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Biomedical subjects

U Moser

Publications and source records attributed to U Moser.

At least 37 records · Page 2Linked to original sources
PubMed1996

Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation.

Laboratory animal models and clinical studies suggest that dietary n-3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.

Acute Disease↗
PubMed1996

[Development of the affect system].

The authors show that the development of the affect system commences with affects of an exclusively communicative nature. These regulate the relationship between subject and object. On a different plane they also provide information on the feeling of self deriving from the interaction. Affect is seen throughout as a special kind of information. One section of the article is given over to intensity regulation and early affect defenses. The development of cognitive processes leads to the integration of affect systems and cognitive structures. In the pre-conceptual concretistic phase, fantasies change the object relation in such a way as to make unpleasant affects disappear. Only at a later stage do fantasies acquire the capacity to deal with affects. Ultimately, the affect system is grounded on an invariant relationship feeling. On a variety of different levels it displays the features typical of situation theory and the theory of the representational world, thus making it possible to entertain complex object relations. In this process the various planes of the affect system are retained and practised. Finally, the authors discuss the consequences of their remarks for the understanding of psychic disturbances and the therapies brought to bear on them.

Affect↗
PubMed1995

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

Animals↗
PubMed1995

Tocopherols and 6-hydroxy-chroman-2-carbonitrile derivatives inhibit vascular smooth muscle cell proliferation by a nonantioxidant mechanism.

The effects of two groups of similar compounds, a series of tocopherols and one of 6-hydroxy-chroman-2-carbonitrile, have been studied in vascular smooth muscle cells. A poor correlation has been found between antiproliferative and antioxidant properties of these molecules. D-alpha-Tocopherol inhibits cell proliferation, while D-alpha-tocopherylquinone has been found neither to inhibit nor to activate. D-beta-Tocopherol, a poor inhibitor of smooth muscle cell proliferation, has been shown to be capable of preventing and reversing the inhibition by D-alpha-tocopherol. It is concluded that the tocopherols and carbonitrile derivatives tested here appear to inhibit smooth muscle cell proliferation by a nonantioxidant mechanism. The competition between D-alpha-tocopherol and D-beta-tocopherol suggests the existence of a common binding site for the two molecules.

Animals↗
PubMed1995

The design and pharmacology of novel selective muscarinic agonists and antagonists.

The muscarinic pharmacology of C1-methyl-substituted chiral compounds related to McN-A-343 and of (R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M1-selective agonist known today (pEC50: M1/rabbit vas deferens = 7.83; M2/guinea-pig atria = 6.35; M3/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA2 value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC50 = 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M1 receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M2-selective antagonist (pA2 = 7.86/atria; pKi = 7.8/rat heart) with lower affinities for the M1 (pA2 = 6.36/rat duodenum; pKi = 7.1/NB-OK 1 cells), M3 (pA2 = 6.92/guinea-pig ileum; pKi = 6.7/rat pancreas) and M4 receptors (pKi = 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H1 receptors (pA2: (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M2 antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M2 receptors in the CNS with PET imaging.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1995

Polyunsaturated fatty acid metabolism of human skin fibroblasts during cellular aging.

The linoleic acid metabolism was studied in serially cultured human skin fibroblasts during 30 passages. Confluent cells were incubated with [U-14C]linoleic acid in serum free medium for 4 h after 3, 6, 12, 18, 24 and 30 passages. The labeled linoleic acid was rapidly incorporated in cell lipids, preferentially into phospholipids (80%), and the distribution within the lipid classes remained constant during the cell cycles. The rate of conversion of [14C]linoleic acid into long chain fatty acids varied with the number of passages. The formation of dihomo-gamma-linolenic acid and of arachidonic acid decreased significantly from 12% to 5% (as % of incorporated linoleic acid) between 3 and 30 serial passages whereas the linoleic acid content increased in the cells from 68% to 83%. The results indicate that the desaturase activities decreased significantly during cellular aging of human skin fibroblasts.

Arachidonic Acids↗
PubMed1995

Vitamin E and vitamin A concentrations in plasma adjusted for cholesterol and triglycerides by multiple regression.

The plasma concentration of vitamins A and E varies with the amount of concurrent lipids and thus requires lipid standardization. The present study compares a new multiple regression-based method for adjusting vitamins A and E concentrations for cholesterol and triglycerides with previous methods (adjustment for cholesterol only, and adjustment for the sum of cholesterol and triglycerides). The results show that the new method can reduce influence of the concurrent lipids.

Adult↗
PubMed1995

Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.

The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens.

The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-preferring antagonists. Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M1 receptors inhibiting neurogenic twitch contractions in the rabbit vas deferens and with affinity data obtained at M1(m1)-M4(m5) receptors in functional studies and binding experiments. The evoked overflow of noradrenaline from sympathetic nerves was enhanced by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and indomethacin, indicating a tonic inhibition by endogenous A1 and P2 purinoceptor agonists and prostanoids, respectively. The stimulation-evoked overflow at 4 Hz was not sensitive to inhibition by the muscarinic agonists methacholine or 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). In contrast, at a stimulation frequency of 1 Hz the evoked noradrenaline release was decreased by muscarinic agonists (EC50): arecaidine propargyl ester (0.062 microM), 4-Cl-McN-A-343 (0.32 microM), 4-(4-fluorophenylcarbamoyloxy)-2-butynyl-N-methyl-pyrrolidinium tosylate (4-F-PyMcN+; 0.48 microM) and methacholine (0.86 microM). The affinity constants of most of the muscarinic antagonists [atropine: pKB = 9.47; (R)-trihexyphenidyl: pKB = 9.18; pirenzepine: pA2 = 7.68; methoctramine: pKB = 6.90] are consistent with estimates of these antagonists at M1(m1) receptors determined in various functional and binding studies. The high antagonistic potency of pirenzepine and (R)-trihexyphenidyl and the agonistic activity of 4-F-PyMcN+ argue for the involvement of M1, and against that of M2 and M3 receptors in the inhibition of evoked noradrenaline overflow. However, the high apparent pKB of 8.30 for himbacine is not in accordance with an M1 receptor; by contrast, it would be compatible with the presence of M2 or M4 receptors. The potencies of the tested muscarinic agonists and antagonists largely agree with those obtained for the inhibition of neurogenic twitch responses (0.05 Hz) in the rabbit vas deferens.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney.

The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.

Animals↗
PubMed1993

New functionally selective muscarinic agonists.

The muscarinic pharmacology of two novel agonists related to McN-A-343, 4-F-PyMcN and 4-F-PyMcN+, has been studied by the use of pharmacological and radioligand binding techniques. Both compounds were potent agonists at M1 receptors in rabbit vas deferens (pEC50 = 6.24 and 6.96) and rat duodenum (pEC50 = 5.47 and 6.38), but very weak partial agonists or competitive antagonists at guinea-pig cardiac M2 and ileal M3 receptors. There was no receptor reserve for 4-F-PyMcN in rabbit vas deferens, for which the potency (pEC50 = 6.24) and apparent affinity (pKA = 5.99 and 6.21) were similar. 4-F-PyMcN+ showed only limited binding selectivity between four muscarinic receptor binding assays with apparent affinity constants (pKi) of 5.8, 5.2, 5.6 and 5.7 for M1, M2, M3 and M4 muscarinic receptor subtypes. The two novel functionally M1-selective agonists may provide useful tools with which to study muscarinic receptor mechanisms. The non-quaternary compound, 4-F-PyMcN, might become a starting point for the development of drugs that selectively affect M1 receptors involved in central cholinergic function.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1993

Use of smokeless tobacco and cigarettes--effects on plasma levels of antioxidant vitamins.

In a population-based sample of 40-49-year-old men, plasma levels of antioxidant vitamins were measured in 17 regular users of smokeless tobacco (oral snuff), 26 regular smokers and 54 non-tobacco users. Vitamin intake by tobacco use was assessed by a food frequency questionnaire in 174 men in the 40-49 year age range. Compared with non-tobacco users, snuff dippers had similar plasma levels of ascorbate, tocopherols and carotenoids, whereas these were all significantly reduced in smokers. Smokers, but not snuff dippers, had plasma levels of ascorbate significantly below those expected from ascorbic acid intake, indicating enhanced expenditure of ascorbate in smokers but not in snuff dippers. The results show that plasma levels of antioxidant vitamins are not reduced in snuff dippers as they are in smokers, possibly as the combined result of higher intake and lower expenditure of ascorbate and tocopherols in those who use smokeless tobacco.

Adult↗