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At least 433 records · Page 24Linked to original sources
PubMed1995

Regulation of alpha 4 beta 2 nicotinic acetylcholine receptors in M10 cells following treatment with nicotinic agents.

The effects of chronic treatment (3 days) with the nicotinic agonists, nicotine and cytisine as well as the antagonists, d-tubocurarine, hexamethonium and dihydro-beta-erythroidine (DH beta E) on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) were investigated in a permanently transfected cell line, M10. The number of alpha 4 beta 2 nAChRs expressed in the cell line was assayed by (-)-[3H]nicotine binding. The two enantiomers of nicotine both significantly increased the number of nAChRs in a concentration dependent manner. No changes in the levels of mRNA for either alpha 4 or beta 2 subunits were found following chronic (-)-nicotine treatment. The effect of (-)-nicotine treatment on the number of nAChRs was partially blocked by the antagonists d-tubocurarine and hexamethonium, but not by dihydro-beta-erythroidine (DH beta E). Chronic exposure of the cells to each of the antagonists did not influence the number of nAChRs. Treatment with the agonist cytisine resulted in a bell-shaped dose-dependent effect on the number of alpha 4 beta 2 nAChRs. In the presence of cytisine (microM) the effect induced by chronic(-)-nicotine treatment on the number of the nAChRs was attenuated. These results indicate that nicotinic agents can induce different regulatory effects in M10 cells due to their individual pharmacological properties as agonist and/or antagonist.

Alkaloids↗
PubMed1995

Isoarecolone-induced enhancement of delayed matching to sample performance in monkeys: role of nicotinic receptors.

Nicotine enhances memory performance in young and aged monkeys performing a version of the delayed matching to sample (DMTS) task. However, the beneficial actions of nicotine are often limited by debilitating side effects. Isoarecolone is a piperidine derivative with nicotine-like activity, but having a slightly different profile of behavioral actions in rodents. In young monkeys, isoarecolone produced a dose-dependent enhancement of the DMTS task on the same day of testing, with a trend towards enhanced performance in animals tested 24 h after administration. Isoarecolone was about 1500-fold less potent than nicotine in enhancing DMTS performance. The ability of isoarecolone to enhance DMTS performance was well correlated with its ability to interact with cortical nicotinic receptors in vitro.

Age Factors↗
PubMed1995

Epibatidine and ABT 418 reveal selective losses of alpha 4 beta 2 nicotinic receptors in Alzheimer brains.

Subtypes of nicotinic acetylcholine receptors (nAChRs) were characterized in human temporal cortex and in a alpha 4 beta 2 nAChR-transfected M10 cell line using the nicotinic agonists epibatidine, ABT 418 and (-)nicotine in competition studies with [3H]nicotine and [3H]cytisine. The three agonists best fitted to an one-site model in M10 cells with the rank of potencies: epibatidine > > (-)-nicotine > ABT 418. Heterogeneous nAChRs were revealed for epibatidine and ABT 418 in the human temporal cortex. Both compounds labelled a major binding site (Ki 0.35 nM and 68.6 nM respectively) and an additional minor binding site with higher affinity (Ki 0.002 nM and 0.86 nM respectively). Corresponding data for (-)nicotine were a major site (Ki 2.80 nM) and an additional minor site with lower affinity (Ki 2150 nM). Selective losses in the major population of nAChR were observed in the temporal cortex of brains from individuals with Alzheimer's disease with all three agonists. This suggested that the alpha 4 beta 2 nAChR subunit might be the most vulnerable in Alzheimer's disease (AD) and a possible target for therapeutic strategies.

Aged↗
PubMed1996

Tacrine interacts with an allosteric activator site on alpha 4 beta 2 nAChRs in M10 cells.

The effect of chronic treatment with the cholinesterase inhibitor tacrine on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) was investigated in a transfected fibroblast cell line, M10. Tacrine significantly increased (+46%; 5 x 10(-8) to 10(-5) M) and decreased (-74%; 2 x 10(-5) to 10(-4) M) the number of nAChRs in the M10 cells in a concentration-dependent manner when using [3H]cytisine as labelled ligand. The mRNA levels for alpha 4 or beta 2 nAChR subunits remained unchanged following the treatment. The tacrine-induced increase in number of nAChRs was significantly blocked by the antagonist mecamylamine (10(-4) M), while tubocurarine (10(-4) M) had no effect. Neither of the antagonists prevented the decrease in the number of nAChRs obtained at the higher concentration of tacrine. Similar to nicotine, tacrine (5 x 10(-5) M) decreased the turnover rate of nAChRs, which might indicate neuroprotective properties. This study demonstrates that tacrine interacts with two sites on nAChRs, where activation of the noncompetitive allosteric site might contribute to the clinical efficacy of tacrine treatment in AD patients.

Alkaloids↗
PubMed1998

Inherited, selective hypoanalgesic response to cytisine in the tail-flick test in CF-1 mice.

This study extends the pharmacological characterization of the genotype- dependent difference in analgesic responsiveness to neuronal nicotinic agonists between CD-1 and CF-1 strains of mice. Acute analgesic potency of cytisine measured by the tail-flick assay differed by > 3200-fold between CD-1 and CF-1 outbred strains of mice. Analgesic non-responsiveness of the CF-1 strain was pharmacologically selective. Morphine produced a dose-dependent analgesic response of similar magnitude in both strains. Other pharmacological actions of cytisine, including inhibition of locomotor activity, induction of seizures and lethality, did not differ between these strains. Hyporesponsiveness to the analgesic action of both nicotine and cytisine was observed in two different CF-1 sublines. Biodistribution of [3H]cytisine in blood did not differ between the CF-1 and CD-1 strains. These pharmacological characteristics indicate that the CD-1-CF-1 strain pair provides a useful pharmacogenetic tool for investigating the mechanistic bases of analgesia induced by nicotinic cholinergic agonists.

Alkaloids↗
PubMed1999

High affinity binding of [3H]epibatidine to rat brain membranes.

Several compounds, such as epibatidine, A-85380, and their analogs, have been identified recently as nAChR ligands whose affinities lie in the low picomolar range. Accurate measurement of such high affinities is fraught with certain technical difficulties, which may account for the inconsistency of previously reported affinities of epibatidine, ranging from 4 to 60 pM. Here, we demonstrate that (+/-)-[3H]epibatidine (1-500 pM) binds to a single population of sites in rat brain with KD of 8 +/- 2 pM. This affinity was confirmed in both kinetic experiments and competition assays with (+/-)-[3H]epibatidine and (-)-[3H]cytisine, which were performed under experimental conditions developed specifically for ligands with subnanomolar affinities. Variations from these conditions decreased the observed affinities.

Alkaloids↗
PubMed1999

2-[18F]F-A-85380: a PET radioligand for alpha4beta2 nicotinic acetylcholine receptors.

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha4beta2 nAChRs (K(D)=50 pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha4beta2 nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[18F]F-A-85380 was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[18F]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects.

Alkaloids↗
PubMed2000

Overall cardiac functional effect of positive inotropic drugs with differing effects on relaxation.

Recent interest in so-called calcium-sensitizing positive inotropic drugs has highlighted the potential problem of a positive effect on force development being offset, at least partially, by the negative effect that many of these drugs have on relaxation. The purpose of this study was to examine the interplay of contraction and relaxation in determining the overall cardiac effect of different positive inotropic drugs. Using a buffer-perfused isolated rabbit heart preparation, we studied four drugs (calcium, dobutamine, EMD 57033, and CGP 48506) that were given at doses sufficient to increase similarly left ventricular pressure-generating capability by approximately 20%. We show that, even though they produce equivalent changes in pressure-generating capability, these four agents produce dissimilar changes in relaxation capability, with dobutamine speeding relaxation, EMD 57033 slowing relaxation, and calcium and CGP 48506 having little effect of relaxation. Similar relative effects were observed for drug-induced changes in the timing of pressure-generation events. These effects combine to produce different drug-induced changes in overall cardiac pump function judged by the relation between cardiac output and heart rate. Dobutamine shifted the maximal cardiac output to a higher heart rate. In contrast, both calcium sensitizers shifted the maximum in cardiac output to a lower heart rate, whereas calcium had no effect. Thus even though positive inotropic drugs may have similar effects on left ventricular pressure generation, the overall benefit of such drugs on ventricular pump function will depend on how the drug also affects ventricular relaxation and ejection capabilities.

Animals↗
PubMed2001

Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes.

Calcium sensitizers increase myocardial contractile function without affecting Ca2+ homeostasis, which might be beneficial in the treatment of patients with heart failure. However, it remains uncertain whether Ca sensitizers induce quantitatively similar inotropic responses in control and failing hearts. To compare their effects in normal versus failing hearts at the cellular level, shortening mechanics and intracellular calcium ([Ca2+]i) transient were simultaneously measured in the left ventricular myocytes isolated from normal dogs (n = 8) and dogs with rapid pacing-induced heart failure (n = 7). CGP 48506 and EMD 57033 exerted a positive inotropic effect in a dose (0.1-3 microM)-dependent manner in both normal and heart failure myocytes. The percent increase of cell shortening magnitude was comparable between the two groups. CGP 48506 and EMD 57033 did not affect the diastolic cell length and resting [Ca2+]i level. They did not affect the duration of [Ca2+]i transient dynamics. Thus Ca2+ sensitizers exerted comparable positive inotropic effects without affecting the rest cell length and rest [Ca2+]i in normal and heart failure myocytes.

Animals↗
PubMed2002

Effect of an orally active Na+/H+ exchange inhibitor, SMP-300, on experimental angina and myocardial infarction models in rats.

The effects of SMP-300, an orally active, potent, and selective Na+/H+ exchange inhibitor, were evaluated and compared with those of nifedipine, propranolol, and nicorandil on three experimental angina models and on myocardial infarction in rats. SMP-300 (0.1-1 mg/kg, p.o.) reduced isoproterenol-induced ST segment depression in a dose-dependent manner. Its maximal effect was comparable to that reported for propranolol and greater than that of nifedipine. SMP-300 (0.3-1 mg/kg) reduced vasopressin-induced ST segment depression in a dose-dependent manner, and its maximal effect was comparable to those of nifedipine and nicorandil. SMP-300 (0.3-1 mg/kg, p.o.) and propranolol (100 mg/kg, p.o.) inhibited coronary artery occlusion-induced T-wave elevation, but nifedipine (3 mg/kg, p.o.) did not. SMP-300 (1 mg/kg, p.o.) reduced myocardial infarct size after 40 min of coronary artery occlusion followed by 24 h of reperfusion, but nifedipine (3 mg/kg, p.o.) or propranolol (100 mg/kg, p.o.) did not. This study provides support for the future use of a Na+/H+ exchange inhibitor as an anti-anginal drug with a novel mode of action.

Administration, Oral↗
PubMed2002

Construction of a high-resolution moiré interferometer for investigating microstructural displacement fields in materials.

A high-magnification moiré interferometer has been constructed with a spatial resolution of the order of 1 microm to measure the local in-plane displacement field associated with a material's microstructure. Laser illumination passes through phase-stepping optics and is delivered to the microscope head by polarization-preserving single-mode optical fibres. The head itself is a compact unit consisting of collimating optics, an objective lens and a charge coupled device (CCD) camera. Thin-phase gratings are cast onto the sample surface with a compliant epoxy resin and coated with ca. 5 nm of gold to enhance the fringe contrast and reduce speckle noise. By switching between the laser illumination and white-light illumination, the underlying microstructure is viewed in exact registration with the measured displacement fields. The application of the instrument is illustrated here by visualization of displacement fields in polymer-bonded explosives (PBXs) during deformation to failure. PBXs are highly filled polymers consisting of up to 95% by weight crystalline explosive bound in a variety of polymeric binders. The mechanical properties of PBXs are highly dependent on the microstructure, and moiré interferometry is an ideal tool for investigating the relationship between the 1-100 microm sized crystals and the displacement fields. Methods such as this are required if computer models of inhomogeneous materials are to be accurately validated.

Azocines↗
PubMed2004

A photoluminescence-based field method for detection of traces of explosives.

We report a photoluminescence-based field method for detecting traces of explosives. In its standard version, the method utilizes a commercially available color spot test kit for treating explosive traces on filter paper after swabbing. The colored products are fluorescent under illumination with a laser that operates on three C-size flashlight batteries and delivers light at 532 nm. In the fluorescence detection mode, by visual inspection, the typical sensitivity gain is a factor of 100. The method is applicable to a wide variety of explosives. In its time-resolved version, intended for in situ work, explosives are tagged with europium complexes. Instrumentation-wise, the time-resolved detection, again visual, can be accomplished in facile fashion. The europium luminescence excitation utilizes a laser operating at 355 nm. We demonstrate the feasibility of CdSe quantum dot sensitization of europium luminescence for time-resolved purposes. This would allow the use of the above 532 nm laser.

Azocines↗
PubMed2006

Effect of iron(III), humic acids and anthraquinone-2,6-disulfonate on biodegradation of cyclic nitramines by Clostridium sp. EDB2.

AIMS: To determine the biodegradation of cyclic nitramines by an anaerobic marine bacterium, Clostridium sp. EDB2, in the presence of Fe(III), humic acids (HA) and anthraquinone-2,6-disulfonate (AQDS). METHODS AND RESULTS: An obligate anaerobic bacterium, Clostridium sp. EDB2, degraded RDX and HMX, and produced similar product distribution including nitrite, methylenedinitramine, nitrous oxide, ammonium, formaldehyde, formic acid and carbon dioxide. Carbon (C) and nitrogen (N) mass balance for RDX products were 87% and 82%, respectively, and for HMX were 88% and 74%, respectively. Bacterial growth and biodegradation of RDX and HMX were stimulated in the presence of Fe(III), HA and AQDS suggesting that strain EDB2 utilized Fe(III), HA and AQDS as redox mediators to transfer electrons to cyclic nitramines. CONCLUSIONS: Strain EDB2 demonstrated a multidimensional approach to degrade RDX and HMX: first, direct degradation of the chemicals; second, indirect degradation by reducing Fe(III) to produce reactive-Fe(II); third, indirect degradation by reducing HA and AQDS which act as electron shuttles to transfer electrons to the cyclic nitramines. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study could be helpful in determining the fate of cyclic nitramine energetic chemicals in the environments rich in Fe(III) and HA.

Anthraquinones↗
PubMed1993

The inhibitory effect of SA3443, a novel cyclic disulfide compound, on alpha-naphthyl isothiocyanate-induced intrahepatic cholestasis in rats.

1. We investigated the effect of SA3443, a novel cyclic disulfide compound, on alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in rats. 2. SA3443 given orally at doses of 100 or 300 mg/kg, three times at 4h intervals, dose-dependently suppressed the elevation of serum total bilirubin, alkaline phosphatase activity and transaminase activities induced by administration of ANIT (80 mg/kg) 3h before the second dosages of SA3443. 3. SA3443 also significantly inhibited the reduction of bile flow in the ANIT-treated rats. 4. These findings indicated that SA3443 had a markedly inhibitory effect on ANIT-induced intrahepatic cholestasis in rats.

1-Naphthylisothiocyanate↗
PubMed1998

Functional contribution of the alpha5 subunit to neuronal nicotinic channels expressed by chick sympathetic ganglion neurones.

1. Heterologous expression studies of the alpha5 subunit of the neuronal acetylcholine receptor (nAChR) gene family have demonstrated that it can participate in the function of ACh-gated channels if co-expressed with another alpha- and a beta-subunit. Previous studies also indicate prominent expression of alpha5 in both central and peripheral nervous systems. The participation of alpha5 in native nAChRs and its functional role in these channels is, however, unknown. 2. In this study, we present evidence that alpha5 has a role in at least two distinct subtypes of nAChR complexes expressed by embryonic chick sympathetic neurones. 3. alpha5 contributes not only to agonist but also to antagonist sensitivity of natively expressed nAChR channels. Functional deletion of the alpha5 subunit by antisense oligonucleotide treatment removes the nAChRs with relatively low affinity to ACh and cytisine. Deletion of alpha5 also eliminates channels that are blocked by the alpha7-specific antagonist methyllycaconitine (MLA) while increasing the percentage of current carried by nAChRs that are sensitive to alpha-bungarotoxin (alpha-BgTx). 4. Single channel analyses indicate that functional deletion of alpha5 results in the deletion of both the 'brief' and 'long' open duration, 50 pS subtypes of nAChR channels while increasing the expression of the 18 pS, alpha-BgTx-sensitive native nAChRs normally detected in sympathetic neurones at later developmental stages. 5. The biophysical and pharmacological profiles of native nAChRs revealed by this study and previous work are discussed in the context of a proposed model of the nAChR channels expressed by chick sympathetic neurones throughout development.

Acetylcholine↗
PubMed2000

Attenuation of length dependence of calcium activation in myofilaments of transgenic mouse hearts expressing slow skeletal troponin I.

We compared sarcomere length (SL) dependence of the Ca2+-force relation of detergent-extracted bundles of fibres dissected from the left ventricle of wild-type (WT) and transgenic mouse hearts expressing slow skeletal troponin I (ssTnI-TG). Fibre bundles from the hearts of the ssTnI-TG demonstrated a complete replacement of the cardiac troponin I (cTnI) by ssTnI. Compared to WT controls, ssTnI-TG fibre bundles were more sensitive to Ca2+ at both short SL (1.9 +/- 0.1 micrometer) and long SL (2.3 +/- 0.1 micrometer). However, compared to WT controls, the increase in Ca2+ sensitivity (change in half-maximally activating free Ca2+; DeltaEC50) associated with the increase in SL was significantly blunted in the ssTnI-TG myofilaments. Agents that sensitize the myofilaments to Ca2+ by promoting the actin-myosin reaction (EMD 57033 and CGP-48506) significantly reduced the length-dependent DeltaEC50 for Ca2+ activation, when SL in WT myofilaments was increased from 1.9 to 2.3 micrometer. Exposure of myofilaments to calmidazolium (CDZ), which binds to cTnC and increases its affinity for Ca2+, sensitized force developed by WT myofilaments to Ca2+ at SL 1.9 micrometer and desensitized the WT myofilaments at SL 2.3 micrometer. There were no significant effects of CDZ on ssTnI-TG myofilaments at either SL. Our results indicate that length-dependent Ca2+ activation is modified by specific changes in thin filament proteins and by agents that promote the actin-myosin interaction. Thus, these in vitro results provide a basis for using these models to test the relative significance of the length dependence of activation in situ.

Actin Cytoskeleton↗