell lines was inhibited by the organic anions probenecid, sulfobromophthalein, and CI-920, but to a lesser extent in F2-MTXrA cells. The inhibitory effects of these anions on transport in F2-MTXrA cells could be attributed to their inhibition of MTX binding to the folate receptor. Although MTX influx in both cell lines was not sodium dependent, removal of extracellular chloride increased influx 2-fold in L1210 cells while markedly inhibiting influx in F2-MTXrA cells. Substitution of Cl- with isethionate or NO3- partially restored influx in the latter cells, whereas SO4(2-) was inhibitory. Anions enhanced MTX binding to folate receptor-beta with isethionate > SO4(2-) > Cl-. Decreasing the buffer pH to 6.2 produced a 69% reduction, and a 260% increase, in MTX influx in L1210 cells and F2-MTXrA cells, respectively. The data indicate that folate receptor-beta-mediated MTX influx has properties fundamentally different from transport mediated by the reduced folate carrier in terms of energy, ion, and pH dependence. There was no evidence indicating that these processes are functionally linked.

Animals↗
PubMed1990

Intercorrelations among monoamine metabolite concentrations in human lumbar CSF are not due to a shared acid transport system.

Intercorrelations among homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-hydroxy-phenylglycol (MHPG) concentrations in lumbar cerebrospinal fluid (CSF) were examined before and after blockade of the acid transport system by probenecid in 59 psychiatric inpatients. The three compounds remained intercorrelated despite acid transport blockade, suggesting that the common transport system does not account for their covariance. Other possibilities to explain the interrelationship among these compounds are discussed.

Acid-Base Equilibrium↗
PubMed1981

Differential pulse voltammetry in brain tissue. II. Detection of 5-hydroxyindoleacetic acid in the rat striatum.

Differential pulse voltammetry with electrochemically treated carbon fiber electrodes was used to study, in anesthetized rats, the alterations of the striatal electrochemical signal appearing at +300 mV (peak 3), following pharmacological manipulation of the animals. Decreases in peak 3 were obtained after injections of NSD 1015, Ro 4-4602 and Clorgyline. This, in conjunction with biochemical measurements, suggested that 5-hydroxyindoleacetic acid (5-HIAA) is, to a considerable extent, responsible for this electrochemical signal. Increases in peak 3 obtained after reserpine, L-tryptophan and D,L-5-HTP, as well as biochemical data reinforced this hypothesis, as did the detection of peak 3 in cerebrospinal fluid and its increase after probenecid injection. The occurrence of a feed-back mechanism is discussed following injection of D,L-5-HTP.

5-Hydroxytryptophan↗
PubMed1982

Choline and PAH transport across blood-CSF barriers: the effect of lithium.

The components of the blood-CSF barrier responsible for the transport of p-aminohippuric acid (PAH) and choline from CSF to blood were identified using in vitro preparations of frog choroid plexus and arachnoid membranes. Choline was transported out of CSF across the arachnoid, while PAH was transported out across the choroid plexus. Probenecid and ouabain blocked both processes. The effect of Li on these transport processes was tested by the addition of 5 mM LiCl to the incubation media. Li increased, by a factor of two, choline transport across the arachnoid, but there was no effect of Li on PAH transport across the plexus. Lithium was passively transported across the choroid plexus, and we suggest that the major transport pathway is through the tight junctions. The steady-state distribution of Li between the choroidal epithelium and the incubation medium was only half that expected for passive distribution. This suggests the existence of sodium/lithium countertransport in these epithelial cell membranes.

Aminohippuric Acids↗
PubMed1983

Differential pulse voltammetry in the dorsal horn of the spinal cord of the anesthetized rat: are the voltammograms related to 5-HT and/or to 5-HIAA?

Treated carbon fiber microelectrodes were used with the differential pulse voltammetry method for in vitro and in vivo determination of indoleamines. Under these conditions a peak of oxidation current which is characteristic of 5-hydroxyindoles is recorded at 280-300 mV. Treated carbon fiber microelectrodes respond in vitro linearly over a large range of concentrations of 5-hydroxytryptamine (5-HT) and of 5-hydroxyindoleacetic acid (5-HIAA), but are 5-8 times more sensitive to 5-HT than to 5-HIAA. In vivo, the question remains as to the exact nature of the peak because the oxidation potentials of 5-HT and 5-HIAA are close together and cannot be monitored separately. Pharmacological investigations were hence carried out in order to characterize the electrochemical signal detected at 300 mV in the dorsal horn of the lumbar spinal cord of chloral hydrate-anesthetized rats. Using 250 micron long carbon fiber microelectrodes, the electrochemical signal stabilizes at 30-90 min and the peak remains constant for up to 210 min. Administration of the monoamine oxidase inhibitor (MAOI) clorgyline produced a progressive decrease of the signal which reached a decrease of 33% of control at 180 min after injection. At this time biochemical measures demonstrated a 117% increase in 5-HT and a 32% decrease in 5-HIAA in the dorsal half of the spinal cord. Reserpine provoked an increase of 20% in the electrochemical peak and the 5-HIAA outflow blocker probenecid gave rise to a sustained plateau of about 60% above control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Lumbar cerebrospinal fluid homovanillic acid concentrations are higher in female than male non-human primates.

Concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were determined in lumbar cerebrospinal fluid from intact male and female Macaca nemestrina. Concentrations of homovanillic acid, but not 5-hydroxyindoleacetic acid were significantly higher in the females under baseline conditions. Following probenecid treatment, 5-hydroxyindoleacetic acid concentrations were significantly elevated over baseline conditions in both sexes although only homovanillic acid concentrations were significantly higher in the female monkeys.

Animals↗
PubMed1987

Does morphine enhance the release of 5-hydroxytryptamine in the rat spinal cord? An in vivo differential pulse voltammetry study.

Differential pulse voltammetry used in combination with an electrochemically treated carbon fiber electrode allowed the detection of 5-hydroxyindoles (5-HI) in the dorsal horn of the urethane-anesthetized rat. Voltammograms were recorded every 3 min for up to 4 h. One component of the signal, peak 3, corresponding to 5-HI and uric acid was first identified separately in vitro as well as in vivo, and then further examined by means of systemic L- and D-trytophan administration and by local application of uricase, respectively. It was found that the height of peak 3 was unaffected by systemic morphine. Even following pretreatment with probenecid, the height of peak 3 was increased only 8.6-13.7% over that with saline, by morphine given either intraperitoneally or intracerebrally into the nucleus raphe magnus. However, these increments of peak 3 were not statistically significant. These findings suggest that the serotonin descending system is unlikely to play an important role in morphine analgesia.

Animals↗
PubMed1991

Kinetic analysis of L-carnitine uptake by the choroid plexus.

Choroid plexuses from the lateral (LVCP) and fourth ventricles (FVCP) of rats or rabbits were incubated in artificial cerebrospinal fluid (CSF) containing 1 microM [14C]L-carnitine with various concentrations of L-carnitine ranging from 0.01 mM to 1.0 mM. The time course of 1 microM [14C]L-carnitine uptake by the choroid plexus indicated that it increased linearly for the first 15 min. Steady-state levels were reached by 30 min with tissue concentrations more than 20 (FVCP)- to 30 (LVCP)-fold greater than the concentration in the medium. The uptake of [14C]L-carnitine was increased with increasing concentrations of the substrate in the medium and this uptake followed Michaelis-Menten kinetics. The uptake by the rat choroid plexus took place against a concentration gradient via a saturable process and kinetic analysis revealed Km of 32 microM (LVCP) and 34 microM (FVCP) and Vmax of 21 (LVCP) and 17 nmol/ml/min (FVCP), respectively. Ouabain inhibited the uptake by 51% (FVCP) and 48% (LVCP) and hypothermia (0 degrees C) produced inhibition by 97% (FVCP) and 96% (LVCP), respectively. However, the uptake of L-carnitine was not sensitive to probenecid or tyrosine, which indicates the presence of an independent carrier for L-carnitine in the choroid plexus. Similar results were obtained with the rabbit choroid plexus.

Animals↗
PubMed1993

Regional blood-brain lactate influx.

Regional blood-to-brain lactate transport was studied in chloral hydrate anesthetized rats using the single pass, dual-label, indicator fractionation, right atrial injection method. Lactate influx was resolved into two components, a saturable, stereospecific (to the L-enantiomer) component and a non-saturable, non-stereospecific diffusional component. The saturable component was found to have a low efficiency and moderate capacity with transport affinity coefficients between 6 and 14 mM and transport maxima of 23-40 mumol/100 g/min in the various brain regions. Lactate transport was not inhibited by probenecid. The diffusional component was determined from D-lactate influx measurements and the regional linear diffusion coefficients ranged from 0.020 to 0.036 ml/g/min. At the usual levels of plasma lactate (1-1.5 mM) these two influx components were about equal. The relative contribution of the non-stereospecific diffusional component was increased at higher plasma lactate concentrations. Lactate clearance, estimated by the total apparent permeability x surface area products was between 6 and 8 ml/100 g/min.

Animals↗
PubMed1975

A syndrome of hypersomnia with automatic behavior.

Five male patients, complaining of daytime sleep attacks, and hav ing a history of automatic behavior, were recorded continously by polygraph for 108 h under two different protocols: (1ents were given specific tests to perform during Phase 1. Six normal males were run as controls during Phase . At the end of the recordings, patients had measurements of homovanillic acid (HVA) and 5 Hydroxy-indol Acetic Acid (5HIAA) in CSF before and after Probenecid testing. Patients appeared to present an abnormal sleep structure, with lack of Stage 3 and 4 NREM sleep, but had no significant increase in total sleep time during 24 h compared to normals. They also had repetitive very short periods of "micro-sleep" which account for their automatic behavior and were responsible for their great decrement in performance compared to normal controls. No CSF HVA and 5HIAA abnormality could be detected. This syndrome, which greatly impairs the social life and working ability of the patients, may be more related to an impairment of the "wakefulness" structures than to a dysfunction of the "sleep" structures.

Adult↗
PubMed1980

[Sleep study of progressive supranuclear paralysis].

From a group of 9 patients suffering from progressive supranuclear palsy 11 polygraphic records and 6 tests with probenecid have been made. The changes in sleep can be correlated with the severity of the clinical picture and the stage of evolution of the disease. They support the hypothesis of a systematic progression of the lesions in the hypnogenic structures of the brain stem.

Aged↗
PubMed1975

Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT.

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.

Analgesics↗
PubMed1975

Evaluation of dopamine metabolism in rat striatum by a gas chromatographic technique.

Dopamine metabolism in rat striatum was evaluated by gas chromatographic quantitation of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The level of DOPAC (5.21 nmoles/g plus or minus 0.40 S.E.M., n equals 12) exceeded that HVA (3.63 nmoles/g plus or minus 0.25 S.E.M., n equals 12). 2 hr following administration of probenecid (200 mg/kg i.p.) the level of striatal HVA was approximately doubled whereas the level of DOPAC was not significantly elevated. Pargyline (75 mg/kg i.p.) poduced a rapid depletion of DOPAC and HVA. the rate of disappearance of DOPAC (t1/2 equals 10 min) exceeded that of HVA (t1/2 equals 18 min). Rates of metabolite formation were computed assuming steady state kinetics. The rate formation of DOPA (20.5 nmoles/g/hr) was much greater than that of HVA (10.1 nmoles/g/hr). We conclude that DOPAC is the major dopamine metabolite in rat striatum and that its measurement may provide the best index of functional neuronal activity in this species.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain.

Homovanillic acid (HVA) was measured in the corpus striatum aan the limbic structures nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after different drug treatments. Clozapine, thioridazine, morphine and physostigmine induced a similar percentage HVA increase in the three brain structures studied. Haloperidol and pimozide induced a higher percentage increase of HVA in the corpus striatum and nucleus accumbens when compared with the olfactory tubercle. Oxotremorine induced the highest HVA levels in the nucleus accumbens. Probenecid induced a significantly higher percentage accumulation of HVA in the limbic structures, especially in the olfactory tubercle. The HVA rise seen after haloperidol was suppressed by pretreatment with p-chlorophenylalanine or amino-oxyacetic acid in all structures studied. After atropine or trihexylphenidyl treatment the HVA rise induced by haloperidol was slightly suppressed in the limbic structures only. Our results suggest that not only under normal conditions but also after treatment with various types of drugs, dopamine metabolism as reflected by the HVA levels, is closely related in the different rat brain structures.

Aminooxyacetic Acid↗