Inhibition of L-methionine uptake and incorporation by chlorpromazine in preimplantation mouse embryos.
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These studies indicate that chlorpromazine causes a rapid inhibition of the uptake and incorporation of L-[Me-3H]methionine in preimplantation mouse embryos in vitro. Concentrations of chlorpromazine from 10-5 M to 10-4 M inhibit L-[Me-3H]methionine uptake and incorporation in late four-cell embryos in 15 min. Concentrations of chlorpromazine from 2 times 10-5 M to 10-4 M inhibit uptake and incorporation in early blastocysts in 15 min to comparable degrees, suggesting that the effect of chlorpromazine on the early blastocyst is primarily on methionine transport, and not on protein synthesis. Lineweaver-Burk plots constructed from 15-min uptake values of methionine in the presence of various concentrations of chlorpromazine indicate that 5 times 10-5 M-chlorpromazine competitively inhibits methionine uptake in blastocysts, while 10-4 M-chlorpromazine non-competitively inhibits transport. Efflux experiments support the idea that chlorpromazine acts as an inhibitor of the active methionine influx processes, and not through acceleration of efflux. It is suggested that chlorpromazine may produce delayed implantation by directly affecting the preimplantation embryo, as well as through its known inhibitory effects on the hormonal functions of the maternal organism. (+info)
Inhibition of 5-hydroxytryptamine-induced human blood platelet aggregation by chlorpromazine and its metabolites.
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1 Blood platelets from normal human subjects were isolated and aggregated in vitro with adenosine diphosphate (ADP) or 5-hydroxytryptamine (5-HT). 2 The effects of chlorpromazine and 7 major metabolites upon 5-HT-induced aggregation were investigated. 3 All the phenothiazines inhibited 5-HT-induced aggregation when added to platelet rich plasma 3 min prior to 5-HT. 4 There were no qualitative differences in the inhibitory effects, but inhibitory potency varied over a wide range. The decreasing order of potency was monodesmethylchlorpromazine, chlorpromazine, 7-hydroxychlorpromazine, didesmethylchlorpromazine, 3,7 -dimethoxy-chlorpromazine, didesmethylchlorpromazine sulphoxide, chlorpromazine sulphoxide, chlorpromazine nitroxide. (+info)
Analysis of drug interactions in combined drug therapy by reflection method.
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AIM: To set up a new method to analyze multidrug interaction in combined drug therapy. METHODS: Based on a dose-effect curve of the combined drugs and the equieffective test, a new mathematical model was set as Q = (Eo - Et)/L (-1 < Q < 1 addition, Q < or = 1 antagonism, Q > or = 1 synergism) where Eo = an observed value (or its fitted value) of combined effect, Et = an expected value of combined effect, and L = an equieffective cutoff between Eo and Et, decided by the equieffective criterion of a special field, the number of data points, and the experimental error. The different types of experimental data were analyzed by the new model. RESULTS: This reflection method could deal with data in combined drug therapy, unnecessary to distinguish between independent and similar action, or exclusive and non-exclusive case among drugs. The number of drugs for combination did not need to be limited. But the experimental data should be enough to fit a dose-effect curve of drugs in combination. If every dose-effect curve of drugs for combination was made, a series of Q values was obtained from all levels of dose-effect for a systematic analysis. To large animal or human experiment, the points of dose-effect of each drug used alone could be reduced to even 1 point. The results of analysis took the criterion of a special field and laboratory error into account in this method. CONCLUSION: The reflection method is an effective method for analysis of multidrug interaction in combined drug therapy. (+info)
Chlorpromazine inhibits hepatocyte apoptosis caused by withdrawal of phenobarbital in mice.
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AIM: To study the inhibitory effect of chlorpromazine (Chl), verapamil, and aspirin on hepatocyte apoptosis induced by the cessation of phenobarbital (Phe) treatment in mice. METHODS: Liver DNA content, ratio of liver weight/body weight, DNA fragmentation, DNA electrophoresis, the end-labeling test (TUNEL), and the morphologic changes of liver cells as indices of liver mass and hepatocyte apoptosis were applied to investigate (1) the kinetic process of hepatocyte proliferation induced by Phe 75 mg.kg-1 i.p. and the regression of hyperplastic liver caused by withdrawal of Phe in mice, (2) the effect of Chl 25 mg.kg-1, verapamil 50 mg.kg-1 or aspirin 60 mg.kg-1 i.p. on mouse hepatocyte apoptosis, and (3) the time course of effects of Chl on the regression of liver size and DNA fragmentation content after withdrawal of Phe. RESULTS: The process of hepatocyte proliferation and regression induced by administration and withdrawal of Phe in mice consisted of 4 phases: proliferation, plateau, rapid regression, and slow regression phases. In the rapid regression phase, the typic changes of hepatocyte apoptosis were found, which was prevented in early period by the Ca(2+)-calmodulin antagonist Chl, but not by verapamil or aspirin. CONCLUSION: The Ca(2+)-calmodulin played an important role in the hepatocyte apoptosis caused by withdrawal of Phe. (+info)
Chronic treatment of C6 glioma cells with antidepressant drugs results in a redistribution of Gsalpha.
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Previous studies have demonstrated that chronic treatment of C6 glioma cells with the antidepressants desipramine and fluoxetine increases the Triton X-100 solubility of the G protein Gsalpha (Toki et al., 1999). The antidepressants also caused a 50% decrease in the amount of Gsalpha localized to caveolae-enriched membrane domains. In this study, laser scanning confocal microscopy reveals that Gsalpha is localized to the plasma membrane as well as the cytosol in both treated and control cells. However, striking differences are seen in the distribution of Gsalpha in the long cellular processes after chronic treatment with these antidepressant drugs. Control cells display Gsalpha along the entire process with an especially high concentration of that G protein at the distal ends. Desipramine- or fluoxetine-treated cells show a more centralized clustering of Gsalpha in the Golgi region of the cell and a drastic reduction of Gsalpha in the cellular processes. There is no change in the distribution of Goalpha after desipramine treatment and the antipsychotic drug chlorpromazine does not alter Gsalpha. These results suggest that antidepressant-induced changes in the association of Gsalpha with the plasma membrane may translate into altered cellular localization of this signal transducing protein. Thus, modification of the coupling between Gs-coupled receptors and adenylyl cyclase may underlie both antidepressant therapy and depressive illnesses. This report also suggests that modification of the membrane domain occupied by Gsalpha might represent a mechanism for chronic antidepressant effects. (+info)
Internalization-competent influenza hemagglutinin mutants form complexes with clathrin-deficient multivalent AP-2 oligomers in live cells.
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Most membrane proteins are endocytosed through clathrin-coated pits via AP-2 adaptor complexes. However, little is known about the interaction of internalization signals with AP-2 in live cells in the absence of clathrin lattices. To investigate this issue, we employed cells cotransfected with pairs of antigenically distinct influenza hemagglutinin (HA) mutants containing different internalization signals of the YXXZ family. To enable studies on the possible association of the naturally trimeric HAs into higher order complexes via binding to AP-2, we exploited the inability of HAs from different influenza strains to form mutual trimers. Thus, we coexpressed HA pairs from different strains (Japan and X:31) bearing similar cytoplasmic tails mutated to include internalization signals. Using antibody-mediated immunofluorescence co-patching on live cells, we demonstrate that internalization-competent HA mutants form higher order complexes and that this clustering depends on the strength of the internalization signal. The clustering persisted in cells treated with hypertonic medium to disperse the clathrin lattices, as validated by co-immunoprecipitation experiments. The clustering of HAs bearing strong internalization signals appears to be mediated via binding to AP-2, as indicated by (i) the coprecipitation of alpha-adaptin with these HAs, even in hypertonically treated cells; (ii) the co-localization (after hypertonic treatment) of AP-2 with antibody-mediated patches of these mutants; and (iii) the dispersal of the higher order HA complexes following chlorpromazine treatment, which removes AP-2 from the plasma membrane. These results suggest that even in the absence of clathrin lattices, AP-2 exists in multivalent complexes capable of simultaneously binding several internalization signals from the same family. (+info)
The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.
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1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism. (+info)
Regulation of erythrocyte ghost membrane mechanical stability by chlorpromazine.
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Chlorpromazine (CPZ), a widely used tranquilizer, is known to induce stomatocytic shape changes in human erythrocytes. However, the effect of CPZ on membrane mechanical properties of erythrocyte membranes has not been documented. In the present study we show that CPZ induces a dose-dependent increase in mechanical stability of erythrocyte ghost membrane. Furthermore, we document that spectrin specifically binds to CPZ intercalated into inside-out vesicles depleted of all peripheral proteins. These findings imply that CPZ-induced mechanical stabilization of the erythrocyte ghost membranes may be mediated by direct binding of spectrin to the bilayer. Membrane active drugs that partition into lipid bilayer can thus induce cytoskeletal protein interactions with the membrane and modulate membrane material properties. (+info)