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At least 307 records · Page 17Linked to original sources
PubMed1987

4-Hydroxy-2,3-trans-nonenal stimulates microsomal lipid peroxidation by reducing the glutathione-dependent protection.

Glutathione (GSH) protects liver microsomes against lipid peroxidation. This is probably due to the reduction of vitamin E radicals by GSH, a reaction catalyzed by a membrane-bound protein. Pretreatment of liver microsomes with 0.1 or 1mM 4-hydroxy-2,3-trans-nonenal (HNE), a major product of lipid peroxidation, reduces the GSH-dependent protection. GSH and vitamin E concentrations are not affected by this pretreatment. Pretreatment with 0.1 mM N-ethyl maleimide (NEM), a synthetic sulfhydryl reagent, resulted in a reduction similar to that with HNE of the GSH-dependent protection against lipid peroxidation. The reduction of the GSH-dependent protection by HNE and NEM is probably the result of inactivation of the membrane-bound protein by covalent binding to an essential SH group on the protein. If the GSH-dependent protection would proceed via the microsomal GSH transferase, pretreatment with NEM, which activates the microsomal GSH transferase, should enhance the GSH-dependent protection. Actually a decrease in the GSH-dependent protection is found. Apparently the GSH-dependent protection does not proceed via the microsomal GSH transferase. Also the microsomal phospholipase A2 is not involved, since addition of 0.1 mM mepacrine, an inhibitor of phospholipase A2, did not preclude the GSH-dependent protection. Once the process of lipid peroxidation, either in vivo or in vitro, has started, the protection of liver microsomes by GSH is less effective. This might be the result of formed HNE. In this way an endproduct of lipid peroxidation stimulates the process that generates this product.

Aldehydes↗
PubMed1991

Activation of the microsomal glutathione S-transferase by metabolites of alpha-methyldopa.

Rat liver microsomes contain a membrane-bound GSH S-transferase (GSH-tr), an enzyme that is involved in the detoxication of xenobiotics. Also located on rat liver microsomes is the cytochrome P450 system, an enzyme complex that catalyzes the conversion of several xenobiotics into reactive intermediates. In this study, it was demonstrated that reactive products from alpha-methyldopa formed by the cytochrome P450 system are able to stimulate microsomal GSH-tr. Also, products formed from alpha-methyldopa that are generated by H2O2-horseradish peroxidase and tyrosinase are able to stimulate the activity of microsomal GSH-tr. GSH was able to prevent the activation of microsomal GSH-tr. Our results indicate that the ortho-quinone or semi-ortho-quinone radical of alpha-methyldopa is responsible for the stimulation of microsomal GSH-tr, probably via arylation of the free sulfhydryl group of microsomal GSH-tr. This conclusion was supported by the observation that 4-methyl-ortho-quinone itself was able to stimulate microsomal GSH-tr via sulfhydryl arylation. Our results are in conformity with the hypothesis that reactive products formed by the cytochrome P450 complex are able to stimulate microsomal GSH-tr and possibly in this way enhance their detoxication.

Animals↗
PubMed1988

Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation.

Reduced glutathione (GSH) delays microsomal lipid peroxidation via the reduction of vitamin E radicals, which is catalyzed by a free radical reductase (Haenen, G.R.M.M. et al. (1987) Arch. Biochem. Biophys. 259, 449-456). Lipoic acid exerts its therapeutic effect in pathologies in which free radicals are involved. We investigated the interplay between lipoic acid and glutathione in microsomal Fe2+ (10 microM)/ascorbate (0.2 mM)-induced lipid peroxidation. Neither reduced nor oxidized lipoic acid (0.5 mM) displayed protection against microsomal lipid peroxidation, measured as thiobarbituric acid-reactive material. Reduced lipoic acid even had a pro-oxidant activity, which is probably due to reduction of Fe3+. Notably, protection against lipid peroxidation was afforded by the combination of oxidized glutathione (GSSG) and reduced lipoic acid. It is shown that this effect can be ascribed completely to reduction of GSSG to GSH by reduced lipoic acid. This may provide a rationale for the therapeutic effectiveness of lipoic acid.

Animals↗
PubMed1987

The effect of ischemia and recirculation, hypoxia and recovery on anti-oxidant factors and beta-adrenoceptor density. Is the damage in the erythrocytes a reflection of brain damage caused by complete cerebral ischemia and by hypoxia?

This investigation was focussed on the gravity of tissue injury caused by complete ischemia (for five min) and hypoxia (for three weeks) in the cerebral cortex (homogenate) and the erythrocyte lysate or the erythrocyte membrane of the rat in order to investigate if the changes that occur in brain tissue are reflected in the erythrocyte. To this end, glutathione (GSH), superoxide dismutase (SOD) and catalase were measured, also alterations in beta-adrenoceptor density under these two conditions were examined. It was found that in ischemia partial parallelism in changes that occur in the central nervous system (cerebral cortex) and the erythrocyte exists. The SOD activity became higher and the beta-adrenoceptor density (measured as specific (-)-[125I] iodocyanopindolol binding) was decreased in both tissues. However after the hypoxic condition we established a decrease in the number of beta-adrenoceptors in the cerebral cortex but an increase in beta-adrenoceptor density in the erythrocyte.

Animals↗
PubMed1987

The early competence genes JE and KC are differentially regulated in murine peritoneal macrophages in response to lipopolysaccharide.

Treatment of murine peritoneal macrophages with bacterial lipopolysaccharide (LPS) has been previously documented to induce accumulation of mRNA for the early or competence genes JE and KC; the data further suggested that multiple pathways existed for the transduction of the LPS signal, since induction of mRNA for JE was related to breakdown of polyphosphoinositides while induction of KC was not (Introna et al. 1987 J. Immunol. 138, 3891). This study provides analysis of the regulation of the expression of these genes by using the nuclear transcription assay. We present evidence that LPS enhanced transcriptional activity of the KC gene, but not of the JE gene. By contrast, serum stimulation of quiescent BALB/c-3T3 fibroblasts induced transcription of the JE and KC genes. The data imply that expression of the KC gene in LPS-treated macrophages is regulated transcriptionally, while that of the JE gene is regulated post-transcriptionally. Furthermore, there appear to be two mechanistic pathways for the induction of JE mRNA depending upon the stimulus and upon the cell type: one involving transcriptional and one post-transcriptional control.

Animals↗
PubMed1987

A disbalance between beta-adrenergic and muscarinic responses caused by hydrogen peroxide in rat airways in vitro.

The effect of hydrogen peroxide on adrenergic and muscarinic responses of rat airway smooth muscle was studied. The trachea muscle and the lung parenchymal strip were contracted with methacholine and relaxed with (-)-isoprenaline. Recording of three (-)-isoprenaline curves on the trachea muscle and the lung parenchymal strip was followed by treatment for 30 min with hydrogen peroxide (H2O2) (1mM) after which a new dose response curve for (-)-isoprenaline was constructed. Using the trachea muscle this treatment with H2O2 resulted in a decrease of 61% of the maximum contraction by methacholine compared with the control and a complete inhibition of the relaxation by (-)-isoprenaline. In the lung parenchymal strip preparation we found, after the same treatment no reduction of the contraction by methacholine and 61% reduction of the relaxation by (-)-isoprenaline, compared with the control. The results demonstrate that the adrenergic response in rat airways is more susceptible to hydrogen peroxide than the muscarinic response.

Animals↗
PubMed1989

High affinity, saturable [3H]mepyramine binding sites on rat liver plasma membrane do not represent histamine H1-receptors. A warning.

Rat liver plasma membrane contains a saturable, high affinity binding site for the labelled histamine H1-antagonist [3H]mepyramine. Nonlinear regression analysis of the performed saturation experiments revealed an equilibrium dissociation constant (Kd) of 7.7 +/- 0.4 nM and a maximal binding capacity (Bmax) of 70.4 +/- 9.5 pmol/mg protein. Specific binding could be inhibited completely by several histaminergic ligands. However, the affinities of the tested H1-antagonists other than mepyramine for this binding site were quite low and the known stereospecificity displayed by the histamine H1-receptor for the enantiomers of chlorpheniramine and pheniramine was not found. Moreover, the H2-selective agonist 4-methylhistamine (Ki = 412 microM) was even more potent than its H1-selective 2-methylderivative (Ki = 772 microM). Since several ethylenediamines were also very potent in displacing [3H]mepyramine we suggest the presence of an ethylenediamine recognition site on rat liver plasma membrane which is unrelated to the histamine H1-receptor. It is stressed that a proper pharmacological characterization of a reported binding site is needed, since we show in this study that [3H]mepyramine, which is frequently used in studies concerning the H1-receptor, labels non-H1-receptor binding sites in rat liver plasma membrane.

Aminopyridines↗
PubMed1989

Modulation of oxidative stress in the gastrointestinal tract and effect on rat intestinal motility.

The amounts of different factors, which are involved in oxygen free radical production or in protection against oxygen radicals, were determined in different parts of the gastrointestinal tract (GI-tract). Glutathione and superoxide dismutase were present in lower amounts within the small intestine compared with the stomach and the large intestine. In the small intestine glutathione peroxidase and catalase both prevailed in the intestinal muscle compared to the mucosa, whereas in the large intestine both enzymes are equally distributed among the mucosa and muscle. Xanthine oxidase was mainly present in the small intestinal mucosa. Taken together, these results suggest that the large intestine is better provided with protective enzymic and non-enzymic factors against oxidative stress than the small intestine. The protective capacity of different intestinal preparations against lipid peroxidation in liver microsomes was assessed, and particularly the mucosal fractions from the small intestine showed a marked protection against lipid peroxidation, which is not easily explained with the presence of the enzymes measured in this study. Pretreatment of intestinal segments with hydrogen peroxide or cumene hydroperoxide resulted in a damaged contractile response of the longitudinal smooth muscle to methacholine in all parts of the GI-tract, expressed in a lower pD2 value and a decreased maximal response. Pretreatment with these peroxides also decreased contractions after depolarization with K+. The large intestine is more sensitive to hydrogen peroxide and cumene hydroperoxide than the small intestine, which parallels with the sensitivity to lipid peroxidation. The results obtained with hydrogen peroxide also correlate well with the catalase activity in the various segments of the intestine. In conclusion, oxidative stress in the GI-tract alters intestinal motility, especially in the large intestine. Probably this does not occur at the level of muscarinic receptors.

Animals↗
PubMed1990

Changes in inositol-1,4,5-trisphosphate binding to hepatic plasma membranes caused by temperature, N-ethylmaleimide and menadione.

We investigated the effects of the sulfhydryl-alkylating agent N-ethylmaleimide (NEM) and menadione--a sulfhydryl-arylating agent, which can undergo redox cycling--on the [3H]inositol-1,4,5-trisphosphate ([3H]IP3) binding properties of rat plasma membranes. Rat liver plasma membranes were incubated for 15 min at 37 degrees with 0.1 mM, 0.2 mM, 0.5 mM NEM or 0.3 mM menadione and subsequently diluted for use in [3H]IP3 binding studies. An incubation as such (15 min at 37 degrees) already caused the dissociation constant (Kd) of [3H]IP3 binding to increase from 1.9 +/- 0.2 nM to 3.4 +/- 0.2 nM, with only a small change in the maximal number of IP3 binding sites (Bmax-values of 401 +/- 32 and 349 +/- 13 fmol/mg protein, respectively). Incubation with NEM (0.1, 0.2 and 0.5 mM) resulted in a dose dependent decrease in the Bmax with 41, 87 and 99%, respectively, without a significant change in the Kd compared to the time matched controls. Menadione (0.3 mM) decreased the Bmax with 54% without affecting the Kd. In contrast to our findings at 37 degrees, incubation of the plasma membranes with NEM (0.5 mM) at 0 degrees for 30 min did not affect [3H]IP3 binding. In order to account for this discrepancy, the reaction rate of NEM with glutathione was examined at both 0 degrees and 37 degrees by recording the changes in the UV-spectrum of NEM (lambda max = 302 nm) after addition of 1 mM NEM to 1 mM glutathione. A similar reaction rate was observed at both temperatures. These data suggest that alkylation of a sulfhydryl-moiety in the IP3-receptor molecule causes inactivation of the receptor function. Since at 0 degrees NEM is still able to react with sulfhydryl groups, but not able to inactivate the IP3-receptor, it can be suggested that the sulfhydryl-moiety of the IP3-receptor is masked and cannot be reached by a sulfhydryl-alkylating agent at 0 degrees.

Animals↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity. I. Class I and class III compounds and lipid peroxidation.

The effect of nineteen antiarrhythmic agents on nonenzymatic lipid peroxidation, using rat hepatic microsomes, was studied. Lipid peroxidation was induced by Fe2(+)-ascorbic acid and assayed spectrophotometrically by measuring the 2-thiobarbituric acid reactive material. The compounds tested have various structural characteristics and represent class I and III of antiarrhythmics as classified by Vaughan Williams. The RM values, derived from reversed-phase thin-layer chromatography, were determined, and sigma f values calculated in order to correlate lipophilicity and antioxidant activity. The antiarrhythmics studied inhibited lipid peroxidation to various degrees. No apparent structural factor could definitely be attributed to this effect and antioxidants are found among both class I and class III compounds. There is a trend toward a parabolic relationship between antioxidant potency and lipophilicity. Three of the tested antiarrhythmics, namely the lipophilic amiodarone, aprindine and asocainol, were very potent antioxidants, and a further investigation of concentration and time dependency of lipid peroxidation was performed. It is suggested that, at least for some antiarrhythmic drugs, antioxidant activity may be part of their mode of action, and that it may form an additional beneficial feature for the treatment of cardiac failure.

Amiodarone↗
PubMed1991

Menadione inhibits the alpha 1-adrenergic receptor-mediated increase in cytosolic free calcium concentration in hepatocytes by inhibiting inositol 1,4,5-trisphosphate-dependent release of calcium from intracellular stores.

In order to establish the mechanism of perturbation of hormonally regulated calcium homeostasis in hepatocytes caused by menadione, the effects of menadione on hepatic alpha 1-adrenergic receptors and on alpha 1-adrenergic receptor-mediated increase in cytosolic free calcium concentration were determined. Menadione had no detectable effect on the alpha 1-adrenergic receptor but significantly inhibited (-)-epinephrine-dependent increases in intracellular free calcium concentration in Quin2 acetoxymethyl ester-loaded hepatocytes. The hormonally induced increase in intracellular free calcium concentration is caused by formation of inositol 1,4,5-trisphosphate (IP3) which binds to a specific receptor and causes a release of intracellular ATP-dependently sequestrated calcium. The IP3-stimulated release of calcium from intracellular pools in hepatocytes was inhibited to a great extent after treatment with menadione. This inhibition could also be observed after treatment of hepatocytes with p-benzoquinone and N-ethylmaleimide and could not be reversed by the thiol-reducing reagent dithiothreitol which indicated covalent binding to an essential free sulfhydryl group. The inhibition of IP3-dependent release of intracellular calcium was accompanied by a large increase in the number of detectable IP3 receptors without any change in the dissociation constant as determined in permeabilized hepatocytes. The increase in IP3 receptors caused by menadione could be reversed by dithiothreitol which suggests the involvement of free sulfhydryl groups. It is concluded that the IP3 receptor plays an important role in the mechanism of menadione-induced perturbation of hormonally regulated calcium homeostasis in rat hepatocytes.

Adrenergic alpha-Antagonists↗
PubMed1991

Histamine H1-receptor-mediated cyclic GMP production in guinea-pig lung tissue is an L-arginine-dependent process.

Histamine produces a rapid and massive increase of the c-GMP level of guinea-pig lung tissue. The EC50 value for this in vitro response is found to be 27 microM and the c-GMP level is maximally 9-fold elevated by 100 microM histamine. The response is stereoselectively inhibited by the enantiomers of chlorpheniramine, indicating H1-receptor involvement. Preincubation of lung tissue with 200 microM NCDC, a phospholipase C inhibitor, reduces the histamine (100 microM) responses to 16 +/- 3% (N = 6) of the control c-GMP production. Inhibition of protein kinase C by 50 microM H-7 does not significantly attenuate the H1-receptor response, whereas omittance of extracellular Ca2+ results in almost complete inhibition of the c-GMP production. The histamine-induced c-GMP response is inhibited by hemoglobin, methylene blue and the antioxidants butylated hydroxytoluene and nordihydroguaretic acid, indicating the involvement of a nitric oxide-dependent activation of soluble guanylate cyclase. This suggestion is supported by the concentration-dependent inhibition of the c-GMP production by NG-monomethyl-L-arginine (NMA). At a concentration of 20 microM NMA the histamine (100 microM) response is inhibited to 34 +/- 8% (N = 6) of the control response. This inhibition is reversed to 127 +/- 20% (N = 6) by the exogenous addition of 1 mM L-arginine. These findings show that after an initial H1-receptor-mediated, phospholipase C-dependent, Ca(2+)-mobilization the enzymatic conversion of L-arginine to nitric oxide is stimulated. This nitric oxide production is finally responsible for the activation of soluble guanylate cyclase, leading to the production of c-GMP.

Animals↗
PubMed1996

Reduction of lipoic acid by lipoamide dehydrogenase.

Racemic lipoic acid is therapeutically applied in pathologies in which free radicals are involved. The in vivo reduction of lipoic acid may play an essential role in its antioxidant effect. It was found that mitochondrial lipoamide dehydrogenase (LipDH, EC 1.8.1.4.) reduces the R-enantiomer 28 times faster than the S-enantiomer of lipoic acid. Moreover, it was observed that the metabolites of lipoic acid, bisnor-, tetranor-, and beta-lipoic acid are poor substrates of LipDH. S-lipoic acid inhibits the reduction of the R enantiomer only at relatively high concentrations. The reduction of R-lipoic acid by mitochondria-rich tissues may proceed smoothly, even if the racemic mixture is applied. This is of importance in elucidating the molecular mechanism of the pharmacotherapeutic effect of lipoic acid.

Animals↗
PubMed1981

Cycloheximide activation of the lordotic response in low-dose, estrogen-treated ovariectomized rats: evidence for modulating inhibitory influences of the limbic system on sexual behavior.

This study tested the effect on intracranially injected cycloheximide (CHX), an inhibitor of protein synthesis, on facilitation of sexual receptivity in ovariectomized rats. The rats received 0.5 microgram estradiol benzoate (EB), s.c. once daily on days 8 through 12 after ovariectomy (OVX). Either CHX (in 0.5 microliter saline) or 0.5 microliter saline was injected into the lateral septum (LS), cortical nucleus (ACO) or medial nucleus of the amygdala or medial preoptic area on day 11 after OVX. The dose of EB was insufficient to facilitate lordotic behavior on day 10 or day 12 after OVX unless CHX was injected into the LS or ACO. Injection of saline did not influence lordosis.

Animals↗