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Biomedical subjects

R Nordmann

Publications and source records attributed to R Nordmann.

At least 55 records · Page 3Linked to original sources
PubMed1985

Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3 alpha, 4a alpha, 10a beta)-1,2,3,4,4a,5,10,10a- -octahydro-6-hydroxy-1-propyl-3-benzo[g]quinolinyl]sulfamide.

The synthesis and preliminary pharmacological evaluation of the optical antipodes of the title compound (+/-)-1 (CV 205-502) is presented. The dopaminomimetic activity is shown to reside entirely in the (-) enantiomer. Crystallographic analysis has proven that the absolute configuration of the active (-) enantiomer corresponds to that of its ergoline analogue 3 (CQ 32-084) and of apomorphine (5).

Aminoquinolines↗
PubMed1985

Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine.

A synthesis of all four diastereoisomeric 3-(tert-butoxycarbonyl)-1,6-dimethoxyoctahydrobenzo[g]quinolines 13a-d is presented. The two trans isomers 13b and 13c have been converted to tricyclic analogues 20 (CV 205-502) and 26 (205-503) of the potent dopaminomimetic ergolines CQ 32-084 and pergolide, respectively. These two compounds combine the essential moiety of apomorphine with the important 8-substituents of ergolines. Preliminary pharmacological evaluation of 20 and 26 suggests that these novel dopamine agonists combine the specificity of apomorphine with the potency, long duration of action, and good oral activity of the ergolines.

Animals↗
PubMed1985

[Biochemical aspects of dependence on alcohol].

Chronic alcohol intoxication is able to modify the lipid structure and fluidity of synaptosomal membranes and influence hereby the activity of some membraneous enzymes and receptors. These changes could play a key role in the development of alcohol tolerance and dependence. This "membraneous hypothesis" allows to explain, at least in part, the influence of nutritional factors as well as of differences in genetic or individual susceptibility on alcohol dependence. It suggests furthermore the possibility of prevention of alcohol dependence through dietary and pharmacological means.

Acetaldehyde↗
PubMed1985

[Superoxide dismutase and catalase activity in HeLa 229 cells infected with Chlamydia trachomatis].

Cytosolic superoxide dismutase (SOD) activity was found to increase with time during HeLa cell culture, this increase being due exclusively to Mn-SOD. Infection of the cells by Chlamydia trachomatis resulted in a further enhancement of this Mn-SOD activity, whereas cytosolic catalase activity was decreased in these infected cells. Superoxide (O-2.) being able to induce Mn-SOD and to inhibit catalase, these data suggest that Chlamydia trachomatis infection could be responsible for an increase in O-2. production by the infected HeLa cells.

Catalase↗
PubMed1985

Discrepancy between the different subcellular activities of rat liver catalase and superoxide dismutases in response to acute ethanol administration.

After acute ethanol administration (2.3 g/kg) peroxisomal and extra-peroxisomal catalase activities were affected in opposite directions. As long as ethanol was present, peroxisomal catalase activity was enhanced, but unaffected by amino-triazole (AT) injection. Extra-peroxisomal catalase activity was decreased during the 24hr following ethanol administration and was also inhibited after AT injection. Whereas mitochondrial manganese-dependent superoxide dismutase (Mn-SOD) was unaffected, the cytosolic Cu,Zn-SOD activity was decreased. The time-course of this decrease suggests that acute ethanol administration affects primarily extra-peroxisomal catalase activity, thus rendering cytosolic superoxide dismutase more exposed to oxygen derivatives.

Alcoholic Intoxication↗
PubMed1984

Stimulatory effects of adenosine, adenosine analogs and insulin on adipose tissue lipoprotein lipase activity and their prevention by phosphodiesterase inhibitors.

Adenosine and its 'Ri'- and 'P'-site analogs, N6-phenylisopropyladenosine and 2'-deoxyadenosine, stimulate, like insulin, lipoprotein lipase (LPL) activity in adipose tissue, an effect which is suppressed by cycloheximide. However, adenosine and its analogs do not potentiate the effects of submaximal insulin concentrations. As addition of cyclic AMP phosphodiesterase inhibitors abolishes the LPL stimulatory effects of insulin, adenosine and its analogs, this study suggests that these LPL effects are mediated through common mechanisms which are likely a decrease in cyclic AMP and an increase in LPL biosynthesis.

Adenosine↗
PubMed1984

Brain membrane disordering after acute in vivo administration of ethanol, isopropanol or t-butanol in rats.

Brain synaptosomal membranes were prepared from rats sacrificed 18 hr after a single intragastric dose of water or of ethanol (100 mmol/kg), when blood ethanol had fallen almost to zero. Fluorescence polarization of DPH, and (Na+ + K+)ATPase activity, were studied in these membranes in the presence of 0, 0.175, 0.3 or 0.7 M ethanol in vitro. After in vivo ethanol, basal ATPase activity was slightly increased, membrane fluidity was unchanged, but both measures showed increased sensitivity to the effects of ethanol in vitro. Similar results were found after an equivalent in vivo dose of isopropanol, but not of t-butanol. These findings indicate that the sensitization to in vitro effects of ethanol or isopropanol, after in vivo treatment with these alcohols, is probably not dependent principally on their lipid solubilities.

1-Propanol↗
PubMed1984

Fatty acid composition of rat liver mitochondrial phospholipids during ethanol inhalation.

Male Sprague-Dawley rats were exposed to increasing concentrations (15-22 mg/l) of ethanol vapor over a 4-day period. Phospholipids were analyzed in liver mitochondria isolated from ethanol-treated and pair-weighted control animals. After a 2-day inhalation period, the proportion of monoenoic acids in total phospholipids increased, whereas that of arachidonic acid decreased. These changes were more striking in phosphatidylcholine (PC) than in phosphatidylethanolamine (PE). The decrease in 20:4 may be related to increased lipid peroxidation. After a 4-day inhalation period, quite different changes in phospholipid fatty acids were found. They consisted in a trend towards a more unsaturated system, the proportion of 20:4 being increased in PC and that of 22:6 in PE. This increase in polyunsaturated acids might be related to a direct ethanol effect on lipid structure and/or metabolism that would be linked to the high blood alcohol level present at this stage of ethanol intoxication.

Animals↗
PubMed1984

Dopaminergic properties of mesulergine (CU 32-085) and its metabolites.

Mesulergine, an 8-alpha-aminoergoline, is now proven to be of utility in the clinic as an antiparkinsonian drug. However, the molecule itself shows in vitro and in vivo antidopaminergic properties. Mesulergine is rapidly metabolized into several pharmacologically active DA agonists. The influence of mesulergine on central DA metabolism in rats is dependent on the route of drug administration. It was possible to determine the different metabolites of this drug in plasma as well as in rat striatum. A correlation between the actual present concentration of the parent drug and DAergic metabolites and the net action on striatal DA metabolism was found. It may be concluded that mesulergine itself lacks DAergic activity but occupies DA receptors and is very rapidly metabolized into potent DA agonists.

Animals↗
PubMed1983

Inhibition in vitro of acyl-CoA dehydrogenases by 2-mercaptoacetate in rat liver mitochondria.

In rat liver hypo-osmotically treated mitochondria, 2-mercaptoacetate inhibits respiration induced by palmitoyl-CoA, octanoate or butyryl-CoA only when the reaction medium is supplemented with ATP. Under this condition, NADH-stimulated respiration is not affected. In liver mitochondrial matrix, the presence of ATP is also required to observe a 2-mercaptoacetate-induced inhibition of acyl-CoA dehydrogenases tested with palmitoyl-CoA, butyryl-CoA or isovaleryl-CoA as substrate. As the oxidation of these substrates is also inhibited by the incubation medium resulting from the reaction of 2-mercaptoacetate with acetyl-CoA synthase, with conditions under which 2-mercaptoacetate has no effect, 2-mercaptoacetyl-CoA seems to be the likely inhibitory metabolite responsible for the effects of 2-mercaptoacetate. Kinetic experiments show that the main effect of the 2-mercaptoacetate-active metabolite is to decrease the affinities of fatty acyl-CoA dehydrogenases towards palmitoyl-CoA or butyryl-CoA and of isovaleryl-CoA dehydrogenase towards isovaleryl-CoA. Addition of N-ethylmaleimide to mitochondrial matrix pre-exposed to 2-mercaptoacetate results in the immediate reversion of the inhibitions of palmitoyl-CoA and isovaleryl-CoA dehydrogenations and in a delayed reversion of butyryl-CoA dehydrogenation. These results led us to conclude that (i) the ATP-dependent conversion of 2-mercaptoacetate into an inhibitory metabolite takes place in the liver mitochondrial matrix and (ii) the three fatty acyl-CoA dehydrogenases and isovaleryl-CoA dehydrogenase are mainly competitively inhibited by this compound. Finally, the present study also suggests that the inhibitory metabolite of 2-mercaptoacetate may bind non-specifically to, or induce conformational changes at, the acyl-CoA binding sites of these dehydrogenases.

Acyl Coenzyme A↗
PubMed1983

Carnitine palmitoyltransferase I. Inhibition by D-galactosamine and role of phospholipids.

Palmitate oxidation by liver mitochondria from rats treated with D-galactosamine (GalN) was markedly inhibited, 3 h after administration. The mitochondrial defect responsible for this inhibition was shown to be an inhibition of the activity of palmitoylcarnitine transferase I (EC 2.3.1.21). Apparent Km of the enzyme remained unchanged whereas apparent V was reduced by 30%. Addition of 10 mM GalN did not impair the activity of palmitoylcarnitine transferase I in mitochondria isolated from normal rats. Inhibition of palmitoylcarnitine biosynthesis by GalN treatment was completely reversed by phospholipid supply. At this stage of intoxication, mitochondrial phospholipid content was decreased whereas incorporation of [14C]palmitate into phospholipids in isolated hepatocytes was drastically inhibited: the phosphatidylcholine/phosphatidylethanolamine ratio was reduced by 33%. The results obtained from these studies show that the depletion of the phospholipid membrane content could account for the altered functional activity of palmitoylcarnitine transferase I.

Acyltransferases↗
PubMed1983

Hepatic lipid peroxidation and mitochondrial susceptibility to peroxidative attacks during ethanol inhalation and withdrawal.

Male Sprague-Dawley rats were exposed to increasing concentrations (15-22 mg/l) of ethanol vapor over a 4-day period. The hepatic lipid peroxide level as well as the sensitivity of mitochondria and microsomes to peroxidative attacks were studied during the early stage of alcohol intoxication, at the end of the inhalation period and, finally, during withdrawal. The level of hepatic lipid peroxide started to increase significantly after the first day of ethanol inhalation, whereas the in vitro mitochondrial sensitivity to peroxidation induced by ADP X Fe3+ in the presence of an O(2)-generating system was still unaltered after a 2-day inhalation period. Both the hepatic peroxide level and the mitochondrial sensitivity to peroxidation were significantly enhanced at the end of the 4-day inhalation period. Such an enhancement was still apparent 24 h after withdrawal, a time at which no more ethanol was present in the blood. Lipid peroxidation returned to normal values only 48 h after withdrawal. Microsomes were less affected than mitochondria by the ethanol treatment. It is suggested that the alterations of lipid peroxidation are related to the presence and/or the metabolism of ethanol at an early stage of inhalation, whereas changes in the membrane structure would be responsible for the maintenance of enhanced lipid peroxidation 24 h after ethanol withdrawal.

Animals↗
PubMed1983

Brain membrane disordering by administration of a single ethanol dose.

There is a bulk of evidence that ethanol exerts an important direct effect on biological membranes, especially in the central nervous system, during chronic administration. Whether membranes are affected after an acute and subacute ethanol administration remains to be demonstrated. Crude synaptic membrane fluidity (checked by fluorescence polarization) together with (Na+ +K+)ATPase activity were therefore examined 18 hours after a single oral ethanol administration (5 g/kg bwt.) to naive rats or to rats previously intubated with ethanol repeatedly during 4 days (increasing the daily dose from 7 to 10 g/kg). The sensitivity of both parameters to different concentrations of ethanol added in vitro (0.175 M-1.400 M) was also determined. Although no changes in the basal intrinsic fluidity were found, (Na+ +K+)ATPase activity increased slightly after administration of ethanol to naive as well as to short-term ethanol intoxicated rats. The fluidizing as well as the ATPase inhibiting effects following the addition of ethanol in vitro were markedly increased 18 hours after ethanol administration to naive rats. Such an hypersensitization seems not to be related to an unspecific stress or to changes in body temperature and was no longer apparent in short-term ethanol intoxicated rats. Disappearance of the acute ethanol induced hypersensitization with further ethanol administration may represent the first stage of tolerance acquisition.

Animals↗
PubMed1983

Liver superoxide dismutases and catalase during ethanol inhalation and withdrawal.

Manganese superoxide dismutase (Mn-SOD) studied during ethanol vapor inhalation shows no changes during the inhalation period (4 days) and a transient increase 12 hours after ethanol withdrawal. A significant decrease in cytosolic Cu-Zn-SOD is found at the end of the inhalation period and was sustained during 48 hours following ethanol withdrawal. It is suggested that this decrease in Cu-Zn-SOD activity might be related to an inactivation of the enzyme linked to the increase in hydroxyl radical production related to ethanol metabolism. Cytosolic catalase is reduced at the end of the ethanol inhalation period. This decrease could be related to an enhanced superoxide radical concentration linked to the reduced Cu-Zn-SOD activity.

Alcohol Withdrawal Delirium↗
PubMed1983

Reduction in severity of physical dependence on ethanol in mice caused by desferrioxamine administration.

Male Swiss mice, when exposed to increasing concentrations of ethanol vapor for a period of 9 days, developed tolerance to as well as physical dependence on ethanol. Desferrioxamine, an iron-chelator and a lipid peroxidation inhibitor, administered to individual mice at a daily dose of 350 mg/kg body weight, caused a reduction in the degree of dependence but not of tolerance. Also, desferrioxamine protected the mice against the reduction in body weight increment observed over the inhalation period. It is suggested that desferrioxamine acts either via inhibiting the ethanol-induced lipid peroxidation, suspected to be involved in dependence, or via a different iron-sensitive mechanism.

Alcohol Withdrawal Delirium↗