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PubMed2004

Characterization of the role of glutathione in repin-induced mitochondrial dysfunction, oxidative stress and dopaminergic neurotoxicity in rat pheochromocytoma (PC12) cells.

Repin, a major constituent in extracts of the plant Centaurea repens is thought to be the active principal responsible for the development of equine nigropallidal encephalomalacia (ENE), a fatal Parkinson-like neurodegenerative disorder in horses. Although the exact mechanism by which ingestion of this weed causes ENE is uncertain, a limited body of experimental evidence suggests a critical role for the glutathione redox system. In the present study, the mechanism of repin neurotoxicity was examined in PC12 cells with a focus on determining the role of glutathione (GSH) in repin-induced mitochondrial dysfunction, oxidative stress and dopaminergic toxicity. The results demonstrate that repin reduced both cellular GSH levels and mitochondrial function in a manner that was time- and concentration-dependent. The repin-induced changes in GSH levels were found to precede the changes in mitochondrial function. Depletion of GSH with a potent GSH depletor (ethacrynic acid (EA)) and a GSH synthesis inhibitor (buthionine sulfoximine (BSO)) prior to repin treatment enhanced the repin-induced mitochondrial change. In addition, repin caused a concentration-dependent decrease in cellular dopamine levels in NGF-differentiated PC12 cells. Increases in intracellular GSH levels induced by pre-treatment with reducing agents (N-acetyl-L-cysteine or reduced glutathione) completely protected the cells from repin-induced mitochondrial and dopaminergic toxicity. Antioxidants, coenzyme-Q and ascorbic acid completely blocked repin-induced dopaminergic toxicity. These data suggest that GSH plays a critical role in repin-induced neurotoxicity and that the maintenance of neuronal redox status may prove to be a useful strategy for the prevention and/or treatment of ENE. The results support the view that GSH depletion, leading to oxidative damage and subsequent mitochondrial dysfunction, may serve as a trigger for neuronal cell death.

Animals↗
PubMed2006

Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo.

We previously demonstrated that copper facilitated the formation of reactive oxygen species, and inhibited pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in animal models of Wilson's disease in vivo. However, direct Cu(2+) toxicity has only been demonstrated for Wilson's disease. We now hypothesize that inhibition of these mitochondrial dehydrogenases might also contribute to many other injuries and disorders that are reactive oxygen species-mediated. We have modeled reactive oxygen species-mediated injuries using inducers of reactive oxygen species such as hydrogen peroxide, ethacrynic acid or menadione, or another redox active metal (Cd(2+)). Here we demonstrated that these toxic exposures were accompanied by an early marked reduction in both pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activities, followed by a decrease in neuronal mitochondrial transmembrane potential and ATP, prior to murine cortical neuronal death. Thiamine (6 mM), and dihydrolipoic acid (50 microM), required cofactors for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (thiamine as thiamine pyrophosphate), attenuated the reactive oxygen species-induced reductions in these enzyme activities, as well as subsequent loss of mitochondrial transmembrane potential and ATP, and neuronal death. We next tested the effect of thiamine supplementation on an in vivo model of reactive oxygen species-mediated injury, transient middle cerebral artery occlusion, and reperfusion in rats. Oral or i.p. thiamine administration reduced the middle cerebral artery occlusion-induced infarct. These data suggest that reactive oxygen species-induced neuronal death may be caused in part by reactive oxygen species-mediated inhibition of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in vivo, and that thiamine or dihydrolipoic acid may constitute potential therapeutic agents not just against Cu(2+) neurotoxicity, but may reduce neuronal degeneration in the broader range of diseases mediated by free radical stress.

Adenosine Triphosphate↗
PubMed2004

Glutathione S-transferases and esterases in placenta after normal and pre-eclamptic pregnancies.

Severe pre-eclampsia reduced significantly (P<0.05) by 68+/-6 per cent (mean+/-sem, n=10) the maximal velocity (V(max)) and, consequently, reduced significantly by 60+/-7 per cent the catalytic efficiency (C(E)) of placental glutathione transferase pi, assayed with ethacrynic acid. Mild and severe pre-eclampsia reduced significantly by 82+/-5 per cent (mean+/-sem, n=5) and by 41+/-5 per cent (mean+/-sem, n=10), respectively, the V(max)and, consequently, reduced significantly by 72+/-7 and by 33+/-13 per cent, respectively, the C(E)of esterase, assayed with p-nitrophenyl acetate. Furthermore, severe pre-eclampsia increased significantly by 296+/-78 per cent the Michaelis-Menten constant (K(m)) of total GST, assayed with chlorodinitrobenzene and, consequently, decreased significantly the C(E)by 83+/-3 per cent. On the other hand, the concentrations of total and non-protein thiols did not change significantly in placental homogenates from patients with mild or severe pre-eclampsia compared to normal pregnancies. These findings would indicate a decreased capacity of the glutathione transferases and esterase detoxification systems to protect the fetus from drugs prescribed to pregnant women suffering pre-eclampsia, mainly in the severe phase.

Adult↗
PubMed2004

Antioxidant gene therapy can protect hearing and hair cells from ototoxicity.

Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. The ototoxic effects of aminoglycosides have been linked to oxidative stress. To determine the feasibility of antioxidant gene therapy for protecting the inner ear against aminoglycoside-induced oxidative stress, we used adenoviral vectors for overexpression of catalase, Cu/Zn superoxide dismutase (SOD1), and Mn superoxide dismutase (SOD2). We inoculated adenoviruses designated Ad.cat, Ad.SOD1, and Ad.SOD2 into the left guinea pig cochlea. Five days later, an ototoxic combination of kanamycin and ethacrynic acid was systemically administered. Artificial perilymph and adenovirus without a gene cassette (Ad.null) were used as controls. Biochemical analysis showed significant increase in catalase and a moderate elevation in SOD2 levels in tissues of the cochlea inoculated with the respective vectors. Auditory brain-stem responses were measured to monitor hearing thresholds. Animals were sacrificed 7 days after the ototoxic insult and their hair cells counted. Hair cells and hearing thresholds were significantly protected by Ad.cat and Ad.SOD2, while results with Ad.SOD1 were inconsistent. Control ears showed no significant protective effects. The results demonstrate that the expression of functional enzymes in the inner ear is feasible using adenoviral-mediated gene delivery. Furthermore, they confirm that reactive oxygen species contribute to aminoglycoside ototoxicity and suggest antioxidant gene therapy as a potential therapeutic strategy to reduce inner ear oxidative stress.

Adenoviridae↗
PubMed2002

Purification and characterization of a novel glutathione S-transferase from Asaphis dichotoma.

An isoenzyme of glutathione S-transferase (adGST) was purified from liver intestine of the seashell (Asaphis dichotoma) by GST-Sepharose 4B affinity chromatography followed by reverse-phase HPLC. The enzyme has a pI value of 4.6 and is composed of two subunits each with a molecular weight of 23kDa. It exhibits different catalytic activities toward the substrates 1-chloro-2,4-dinitrobenzene, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, ethacrynic acid, and p-nitrophenyl acetate and, fascinatingly, shows high activity toward CDNB. The amino acid composition of adGST was determined and found to be very similar to the Sloane squid GSTs. N-terminal analysis of the first 15 residues of adGST revealed that it has 73% sequence identity with the pig roundworm GSTs. The adGST shows characteristics similar to those of class sigma GSTs, as was indicated by its substrate specificity, N-terminal amino acid sequence, and amino acid composition.

Amino Acid Sequence↗
PubMed1998

Kinetic characterization of a membrane-specific ATPase from rat osseous plate and its possible significance on endochodral ossification.

Treatment with phosphatidylinositol-specific phospholipase C of rat osseous plate membranes released up to 90-95% of alkaline phosphatase, but a specific ATPase activity (optimum pH = 7.5) remained bound to the membrane. The hydrolysis of ATP by this ATPase was negligible in the absence of magnesium or calcium ions. However, at millimolar concentrations of magnesium and calcium ions, the membrane-specific ATPase activity increased to about 560-600 U/mg, exhibiting two classes of ATP-hydrolysing sites, and site-site interactions. GTP, UTP, ITP, and CTP were also hydrolyzed by the membrane-specific ATPase. Oligomycin, ouabain, bafilomycin A1, thapsigargin, omeprazole, ethacrynic acid and EDTA slightly affected membrane-specific ATPase activity, while vanadate produced a 18% inhibition. The membrane-specific ATPase activity was insensitive to theophylline, but was inhibited 40% by levamisole. These data suggested that the membrane-specific ATPase activity present in osseous plate membranes, and alkaline phosphatase, were different proteins.

Adenosine Triphosphatases↗
PubMed1997

Denitrosation of 1,3-dimethyl-2-cyano-1-nitrosoguanidine in rat primary hepatocyte cultures.

N-Nitrosoguanidines are potential carcinogens. However, the toxicity of these agents is attenuated significantly in laboratory rodents by processes that remove the nitroso group to generate the relatively innocuous parent guanidinium compound. The denitrosation of 1,3-dimethyl-2-cyano-1-nitrosoguanidine (CyanoDMNG) mediated by rat hepatocytes in primary culture was investigated. At concentrations < or = 200 microM, applied CyanoDMNG was converted efficiently to 1,3-dimethyl-2-cyanoguanidine (CyanoDMG). In trials using 50 microM CyanoDMNG (5 mL dosing solutions), it was demonstrated that hepatocytes are capable of denitrosating a 40 microM concentration of the applied compound with little change in the total or oxidized glutathione levels. The process was inhibited by coincidently applied ethacrynic acid, a glutathione transferase inhibitor. Reduction of hepatocyte glutathione to 20% of control levels by buthionine sulfoximine pretreatment had little effect on CyanoDMG production; total depletion of cytosolic glutathione by diethyl maleate pretreatment arrested CyanoDMNG processing. Hepatocyte-mediated CyanoDMNG denitrosation did not generate nitrite; nitrate yields were 10% relative to the CyanoDMG produced. The mercuric chloride/azo dye response of cultures lysed at times during 50 microM CyanoDMNG processing indicated intact CyanoDMNG as the only dye-sensitive material present. At applied CyanoDMNG > 100 microM, S-nitrosoglutathione (GSNO) yields were detectable; 4 microM GSNO was generated (concentration in 5 mL lysates) and maintained during 60 min at the 200 microM CyanoDMNG treatment level; this yield decayed if CyanoDMNG was withdrawn. Based on these and previous findings, it is hypothesized that CyanoDMNG is converted to CyanoDMG and GSNO by glutathione transferases and that GSNO is catabolized to eventually regenerate reduced glutathione. The fate of most of the NO moiety released remains to be determined.

Animals↗
PubMed1998

Cell-mediated biotransformation of S-nitrosoglutathione.

Spontaneous release of nitric oxide (NO) from S-nitrosothiols cannot explain their bioactivity, suggesting a role for cellular metabolism or receptors. Using immortalised cells and human platelets, we have identified a cell-mediated mechanism for the biotransformation of the physiological S-nitrosothiol compound S-nitrosoglutathione (GSNO) into nitrite. We suggest the name "GSNO lyase" for this activity. GSNO lyase activity varied between cell types, being highest in a fibroblast cell line and lowest in platelets. In NRK 49F fibroblasts, GSNO lyase mediated a saturable, GSNO concentration-dependent accumulation of nitrite in conditioned medium, which was inhibited both by transition metal chelators, and by subjecting cells to oxidative stress using a combination of the thiol oxidant diamide and Zn2+, a glutathione reductase inhibitor. Activity was resistant, however, to both acivicin, an inhibitor of gamma-glutamyl transpeptidase (EC 2.3.2.2), and to ethacrynic acid, an inhibitor of Pi class glutathione-S-transferases (EC 2.5.1.18), thus neither of these enzymes could account for NO release. Although GSNO lyase does not explain the platelet-selective pharmacological properties of GSNO, cellular biotransformation suggests therapeutic avenues for targeted delivery of NO to other tissues.

Animals↗
PubMed2001

Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta.

4-Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) has been identified as one of the strongest nitrosamine carcinogens in tobacco products in all species tested. Carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. In previous investigations, we have identified a microsomal NNK carbonyl reductase as being identical to 11beta-hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Recently, we provided evidence that carbonyl reduction of NNK does also take place in cytosol from mouse and human liver and lung. In human liver cytosol, carbonyl reductase, a SDR enzyme, and AKR1C1, AKR1C2 and AKR1C4 from the aldo-keto reductase (AKR) superfamily were demonstrated to be responsible for NNK reduction. Since NNK and/or its metabolites can diffuse through the placenta and reach fetal tissues, we now investigated NNK carbonyl reduction in the cytosolic fraction of human placenta in addition to that in microsomes. Concluding from the sensitivity to menadione, ethacrynic acid, rutin and quercitrin as specific inhibitors, mainly carbonyl reductase (EC 1.1.1.184) seems to perform this reaction in human placenta cytosol. The presence of carbonyl reductase was confirmed by RT-PCR. This is the first report to provide evidence that NNAL formation in placenta is mediated by carbonyl reductase.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

Substrate specificity of mouse aldo-keto reductase AKR7A5.

We have determined the substrate specificity of a mouse aldo-keto reductase (AKR) AKR7A5, an enzyme that is similar to rat aflatoxin aldehyde reductase (AKR7A1) and to human brain succinic semialdehyde reductase (AKR7A2). Previously, we have shown that the mouse enzyme is present in a range of tissues including liver, kidney, testis and brain, and is able to reduce several carbonyl compounds, including succinic semialdehyde, 2-carboxybenzaldehyde, 4-nitrobenzaldehyde and 9,10-phenanthrenequinone [FEBS Lett. 523 (2002) 213]. It has been suggested that it may represent the mouse equivalent of human succinic semialdehyde reductase which is responsible for the biosynthesis of gamma-hydroxybutyrate. In this study, we show that the enzyme is also able to reduce other aromatic aldehydes such as 4-chloro-3-nitrobenzaldehyde, and 3-nitrobenzaldehyde, and has particular high specific activity towards dicarbonyls such as acenapthenequinone, 2,3-bornanedione (camphorquinone), and phenylglyoxal. It has low specific activity towards ketones, and alpha,beta-unsaturated carbonyls such as acrolein and 4-hydroxynonal. The enzyme is inhibited by several compounds including quercitin, ethacrynic acid, indomethacin and sodium valproate. Developing selective inhibitors may lead to a means of modifying the activity of the enzyme in vivo.

Alcohol Oxidoreductases↗
PubMed2003

Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone.

Neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone have been shown to be synthesized from progesterone in animal brains. Comparison of kinetic constants for the neuroactive steroids and their precursors among four human 3(20)alpha-hydroxysteroid dehydrogenases (AKR1C1-AKR1C4) suggests that AKR1C1 and AKR1C2 are involved in the catabolism and synthesis, respectively, of the neuroactive steroids in the human brain. In our efforts to identify agents that would specifically inhibit the two enzymes, benzbromarone and 3',3",5',5"-tetrabromophenolphthalein were found to be relatively selective and potent inhibitors of AKR1C1. Kinetic analyses in the oxidoreduction catalyzed by AKR1C1 in the presence of the inhibitors suggest that the inhibitors bind to the enzyme-NADP(H) complex (K(i)=0.7 nM) in the ordered bi-bi pathway, including an isomerization step. The inhibitors effectively also decreased the reduction of 3alpha,5alpha-THP to its 20alpha-hydroxy metabolite in HepG2 cells treated with ethacrynic acid.

20-Hydroxysteroid Dehydrogenases↗
PubMed1996

Combined effects of ethanol and cigarette smoke on hepatic and pulmonary xenobiotic metabolizing enzymes in rats.

The combined effects of ethanol (EtOH) and cigarette smoke (CS) on hepatic and pulmonary monooxygenase (MO) activities (aniline 4-hydroxylase (AH), aminopyrine N-demethylase (AMND), 7-ethoxyresorufin O-deethylase (EROD), p-nitroanisole O-demethylase (p-NAOD)), lipid peroxidation (LP) and reduced glutathione (GSH) levels and glutathione S-transferase (GST) activities toward several substrates (l-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP)) were determined and compared with those of EtOH or CS alone in rats. When the male adult rats (225-275 g) were treated with 10% EtOH (v/v) in their drinking for 21 days AH, AMND and EROD activities and LP and GSH levels increased significantly whereas GST activity for EAA decreased significantly in liver as compared to controls. EtOH did not change the hepatic p-NAOD and GST activities toward CDNB, DCNB and ENPP. In lung, EtOH increased GST activities toward CDNB and ENPP and LP level but decreased GST activity toward DCNB, significantly. No alterations were noted in pulmonary MO activities and GST activity toward EAA and GSH level by EtOH treatment. When the animals were exposed to CS five times a day, with 1 h intervals, for 3 days in a chamber where smoke and fresh air lead alternatively, AMND, EROD and p-NAOD activities, GST activity toward EAA and GSH level increased but LP level and GST activity for ENPP decreased significantly in liver. CS did not alter the hepatic AH and GST activities toward CDNB and DCNB. In lung, CS increased AH, EROD and p-NAOD activities and LP and GSH levels and decreased all the GST activities studied significantly. CS had no influence on pulmonary AMND activity. For the combined treatment, the animals were treated with 10% EtOH (v/v) in their drinking water for 21 days and during the last 3 days they were exposed to CS five times a day, with 1 h intervals, in a chamber where smoke and fresh air lead alternatively. In these animals, augmentation of elevations were noted in AH and p-NAOD activities and LP and GSH levels but not in EROD and AMND activities in liver. Combined treatment significantly decreased GST activity toward CDNB, ameliorated the alteration caused by either EtOH or CS treatment alone on GST activity toward EAA and potentiated the depression of GST activity toward ENPP to a greater degree. No change was observed in GST activity toward DCNB. In lung, combined treatment potentiated the elevations of AMND and p-NAOD activities and LP level and not those of AH and EROD activities. GST activities toward CDNB, DCNB and ENPP were highly elevated by the combined treatment. No changes were observed in pulmonary GSH level and GST activity for EAA by the combined treatment. These results reveal that the regulations of the hepatic and pulmonary MO and GST are differentially influenced by EtOH, CS and the combined treatment.

Aminopyrine N-Demethylase↗
PubMed1997

Modulation of glutathione conjugation in vivo: how to decrease glutathione conjugation in vivo or in intact cellular systems in vitro.

Glutathione conjugation is involved in detoxification and toxification of a variety of electrophilic substrates. Thus it plays a major role in protection against reactive intermediates. At the same time this conjugation may cause resistance of tumor cells against certain cytostatics. In this review the methods available to decrease glutathione conjugation in vivo are discussed. So far the only in vivo active inhibitors of glutathione S-transferases are ethacrynic acid and a number of glutathione-derived structures; the latter seem very promising for further development. For (chronic) glutathione-depletion, buthionine sulfoximine is most effective, and surprisingly safe in clinical studies. Diethylmaleate can be used for acute depletion. Inhibition of glutathione transferases offers advantages over glutathione depletion as a method of decreasing glutathione conjugation since inhibition may be accomplished without changing the activities of other glutathione-dependent reactions in the cell. However, clinically safe, in vivo effective and isoenzyme-selective glutathione S-transferase inhibitors have not yet been developed.

Animals↗
PubMed1994

Comparison of derivatization procedures for the determination of diuretics in urine by gas chromatography-mass spectrometry.

Three different GC-MS screening procedures, which use different ways of derivatization (methylation), are compared. In the first one, derivatization with iodomethane in acetone and a previous solid-liquid extraction is used; the second one is based on an extractive alkylation method using iodomethane in toluene (liquid-liquid extraction); and the last one is flash methylation by pyrolysis of tetraalkylammonium salts in the injector of the gas chromatograph using trimethylanilinium as the derivatization agent. The speed of the extraction, reproducibility and accuracy have been compared for 20 diuretics including the ones most often used in sports, such as bumetanide, ethacrynic acid, acetazolamide, dichlorphenamide, furosemide, hydroflumethiazide, hydrochlorothiazide and chlorthalidone; they have also been applied to the two uricosuric agents probenecid and benzbromarone.

Diuretics↗
PubMed2003

Engineering a new C-terminal tail in the H-site of human glutathione transferase P1-1: structural and functional consequences.

We have sought the structural basis for the differing substrate specificities of human glutathione transferase P1-1 (class Pi) and human glutathione transferase A1-1 (class Alpha) by adding an extra helix (helix 9), found in the electrophilic substrate-binding site (H-site) of the human class Alpha enzyme, at the C terminus of the human class Pi enzyme. This class Pi-chimera (CODA) was expressed in Escherichia coli, purified and characterized by kinetic and crystallographic approaches. The presence of the newly engineered tail in the H-site of the human Pi enzyme alters its catalytic properties towards those exhibited by the human Alpha enzyme, as assessed using cumene hydroperoxide (diagnostic for class Alpha enzymes) and ethacrynic acid (diagnostic for class Pi) as co-substrates. There is a change of substrate selectivity in the latter case, as the k(cat)/K(m)(EA) value decreases about 70-fold, compared to that of class Pi. With 1-chloro-2,4-dinitrobenzene as co-substrate there is a loss of catalytic activity to about 2% with respect to that of the Pi enzyme. Crystallographic and kinetic studies of the class Pi-chimera provide important clues to explain these altered catalytic properties. The new helix forms many complimentary interactions with the rest of the protein and re-models the original electrophilic substrate-binding site towards one that is more enclosed, albeit flexible. Of particular note are the interactions between Glu205 of the new tail and the catalytic residues, Tyr7 and Tyr108, and the thiol moiety of glutathione (GSH). These interactions may provide an explanation of the more than one unit increase in the pK(a) value of the GSH thiolate and affect both the turnover number and GSH binding, using 1-chloro-2,4-dinitrobenzene as co-substrate. The data presented are consistent with the engineered tail adopting a highly mobile or disordered state in the apo form of the enzyme.

Apoenzymes↗
PubMed1999

Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.

Sensorineural hearing loss (SNHL) is a significant neurologic morbidity in survivors of neonatal congenital diaphragmatic hernia (CDH), with a reported incidence of up to 60%. In a historical cohort study of 37 neonates with CDH, we investigated the use of pancuronium bromide (PB) and common ototoxic drugs during the neonatal period and their relationship to SNHL in childhood survivors. Survivors with SNHL (n = 23) had significantly higher cumulative dose of PB administered during the neonatal illness than survivors without SNHL (n = 14). The cumulative dose and duration of PB use significantly correlated (r = 0.66-0.81) and independently predicted (adjusted r (2) = 0.42-0.64) the greatest intensity (in decibels) and the widest band (lowest frequency in hertz) loss of SNHL. No differences were identified between survivors with and without SNHL regarding demographic and neonatal characteristics (including oxygenation and ventilation variables and the cumulative dose and duration of therapy with aminoglycosides, vancomycin, and furosemide), although survivors with SNHL had received a modestly higher cumulative dose of ethacrynic acid than survivors without SNHL. Although we show that prolonged administration of PB during the neonatal period is associated with SNHL in childhood survivors of CDH, further multicenter studies are required to investigate the possible etiologies of SNHL in this high-risk population.

Alberta↗
PubMed2002

Nipradilol induces vasodilation of canine isolated posterior ciliary artery via stimulation of the guanylyl cyclase-cGMP pathway.

We examined the effect of nipradilol on contraction of the posterior ciliary artery induced by high potassium or norepinephrine and on cyclic GMP (cGMP) levels in the posterior ciliary artery of dogs. Nipradilol caused dose-dependent relaxation of KCl-and norepinephrine-induced contractions of posterior ciliary artery. The relaxant effect of nipradilol on norepinephrine-contracted ciliary artery was significantly greater than that on KCl-contracted ciliary artery. In KCl-contracted ciliary artery, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10(-4) M) did not alter the relaxant effect of nipradilol, whereas 1H-1,2,4-oxadiazolo-4,3-a-quinoxalin-1-one (ODQ, 10(-6) M) significantly inhibited this effect. Ethacrynic acid at 10(-5) M, sulfasalazine at 10(-4) M and S-decylglutathione at 10(-4) M (glutathione S-transferase inhibitors) did not inhibit the relaxant effect of nipradilol. In addition, nipradilol produced dose-dependent increases in cGMP levels in the canine posterior ciliary artery. These findings indicate that nipradilol-induced vasorelaxation in the canine posterior ciliary artery occurs via stimulation of the guanylyl cyclase-cGMP pathway.

Adrenergic beta-Antagonists↗
PubMed2002

Induction of cytosolic glutathione S-transferases from Atlantic eel (Anguilla Anguilla) after intraperitoneal treatment with polychlorinated biphenyls.

Glutathione S-transferases (GST) are phase II biotransformation enzymes influenced by exposure to foreign compounds and are proposed as biomarkers of environmental pollution. The hepatic and renal cytosolic GST isoenzymes from juvenile Atlantic eels were isolated and partially characterized. In both organs, three different GST isoenzymes were purified using HPLC and the final subcellular purified fraction resulted in enzymatic subunits of approximately 24,500 Da. Total GST activity was significantly higher towards the substrate 1-chloro-2,4-dinitrobenzene (CDNB) than the ethacrynic acid (ETHA). Induction of isoenzymes of GST was studied after intraperitoneal treatment with a single dose (25 mg/kg bw) of a polychlorinated biphenyls mixture. In the hepatic cytosol, an inductory effect on the major enzymatic isoform was observed when comparing treated with control eels. This was directly related to statistically significant (P < 0.05) differences in total GST activity toward the CDNB between treated and control groups, with an increase of 33.6% of GST total activity measured in the last subcellular purified samples. In the kidney cytosol, PCB treatment did not affect GST activity. Significant differences were observed when analyzing the effect of PCB treatment on the main GST subunit height (retention time of 27 min). These results indicate that hepatic GST profiles could be considered as a good tool in environmental studies as specific biomarkers of contamination.

Anguilla↗