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Sample records for norepinephrine inhibits smooth

  1. Endoluminal norepinephrine inhibits smooth muscle activity of the pig pyeloureter by stimulation of beta-adrenoceptors without side effects

    DEFF Research Database (Denmark)

    Mortensen, Jens; Holst, Uffe; Jacobsen, Jørn Skibsted

    2008-01-01

    of pyeloureter and to reveal possible side effects on cardiovascular and renal functions. Renal pelvis was perfused, while pelvic pressure, cardiovascular and renal functional parameters were recorded. In group A, a pelvic pressure increase was examined during pressure flow studies with norepinephrine solutions......It has been demonstrated in pigs that endoluminal administration of norepinephrine reduces the increase in renal pelvic pressure during perfusion. The purposes were to describe concentration-response relationship and receptor mechanism of the effect of norepinephrine on muscle function...... a renal pelvis pressure increase to perfusion in a dose-related way without side effects. Endoluminal norepinephrine is safe in pigs and may be useful under endoscopy of the pyeloureter....

  2. Influence of norepinephrine transporter inhibition on hemodynamic response to hypergravitation

    OpenAIRE

    Strempel, Sebastian

    2011-01-01

    Background: Sympathetically-mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness (g-LOC). Norepinephrine transporter (NET) inhibition prevents neurally-mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus, it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. Methods. We performed a double-blind, randomized...

  3. Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

    Science.gov (United States)

    Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

    2008-03-01

    Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

  4. Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

    Science.gov (United States)

    Wan, Jingjing; Brust, Andreas; Bhola, Rebecca F; Jha, Prerna; Mobli, Mehdi; Lewis, Richard J; Christie, Macdonald J; Alewood, Paul F

    2016-05-01

    Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  5. Development of norepinephrine transporter reuptake inhibition assays using SK-N-BE(2C cells

    Directory of Open Access Journals (Sweden)

    Ann M. Decker

    2018-05-01

    Full Text Available This report describes efforts to develop and validate novel norepinephrine transporter reuptake inhibition assays using human neuroblastoma SK-N-BE(2C cells in 24-well format. Before conducting the assays, the SK-N-BE(2C cells were first evaluated for their ability to uptake [3H]norepinephrine and were shown to have a saturable uptake with a KM value of 416 nM. Using this determined KM value, reuptake inhibition assays were then conducted with a variety of ligands including antidepressants, as well as piperazine and phenyltropane derivatives. The results obtained with the SK-N-BE(2C cells indicate that this model system can detect a range of ligand potencies, which compare well with other established transporter assays. Our data suggest that SK-N-BE(2C cells have potential utility to serve as another model system to detect norepinephrine reuptake inhibition activity.

  6. Depletion of rat cortical norepinephrine and the inhibition of [3H]norepinephrine uptake by xylamine does not require monoamine oxidase activity

    International Nuclear Information System (INIS)

    Dudley, M.W.

    1988-01-01

    Inhibition of monoamine oxidase A through pretreatment of rats with clorgyline or the pro-drug MDL 72,394 did not block the amine-depleting action of xylamine. Xylamine treatment resulted in a loss of approximately 60% of the control level of norepinephrine in the cerebral cortex. A 1-hr pretreatment, but not a 24-hr pretreatment, with the monoamine oxidase B inhibitor, L-deprenyl, prevented the depletion of norepinephrine by xylamine. In addition, pretreatment with MDL 72,974, a monoamine oxidase B inhibitor without amine-releasing or uptake - inhibiting effects, did not prevent cortical norepinephrine levels. Inhibition of monoamine oxidase by either MDL 72,974 or MDL 72,394 did not prevent the inhibition of [ 3 H]norepinephrine uptake into rat cortical synaptosomes by xylamine. These data indicate that monoamine oxidase does not mediate the amine-releasing or uptake inhibiting properties of xylamine. The protection afforded by L-deprenyl following a 1-hr pretreatment most probably was due to accumulation of its metabolite, L-amphetamine, which would inhibit the uptake carrier. A functional carrier is required for depletion since desipramine administered 1 hr prior to xylamine, was also able to prevent depletion of norepinephrine

  7. Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

    Directory of Open Access Journals (Sweden)

    Elizabeth Thomas Cox

    2011-06-01

    Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

  8. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    NARCIS (Netherlands)

    Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; van der Hart, Marieke; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

    2012-01-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood

  9. Norepinephrine inhibition of mesenchymal stem cell and chondrogenic progenitor cell chondrogenesis and acceleration of chondrogenic hypertrophy.

    Science.gov (United States)

    Jenei-Lanzl, Zsuzsa; Grässel, Susanne; Pongratz, Georg; Kees, Frieder; Miosge, Nicolai; Angele, Peter; Straub, Rainer H

    2014-09-01

    Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)-dependent and cartilage progenitor cell (CPC)-dependent chondrogenesis. Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific β-adrenergic receptor (β-AR) agonist isoproterenol, and the specific β-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation. TH+ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, β-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy. Our findings demonstrate NE-dependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options. Copyright © 2014 by the American College of

  10. Modulation of attentional inhibition by norepinephrine and cortisol after psychological stress.

    Science.gov (United States)

    Skosnik, P D; Chatterton, R T; Swisher, T; Park, S

    2000-04-01

    Two of the most salient physiological responses to stress are increased norepinephrine (NE) and cortisol (CORT) activities. However, it is unclear how these neurochemical events affect cognition, especially attention. We examined the effects of mild psychological stress on selective attention, as assessed by the negative priming (NP) paradigm. Salivary measures of the stress hormone CORT and alpha-amylase (a correlate of NE) were assayed to probe the relationship between the stress response and attentional inhibition. Healthy subjects (N = 20) engaged in the attention task, which was then followed by 15 min of a stressful video game before a return to the attentional task. Baseline saliva samples were obtained before the experiment began, 1 min after the video-game stressor, and 20 min post-stress. Subjects showed a significant reduction in NP and a decrease in reaction time (RT) after the video game. Moreover, alpha-amylase levels increased significantly after the stressor, indicating the role of NE in the acute stress response. While CORT levels remained unchanged after stress, CORT correlated significantly with both NP scores and RT after the stressor. These results imply that mild psychological stress can significantly alter attentional processes. Given the increase in alpha-amylase and the correlation between attention and CORT after stress, it seems likely that attentional processes are under tight control by brain systems which mediate the fight-or-flight response.

  11. Vardenafil inhibiting parasympathetic function of tracheal smooth muscle.

    Science.gov (United States)

    Lee, Fei-Peng; Chao, Pin-Zhir; Wang, Hsing-Won

    2018-07-01

    Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10 -6  M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10 -5  M or above elicited a significant relaxation response to 10 -6  M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle. Copyright © 2018. Published by Elsevier Taiwan LLC.

  12. Prejunctional inhibition of norepinephrine release caused by acetylcholine in the human saphenous vein

    International Nuclear Information System (INIS)

    Rorie, D.K.; Rusch, N.J.; Shepherd, J.T.; Vanhoutte, P.M.; Tyce, G.M.

    1981-01-01

    We performed experiments to determine whether or not acetylcholine exerts a prejunctional inhibitory effect on adrenergic neurotransmission in the human blood vessel wall. Rings of human greater saphenous veins were prepared 2 to 15 hours after death and mounted for isometric tension recording in organ chambers filled with Krebs-Ringer solution. Acetylcholine depressed contractile responses to electric activation of the sympathetic nerve endings significantly more than those to exogenous norepinephrine; the relaxations caused by the cholinergic transmitter were antagonized by atropine. Helical strips were incubated with [/sub 3/H]norepinephrine and mounted for superfusion. Electric stimulation augmented the fractional release of labeled norepinephrine. Acetylcholine caused a depression of the evoked /sub 3/H release which was antagonized by atropine but not by hexamethonium. These experiments demonstrate that, as in animal cutaneous veins, there are prejunctional inhibitory muscarinic receptors on the adrenergic nerve endings in the human saphenous vein. By contrast, the human vein also contains postjunctional inhibitory muscarinic receptors

  13. Cocaine inhibits extraneuronal O-methylation of exogenous norepinephrine in nasal and oral tissues of the rabbit

    International Nuclear Information System (INIS)

    de la Lande, I.S.; Parker, D.A.S.; Proctor, C.H.; Marino, V.; Mackay-Sim, A.

    1987-01-01

    Nasal mucosa (respirator and olfactory) and lingual gingiva of the rabbit were depleted of their sympathetic nerves by superior cervical ganglionectomy. In the innervated nasal mucosa, exogenous tritiated norepinephrine ( 3 H-NE) was metabolized mainly to tritiated 3,4-dihydroxyphenylethylene glycol ( 3 HDOPEG) and 3,4-dihydroxy mandelic acid ( 3 HDOMA), whereas after denervation it was metabolized mainly to tritiated normetanephrine ( 3 HNMN). In the denervated mucosa, cocaine(30umol/l) inhibited 3 HNMN formation by 50-60%. Cocaine also inhibited 3 HNMN formation by 60% in the denervated lingual gingiva. It is concluded that the tissues metabolize 3 H-NE via a cocaine-sensitive extraneuronal uptake and O-methylating system similar to that which has been shown to be present in dental pulp. 17 references, 1 table

  14. Norepinephrine-induced alteration in the coupling of α1-adrenergic receptor occupancy to calcium efflux in rabbit aortic smooth muscle cells

    International Nuclear Information System (INIS)

    Colucci, W.S.; Alexander, R.W.

    1986-01-01

    To determine whether α-adrenergic desensitization of vascular smooth muscle is due to an alteration in α 1 -adrenergic receptor coupling, the authors determined the relationship between receptor occupancy and maximal receptor-coupled Ca 2+ efflux in cultured rabbit aortic smooth muscle cells (i) under basal conditions as defined by receptor inactivation with phenoxybenzamine and (ii) after 48 hr of exposure to several concentrations of 1-norepinephrine (NE). Neither phenoxybenzamine nor NE exposure caused a change in binding affinity for [ 3 H]prazosin or NE. Maximal [ 3 H]prazosin binding capacity and maximal NE-stimulated 45 Ca 2+ efflux decreased progressively with exposure of incubated cells to increasing concentrations of phenoxybenzamine or NE. An approximately 80% decrease in maximal [ 3 H]prazosin binding capacity caused by either phenoxybenzamine or NE resulted in complete loss of NE-stimulated 45 Ca 2+ efflux, indicating that under these conditions approximately 20% of α 1 -adrenergic receptors are not coupled to the Ca 2+ efflux. Under basal conditions, the relationship between maximal [ 3 H]prazosin binding capacity and maximal NE-stimulated 45 Ca 2+ efflux was markedly nonlinear, so that a near maximal response could be elicited by occupancy of only approximately 40% of the receptors. Thus, an alteration in occupancy-response coupling at a step proximal to Ca 2+ mobilization and/or influx, rather than a reduction in receptor number, is of primary importance in the process of agonist-induced α-adrenergic receptor desensitization of vascular smooth muscle cells

  15. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    International Nuclear Information System (INIS)

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-01-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with 3 H-norepinephrine ( 3 H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals

  16. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    International Nuclear Information System (INIS)

    Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; Hart, Marieke van der; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

    2012-01-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  17. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    Energy Technology Data Exchange (ETDEWEB)

    Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Wisialowski, Todd A. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Cremers, Thomas; Hart, Marieke van der [Brains On-Line B.V., University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen (Netherlands); Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States)

    2012-11-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  18. Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

    Science.gov (United States)

    Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

    2010-01-01

    Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. PMID:20393461

  19. Alteration effect of the PGFsub(2α) inhibition on the 3H-norepinephrine release caused by α2 receptor blocking, sodium loading and 4-aminopyridine addition in isolated pulmonary arteries of rabbit

    International Nuclear Information System (INIS)

    Bunyevacs, Zs.; Toeroek, T.; Hadhazy, P.; Magyar, K.; Feher, L.; Vizi, E.Sz.

    1983-01-01

    The tritium labelled norepinephrine release was measured in isolated pulmonary artery of rabbit. If the 3 H-norepinephrine release was induced by nerves stimulated with electric current, the PGFsub(2α) inhibited the release by 62%. In the presence of Yohimbin the inhibitory effect of FGFsub(2α) was increased to 78.8%. If the Na + pump activity was reduced by potassium-free medium the PGFsub(2α) inhibition remained at 62%. In the presence of 4-aminopyridine the potassium channel was blocked and the PGFsub(2α) inhibition decreased to 32.1%. The endogen prostaglandin may serve as a modulator of the neurotransmitter release. (L.G.)

  20. SREBP inhibits VEGF expression in human smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Motoyama, Koka [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Fukumoto, Shinya [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Koyama, Hidenori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Emoto, Masanori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Shimano, Hitoshi [Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki (Japan); Maemura, Koji [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo (Japan); Nishizawa, Yoshiki [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan)

    2006-03-31

    Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs.

  1. SREBP inhibits VEGF expression in human smooth muscle cells

    International Nuclear Information System (INIS)

    Motoyama, Koka; Fukumoto, Shinya; Koyama, Hidenori; Emoto, Masanori; Shimano, Hitoshi; Maemura, Koji; Nishizawa, Yoshiki

    2006-01-01

    Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs

  2. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

    Science.gov (United States)

    Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

    2008-01-02

    Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

  3. Role of calcium in phosphoinositide metabolism and inhibition of norepinephrine transport into synaptic vesicles by amphetamine analogs

    International Nuclear Information System (INIS)

    Knepper, S.M.

    1985-01-01

    Norepinephrine-(NE) and calcium ionophore A23187-stimulated phosphoinositide (PIn) metabolism in rat brain slices was studied under varying calcium conditions. Tissue was labelled with 3 H-myo-inositol and 3 H-inositol phosphates (IPn), products of PIn metabolism were measured. In the absence of media calcium the response to NE was decreased while that to A23187 was little affected A23187 can release calcium from intracellular stores. Basal and stimulated accumulation of 3 H-IPn was reversibly antagonized with EGTA by addition of calcium. Using calcium buffers, approximately 10 -7 M free calcium was required to support hydrolysis. Free intracellular calcium is maintained at approximately this level. Thus calcium is required for PIn hydrolysis but appears to play a permissive role, basal levels being sufficient to support metabolism. Conformationally-defined (rigid) and -restricted (semi-rigid) analogs of the most stable conformations of amphetamine, antiperiplanar (exo) and gauche (endo), were utilized to probe the conformational requirements of vesicular NE transport. Analogs tested were 2-aminotetralin (2AT), 3-methyltetrahydroisoquinoline, anti- and syn-9-aminobenzobicyclo[2.2.1]heptene, and endo and exo conformers of 2-aminobenzobicyclo[2.2.1]heptene and 2-aminobenzobicyclo[2.2.2]octene

  4. Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.

    Science.gov (United States)

    Kielbasa, William; Lobo, Evelyn

    2015-12-01

    Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker. © 2015, The American College of Clinical Pharmacology.

  5. A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

    Science.gov (United States)

    Kielbasa, William; Pan, Alan; Pereira, Alvaro

    2015-03-01

    Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  6. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    International Nuclear Information System (INIS)

    Karki, Rajendra; Kim, Seong-Bin; Kim, Dong-Wook

    2013-01-01

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  7. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    Energy Technology Data Exchange (ETDEWEB)

    Karki, Rajendra [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City (United States); Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of); Kim, Seong-Bin [Jeollanamdo Development Institute for Korean Traditional Medicine, Jangheung gun, Jeollanamdo (Korea, Republic of); Kim, Dong-Wook, E-mail: dbkim@mokpo.ac.kr [Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of)

    2013-12-10

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  8. Efeito da ropivacaína na recaptação neuronal de noradrenalina em músculo liso Efecto de la ropivacaína en la recaptación neuronal de noradrenalina en un músculo liso Effect of ropivacaine on neuronal norepinephrine reuptake in smooth muscle

    Directory of Open Access Journals (Sweden)

    Carlos Alberto de Souza Martins

    2005-10-01

    ón-efecto de noradrenalina en la ausencia o en la presencia de la ropivacaína. En otra serie de experimentos los ratones fueron tratados con reserpina (10 mg.kg-1, por la via intraperitoneal para evaluar la reactividad de los conductos deferentes a la tiramina o noradrenalina, en la ausencia o presencia de la ropivacaína. RESULTADOS: La ropivacaína en las concentraciones de 5 ó 10 µg.mL-1 potenció el efecto máximo (Emax de la noradrenalina en un 47% y 35%, respectivamente, mientras que en las concentraciones de 50 ó 100 µg.mL-1 inhibió el efecto máximo producido por este agonista. En conductos deferentes separados de ratones reserpinizados, la ropivacaína (10 ó 20 µg.mL-1 potenció (150% y 25%, respectivamente las contracciones inducidas por la noradrenalina, mientras que las concentraciones de 50 ó 100 µg.mL-1 no alteraron las respuestas a la noradrenalina. CONCLUSIONES: Los resultados logrados permiten concluir que la ropivacaína bloquea la recaptación neuronal de noradrenalina por los terminales nerviosos simpáticos.BACKGROUND AND OBJECTIVES: In addition to local anesthetic action, ropivacaine has clinically significant vasoconstrictor effects, which may be observed at infiltrative anesthesia, making it an important anesthetic for field blockade. This study aimed at characterizing the constrictor mechanism of ropivacaine on smooth muscles. METHODS: Norepinephrine concentration-effect curves in the absence or presence of ropivacaine were plotted on isolated preparations of vas deferens of rats. In another series of experiments rats were treated with reserpine (10 mg.kg-1, i.p. to evaluate vas deferens reactivity to tyramine or norepinephrine, in the absence or presence of ropivacaine. RESULTS: Ropivacaine 5 or 10 µg.mL-1 potentiated maximum norepinephrine effect (Emax in 47% and 35%, respectively, while higher concentrations (50 or 100 µg.mL-1 inhibited its maximum effect. In isolated vas deferens of rats treated with reserpine, ropivacaine (10 or 20 µg

  9. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition.

    Science.gov (United States)

    Findeisen, Hannes M; Gizard, Florence; Zhao, Yue; Qing, Hua; Heywood, Elizabeth B; Jones, Karrie L; Cohn, Dianne; Bruemmer, Dennis

    2011-04-01

    Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive. In the present study, we investigated the role of histone deacetylase (HDAC) inhibition in SMC proliferation and neointimal remodeling. We demonstrate that mitogens induce transcription of HDAC 1, 2, and 3 in SMC. Short interfering RNA-mediated knockdown of either HDAC 1, 2, or 3 and pharmacological inhibition of HDAC prevented mitogen-induced SMC proliferation. The mechanisms underlying this reduction of SMC proliferation by HDAC inhibition involve a growth arrest in the G(1) phase of the cell cycle that is due to an inhibition of retinoblastoma protein phosphorylation. HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). Furthermore, HDAC inhibition repressed mitogen-induced cyclin D1 mRNA expression and cyclin D1 promoter activity. As a result of this differential cell cycle-regulatory gene expression by HDAC inhibition, the retinoblastoma protein retains a transcriptional repression of its downstream target genes required for S phase entry. Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury. These findings identify HDAC as a critical component of a transcriptional cascade regulating SMC proliferation and suggest that HDAC might play a pivotal role in the development of proliferative vascular diseases, including atherosclerosis and in-stent restenosis.

  10. Structure activity correlations in the inhibition of brain synaptosomal 3H-norepinephrine uptake by phenethylamine analogs. The role of α-alkyl side chain and methoxyl ring substitutions

    International Nuclear Information System (INIS)

    Makriyannis, A.; Bowerman, D.; Sze, P.Y.; Fournier, D.; Jong, A.P. de

    1982-01-01

    α-Ethylphenethylamine proved to be a weaker inhibitor of rat brain synaptosomal [ 3 H]norepinephrine ([ 3 H]NE) uptake than amphetamine, while 2-amino-tetralin and 2-amino-1,2-dihydronaphtalene, compounds in which the α-side chain ethyl group is tied to the aromatic ring have a similar inhibiting potency as amphetamine. Hallucinogenic polymethoxy substituted phenethylamine analogs have very low inhibitory potencies indicating that inhibition of NE-reuptake in brain noradrenergic neurons is not associated with the drug-induced hallucinogenic syndrome. (Auth.)

  11. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

    Directory of Open Access Journals (Sweden)

    Jun Aono, MD, PhD

    2016-01-01

    Full Text Available Proliferation of smooth muscle cells (SMCs during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT, indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.

  12. Inhibition of NF-κB activity in rabbit vascular smooth muscle cells by lovastatin

    International Nuclear Information System (INIS)

    Luan Zhaoxia; Lan Xiaoli

    2003-01-01

    Nuclear factor NF-κB is believed to play an important role in regulating the production of matrix metalloproteinase (MMPs), which induce atherosclerosis, restenosis and plaque rupture. We incubated rabbit vascular smooth muscle cells (RVSMCs) with 5 μmol/L lovastatin in the presence of IL-1-α and PDGF BB (20 μg/L, respectively) to study whether lovastatin inhibited NF-κB binding activity induced by IL-1 and PDGF. The NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); MMP-1 and MMP-3 were measured by western blotting; and MMP-9 was detected by zymography. The result showed that lovastatin strongly reduced NF-κB activity upregulated by IL-1 combined with PDGF, and lovastatin also dose-dependently inhibited the expression of MMP-1, -3 and -9 induced by IL-1 and PDGF. It suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction

  13. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.

    Science.gov (United States)

    Kimura, Tomomi E; Duggirala, Aparna; Smith, Madeleine C; White, Stephen; Sala-Newby, Graciela B; Newby, Andrew C; Bond, Mark

    2016-01-01

    Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Influence of calcium-dependent potassium channel blockade and nitric oxide inhibition on norepinephrine-induced contractions in two forms of genetic hypertension

    Czech Academy of Sciences Publication Activity Database

    Líšková, Silvia; Petrová, M.; Karen, Petr; Kuneš, Jaroslav; Zicha, Josef

    2010-01-01

    Roč. 4, č. 3 (2010), s. 128-134 ISSN 1933-1711 R&D Projects: GA AV ČR(CZ) IAA500110902 Institutional research plan: CEZ:AV0Z50110509 Keywords : potassium channels * nitric oxide * norepinephrine Subject RIV: ED - Physiology Impact factor: 0.931, year: 2010

  15. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.

    Science.gov (United States)

    Aono, Jun; Ruiz-Rodriguez, Ernesto; Qing, Hua; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-01-01

    The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC

  16. Inhibition of human arterial smooth muscle (HASM) cell proliferation and collagen synthesis by protamine

    International Nuclear Information System (INIS)

    Drucker, D.E.; Graham, M.F.; Diegelmann, R.F.; Greenfield, L.J.

    1986-01-01

    Atherosclerotic plaques result from vascular smooth muscle cell proliferation and collagen deposition. The authors have been studying factors which modulate HASM cell proliferation and collagen synthesis. HASM cells were isolated from the media of normal human thoracic and infrarenal aortas and grown in vitro. Cell numbers were determined by direct counting and collagen synthesis was measured by incorporation of 3 H-proline into collagenase-digestible protein. In this study, protamine (200 μg/ml) was tested and found to cause a 55% reduction of HASM cell proliferation which was reversible when the cells were returned to control medium or when heparin (100 μg/ml) was added with protamine. Protamine caused a constant 33% decrease in non-collagen protein (NCP) synthesis per cell. In contrast, collagen synthesis was inhibited in dose dependent fashion (88% reduction at 200 μg/ml). Protamine blocks HASM cell proliferation and specifically inhibits collagen production. The exact mechanism of this inhibition is unclear but may be related to a transcriptional event since protamine has a high affinity for DNA

  17. Stoichiometry of Na/Ca antiport obtained by magnesium inhibition in cultured vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Smith, J.B.; Higgins, B.L.; Smith, L.

    1987-01-01

    Cultured smooth muscle cells from rat aorta were loaded with Na, and Na/Ca antiport was assayed by measuring the initial rates of 45 Ca influx and 22 Na efflux. The replacement of extracellular Na with other monovalent ions, usually N-methyl-D-glucamine (NMG), was essential for obtaining significant antiport activity. Mg competitively inhibited 45 Ca influx via the antiporter (Ki = 100 uM). External Ca stimulated 22 Na efflux as expected for antiport activity. Mg did not stimulate 22 Na efflux indicating that Mg is not transported by the antiporter. Mg inhibited Ca-stimulated 22 Na efflux as expected from the 45 Ca influx data. The stoichiometry of the antiporter was calculated from the changes in the rates of 45 Ca influx and 22 Na efflux at 3 Mg concentrations: 2.87 +/- 0.25 (mean +/- SE, n=5). The replacement of external NMG with potassium, but not other monovalent ions (choline, Li), decreased the potency of Mg as an inhibitor of Na/Ca antiport by about 6 fold. Other divalent cations (Co, Mn, Cd, Ba) inhibited Na/Ca antiport and high external potassium decreased the potency of each by about 6 fold. The order of effectiveness of the divalent cations as inhibitors of Na/Ca antiport (Cd>Mn>Co>Ba>Mg) correlated with the crystal ionic radius of the cation

  18. Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

    Energy Technology Data Exchange (ETDEWEB)

    Son, Dong Ju [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Kim, Soo Yeon [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Han, Seong Su [University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA (United States); Kim, Chan Woo [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Department of Bioinspired Science, Ehwa Womans University, Seoul (Korea, Republic of); Kumar, Sandeep [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Park, Byeoung Soo [Nanotoxtech Co., Ansan (Korea, Republic of); Lee, Sung Eun [Division of Applied Biology and Chemistry, Kyungpook National University, Daegu (Korea, Republic of); Yun, Yeo Pyo [College of Pharmacy, Chungbuk National University, Cheongju (Korea, Republic of); Jo, Hanjoong, E-mail: hjo@emory.edu [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Department of Bioinspired Science, Ehwa Womans University, Seoul (Korea, Republic of); Park, Young Hyun, E-mail: pyh012@sch.ac.kr [Department of Food Science and Nutrition, College of Natural Sciences, Soonchunhyang University, Asan (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Anti-atherogenic effect of PL was examined using partial carotid ligation model in ApoE KO mice. Black-Right-Pointing-Pointer PL prevented atherosclerotic plaque development, VSMCs proliferation, and NF-{kappa}B activation. Black-Right-Pointing-Pointer Piperlongumine reduced vascular smooth muscle cell activation through PDGF-R{beta} and NF-{kappa}B-signaling. Black-Right-Pointing-Pointer PL may serve as a new therapeutic molecule for atherosclerosis treatment. -- Abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-{kappa}B) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C{gamma}1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-{kappa}B-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.

  19. Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping, E-mail: wpxie@njmu.edu.cn; Wang, Hong, E-mail: hongwang@njmu.edu.cn

    2015-08-15

    Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation and migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that Ipt

  20. Protocatechuic aldehyde inhibits migration and proliferation of vascular smooth muscle cells and intravascular thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Chang Yoon [The Hotchkiss School, Lakeville, CT (United States); Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, and Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University College of Medicine, Seoul (Korea, Republic of); Ku, Cheol Ryong [Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, and Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cho, Yoon Hee, E-mail: wooriminji@gmail.com [Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, and Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lee, Eun Jig, E-mail: ejlee423@yuhs.ac [Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, and Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University College of Medicine, Seoul (Korea, Republic of); Endocrinology, Northwestern University Feinberg School of Medicine, Chicago, IL (United States)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer Protocatechuic aldehyde (PCA) inhibits ROS production in VSMCs. Black-Right-Pointing-Pointer PCA inhibits proliferation and migration in PDGF-induced VSMCs. Black-Right-Pointing-Pointer PCA has anti-platelet effects in ex vivo rat whole blood. Black-Right-Pointing-Pointer We report the potential therapeutic role of PCA in atherosclerosis. -- Abstract: The migration and proliferation of vascular smooth muscle cells (VSMCs) and formation of intravascular thrombosis play crucial roles in the development of atherosclerotic lesions. This study examined the effects of protocatechuic aldehyde (PCA), a compound isolated from the aqueous extract of the root of Salvia miltiorrhiza, an herb used in traditional Chinese medicine to treat a variety of vascular diseases, on the migration and proliferation of VSMCs and platelets due to platelet-derived growth factor (PDGF). DNA 5-bromo-2 Prime -deoxy-uridine (BrdU) incorporation and wound-healing assays indicated that PCA significantly attenuated PDGF-induced proliferation and migration of VSMCs at a pharmacologically relevant concentration (100 {mu}M). On a molecular level, we observed down-regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathways, both of which regulate key enzymes associated with migration and proliferation. We also found that PCA induced S-phase arrest of the VSMC cell cycle and suppressed cyclin D2 expression. In addition, PCA inhibited PDGF-BB-stimulated reactive oxygen species production in VSMCs, indicating that PCA's antioxidant properties may contribute to its suppression of PDGF-induced migration and proliferation in VSMCs. Finally, PCA exhibited an anti-thrombotic effect related to its inhibition of platelet aggregation, confirmed with an aggregometer. Together, these findings suggest a potential therapeutic role of PCA in the treatment of atherosclerosis and angioplasty-induced vascular restenosis.

  1. PPARγ ligand ciglitazone inhibits TNFα-induced ICAM-1 in human airway smooth muscle cells

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    Chien-Da Huang

    2014-08-01

    Full Text Available Background: Modification of human airway smooth muscle (ASM function by proinflammatory cytokines has been regarded as a potential mechanism underlying bronchial hyperresponsiveness in asthma. Human ASM cells express intercellular adhesion molecule (ICAM-1 in response to cytokines. Synthetic ligands for peroxisome proliferator-activated receptor (PPARγ reportedly possess anti-inflammatory and immunomodulatory properties. In this study, we examined whether ciglitazone, a synthetic PPARγ ligand, can modulate the basal and tumor necrosis factor (TNFα-induced ICAM1 gene expression in human ASM cells. Methods: Human ASM cells were treated with TNFα. ICAM-1 expression was assessed by flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR analysis. PPARγ activity was inhibited by target-specific small interfering (si RNA targeting PPARγ and GW9662, a PPARγ antagonist. Activity of nuclear factor (NF-κB was assessed by using immunoblot analysis, immune-confocal images, and electrophoretic mobility shift assay (EMSA. Results: By flow cytometry, ciglitazone alone had no effect on ICAM-1 expression in ASM cells, but inhibited ICAM-1 expression in response to TNFα (10 ng/ml in a dose-dependent manner (1-10 μM. It also inhibited TNFα-induced ICAM1 gene expression by RT-PCR analysis. Knockdown of PPARγ gene by target-specific siRNA targeting PPARγ enhanced ICAM-1 expression and the inhibitory effect of ciglitazone on TNFα-induced ICAM-1 expression was reversed by PPARγ siRNA and GW9662. SN-50 (10 μg/ml, an inhibitor for nuclear translocation of NF-κB, inhibited TNFα-induced ICAM-1 expression. Ciglitazone did not prevent TNFα-induced degradation of the cytosolic inhibitor of NF-κB (IκB, but inhibited the nuclear translocation of p65 induced by TNFα and suppressed the NF-κB/DNA binding activity. Conclusion: These findings suggest that ciglitazone inhibits TNFα-induced ICAM1 gene expression in human ASM cells through

  2. Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Jie Su

    2015-01-01

    Full Text Available Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II- induced proliferation and migration of vascular smooth muscle cells (VSMCs. Dichlorofluorescein diacetate (DCFH-DA staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS.

  3. Triptolide inhibits TGF-β1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ming; Lv, Zhiqiang; Huang, Linjie [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China); Zhang, Wei [Department of Geratology, the Second People' s Hospital of Shenzhen, Shenzhen 518000 (China); Lin, Xiaoling; Shi, Jianting; Zhang, Wei; Liang, Ruiyun [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China); Jiang, Shanping, E-mail: shanpingjiang@126.com [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China)

    2015-02-15

    Background: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-β1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. Methods: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-β1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. Results: Triptolide significantly inhibited TGF-β1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-β1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. Conclusions: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway. - Highlights: • In this study, rat airway smooth muscle cells were cultured and made synchronized. • Triptolide inhibited TGF-β1-induced airway smooth muscle cells proliferation. • Triptolide inhibited ASMCs proliferation via negative regulation of Smad signaling pathway.

  4. Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-01-01

    Highlights: ► PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. ► Metformin suppressed TNF-α-induced COX-2 and iNOS mRNA expression. ► Compound C and bpv (pic) increased iNOS and COX-2 protein expression. ► NF-κB activation was restored by inhibiting AMPK and PTEN. ► AMPK and PTEN regulated TNF-α-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK–PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the

  5. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  6. Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation.

    Science.gov (United States)

    Ambhore, Nilesh Sudhakar; Katragadda, Rathnavali; Raju Kalidhindi, Rama Satyanarayana; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S; Sathish, Venkatachalem

    2018-04-20

    Airway smooth muscle (ASM) cell hyperplasia driven by persistent inflammation is a hallmark feature of remodeling in asthma. Sex steroid signaling in the lungs is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men. Our previous studies demonstrated that estrogen receptor (ER) expression increases in asthmatic human ASM; however, very limited data are available regarding differential roles of ERα vs. ERβ isoforms in human ASM cell proliferation. In this study, we evaluated the effect of selective ERα and ERβ modulators on platelet-derived growth factor (PDGF)-stimulated ASM proliferation and the mechanisms involved. Asthmatic and non-asthmatic primary human ASM cells were treated with PDGF, 17β-estradiol, ERα-agonist and/or ERβ-agonist and/or G-protein-coupled estrogen receptor 30 (GPR30/GPER) agonist and proliferation was measured using MTT and CyQuant assays followed by cell cycle analysis. Transfection of small interfering RNA (siRNA) ERα and ERβ significantly altered the human ASM proliferation. The specificity of siRNA transfection was confirmed by Western blot analysis. Gene and protein expression of cell cycle-related antigens (PCNA and Ki67) and C/EBP were measured by RT-PCR and Western analysis, along with cell signaling proteins. PDGF significantly increased ASM proliferation in non-asthmatic and asthmatic cells. Treatment with PPT showed no significant effect on PDGF-induced proliferation, whereas WAY interestingly suppressed proliferation via inhibition of ERK1/2, Akt, and p38 signaling. PDGF-induced gene expression of PCNA, Ki67 and C/EBP in human ASM was significantly lower in cells pre-treated with WAY. Furthermore, WAY also inhibited PDGF-activated PCNA, C/EBP, cyclin-D1, and cyclin-E. Overall, we demonstrate ER isoform-specific signaling in the context of ASM proliferation. Activation of ERβ can diminish remodeling in human ASM by inhibiting pro-proliferative signaling pathways

  7. Kaempferol inhibits vascular smooth muscle cell migration by modulating BMP-mediated miR-21 expression.

    Science.gov (United States)

    Kim, Kwangho; Kim, Sunghwan; Moh, Sang Hyun; Kang, Hara

    2015-09-01

    Bioflavonoids are known to induce cardioprotective effects by inhibiting vascular smooth muscle cell (VSMC) proliferation and migration. Kaempferol has been shown to inhibit VSMC proliferation. However, little is known about the effect of kaempferol on VSMC migration and the underlying molecular mechanisms. Our studies provide the first evidence that kaempferol inhibits VSMC migration by modulating the BMP4 signaling pathway and microRNA expression levels. Kaempferol activates the BMP signaling pathway, induces miR-21 expression and downregulates DOCK4, 5, and 7, leading to inhibition of cell migration. Moreover, kaempferol antagonizes the PDGF-mediated pro-migratory effect. Therefore, our study uncovers a novel regulatory mechanism of VSMC migration by kaempferol and suggests that miRNA modulation by kaempferol is a potential therapy for cardiovascular diseases.

  8. External beam irradiation inhibits neointimal hyperplasia after injury-induced arterial smooth muscle cell proliferation

    International Nuclear Information System (INIS)

    Schaefer, U.; Micke, O.; Dorszewski, A.; Breithardt, G.; Willich, N.

    1996-01-01

    Purpose/Objective: Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by smooth muscle cell proliferation. This study examines the effects of external beam irradiation on neointimal proliferation after external injury to the central artery of the rabbit ear. Materials and Methods: 30 male New Zealand White rabbits were used in this study. Crush lesions were performed on each ear under general anesthesia and bilateral auricular nerve blockade. A single dose of 12 Gy (n=10), 16 Gy (n=10), or 20 Gy (n=10) gamma radiation was delivered to the left or right central artery of the ear 24 hours after injury; the contralateral central artery served as control. All rabbits were sacrificed after twenty-one days and the central arteries of the ear were fixed for morphometric measurements. Results: Mean (± SD) neointimal area was 0.062 ± 0.005 mm 2 (12 Gy), 0.022 ± 0.005 mm 2 (16 Gy) and 0.028 ± 0.006 mm 2 in irradiated arteries compared with 0.081 ± 0.009 mm 2 in the control group. Mean (± SD) luminal area was 0.049 ± 0.004 mm 2 (12 Gy), 0.059 ± 0.002 mm 2 (16 Gy) and 0.072 ± 0.006 mm 2 (24 Gy) in irradiated arteries compared with 0.043 ± 0.008 mm 2 in the control group. The difference in neointimal and luminal area between control and irradiated arteries was significant (p<0.05) only for the 16 and 20 Gy group compared to control. Conclusion: We conclude that in this model, external beam X-ray irradiation was successful in reducing neointimal proliferation after injury of the central artery of the rabbit ear. Marked reductions in neointimal proliferation were demonstrated in vessels subjected to 16 and 20 Gy radiation, a less prominent effect was noted for 12 Gy. Whether this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation

  9. Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

    International Nuclear Information System (INIS)

    Pei, Qing-Mei; Jiang, Ping; Yang, Min; Qian, Xue-Jiao; Liu, Jiang-Bo; Kim, Sung-Ho

    2016-01-01

    Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

  10. Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Pei, Qing-Mei, E-mail: 34713316@qq.com [Department of Radiology, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin (China); Jiang, Ping, E-mail: jiangping@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Yang, Min, E-mail: YangMin@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Qian, Xue-Jiao, E-mail: qianxuejiao@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Liu, Jiang-Bo, E-mail: LJB1984@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Kim, Sung-Ho, E-mail: chenghao0726@hotmail.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China)

    2016-10-01

    Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

  11. Inhibition of MAPK and PKC pathways by 60Co γ-radiation in cultured vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Jia Guanghong; Ma Yexin; Xiao Jianming

    2002-01-01

    Objective: To investigate the signal transduction pathways inhibited by 60 Co γ-radiation in cultured vascular smooth muscle cells (VSMC). Methods: The cultured VSMC were irradiated with 60 Co γ-radiation of 3.5, 7.0 and 14 Gy respectively. VSMC proliferation was measured by 3 H-TdR incorporation, while PKC, MAPK activities were determined by radioactivity assay. Results: Proliferation of VSMC was inhibited by 7.0, 14 Gy 60 Co γ-irradiation and the activities of PKC, MAPK were decreased significantly. Conclusion: Inhibitory effect of 7.0, 14 Gy 60 Co γ-irradiation on proliferation of VSMC might be resulted from decrease of the activity of PKC, MAPK

  12. Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.

    Science.gov (United States)

    Hayashi, Ken'ichiro; Nakamura, Seiji; Nishida, Wataru; Sobue, Kenji

    2006-12-01

    During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.

  13. Bone Morphogenetic Protein-Induced Msx1 and Msx2 Inhibit Myocardin-Dependent Smooth Muscle Gene Transcription▿

    Science.gov (United States)

    Hayashi, Ken'ichiro; Nakamura, Seiji; Nishida, Wataru; Sobue, Kenji

    2006-01-01

    During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22α and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription. PMID:17030628

  14. α-Trinositol inhibits FGF-stimulated growth of smooth muscle and breast cancer cells

    International Nuclear Information System (INIS)

    Siren, Matti J.; Vainiomaeki, Maija; Vaeaenaenen, Kalervo; Haerkoenen, Pirkko

    2004-01-01

    α-Trinositol (D-myo-inositol-1,2,6-trisphosphate), an isomer of the intracellular messenger IP 3 , has been studied for its anti-inflammatory and other effects in animal experiments and in human. The mechanisms of action remain unknown. Several human pathologies are associated with uncontrolled production of fibroblast growth factors (FGFs). FGF-2 induces vascular smooth muscle cell proliferation, which contributes to restenosis after coronary balloon angioplasty. The expression of several FGFs is also increased in tumors. We studied the effects of the water- and lipid-soluble derivatives of α-trinositol on the FGF-2- and/or FGF-8-induced proliferation of human pulmonary artery smooth muscle cells (HPASMC) and S115 mouse breast cancer cells. α-Trinositol decreased the FGF-mediated proliferation of HPASMC and S115 cells. Membrane permeability did not seem obligatory since the lipid-soluble form of α-trinositol was less effective than the water-soluble derivative. These results suggest a new biological function for certain phosphoinositides in the modulation of FGF-regulated processes

  15. 3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury.

    Directory of Open Access Journals (Sweden)

    Hongjing Guan

    Full Text Available 3,3'Diindolylmethane (DIM, a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.DIM dose-dependently inhibited the platelet-derived growth factor (PDGF-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK 4/6 as well as an increase in p27(Kip1 levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptorβ (PDGF-Rβ and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK3β, extracellular signal-regulated kinase1/2 (ERK1/2, and signal transducers and activators of transcription 3 (STAT3. Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.These results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-Rβ and the

  16. K-252a, a novel microbial product, inhibits smooth muscle myosin light chain kinase

    International Nuclear Information System (INIS)

    Nakanishi, S.; Yamada, K.; Kase, H.; Nakamura, S.; Nonomura, Y.

    1988-01-01

    Effects of K-252a, purified from the culture broth of Nocardiopsis sp., on the activity of myosin (light chain kinase were investigated. 1) K-252a affected three characteristic properties of chicken gizzard myosin-B, natural actomyosin, to a similar degree: the Ca 2+ -dependent activity of ATPase, superprecipitation, and the phosphorylation of the myosin light chain. 2) K-252a inhibited the activities of the purified myosin light chain kinase and a Ca 2+ -independent form of the enzyme which was constructed by cross-linking of myosin light chain kinase and calmodulin using glutaraldehyde. The degrees of inhibition by 3 x 10 -6 M K-252a were 69 and 48% of the control activities with the purified enzyme and the cross-linked complex, respectively. Chlorpromazine (3 x 10 -4 M), a calmodulin antagonist, inhibited the native enzyme, but not the cross-linked one. These results suggested that K-252a inhibited myosin light chain kinase by direct interaction with the enzyme, whereas chlorpromazine suppressed the enzyme activation by interacting with calmodulin. 3) The inhibition by K-252a of the cross-linked kinase was affected by the concentration of ATP, a phosphate donor. The concentration causing 50% inhibition was two orders magnitude lowere in the presence of 100 μM ATP than in the presence of 2 mM ATP. 4) Kinetic analyses using [γ- 32 P]ATP indicated that the inhibitory mode of K-252a was competitive with respect to ATP. These results suggest that K-252a interacts at the ATP-binding domain of myosin light chain kinase

  17. Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia.

    Science.gov (United States)

    Tuan, Nguyen Quoc; Lee, Do-Hyung; Oh, Joonseok; Kim, Chung Sub; Heo, Kyung-Sun; Myung, Chang-Seon; Na, MinKyun

    2017-07-28

    The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M.  charantia, utilizing diverse chromatographic and spectroscopic techniques. In particular, the 2D structure of 1 was confirmed utilizing the long-range HSQMBC NMR pulse, capable of measuring heteronuclear long-range correlations ( 4-6 J CH ). The cucurbitanes were also assessed for their inhibitory activity against PDGF-induced VSMC proliferation. This current study may constitute a basis for developing those chemotypes into sensible pharmacophores alleviating cardiovascular disorders.

  18. Inhibition of vascular smooth muscle cell proliferation by Gentiana lutea root extracts.

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    Rushendhiran Kesavan

    Full Text Available Gentiana lutea belonging to the Gentianaceae family of flowering plants are routinely used in traditional Serbian medicine for their beneficial gastro-intestinal and anti-inflammatory properties. The aim of the study was to determine whether aqueous root extracts of Gentiana lutea consisting of gentiopicroside, gentisin, bellidifolin-8-O-glucoside, demethylbellidifolin-8-O-glucoside, isovitexin, swertiamarin and amarogentin prevents proliferation of aortic smooth muscle cells in response to PDGF-BB. Cell proliferation and cell cycle analysis were performed based on alamar blue assay and propidium iodide labeling respectively. In primary cultures of rat aortic smooth muscle cells (RASMCs, PDGF-BB (20 ng/ml induced a two-fold increase in cell proliferation which was significantly blocked by the root extract (1 mg/ml. The root extract also prevented the S-phase entry of synchronized cells in response to PDGF. Furthermore, PDGF-BB induced ERK1/2 activation and consequent increase in cellular nitric oxide (NO levels were also blocked by the extract. These effects of extract were due to blockade of PDGF-BB induced expression of iNOS, cyclin D1 and proliferating cell nuclear antigen (PCNA. Docking analysis of the extract components on MEK1, the upstream ERK1/2 activating kinase using AutoDock4, indicated a likely binding of isovitexin to the inhibitor binding site of MEK1. Experiments performed with purified isovitexin demonstrated that it successfully blocks PDGF-induced ERK1/2 activation and proliferation of RASMCs in cell culture. Thus, Gentiana lutea can provide novel candidates for prevention and treatment of atherosclerosis.

  19. Inhibition of vascular smooth muscle cell proliferation by Gentiana lutea root extracts.

    Science.gov (United States)

    Kesavan, Rushendhiran; Potunuru, Uma Rani; Nastasijević, Branislav; T, Avaneesh; Joksić, Gordana; Dixit, Madhulika

    2013-01-01

    Gentiana lutea belonging to the Gentianaceae family of flowering plants are routinely used in traditional Serbian medicine for their beneficial gastro-intestinal and anti-inflammatory properties. The aim of the study was to determine whether aqueous root extracts of Gentiana lutea consisting of gentiopicroside, gentisin, bellidifolin-8-O-glucoside, demethylbellidifolin-8-O-glucoside, isovitexin, swertiamarin and amarogentin prevents proliferation of aortic smooth muscle cells in response to PDGF-BB. Cell proliferation and cell cycle analysis were performed based on alamar blue assay and propidium iodide labeling respectively. In primary cultures of rat aortic smooth muscle cells (RASMCs), PDGF-BB (20 ng/ml) induced a two-fold increase in cell proliferation which was significantly blocked by the root extract (1 mg/ml). The root extract also prevented the S-phase entry of synchronized cells in response to PDGF. Furthermore, PDGF-BB induced ERK1/2 activation and consequent increase in cellular nitric oxide (NO) levels were also blocked by the extract. These effects of extract were due to blockade of PDGF-BB induced expression of iNOS, cyclin D1 and proliferating cell nuclear antigen (PCNA). Docking analysis of the extract components on MEK1, the upstream ERK1/2 activating kinase using AutoDock4, indicated a likely binding of isovitexin to the inhibitor binding site of MEK1. Experiments performed with purified isovitexin demonstrated that it successfully blocks PDGF-induced ERK1/2 activation and proliferation of RASMCs in cell culture. Thus, Gentiana lutea can provide novel candidates for prevention and treatment of atherosclerosis.

  20. Inhaled corticosteroids inhibit substance P receptor expression in asthmatic rat airway smooth muscle cells

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    Li Miao

    2012-12-01

    Full Text Available Abstract Background Neurokinins (NKs participate in asthmatic airway inflammation, but the effects of NKs on airway smooth muscle cells (ASMCs and those of corticosteroids on NKs are unknown. Methods To investigate the effect of budesonide on substance P (NK-1 receptor (NK-1R expression in the lung and ASMCs, 45 Wistar rats were randomly divided into three groups: control, asthmatic, and budesonide treatment. Aerosolized ovalbumin was used to generate the asthmatic rat model, and budesonide was administered after ovalbumin inhalation. On day 21, bronchial responsiveness tests, bronchoalveolar lavage, and cell counting were conducted. NK-1R protein expression in the lung was investigated by immunohistochemistry and image analysis. Primary rat ASMC cultures were established, and purified ASMCs of the fourth passage were collected for mRNA and protein studies via real-time RT-PCR, immunocytochemistry, and image analysis. Results NK-1R mRNA and protein expression in the budesonide treatment group rat’s lung and ASMCs were less than that in the asthmatic group but greater than that in the control group. Conclusions NK-1R is involved in the pathogenesis of asthma and that budesonide may downregulate the expression of NK-1R in the ASMCs and airways of asthmatic rats, which may alleviate neurogenic airway inflammation.

  1. The flavonoid quercetin induces apoptosis and inhibits JNK activation in intimal vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Perez-Vizcaino, Francisco; Bishop-Bailley, David; Lodi, Federica; Duarte, Juan; Cogolludo, Angel; Moreno, Laura; Bosca, Lisardo; Mitchell, Jane A.; Warner, Timothy D.

    2006-01-01

    Quercetin, the most abundant dietary flavonol, exerts vasodilator, anti-hypertensive, and anti-atherogenic effects and reduces the vascular remodelling associated with elevated blood pressure. Here, we have compared the effects of quercetin in intimal- and medial-type rat vascular smooth muscle cells (VSMC) in culture. After 48 h, quercetin reduced the viability of a polyclonal intimal-type cell line derived from neonatal aorta but not of a medial-type cell line derived from adult aorta. These differential effects were similar in both proliferating and quiescent VSMC. Quercetin also preferentially reduced the viability of intimal-type over medial-type VSMC in primary cultures derived from balloon-injured carotid arteries. The effects of quercetin on cell viability were mainly dependent upon induction of apoptosis, as demonstrated by nuclear condensation and fragmentation, and were unrelated to PPARγ, pro-oxidant effects or nitric oxide. The expression of MAPKs (ERK, p38, and JNK) and ERK phosphorylation were not different between intimal- and medial-type VSMC. p38 phosphorylation was negligible in both cell types. Medial-type showed a weak JNK phosphorylation while this was markedly increased in intimal-type cells. Quercetin reduced JNK phosphorylation but had no consistent effect on ERK phosphorylation. In conclusion, quercetin preferentially produced apoptosis in intimal-type compared to medial-type VSMC. This might play a role in the anti-atherogenic and anti-hypertensive effects of quercetin

  2. Vitisin B, a resveratrol tetramer, inhibits migration through inhibition of PDGF signaling and enhancement of cell adhesiveness in cultured vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Ong, Eng-Thaim; Hwang, Tsong-Long; Huang, Yu-Ling; Lin, Chwan-Fwu; Wu, Wen-Bin

    2011-01-01

    Vascular smooth muscle cells (VSMCs) play an important role in normal vessel formation and in the development and progression of cardiovascular diseases. Grape plants contain resveratrol monomer and oligomers and drinking of wine made from grape has been linked to 'French Paradox'. In this study we evaluated the effect of vitisin B, a resveratrol tetramer, on VSMC behaviors. Vitisin B inhibited basal and PDGF-induced VSMC migration. Strikingly, it did not inhibit VSMC proliferation but inversely enhanced cell cycle progression and proliferation. Among the tested resveratrol oligomers, vitisin B showed an excellent inhibitory activity and selectivity on PDGF signaling. The anti-migratory effect by vitisin B was due to direct inhibition on PDGF signaling but was independent of interference with PDGF binding to VSMCs. Moreover, the enhanced VSMC adhesiveness to matrix contributed to the anti-migratory effect by vitisin B. Fluorescence microscopy revealed an enhanced reorganization of actin cytoskeleton and redistribution of activated focal adhesion proteins from cytosol to the peripheral edge of the cell membrane. This was confirmed by the observation that enhanced adhesiveness was repressed by the Src inhibitor. Finally, among the effects elicited by vitisin B, only the inhibitory effect toward basal migration was partially through estrogen receptor activation. We have demonstrated here that a resveratrol tetramer exhibited dual but opposite actions on VSMCs, one is to inhibit VSMC migration and the other is to promote VSMC proliferation. The anti-migratory effect was through a potent inhibition on PDGF signaling and novel enhancement on cell adhesion. - Highlights: → Several resveratrol oligomers from grape plants are examined on VSMC behaviors. → Tetraoligomer vitisin B shows excellent inhibitory activity and selectivity. → It exerts dual but opposing actions: anti-migratory and pro-proliferative effects. → The anti-migratory effect results from anti

  3. Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

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    Weissmann Norbert

    2005-11-01

    Full Text Available Abstract Background The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH in rats. Methods CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii the anti-remodeling effect of long-term inhalation of tolafentrine (iii the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. Results Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks, cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers, after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery

  4. Overexpression of membrane sialic acid-specific sialidase Neu3 inhibits matrix metalloproteinase-9 expression in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Moon, Sung-Kwon; Cho, Seung-Hak; Kim, Kyung-Woon; Jeon, Jae Heung; Ko, Jeong-Heon; Kim, Bo Yeon; Kim, Cheorl-Ho

    2007-01-01

    The ganglioside-specific sialidase Neu3 has been suggested to participate in cell growth, migration, and differentiation. Recent reports suggest that sialidase may be involved in intimal thickening, an early stage in the development of atherosclerosis. However, the role of the Neu3 gene in vascular smooth muscle cells (VSMC) responses has not yet been elucidated. To determine whether a Neu3 is able to modulate VSMC growth, the effect of overexpression of the Neu3 gene on cell proliferation was examined. However, the results show that the overexpression of this gene has no effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of TNF-α. Because atherogenic effects need not be limited to proliferation, we decided to examine whether Neu3 exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-α-induced VSMC. The expression of the Neu3 gene led to the inhibition of TNF-α-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, Neu3 gene expression strongly decreased MMP-9 promoter activity in response to TNF-α. This inhibition was characterized by the down-regulation of MMP-9, which was transcriptionally regulated at NF-κB and activation protein-1 (AP-1) sites in the MMP-9 promoter. These findings suggest that the Neu3 gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis

  5. Vasostatin-2 inhibits cell proliferation and adhesion in vascular smooth muscle cells, which are associated with the progression of atherosclerosis

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    Hou, Jianghong, E-mail: jianghonghou@163.com [Department of Cardiovascular, Weinan Center Hospital, The Middle of Victory Avenue, Linwei District, Weinan City 714000 (China); Xue, Xiaolin [Department of Cardiovascular, The First Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710061 (China); Li, Junnong [Department of Cardiovascular, Weinan Center Hospital, The Middle of Victory Avenue, Linwei District, Weinan City 714000 (China)

    2016-01-22

    Recently, the serum expression level of vasostatin-2 was found to be reduced and is being studied as an important indicator to assess the presence and severity of coronary artery disease; the functional properties of vasostatin-2 and its relationship with the development of atherosclerosis remains unclear. In this study, we attempted to detect the expression of vasostatin-2 and its impact on human vascular smooth muscle cells (VSMCs). Quantitative real-time PCR (qRT-PCR) and western blot were used to assess the expression level of vasostatin-2 in VSMCs between those from atherosclerosis and disease-free donors; we found that vasostatin-2 was significantly down-regulated in atherosclerosis patient tissues and cell lines. In addition, the over-expression of vasostatin-2 apparently inhibits cell proliferation and migration in VSMCs. Gain-of-function in vitro experiments further show that vasostatin-2 over-expression significantly inhibits inflammatory cytokines release in VSMCs. In addition, cell adhesion experimental analysis showed that soluble adhesion molecules (sICAM-1, sVCAM-1) had decreased expression when vasostatin-2 was over-expressed in VSMCs. Therefore, our results indicate that vasostatin-2 is an atherosclerosis-related factor that can inhibit cell proliferation, inflammatory response and cell adhesion in VSMCs. Taken together, our results indicate that vasostatin-2 could serve as a potential diagnostic biomarker and therapeutic option for human atherosclerosis in the near future. - Highlights: • Vasostatin-2 levels were down-regulated in atherosclerosis patient tissues and VSMCs. • Ectopic expression of vasostatin-2 directly affects cell proliferation and migration in vitro. • Ectopic expression of vasostatin-2 protein affects pro-inflammatory cytokines release in VSMCs. • Ectopic expression of vasostatin-2 protein affects cell adhesion in VSMCs.

  6. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies

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    Seidel Petra

    2012-10-01

    Full Text Available Abstract Background Activated mast cells are present within airway smooth muscle (ASM bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide, long-acting β2-agonists (salmeterol, formoterol and thiazolidinediones (ciglitazone, rosiglitazone on CXCL10 production by ASM cells (ASMC from people with and without asthma were investigated in vitro. Methods Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher’s post-hoc test. Results Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix. The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production. Conclusions Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

  7. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies.

    Science.gov (United States)

    Seidel, Petra; Alkhouri, Hatem; Lalor, Daniel J; Burgess, Janette K; Armour, Carol L; Hughes, J Margaret

    2012-10-04

    Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test. Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production. Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

  8. Rock Tea extract (Jasonia glutinosa) relaxes rat aortic smooth muscle by inhibition of L-type Ca(2+) channels.

    Science.gov (United States)

    Valero, Marta Sofía; Oliván-Viguera, Aida; Garrido, Irene; Langa, Elisa; Berzosa, César; López, Víctor; Gómez-Rincón, Carlota; Murillo, María Divina; Köhler, Ralf

    2015-12-01

    In traditional herbal medicine, Rock Tea (Jasonia glutinosa) is known for its prophylactic and therapeutic value in various disorders including arterial hypertension. However, the mechanism by which Rock Tea exerts blood pressure-lowering actions has not been elucidated yet. Our aim was to demonstrate vasorelaxing effects of Rock Tea extract and to reveal its possible action mechanism. Isometric myography was conducted on high-K+-precontracted rings from rat thoracic aorta and tested extracts at concentrations of 0.5-5 mg/ml. Whole-cell patch-clamp experiments were performed in rat aortic vascular smooth muscle cells (line A7r5) to determine blocking effects on L-type Ca(2+) channels. Rock Tea extract relaxed the aorta contracted by high [K+] concentration dependently with an EC50 of ≈2.4 mg/ml and produced ≈75 % relaxation at the highest concentration tested. The L-type Ca(2+) channel blocker, verapamil (10(-6) M), had similar effects. Rock Tea extract had no effect in nominally Ca(2+)-free high-K(+) buffer but significantly inhibited contractions to re-addition of Ca(2+). Rock Tea extract inhibited the contractions induced by the L-type Ca(2+) channel activator Bay K 8644 (10(-5) M) and by phenylephrine (10(-6) M). Rock Tea extract and Y-27632 (10(-6) M), Rho-kinase inhibitor, had similar effects and the respective effects were not additive. Patch-clamp experiments demonstrated that Rock Tea extract (2.5 mg/ml) virtually abolished L-type Ca(2+) currents in A7r5. We conclude that Rock Tea extract produced vasorelaxation of rat aorta and that this relaxant effect is mediated by inhibition of L-type Ca(2+) channels. Rock Tea extracts may be of phytomedicinal value for prevention and adjuvant treatment of hypertension and other cardiovascular diseases.

  9. α-Iso-Cubebene Inhibits PDGF-Induced Vascular Smooth Muscle Cell Proliferation by Suppressing Osteopontin Expression

    Science.gov (United States)

    Jang, Min A.; Lee, Seung Jin; Baek, Seung Eun; Park, So Youn; Choi, Young Whan; Kim, Chi Dae

    2017-01-01

    α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms. Thus, we examined the effect of ICB on vascular smooth muscle cell (VSMC) proliferation, a key feature of diverse vascular diseases. When VSMCs primary cultured from rat thoracic aorta were stimulated with PDGF (1–10 ng/ml), cell proliferation and osteopontin (OPN) expression were concomitantly up-regulated, but these effects were attenuated when cells were treated with MPIIIB10, a neutralizing monoclonal antibody for OPN. In aortic tissues exposed to PDGF, sprouting VSMC numbers increased, which was attenuated in tissues from OPN-deficient mice. Furthermore, VSMC proliferation and OPN expression induced by PDGF were attenuated dose-dependently by ICB (10 or 30 μg/ml). Reporter assays conducted using OPN promoter-luciferase constructs showed that the promoter region 538–234 bp of the transcription start site was responsible for transcriptional activity enhancement by PDGF, which was significantly inhibited by ICB. Putative binding sites for AP-1 and C/EBPβ in the indicated promoter region were suggested by TF Search, and increased binding of AP-1 and C/EBPβ in PDGF-treated VSMCs was demonstrated using a ChIP assay. The increased bindings of AP-1 and C/EBPβ into OPN promoter were attenuated by ICB. Moreover, the PDGF-induced expression of OPN was markedly attenuated in VSMCs transfected with siRNA for AP-1 and C/EBPβ. These results indicate that ICB inhibit VSMC proliferation by inhibiting the AP-1 and C/EBPβ signaling pathways and thus downregulating OPN expression. PMID:28114367

  10. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  11. Camptothecin inhibits platelet-derived growth factor-BB-induced proliferation of rat aortic vascular smooth muscle cells through inhibition of PI3K/Akt signaling pathway

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    Park, Eun-Seok [Department of Applied Biochemistry, Division of Life Science, College of Health and Biomedical Science, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Kang, Shin-il [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of); Yoo, Kyu-dong [Hazardous Substances Analysis Division, Gwangju Regional Food and Drug Administration, Gwangju (Korea, Republic of); Lee, Mi-Yea [Department of Nursing Kyungbok University, Pocheon (Korea, Republic of); Yoo, Hwan-Soo; Hong, Jin-Tae [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of); Shin, Hwa-Sup [Department of Applied Biochemistry, Division of Life Science, College of Health and Biomedical Science, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Kim, Bokyung [Department of Physiology, Konkuk Medical School, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Yun, Yeo-Pyo, E-mail: ypyun@chungbuk.ac.kr [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of)

    2013-04-15

    The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is a major cause of vascular disorders such as atherosclerosis and restenosis after angioplasty. In this study, we investigated not only the inhibitory effects of camptothecin (CPT) on PDGF-BB-induced VSMC proliferation, but also its molecular mechanism of this inhibition. CPT significantly inhibited proliferation with IC50 value of 0.58 μM and the DNA synthesis of PDGF-BB-stimulated VSMCs in a dose-dependent manner (0.5–2 μM ) without any cytotoxicity. CPT induced the cell cycle arrest at G0/G1 phase. Also, CPT decreased the expressions of G0/G1-specific regulatory proteins including cyclin-dependent kinase (CDK)2, cyclin D1 and PCNA in PDGF-BB-stimulated VSMCs. Pre-incubation of VSMCs with CPT significantly inhibited PDGF-BB-induced Akt activation, whereas CPT did not affect PDGF-receptor beta phosphorylation, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and phospholipase C (PLC)-γ1 phosphorylation in PDGF-BB signaling pathway. Our data showed that CPT pre-treatment inhibited VSMC proliferation, and that the inhibitory effect of CPT was enhanced by LY294002, a PI3K inhibitor, on PDGF-BB-induced VSMC proliferation. In addition, inhibiting the PI3K/Akt pathway by LY294002 significantly enhanced the suppression of PCNA expression and Akt activation by CPT. These results suggest that the anti-proliferative activity of CPT is mediated in part by downregulating the PI3K/Akt signaling pathway. - Highlights: ► CPT inhibits proliferation of PDGF-BB-induced VSMC without cytotoxicity. ► CPT arrests the cell cycle in G0/G1 phase by downregulation of cyclin D1 and CDK2. ► CPT significantly attenuates Akt phosphorylation in PDGF-BB signaling pathway. ► LY294002 enhanced the inhibitory effect of CPT on VSMC proliferation. ► Thus, CPT is mediated by downregulating the PI3K/Akt signaling pathway.

  12. Camptothecin inhibits platelet-derived growth factor-BB-induced proliferation of rat aortic vascular smooth muscle cells through inhibition of PI3K/Akt signaling pathway

    International Nuclear Information System (INIS)

    Park, Eun-Seok; Kang, Shin-il; Yoo, Kyu-dong; Lee, Mi-Yea; Yoo, Hwan-Soo; Hong, Jin-Tae; Shin, Hwa-Sup; Kim, Bokyung; Yun, Yeo-Pyo

    2013-01-01

    The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is a major cause of vascular disorders such as atherosclerosis and restenosis after angioplasty. In this study, we investigated not only the inhibitory effects of camptothecin (CPT) on PDGF-BB-induced VSMC proliferation, but also its molecular mechanism of this inhibition. CPT significantly inhibited proliferation with IC50 value of 0.58 μM and the DNA synthesis of PDGF-BB-stimulated VSMCs in a dose-dependent manner (0.5–2 μM ) without any cytotoxicity. CPT induced the cell cycle arrest at G0/G1 phase. Also, CPT decreased the expressions of G0/G1-specific regulatory proteins including cyclin-dependent kinase (CDK)2, cyclin D1 and PCNA in PDGF-BB-stimulated VSMCs. Pre-incubation of VSMCs with CPT significantly inhibited PDGF-BB-induced Akt activation, whereas CPT did not affect PDGF-receptor beta phosphorylation, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and phospholipase C (PLC)-γ1 phosphorylation in PDGF-BB signaling pathway. Our data showed that CPT pre-treatment inhibited VSMC proliferation, and that the inhibitory effect of CPT was enhanced by LY294002, a PI3K inhibitor, on PDGF-BB-induced VSMC proliferation. In addition, inhibiting the PI3K/Akt pathway by LY294002 significantly enhanced the suppression of PCNA expression and Akt activation by CPT. These results suggest that the anti-proliferative activity of CPT is mediated in part by downregulating the PI3K/Akt signaling pathway. - Highlights: ► CPT inhibits proliferation of PDGF-BB-induced VSMC without cytotoxicity. ► CPT arrests the cell cycle in G0/G1 phase by downregulation of cyclin D1 and CDK2. ► CPT significantly attenuates Akt phosphorylation in PDGF-BB signaling pathway. ► LY294002 enhanced the inhibitory effect of CPT on VSMC proliferation. ► Thus, CPT is mediated by downregulating the PI3K/Akt signaling pathway

  13. Magnesium Inhibits Wnt/β-Catenin Activity and Reverses the Osteogenic Transformation of Vascular Smooth Muscle Cells

    Science.gov (United States)

    Montes de Oca, Addy; Guerrero, Fatima; Martinez-Moreno, Julio M.; Madueño, Juan A.; Herencia, Carmen; Peralta, Alan; Almaden, Yolanda; Lopez, Ignacio; Aguilera-Tejero, Escolastico; Gundlach, Kristina; Büchel, Janine; Peter, Mirjam E.; Passlick-Deetjen, Jutta; Rodriguez, Mariano; Muñoz-Castañeda, Juan R.

    2014-01-01

    Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro

  14. Bupivacaine inhibits large conductance, voltage- and Ca2+- activated K+ channels in human umbilical artery smooth muscle cells

    Science.gov (United States)

    Martín, Pedro; Enrique, Nicolás; Palomo, Ana R. Roldán; Rebolledo, Alejandro; Milesi, Veronica

    2012-01-01

    Bupivacaine is a local anesthetic compound belonging to the amino amide group. Its anesthetic effect is commonly related to its inhibitory effect on voltage-gated sodium channels. However, several studies have shown that this drug can also inhibit voltage-operated K+ channels by a different blocking mechanism. This could explain the observed contractile effects of bupivacaine on blood vessels. Up to now, there were no previous reports in the literature about bupivacaine effects on large conductance voltage- and Ca2+-activated K+ channels (BKCa). Using the patch-clamp technique, it is shown that bupivacaine inhibits single-channel and whole-cell K+ currents carried by BKCa channels in smooth muscle cells isolated from human umbilical artery (HUA). At the single-channel level bupivacaine produced, in a concentration- and voltage-dependent manner (IC50 324 µM at +80 mV), a reduction of single-channel current amplitude and induced a flickery mode of the open channel state. Bupivacaine (300 µM) can also block whole-cell K+ currents (~45% blockage) in which, under our working conditions, BKCa is the main component. This study presents a new inhibitory effect of bupivacaine on an ion channel involved in different cell functions. Hence, the inhibitory effect of bupivacaine on BKCa channel activity could affect different physiological functions where these channels are involved. Since bupivacaine is commonly used during labor and delivery, its effects on umbilical arteries, where this channel is highly expressed, should be taken into account. PMID:22688134

  15. Botulinum Toxin Type A Inhibits α-Smooth Muscle Actin and Myosin II Expression in Fibroblasts Derived From Scar Contracture.

    Science.gov (United States)

    Chen, Minliang; Yan, Tongtong; Ma, Kui; Lai, Linying; Liu, Chang; Liang, Liming; Fu, Xiaobing

    2016-09-01

    Scar contracture (SC) is one of the most common complications resulting from major burn injuries. Numerous treatments are currently available but they do not always yield excellent therapeutic results. Recent reports suggest that botulinum toxin type A (BTXA) is effective at reducing SC clinically, but the molecular mechanism for this action is unknown. α-Smooth muscle actin (α-SMA) and myosin II are the main components of stress fibers, which are the contractile structures of fibroblasts. The effects of BTXA on α-SMA and myosin II in SC are still unknown. This study aimed to explore the effect of BTXA on α-SMA and myosin II expression in fibroblasts derived from SC and to elucidate its actual mechanism further. Fibroblasts were isolated from tissue specimens of SC. Fibroblasts were cultured in Dulbecco modified Eagle medium with different concentrations of BTXA and their proliferation was analyzed through the tetrazolium-based colorimetric method at 1, 4, and 7 days. Proteins of α-SMA and myosin II were checked using Western blot in fibroblasts treated with different concentrations of BTXA at 1, 4, and 7 days. Fibroblasts without BTXA treatment had a higher proliferation than that in other groups, which indicated that the proliferation of fibroblasts was significantly inhibited by BTXA (P < 0.05). Proteins of α-SMA and myosin II between fibroblasts with BTXA and fibroblasts without BTXA are statistically significant (P < 0.05). These results suggest that BTXA effectively inhibited the growth of fibroblasts derived from SC and reduced the expression of α-SMA and myosin II, which provided theoretical support for the application of BTXA to control SC.

  16. Leptin Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by Angiotensin II through Nitric Oxide-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Amaia Rodríguez

    2010-01-01

    Full Text Available Objective. This study was designed to investigate whether leptin modifies angiotensin (Ang II-induced proliferation of aortic vascular smooth muscle cells (VSMCs from 10-week-old male Wistar and spontaneously hypertensive rats (SHR, and the possible role of nitric oxide (NO. Methods. NO and NO synthase (NOS activity were assessed by the Griess and 3H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Results. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Conclusion. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.

  17. Betulinic Acid Inhibits Growth of Cultured Vascular Smooth Muscle Cells In Vitro by Inducing G1 Arrest and Apoptosis

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    Raja Kumar Vadivelu

    2012-01-01

    Full Text Available Betulinic acid is a widely available plant-derived triterpene which is reported to possess selective cytotoxic activity against cancer cells of neuroectodermal origin and leukemia. However, the potential of betulinic acid as an antiproliferative and cytotoxic agent on vascular smooth muscle (VSMC is still unclear. This study was carried out to demonstrate the antiproliferative and cytotoxic effect of betulinic acid on VSMCs using 3-[4,5-dimethylthizol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay, flow cytometry cell cycle assay, BrdU proliferation assay, acridine orange/propidium iodide staining, and comet assay. Result from MTT and BrdU assays indicated that betulinic acid was able to inhibit the growth and proliferation of VSMCs in a dose-dependent manner with IC50 of 3.8 μg/mL significantly (P<0.05. Nevertheless, betulinic acid exhibited G1 cell cycle arrest in flow cytometry cell cycle profiling and low level of DNA damage against VSMC in acridine orange/propidium iodide and comet assay after 24 h of treatment. In conclusion, betulinic acid induced G1 cell cycle arrest and dose-dependent DNA damage on VSMC.

  18. Genipin inhibits TNF-α-induced vascular smooth muscle cell proliferation and migration via induction of HO-1.

    Directory of Open Access Journals (Sweden)

    Fengrong Jiang

    Full Text Available Vascular smooth muscle cell (VSMC proliferation and migration triggered by inflammatory stimuli contributes importantly to the pathogenesis of atherosclerosis and restenosis. On the other hand, genipin, an aglycon of geniposide, exhibits diverse pharmacological functions such as antitumor and anti-inflammatory effects. The protective effects of genipin on the cardiovascular system have also been reported. However, the molecular mechanism involved remains unknown. This study aimed to elucidate the precise function of genipin in VSMCs, focusing particularly on the role of heme oxygenase-1 (HO-1, a potent anti-inflammatory enzyme. We found that pretreatment of genipin induced HO-1 mRNA and protein levels, as well as its activity in VSMCs. Genipin inhibited TNF-α-induced VSMC proliferation and migration in a dose-dependent manner. At the molecular level, genipin prevented ERK/MAPK and Akt phosphorylation while left p38 MAPK and JNK unchanged. Genipin also blocked the increase of ROS generation induced by TNF-α. More importantly, the specific HO-1 siRNA partially abolished the beneficial effects of genipin on VSMCs. These results suggest that genipin may serve as a novel drug in the treatment of these pathologies by inducing HO-1 expression/activity and subsequently decreasing VSMC proliferation and migration.

  19. Inhibition effect of Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis and their related products on human colonic smooth muscle in vitro.

    Directory of Open Access Journals (Sweden)

    Jing Gong

    Full Text Available To investigate the effects of four strains, generally used in clinic, including Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis, and their related products on human colonic smooth muscle in vitro.Human colonic circular muscle strips obtained from disease-free margins of resected segments from 25 patients with colorectal cancer were isometrically examined in a constant-temperature organ bath and exposed to different concentrations of living bacteria, sonicated cell fractions and cell-free supernatant (CFS. The area under the curve (AUC representing the contractility of smooth muscle strips was calculated.(1 The four living probiotics inhibited the contractility of human colonic muscle strips only at high concentration (1010 CFUs/mL, all P0.05.Four common probiotics related products, including the sonicated cell fractions and the CFS, obviously inhibited human colonic smooth muscles strips contraction in a dose-dependent manner. Only high concentration living probiotics (1010 CFUs/mL can inhibit the colonic smooth muscles strips contraction. The NO pathway may be partly involved in the inhibitory effect of CFS from Streptococcus thermophilus and Enterococcus faecalis.

  20. Danshensu prevents hypoxic pulmonary hypertension in rats by inhibiting the proliferation of pulmonary artery smooth muscle cells via TGF-β-smad3-associated pathway.

    Science.gov (United States)

    Zhang, Ning; Dong, Mingqing; Luo, Ying; Zhao, Feng; Li, Yongjun

    2018-02-05

    Hypoxic pulmonary hypertension is characterized by the remodeling of pulmonary artery. Previously we showed that tanshinone IIA, one lipid-soluble component from the Chinese herb Danshen, ameliorated hypoxic pulmonary hypertension by inhibiting pulmonary artery remodeling. Here we explored the effects of danshensu, one water-soluble component of Danshen, on hypoxic pulmonary hypertension and its mechanism. Rats were exposed to hypobaric hypoxia for 4 weeks to develop hypoxic pulmonary hypertension along with administration of danshensu. Hemodynamics and pulmonary arterial remodeling index were measured. The effects of danshensu on the proliferation of primary pulmonary artery smooth muscle cells and transforming growth factor-β-smad3 pathway were assessed in vitro. Danshensu significantly decreased the right ventricle systolic pressure, the right ventricle hypertrophy and pulmonary vascular remodeling index in hypoxic pulmonary hypertension rats. Danshensu also reduced the increased expression of transforming growth factor-β and phosphorylation of smad3 in pulmonary arteries in hypoxic pulmonary hypertension rats. In vitro, danshensu inhibited the hypoxia- or transforming growth factor-β-induced proliferation of primary pulmonary artery smooth muscle cells. Moreover, danshensu decreased the hypoxia-induced expression and secretion of transforming growth factor in primary pulmonary adventitial fibroblasts and NR8383 cell line, inhibited the hypoxia or transforming growth factor-β-induced phosphorylation of smad3 in rat primary pulmonary artery smooth muscle cells. These results demonstrate that danshensu ameliorates hypoxic pulmonary hypertension in rats by inhibiting the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, and the inhibition effects is associated with transforming growth factor-β-smad3 pathway. Therefore danshensu may be a potential treatment for hypoxic pulmonary hypertension. Copyright © 2017 Elsevier B.V. All rights

  1. Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy

    International Nuclear Information System (INIS)

    Brush, J.E. Jr.; Eisenhofer, G.; Garty, M.; Stull, R.; Maron, B.J.; Cannon, R.O. III; Panza, J.A.; Epstein, S.E.; Goldstein, D.S.

    1989-01-01

    We examined the uptake and release of norepinephrine in the cardiac circulation and other regional vascular beds in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 control subjects during simultaneous infusion of tracer-labeled norepinephrine and isoproterenol. Cardiac neuronal uptake of norepinephrine was assessed by comparing regional removal of tracer-labeled norepinephrine with that of tracer-labeled isoproterenol (which is not a substrate for neuronal uptake) and by the relation between production of dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, and regional spillover of norepinephrine. Cardiac extraction of norepinephrine averaged 59 +/- 17% in the patients with HCM, significantly less than in the control subjects (79 +/- 13%, p less than 0.05), whereas cardiac extraction of isoproterenol was similar in the two groups (13 +/- 23% versus 13 +/- 14%), indicating that neuronal uptake of norepinephrine was decreased in the patients with HCM. The cardiac arteriovenous difference in norepinephrine was significantly larger in the patients with HCM than in the control subjects (73 +/- 77 versus 13 +/- 50 pg/ml, p less than 0.05), as was the product of the arteriovenous difference in norepinephrine and coronary blood flow (7.3 +/- 7.3 versus 0.8 +/- 3.0 ng/min, p less than 0.05)

  2. Overexpression of Mitofusin 2 inhibited oxidized low-density lipoprotein induced vascular smooth muscle cell proliferation and reduced atherosclerotic lesion formation in rabbit

    International Nuclear Information System (INIS)

    Guo Yanhong; Chen Kuanghueih; Gao Wei; Li Qian; Chen Li; Wang Guisong; Tang Jian

    2007-01-01

    Our previous studies have implies that Mitofusin 2 (Mfn2), which was progressively reduced in arteries from ApoE -/- mice during the development of atherosclerosis, may take part in pathogenesis of atherosclerosis. In this study, we found that overexpression of Mfn2 inhibited oxidized low-density lipoprotein or serum induced vascular smooth muscle cell proliferation by down-regulation of Akt and ERK phosphorylation. Then we investigated the in vivo role of Mfn2 on the development of atherosclerosis in rabbits using adenovirus expressing Mitofusin 2 gene (AdMfn2). By morphometric analysis we found overexpression of Mfn2 inhibited atherosclerotic lesion formation and intima/media ratio by 66.7% and 74.6%, respectively, compared with control group. These results suggest that local Mfn2 treatment suppresses the development of atherosclerosis in vivo in part by attenuating the smooth muscle cell proliferation induced by lipid deposition and vascular injury

  3. The Integrin-blocking Peptide RGDS Inhibits Airway Smooth Muscle Remodeling in a Guinea Pig Model of Allergic Asthma

    NARCIS (Netherlands)

    Dekkers, Bart G. J.; Bos, I. Sophie T.; Gosens, Reinoud; Halayko, Andrew J.; Zaagsma, Johan; Meurs, Herman

    2010-01-01

    Rationale: Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyper-responsiveness in asthma. The mechanisms driving these changes are, however, incompletely understood. Recently, an important role for extracellular matrix proteins in

  4. Bone Morphogenetic Protein-Induced Msx1 and Msx2 Inhibit Myocardin-Dependent Smooth Muscle Gene Transcription▿

    OpenAIRE

    Hayashi, Ken'ichiro; Nakamura, Seiji; Nishida, Wataru; Sobue, Kenji

    2006-01-01

    During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene ex...

  5. MicroRNA expression profile and functional analysis reveal their roles in contact inhibition and its disruption switch of rat vascular smooth muscle cells.

    Science.gov (United States)

    Sun, Ye-Ying; Qin, Shan-Shan; Cheng, Yun-Hui; Wang, Chao-Yun; Liu, Xiao-Jun; Liu, Ying; Zhang, Xiu-Li; Zhang, Wendy; Zhan, Jia-Xin; Shao, Shuai; Bian, Wei-Hua; Luo, Bi-Hui; Lu, Dong-Feng; Yang, Jian; Wang, Chun-Hua; Zhang, Chun-Xiang

    2018-05-01

    Contact inhibition and its disruption of vascular smooth muscle cells (VSMCs) are important cellular events in vascular diseases. But the underlying molecular mechanisms are unclear. In this study we investigated the roles of microRNAs (miRNAs) in the contact inhibition and its disruption of VSMCs and the molecular mechanisms involved. Rat VSMCs were seeded at 30% or 90% confluence. MiRNA expression profiles in contact-inhibited confluent VSMCs (90% confluence) and non-contact-inhibited low-density VSMCs (30% confluence) were determined. We found that multiple miRNAs were differentially expressed between the two groups. Among them, miR-145 was significantly increased in contact-inhibited VSMCs. Serum could disrupt the contact inhibition as shown by the elicited proliferation of confluent VSMCs. The contact inhibition disruption accompanied with a down-regulation of miR-145. Serum-induced contact inhibition disruption of VSMCs was blocked by overexpression of miR-145. Moreover, downregulation of miR-145 was sufficient to disrupt the contact inhibition of VSMCs. The downregulation of miR-145 in serum-induced contact inhibition disruption was related to the activation PI3-kinase/Akt pathway, which was blocked by the PI3-kinase inhibitor LY294002. KLF5, a target gene of miR-145, was identified to be involved in miR-145-mediated effect on VSMC contact inhibition disruption, as it could be inhibited by knockdown of KLF5. In summary, our results show that multiple miRNAs are differentially expressed in contact-inhibited VSMCs and in non-contact-inhibited VSMCs. Among them, miR-145 is a critical gene in contact inhibition and its disruption of VSMCs. PI3-kinase/Akt/miR-145/KLF5 is a critical signaling pathway in serum-induced contact inhibition disruption. Targeting of miRNAs related to the contact inhibition of VSMCs may represent a novel therapeutic approach for vascular diseases.

  6. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies

    OpenAIRE

    Seidel Petra; Alkhouri Hatem; Lalor Daniel J; Burgess Janette K; Armour Carol L; Hughes J

    2012-01-01

    Abstract Background Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. Methods Confluent serum-deprived ce...

  7. DOPA, norepinephrine, and dopamine in rat tissues

    DEFF Research Database (Denmark)

    Eldrup, E; Richter, Erik; Christensen, N J

    1989-01-01

    We studied the effect of unilateral sympathectomy on rat quadriceps and gastrocnemius muscle concentrations of endogenous dihydroxyphenylalanine (DOPA), dopamine (DA), and norepinephrine (NE) and assessed the relationships between these catecholamines in several rat tissues. Catecholamines were...

  8. Norepinephrine turnover in brown adipose tissue is stimulated by a single meal

    International Nuclear Information System (INIS)

    Glick, Z.; Raum, W.J.

    1986-01-01

    A single meal stimulates brown adipose tissue (BAT) thermogenesis in rats. In the present study the role of norepinephrine in this thermogenic response was assessed from the rate of its turnover in BAT after a single test meal. For comparison, norepinephrine turnover was determined in the heart and spleen. A total of 48 male Wistar rats (200 g) were trained to eat during two feeding sessions per day. On the experimental day, one group (n = 24) was meal deprived and the other (n = 24) was given a low-protein high-carbohydrate test meal for 2 h. The synthesis inhibition method with α-methyl-p-tyrosine was employed to determine norepinephrine turnover from its concentration at four hourly time points after the meal. Tissue concentrations of norepinephrine were determined by radioimmunoassay. Norepinephrine concentration and turnover rate were increased more than threefold in BAT of the meal-fed compared with the meal-deprived rats. Neither were significantly altered by the meal in the heart or spleen. The data suggest that norepinephrine mediates a portion of the thermic effect of meals that originate in BAT

  9. Single Nisoldipine-Sensitive Calcium Channels in Smooth Muscle Cells Isolated from Rabbit Mesenteric Artery

    Science.gov (United States)

    Worley, Jennings F.; Deitmer, Joachim W.; Nelson, Mark T.

    1986-08-01

    Single smooth muscle cells were enzymatically isolated from the rabbit mesenteric artery. At physiological levels of external Ca, these cells were relaxed and contracted on exposure to norepinephrine, caffeine, or high levels of potassium. The patch-clamp technique was used to measure unitary currents through single channels in the isolated cells. Single channels were selective for divalent cations and exhibited two conductance levels, 8 pS and 15 pS. Both types of channels were voltage-dependent, and channel activity occurred at potentials positive to -40 mV. The activity of both channel types was almost completely inhibited by 50 nM nisoldipine. These channels appear to be the pathways for voltage-dependent Ca influx in vascular smooth muscle and may be the targets of the clinically used dihydropyridines.

  10. The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K{sup +} channels in rabbit coronary arterial smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hongliang; Hong, Da Hye; Kim, Han Sol; Kim, Hye Won [Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701 (Korea, Republic of); Jung, Won-Kyo [Department of Biomedical Engineering, Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan 608-737 (Korea, Republic of); Na, Sung Hun [Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, 200-701 (Korea, Republic of); Jung, In Duk; Park, Yeong-Min [Department of Immunology, Lab of Dendritic Cell Differentiation and Regulation, College of Medicine, Konkuk University, Chungju 380-701 (Korea, Republic of); Choi, Il-Whan, E-mail: cihima@inje.ac.kr [Department of Microbiology, Inje University College of Medicine, Busan, 614-735 (Korea, Republic of); Park, Won Sun, E-mail: parkws@kangwon.ac.kr [Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 200-701 (Korea, Republic of)

    2015-06-15

    We investigated the effects of the calmodulin inhibitor CGS 9343B on voltage-dependent K{sup +} (Kv) channels using whole-cell patch clamp technique in freshly isolated rabbit coronary arterial smooth muscle cells. CGS 9343B inhibited Kv currents in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC{sub 50}) value of 0.81 μM. The decay rate of Kv channel inactivation was accelerated by CGS 9343B. The rate constants of association and dissociation for CGS 9343B were 2.77 ± 0.04 μM{sup −1} s{sup −1} and 2.55 ± 1.50 s{sup −1}, respectively. CGS 9343B did not affect the steady-state activation curve, but shifted the inactivation curve toward to a more negative potential. Train pulses (1 or 2 Hz) application progressively increased the CGS 9343B-induced Kv channel inhibition. In addition, the inactivation recovery time constant was increased in the presence of CGS 9343B, suggesting that CGS 9343B-induced inhibition of Kv channel was use-dependent. Another calmodulin inhibitor, W-13, did not affect Kv currents, and did not change the inhibitory effect of CGS 9343B on Kv current. Our results demonstrated that CGS 9343B inhibited Kv currents in a state-, time-, and use-dependent manner, independent of calmodulin inhibition. - Highlights: • We investigated the effects of CGS 9394B on Kv channels. • CGS 9394B inhibited Kv current in a state-, time-, and use-dependent manner. • Caution is required when using CGS 9394B in vascular function studies.

  11. Transforming growth factor β inhibits platelet derived growth factor-induced vascular smooth muscle cell proliferation via Akt-independent, Smad-mediated cyclin D1 downregulation.

    Directory of Open Access Journals (Sweden)

    Abel Martin-Garrido

    Full Text Available In adult tissue, vascular smooth muscle cells (VSMCs exist in a differentiated phenotype, which is defined by the expression of contractile proteins and lack of proliferation. After vascular injury, VSMC adopt a synthetic phenotype associated with proliferation, migration and matrix secretion. The transition between phenotypes is a consequence of the extracellular environment, and in particular, is regulated by agonists such as the pro-differentiating cytokine transforming growth factor β (TGFβ and the pro-proliferative cytokine platelet derived growth factor (PDGF. In this study, we investigated the interplay between TGFβ and PDGF with respect to their ability to regulate VSMC proliferation. Stimulation of human aortic VSMC with TGFβ completely blocked proliferation induced by all isoforms of PDGF, as measured by DNA synthesis and total cell number. Mechanistically, PDGF-induced Cyclin D1 mRNA and protein expression was inhibited by TGFβ. TGFβ had no effect on PDGF activation of its receptor and ERK1/2, but inhibited Akt activation. However, constitutively active Akt did not reverse the inhibitory effect of TGFβ on Cyclin D1 expression even though inhibition of the proteasome blocked the effect of TGFβ. siRNA against Smad4 completely reversed the inhibitory effect of TGFβ on PDGF-induced Cyclin D1 expression and restored proliferation in response to PDGF. Moreover, siRNA against KLF5 prevented Cyclin D1 upregulation by PDGF and overexpression of KLF5 partially reversed TGFβ-induced inhibition of Cyclin D1 expression. Taken together, our results demonstrate that KLF5 is required for PDGF-induced Cyclin D1 expression, which is inhibited by TGFβ via a Smad dependent mechanism, resulting in arrest of VSMCs in the G1 phase of the cell cycle.

  12. Transforming growth factor β inhibits platelet derived growth factor-induced vascular smooth muscle cell proliferation via Akt-independent, Smad-mediated cyclin D1 downregulation.

    Science.gov (United States)

    Martin-Garrido, Abel; Williams, Holly C; Lee, Minyoung; Seidel-Rogol, Bonnie; Ci, Xinpei; Dong, Jin-Tang; Lassègue, Bernard; Martín, Alejandra San; Griendling, Kathy K

    2013-01-01

    In adult tissue, vascular smooth muscle cells (VSMCs) exist in a differentiated phenotype, which is defined by the expression of contractile proteins and lack of proliferation. After vascular injury, VSMC adopt a synthetic phenotype associated with proliferation, migration and matrix secretion. The transition between phenotypes is a consequence of the extracellular environment, and in particular, is regulated by agonists such as the pro-differentiating cytokine transforming growth factor β (TGFβ) and the pro-proliferative cytokine platelet derived growth factor (PDGF). In this study, we investigated the interplay between TGFβ and PDGF with respect to their ability to regulate VSMC proliferation. Stimulation of human aortic VSMC with TGFβ completely blocked proliferation induced by all isoforms of PDGF, as measured by DNA synthesis and total cell number. Mechanistically, PDGF-induced Cyclin D1 mRNA and protein expression was inhibited by TGFβ. TGFβ had no effect on PDGF activation of its receptor and ERK1/2, but inhibited Akt activation. However, constitutively active Akt did not reverse the inhibitory effect of TGFβ on Cyclin D1 expression even though inhibition of the proteasome blocked the effect of TGFβ. siRNA against Smad4 completely reversed the inhibitory effect of TGFβ on PDGF-induced Cyclin D1 expression and restored proliferation in response to PDGF. Moreover, siRNA against KLF5 prevented Cyclin D1 upregulation by PDGF and overexpression of KLF5 partially reversed TGFβ-induced inhibition of Cyclin D1 expression. Taken together, our results demonstrate that KLF5 is required for PDGF-induced Cyclin D1 expression, which is inhibited by TGFβ via a Smad dependent mechanism, resulting in arrest of VSMCs in the G1 phase of the cell cycle.

  13. Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Hyo Jung; Ham, Sun Ah; Paek, Kyung Shin; Hwang, Jung Seok; Jung, Si Young; Kim, Min Young; Jin, Hanna; Kang, Eun Sil; Woo, Im Sun; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Han, Chang Woo; Seo, Han Geuk

    2011-01-01

    Research highlights: → Activation of PPARδ by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. → Agonist-activated PPARδ suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. → GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. → Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPARδ-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  14. The Oligo Fucoidan Inhibits Platelet-Derived Growth Factor-Stimulated Proliferation of Airway Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Chao-Huei Yang

    2016-01-01

    Full Text Available In the pathogenesis of asthma, the proliferation of airway smooth muscle cells (ASMCs is a key factor in airway remodeling and causes airway narrowing. In addition, ASMCs are also the effector cells of airway inflammation. Fucoidan extracted from marine brown algae polysaccharides has antiviral, antioxidant, antimicrobial, anticlotting, and anticancer properties; however, its effectiveness for asthma has not been elucidated thus far. Platelet-derived growth factor (PDGF-treated primary ASMCs were cultured with or without oligo-fucoidan (100, 500, or 1000 µg/mL to evaluate its effects on cell proliferation, cell cycle, apoptosis, and Akt, ERK1/2 signaling pathway. We found that PDGF (40 ng/mL increased the proliferation of ASMCs by 2.5-fold after 48 h (p < 0.05. Oligo-fucoidan reduced the proliferation of PDGF-stimulated ASMCs by 75%–99% after 48 h (p < 0.05 and induced G1/G0 cell cycle arrest, but did not induce apoptosis. Further, oligo-fucoidan supplementation reduced PDGF-stimulated extracellular signal-regulated kinase (ERK1/2, Akt, and nuclear factor (NF-κB phosphorylation. Taken together, oligo-fucoidan supplementation might reduce proliferation of PDGF-treated ASMCs through the suppression of ERK1/2 and Akt phosphorylation and NF-κB activation. The results provide basis for future animal experiments and human trials.

  15. Inhibition of DNA nanotube-conjugated mTOR siRNA on the growth of pulmonary arterial smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Zaichun You

    2015-12-01

    Full Text Available Here we provide raw and processed data and methods behind mTOR siRNA loaded DNA nanotubes (siRNA-DNA-NTs in the growth of pulmonary arterial smooth muscle cells (PASMCs under both normoxic and hypoxic condition, and also related to (You et al., Biomaterials, 2015, 67:137–150, [1]. The MTT analysis, Semi-quantitative RT-PCR data presented here were used to probe cytotoxicity of mTOR siRNA-DNA-NT complex in its TAE-Mg2+ buffer. siRNA-DNA-NTs have a lower cytotoxicity and higher transfection efficiency and can, based on inhibition of mTOR expression, decrease PASMCs growth both hypoxic and normal condition.

  16. Inhibition of 5-alpha-reductase activity induces stromal remodeling and smooth muscle de-differentiation in adult gerbil ventral prostate.

    Science.gov (United States)

    Corradi, Lara S; Góes, Rejane M; Carvalho, Hernandes F; Taboga, Sebastião R

    2004-06-01

    Prostatic differentiation during embryogenesis and its further homeostatic state maintenance during adult life depend on androgens. Dihydrotestosterone, which is synthesized from testosterone by 5 alpha-reductase (5 alpha-r), is the active molecule triggering androgen action within the prostate. In the present work, we examined the effects of 5 alpha-reductase inhibition by finasteride in the ventral prostate (VP) of the adult gerbil, employing histochemical and electron microscopy techniques to demonstrate the morphological and organizational changes of the organ. After 10 days of finasteride treatment at a dose of 100 mg/kg/day, the prostatic complex (VP and dorsolateral prostate) absolute weight was reduced to about 18%. The epithelial cells became short and cuboidal, with less secretory blebs and reduced acid phosphatase activity. The luminal sectional area diminished, suggestive of decreased secretory activity. The stromal/epithelial ratio increased, the stroma becoming thicker but less cellular. There was a striking accumulation of collagen fibrils, which was accompanied by an increase in deposits of amorphous granular material adjacent to the basal lamina and in the clefts between smooth muscle cells (SMC). Additionally, the periacinar smooth muscle became loosely packed. Some SMC were atrophic and showed a denser array of the cytoskeleton, whereas other SMC had a highly irregular outline with numerous spine-like projections. The present data indicate that 5 alpha-r inhibition causes epithelial and stromal changes by affecting intra-prostatic hormone levels. These alterations are probably the result of an imbalance of the homeostatic interaction between the epithelium and the underlying stroma.

  17. U-61,431F, a stable prostacyclin analogue, inhibits the proliferation of bovine vascular smooth muscle cells with little antiproliferative effect on endothelial cells

    International Nuclear Information System (INIS)

    Shirotani, M.; Yui, Y.; Hattori, R.; Kawai, C.

    1991-01-01

    The effects of U-61,431F, ciprostene, a stable prostacyclin analogue, were examined on the proliferation of cultured quiescent bovine aortic endothelial cells (EC) and smooth muscle cells (SMC). After stimulation with 5% fetal calf serum, U-61,431F suppressed both the DNA synthesis and proliferation of SMC dose-dependently at the concentration of 3-100 microM, but had no effect on either of them in EC at a concentration of up to 30 microM. The inhibitory effect on DNA synthesis was greater in SMC than in EC at 3-50 microM. When SMC were stimulated with platelet-derived growth factor (PDGF) for 2 hrs followed by a 22-hr incubation with insulin, U-61,431F (1-50 microM) administered at the time of PDGF stimulation did not inhibit DNA synthesis. SMC initiated and terminated DNA synthesis at about 15-18 h and 24 h after stimulation with serum, respectively. Inhibition of DNA synthesis in serum-stimulated SMC as a function of the addition time of U-61,431F reduced at 3-12 h after the stimulation. U-61,431F raised the cyclic AMP (cAMP) content in SMC. Moreover, a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and a more specific cAMP phosphodiesterase inhibitor, Ro 20-1724, augmented the inhibition of DNA synthesis in SMC concomitant with further elevation of cAMP level. These results suggest that U-61,431F inhibits DNA synthesis of SMC acting in the progression stage rather than in the competence stage, with little antiproliferative effect on EC. cAMP may play an important role in its antiproliferative action in SMC

  18. Inhibition of hydrogen sulfide on the proliferation of vascular smooth muscle cells involved in the modulation of calcium sensing receptor in high homocysteine

    International Nuclear Information System (INIS)

    Wang, Yuwen; Wang, Xiyao; Liang, Xiaohui; Wu, Jichao; Dong, Shiyun; Li, Hongzhu; Jin, Meili; Sun, Dianjun; Zhang, Weihua; Zhong, Xin

    2016-01-01

    Hyperhomocysteinemia induces the proliferation of vascular smooth muscle cells (VSMCs). Hydrogen sulfide (H 2 S) inhibits the phenotype switch of VSMCs and calcium-sensing receptor (CaSR) regulated the production of endogenous H 2 S. However, whether CaSR inhibits the proliferation of VSMCs by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H 2 S) pathway in high homocysteine (HHcy) has not been previously investigated. The intracellular calcium concentration, the concentration of H 2 S, the cell viability, the proliferation and the expression of proteins of cultured VSMCs from rat thoracic aortas were measured, respectively. The results showed that the [Ca 2+ ] i and the expression of p-CaMK and CSE increased upon treatment with CaSR agonist. In HHcy, the H 2 S concentration decrease, the proliferation and migration rate increased, the expression of Cyclin D1, PCNA, Osteopontin and p-Erk1/2 increased while the α-SM actin, P21 Cip/WAK−1 and Calponin decreased. The CaSR agonist or exogenous H 2 S significantly reversed the changes of VSMCs caused by HHcy. In conclusion, our results demonstrated that CaSR regulate the endogenous CSE/H 2 S is related to the PLC-IP 3 receptor and CaM signal pathways which inhibit the proliferation of VSMCs, and the latter is involved in the Erk1/2 dependent signal pathway in high homocysteine. - Highlights: • CaSR activation increased the production of endogenous H 2 S in high homocysteine VSMCs. • CaSR modulated the CSE/H 2 S are related to the PLC-IP 3 R and Ca 2+ -CaM signal pathways. • Inhibition of H 2 S on the proliferation of VSMCs is involved in the Erk1/2 pathway. • Explore the potential roles of CaSR in regulating VSMCs proliferation in high homocysteine.

  19. Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.

    Science.gov (United States)

    Simakova, Maria N; Bisen, Shivantika; Dopico, Alex M; Bukiya, Anna N

    2017-12-01

    Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium-gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Corynoxeine isolated from the hook of Uncaria rhynchophylla inhibits rat aortic vascular smooth muscle cell proliferation through the blocking of extracellular signal regulated kinase 1/2 phosphorylation.

    Science.gov (United States)

    Kim, Tack-Joong; Lee, Ju-Hyun; Lee, Jung-Jin; Yu, Ji-Yeon; Hwang, Bang-Yeon; Ye, Sang-Kyu; Shujuan, Li; Gao, Li; Pyo, Myoung-Yun; Yun, Yeo-Pyo

    2008-11-01

    The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. Uncaria rhynchophylla is traditional Chinese herb that has been applied to the treatment of convulsive disorders, such as epilepsy, in China. In the present study, we examined whether corynoxeine exerts inhibitory effects on platelet-derived growth factor (PDGF)-BB-induced rat aortic VSMC proliferation and the possible mechanism of such effects. Pre-treatment of VSMCs with corynoxeine (5-50 microM) for 24 h resulted in significant decreases in cell number without any cytotoxicity; the inhibition percentages were 25.0+/-12.5, 63.0+/-27.5 and 88.0+/-12.5% at 5, 20 and 50 microM, respectively. Also, corynoxeine significantly inhibited the 50 ng/ml PDGF-BB-induced DNA synthesis of VSMCs in a concentration-dependent manner without any cytotoxicity; the inhibitions were 32.8+/-11.0, 51.8+/-8.0 and 76.9+/-7.4% at concentrations of 5, 20 and 50 microM, respectively. Pre-incubation of VSMCs with corynoxeine significantly inhibited PDGF-BB-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, whereas corynoxeine had no effects on mitogen-activated protein kinase (MAPK/ERK)-activating kinase 1 and 2 (MEK1/2), Akt, or phospholipase C (PLC)gamma1 activation or on PDGF receptor beta (PDGF-Rbeta) phosphorylation. These results suggest that corynoxeine is a potent ERK1/2 inhibitor of key PDGF-BB-induced VSMC proliferation and may be useful in the prevention and treatment of vascular diseases and restenosis after angioplasty.

  1. ASIC-like currents in freshly isolated cerebral artery smooth muscle cells are inhibited by endogenous oxidase activity.

    Science.gov (United States)

    Chung, Wen-Shuo; Farley, Jerry M; Drummond, Heather A

    2011-01-01

    The aim of this study was to determine if VSMC ASIC-like currents are regulated by oxidative state. We used whole-cell patch clamp of isolated mouse cerebral VSMCs to determine if 1) reducing agents, such as DTT and GSH, and 2) inhibition of endogenous oxidase activity from NADPH and Xanthine oxidases potentiate active currents and activate electrically silent currents. Pretreatment with 2 mM DTT or GSH, increased the mean peak amplitude of ASIC-like currents evoked by pH 6.0 from 0.4 ± 0.1 to 14.9 ± 3.6 pA/pF, and from 0.9 ± 0.3 to 11.3 ± 2.4 pA/pF, respectively. Pretreatment with apocynin, a NADPH oxidase inhibitor, mimics the effect of the reducing agents, with the mean peak current amplitude increased from 0.9 ± 0.5 to 7.0 ± 2.6 pA/pF and from 0.5 ± 0.2 to 26.4 ± 6.8 pA/pF by 50 and 200 μM apocynin, respectively. Pretreatment with allopurinol, a xanthine oxidase inhibitor, also potentiates the VSMC ASIC-like activity. These findings suggest that VSMC ASIC-like channels are regulated by oxidative state and may be inhibited by basal endogenous oxidative sources such as NADPH and xanthine oxidase. Copyright © 2011 S. Karger AG, Basel.

  2. Extracellular acidosis and very low [Na+ ] inhibit NBCn1- and NHE1-mediated net acid extrusion from mouse vascular smooth muscle cells.

    Science.gov (United States)

    Bonde, L; Boedtkjer, E

    2017-10-01

    The electroneutral Na + , HCO3- cotransporter NBCn1 and Na + /H + exchanger NHE1 regulate acid-base balance in vascular smooth muscle cells (VSMCs) and modify artery function and structure. Pathological conditions - notably ischaemia - can dramatically perturb intracellular (i) and extracellular (o) pH and [Na + ]. We examined effects of low [Na + ] o and pH o on NBCn1 and NHE1 activity in VSMCs of small arteries. We measured pH i by 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-based fluorescence microscopy of mouse mesenteric arteries and induced intracellular acidification by NH4+ prepulse technique. NBCn1 activity - defined as Na + -dependent, amiloride-insensitive net base uptake with CO 2 /HCO3- present - was inhibited equally when pH o decreased from 7.4 (22 mm HCO3-/5% CO 2 ) by metabolic (pH o 7.1/11 mm HCO3-: 22 ± 8%; pH o 6.8/5.5 mm HCO3-: 61 ± 7%) or respiratory (pH o 7.1/10% CO 2 : 35 ± 11%; pH o 6.8/20% CO 2 : 56 ± 7%) acidosis. Extracellular acidosis more prominently inhibited NHE1 activity - defined as Na + -dependent net acid extrusion without CO 2 /HCO3- present - at both pH o 7.1 (45 ± 9%) and 6.8 (85 ± 5%). Independently of pH o , lowering [Na + ] o from 140 to 70 mm reduced NBCn1 and NHE1 activity respiratory (ΔpH i /ΔpH o  = 71 ± 4%) than metabolic (ΔpH i /ΔpH o  = 30 ± 7%) acidosis. Extracellular acidification inhibits NBCn1 and NHE1 activity in VSMCs. NBCn1 is equivalently inhibited when pCO 2 is raised or [HCO3-] o decreased. Lowering [Na + ] o inhibits NBCn1 and NHE1 markedly only below the typical physiological and pathophysiological range. We propose that inhibition of Na + -dependent net acid extrusion at low pH o protects against cellular Na + overload at the cost of intracellular acidification. © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  3. Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.

    Science.gov (United States)

    Chen, Yu-Ying; Hsu, Ming-Jen; Hsieh, Cheng-Ying; Lee, Lin-Wen; Chen, Zhih-Cherng; Sheu, Joen-Rong

    2014-01-01

    Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  4. The PPARα/p16INK4a Pathway inhibits Vascular Smooth Muscle Cell Proliferation by repressing Cell Cycle-dependent Telomerase Activation

    Science.gov (United States)

    Gizard, Florence; Nomiyama, Takashi; Zhao, Yue; Findeisen, Hannes M.; Heywood, Elizabeth B.; Jones, Karrie L.; Staels, Bart; Bruemmer, Dennis

    2009-01-01

    Peroxisome Proliferator-Activated Receptor (PPAR) α, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARα activation suppresses G1→S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16INK4a (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARα is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARα activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect which was dependent on p16. The inhibition of cell proliferation by PPARα activation was lost in VSMC following TERT overexpression or knock-down, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARα. Finally, we demonstrate that PPARα agonists suppress telomerase activation during the proliferative response following vascular injury indicating that these findings are applicable in vivo. In concert, these results demonstrate that the anti-proliferative effects of PPARα in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. PMID:18818403

  5. Norepinephrine kinetics during insulin-induced hypoglycemia

    DEFF Research Database (Denmark)

    Hilsted, J; Christensen, N J; Larsen, S

    1985-01-01

    Norepinephrine (NE) kinetics (plasma appearance rate, clearance, and forearm extraction) were measured during insulin-induced hypoglycemia in six healthy subjects. NE clearance did not change during hypoglycemia, indicating that the increase in plasma NE during hypoglycemia is due to an increased...

  6. Leptin promotes osteoblast differentiation and mineralization of primary cultures of vascular smooth muscle cells by inhibiting glycogen synthase kinase (GSK)-3{beta}

    Energy Technology Data Exchange (ETDEWEB)

    Zeadin, Melec G.; Butcher, Martin K.; Shaughnessy, Stephen G. [Department of Medicine, McMaster University, Hamilton, ON (Canada); Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (Canada); Werstuck, Geoff H., E-mail: Geoff.Werstuck@taari.ca [Department of Medicine, McMaster University, Hamilton, ON (Canada); Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (Canada)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Leptin promotes osteoblast differentiation of primary smooth muscle cells. Black-Right-Pointing-Pointer Leptin regulates the expression of genes involved in osteoblast differentiation. Black-Right-Pointing-Pointer Constitutively active GSK-3{beta} attenuates leptin-induced osteoblast differentiation. Black-Right-Pointing-Pointer This suggests that leptin signals through GSK-3{beta} to promote osteoblast differentiation. -- Abstract: In this study, we begin to investigate the underlying mechanism of leptin-induced vascular calcification. We found that treatment of cultured bovine aortic smooth muscle cells (BASMCs) with leptin (0.5-4 {mu}g/ml) induced osteoblast differentiation in a dose-dependent manner. Furthermore, we found that leptin significantly increased the mRNA expression of osteopontin and bone sialoprotein, while down-regulating matrix gla protein (MGP) expression in BASMCs. Key factors implicated in osteoblast differentiation, including members of the Wnt signaling pathway, were examined. Exposure to leptin enhanced phosphorylation of GSK-3{beta} on serine-9 thereby inhibiting activity and promoting the nuclear accumulation of {beta}-catenin. Transfection of BASMCs with an adenovirus that expressed constitutively active GSK-3{beta} (Ad-GSK-3{beta} S9A) resulted in a >2-fold increase in GSK-3{beta} activity and a significant decrease in leptin-induced alkaline phosphatase (ALP) activity. In addition, qRT-PCR analysis showed that GSK-3{beta} activation resulted in a significant decrease in the expression of osteopontin and bone sialoprotein, but a marked increase in MGP mRNA expression. When taken together, our results suggest a mechanism by which leptin promotes osteoblast differentiation and vascular calcification in vivo.

  7. KCl stimulation increases norepinephrine transporter function in PC12 cells.

    Science.gov (United States)

    Mandela, Prashant; Ordway, Gregory A

    2006-09-01

    The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [3H]NE uptake via the NET and simultaneously increased [3H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca2+. Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [3H]NE uptake but did not block KCl-stimulated increases in [3H]NE uptake. In contrast, PMA increased [3H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca2+-activated signaling cascades with KN93 (a Ca2+ calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [3H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [3H]NE release. KCl-stimulated increases in [3H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca2+, different intracellular mechanisms mediate these two events.

  8. Inhibition of hydrogen sulfide on the proliferation of vascular smooth muscle cells involved in the modulation of calcium sensing receptor in high homocysteine

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuwen; Wang, Xiyao [Department of Clinical Laboratory, The second Affiliated Hospital of Harbin Medical University, Harbin 150081 (China); Liang, Xiaohui [Department of Radiology, Central Hospital of the Red Cross, Harbin 150080 (China); Wu, Jichao; Dong, Shiyun; Li, Hongzhu [Department of Pathophysiology, Harbin Medical University, Harbin 150081 (China); Jin, Meili [Department of Clinical Laboratory, The second Affiliated Hospital of Harbin Medical University, Harbin 150081 (China); Sun, Dianjun [Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150086 (China); Zhang, Weihua [Department of Pathophysiology, Harbin Medical University, Harbin 150081 (China); Zhong, Xin, E-mail: xzhong1111@163.com [Department of Pathophysiology, Harbin Medical University, Harbin 150081 (China)

    2016-09-10

    Hyperhomocysteinemia induces the proliferation of vascular smooth muscle cells (VSMCs). Hydrogen sulfide (H{sub 2}S) inhibits the phenotype switch of VSMCs and calcium-sensing receptor (CaSR) regulated the production of endogenous H{sub 2}S. However, whether CaSR inhibits the proliferation of VSMCs by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H{sub 2}S) pathway in high homocysteine (HHcy) has not been previously investigated. The intracellular calcium concentration, the concentration of H{sub 2}S, the cell viability, the proliferation and the expression of proteins of cultured VSMCs from rat thoracic aortas were measured, respectively. The results showed that the [Ca{sup 2+}]{sub i} and the expression of p-CaMK and CSE increased upon treatment with CaSR agonist. In HHcy, the H{sub 2}S concentration decrease, the proliferation and migration rate increased, the expression of Cyclin D1, PCNA, Osteopontin and p-Erk1/2 increased while the α-SM actin, P21{sup Cip/WAK−1} and Calponin decreased. The CaSR agonist or exogenous H{sub 2}S significantly reversed the changes of VSMCs caused by HHcy. In conclusion, our results demonstrated that CaSR regulate the endogenous CSE/H{sub 2}S is related to the PLC-IP{sub 3} receptor and CaM signal pathways which inhibit the proliferation of VSMCs, and the latter is involved in the Erk1/2 dependent signal pathway in high homocysteine. - Highlights: • CaSR activation increased the production of endogenous H{sub 2}S in high homocysteine VSMCs. • CaSR modulated the CSE/H{sub 2}S are related to the PLC-IP{sub 3}R and Ca{sup 2+}-CaM signal pathways. • Inhibition of H{sub 2}S on the proliferation of VSMCs is involved in the Erk1/2 pathway. • Explore the potential roles of CaSR in regulating VSMCs proliferation in high homocysteine.

  9. Smooth manifolds

    CERN Document Server

    Sinha, Rajnikant

    2014-01-01

    This book offers an introduction to the theory of smooth manifolds, helping students to familiarize themselves with the tools they will need for mathematical research on smooth manifolds and differential geometry. The book primarily focuses on topics concerning differential manifolds, tangent spaces, multivariable differential calculus, topological properties of smooth manifolds, embedded submanifolds, Sard’s theorem and Whitney embedding theorem. It is clearly structured, amply illustrated and includes solved examples for all concepts discussed. Several difficult theorems have been broken into many lemmas and notes (equivalent to sub-lemmas) to enhance the readability of the book. Further, once a concept has been introduced, it reoccurs throughout the book to ensure comprehension. Rank theorem, a vital aspect of smooth manifolds theory, occurs in many manifestations, including rank theorem for Euclidean space and global rank theorem. Though primarily intended for graduate students of mathematics, the book ...

  10. Mechanism of palytoxin-induced [3H]norepinephrine release from a rat pheochromocytoma cell line

    International Nuclear Information System (INIS)

    Tatsumi, M.; Takahashi, M.; Ohizumi, Y.

    1984-01-01

    Palytoxin, isolated from the zoanthid Palytoha species, is one of the most potent marine toxins. Palytoxin caused a release of [ 3 H]norepinephrine from clonal rat pheochromocytoma cells in a concentration-dependent manner. This releasing action of palytoxin was markedly inhibited or abolished by Co 2+ or Ca 2+ -free medium, but was not modified by tetrodotoxin. The release of [ 3 H]norepinephrine induced by a low concentration of palytoxin was abolished in sodium-free medium and increased as the external Na+ concentrations were increased, but the release induced by a high concentration was unaffected by varying the concentration of external Na + . The release of [ 3 H]norepinephrine induced by both concentrations of palytoxin increased with increasing Ca 2+ concentrations. Palytoxin caused a concentration-dependent increase in 22 Na and 45 Ca influxes into pheochromocytoma cells. The palytoxin-induced 45 Ca influx was markedly inhibited by Co 2+ , whereas the palytoxin-induced 22 Na influx was not affected by tetrodotoxin. These results suggest that in pheochromocytoma cells the [ 3 H]norepinephrine release induced by lower concentrations of palytoxin is primarily brought about by increasing tetrodotoxin-insensitive Na + permeability across the cell membrane, whereas that induced by higher concentrations is mainly caused by a direct increase in Ca 2+ influx into them

  11. Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Yu-Ying Chen

    2014-01-01

    Full Text Available Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α. Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK, Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  12. Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Ae-Rang Hwang

    Full Text Available Advanced glycation endproduct (AGE-induced vascular smooth muscle cell (VSMC proliferation and reactive oxygen species (ROS production are emerging as important mechanisms of diabetic vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration. In cultured VSMCs, statins upregulated Nrf2-related antioxidant gene, NQO1 and HO-1, via an ERK5-dependent Nrf2 pathway. Inhibition of ERK5 by siRNA or BIX02189 (a specific ERK5 inhibitor reduced the statin-induced upregulations of Nrf2, NQO1, and HO-1. Furthermore, fluvastatin was found to significantly increase ARE promoter activity through ERK5 signaling, and to inhibit AGE-induced VSMC proliferation and migration as determined by MTT assay, cell counting, FACS analysis, a wound scratch assay, and a migration chamber assay. In addition, AGE-induced proliferation was diminished in the presence of Ad-CA-MEK5α encoding a constitutively active mutant form of MEK5α (an upstream kinase of ERK5, whereas depletion of Nrf2 restored statin-mediated reduction of AGE-induced cell proliferation. Moreover, fluvastatin suppressed the protein expressions of cyclin D1 and Cdk4, but induced p27, and blocked VSMC proliferation by regulating cell cycle. These results suggest statin-induced activation of an ERK5-dependent Nrf2 pathway reduces VSMC proliferation and migration induced by AGEs, and that the ERK5-Nrf2 signal module be viewed as a potential therapeutic target of vasculopathy in patients with diabetes and complications of the disease.

  13. Inhibition of Vascular Smooth Muscle Growth via Signaling Crosstalk between AMP-Activated Protein Kinase and cAMP-Dependent Protein Kinase

    Directory of Open Access Journals (Sweden)

    Joshua Daniel Stone

    2012-10-01

    Full Text Available Abnormal vascular smooth muscle (VSM growth is central in the pathophysiology of vascular disease yet fully effective therapies to curb this growth are lacking. Recent findings from our lab and others support growth control of VSM by adenosine monophosphate (AMP-based approaches including the metabolic sensor AMP-activated protein kinase (AMPK and cAMP-dependent protein kinase (PKA. Molecular crosstalk between AMPK and PKA has been previously suggested, yet the extent to which this occurs and its biological significance in VSM remains unclear. Considering their common AMP backbone and similar signaling characteristics, we hypothesized that crosstalk exists between AMPK and PKA in the regulation of VSM growth. Using rat primary VSM cells, the AMPK agonist AICAR increased AMPK activity and phosphorylation of the catalytic Thr172 site on AMPK. Interestingly, AICAR also phosphorylated a suspected PKA-inhibitory Ser485 site on AMPK, and these cumulative events were reversed by the PKA inhibitor PKI suggesting possible PKA-mediated regulation of AMPK. AICAR also increased PKA activity in a reversible fashion. The cAMP stimulator forskolin increased PKA activity and completely ameliorated Ser/Thr protein phosphatase-2C activity, suggesting a potential mechanism of AMPK modulation by PKA since inhibition of PKA by PKI reduced AMPK activity. Functionally, AMPK inhibited serum-stimulated cell cycle progression and cellular proliferation; however, PKA failed to do so. Moreover, AMPK and PKA reduced PDGF-β-stimulated VSM cell migration. Collectively, these results show that AMPK is capable of reducing VSM growth in both anti-proliferative and anti-migratory fashions. Furthermore, these data suggest that AMPK may be modulated by PKA and that positive feedback may exist between these two systems. These findings reveal a discrete nexus between AMPK and PKA in VSM and provide basis for metabolically-directed targets in reducing pathologic VSM growth.

  14. Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway

    Directory of Open Access Journals (Sweden)

    Zhenli Luo

    2017-01-01

    Full Text Available In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE−/− mice by high fat and cholesterol diet (HFD for 16 weeks. Rapamycin and 3-Methyladenine (MA were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-β-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression.

  15. Terminalia chebula Fructus Inhibits Migration and Proliferation of Vascular Smooth Muscle Cells and Production of Inflammatory Mediators in RAW 264.7

    Directory of Open Access Journals (Sweden)

    Hyun-Ho Lee

    2015-01-01

    Full Text Available Pathogenesis of atherosclerosis and neointima formation after angioplasty involves vascular smooth muscle cells (VSMCs migration and proliferation followed by inflammatory responses mediated by recruited macrophages in the neointima. Terminalia chebula is widely used traditional medicine in Asia for its beneficial effects against cancer, diabetes, and bacterial infection. The study was designed to determine whether Terminalia chebula fructus water extract (TFW suppresses VSMC migration and proliferation and inflammatory mediators production in macrophage (RAW 264.7. Our results showed that TFW possessed strong antioxidative effects in 1,1-diphenyl-2-picryl hydrazyl (DPPH scavenging and lipid peroxidation assays. In addition, TFW reduced nitric oxide (NO production, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2 expression in RAW 264.7 cells. Also, TFW inhibited platelet-derived growth factor (PDGF-BB induced VSMC migration as determined by wound healing and Boyden chamber assays. The antimigratory effect of TFW was due to its inhibitory effect on metalloproteinase-9 (MMP-9 expression, focal adhesion kinase (FAK activation, and Rho-family of small GTPases (Cdc42 and RhoA expression in VSMCs. Furthermore, TFW suppressed PDGF-BB induced VSMC proliferation by downregulation of mitogen activated protein kinases (MAPKs signaling molecules. These results suggest that TFW could be a beneficial resource in the prevention of atherosclerosis.

  16. Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway.

    Science.gov (United States)

    Zhang, Lin; Pu, Zhichen; Wang, Junsong; Zhang, Zhifeng; Hu, Dongmei; Wang, Junjie

    2014-05-09

    Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by enhanced pulmonary artery smooth muscle cell (PASMCs) proliferation and suppressed apoptosis. However, the potential mechanism of baicalin in the regulation of PASMC proliferation and the prevention of cardiovascular diseases remains unexplored. To test the effects of baicalin on hypoxia, we used rats treated with or without baicalin (100 mg·kg⁻¹ each rat) at the beginning of the third week after hypoxia. Hemodynamic and pulmonary pathomorphology data showed that right ventricular systolic pressures (RVSP), the weight of the right ventricle/left ventricle plus septum (RV/LV + S) ratio and the medial width of pulmonary arterioles were much higher in chronic hypoxia. However, baicalin treatment repressed the elevation of RVSP, RV/LV + S and attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia. Additionally, baicalin (10 and 20 μmol·L⁻¹) treatment suppressed the proliferation of PASMCs and attenuated the expression of hypoxia-inducible factor-α (HIF-α) under hypoxia exposure. Meanwhile, baicalin reversed the hypoxia-induced reduction of p27 and increased AKT/protein kinase B phosphorylation p-AKT both in vivo and in vitro. These results suggested that baicalin could effectively attenuate PVSR and hypoxic pulmonary hypertension.

  17. Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway.

    Science.gov (United States)

    Qiu, Cuiting; Zheng, Haijun; Tao, Huiren; Yu, Wenjun; Jiang, Xiaoyu; Li, Aiqin; Jin, Hui; Lv, Anlin; Li, Huan

    2017-09-01

    Vascular calcification is associated with cardiovascular disease as a complication of hypertension, hyperlipidemia, diabetes mellitus, and chronic kidney disease. Vitamin K2 (VK2) delays vascular calcification by an unclear mechanism. Moreover, apoptosis modulates vascular smooth muscle cell (VSMC) calcification. This paper aimed to study VK2-modified VSMC calcification and survival cell signaling mediated by growth arrest-specific gene 6 (Gas6) and its tyrosine kinase receptor Axl. Primary-cultured VSMCs were dose-dependently treated with VK2 in the presence of calcification medium for 8 days, or pre-treated for 1 h with/without the Axl inhibitor R428 (2 μmol/L) or the caspase inhibitor Z-VAD-fmk (20 μmol/L) followed by treatment with VK2 (10 μmol/L) or rmGas6 (200 nmol/L) in calcification medium for 8 days. Calcium deposition was determined by the o-cresolphthalein complexone assay and Alizarin Red S staining. Apoptosis was determined by TUNEL and flow cytometry using Annexin V-FITC and propidium iodide staining. Western blotting detected the expressions of Axl, Gas6, p-Akt, Akt, and Bcl2. VK2 significantly inhibited CaCl 2 - and β-sodium glycerophosphate (β-GP)-induced VSMC calcification and apoptosis, which was dependent on restored Gas6 expression and activated downstream signaling by Axl, p-Akt, and Bcl2. Z-VAD-fmk significantly inhibited CaCl 2 - and β-GP-induced VSMC calcification and apoptosis. Augmented recombinant mouse Gas6 protein (rmGas6) expression significantly reduced VSMC calcification and apoptosis. Furthermore, the Gas6/Axl interaction was inhibited by R428, which abolished the preventive effect of VK2 on CaCl 2 - and β-GP-induced apoptosis and calcification. These results suggest that Gas6 is critical in VK2-mediated functions that attenuate CaCl 2 - and β-GP-induced VSMC calcification by blocking apoptosis.

  18. Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC2−/− Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM

    Science.gov (United States)

    Lesma, Elena; Grande, Vera; Ancona, Silvia; Carelli, Stephana; Di Giulio, Anna Maria; Gorio, Alfredo

    2008-01-01

    Background Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2−/− ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2−/− ASM cell proliferation is EGF-dependent. Methods and Findings Effects of EGF on proliferation of TSC2−/− ASM cells and TSC2−/− ASM cells transfected with TSC2 gene were determined. In contrast to TSC2−/− ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2−/− ASM cells. Exposure of TSC2−/− ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2−/− cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2−/− ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2−/− ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed. Conclusion Our results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC−/− ASM cells, and such EGF-dependency is the result of the lack of tuberin. PMID:18958173

  19. Apelin-13 inhibits large-conductance Ca2+-activated K+ channels in cerebral artery smooth muscle cells via a PI3-kinase dependent mechanism.

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    Amit Modgil

    Full Text Available Apelin-13 causes vasoconstriction by acting directly on APJ receptors in vascular smooth muscle (VSM cells; however, the ionic mechanisms underlying this action at the cellular level remain unclear. Large-conductance Ca(2+-activated K(+ (BKCa channels in VSM cells are critical regulators of membrane potential and vascular tone. In the present study, we examined the effect of apelin-13 on BK(Ca channel activity in VSM cells, freshly isolated from rat middle cerebral arteries. In whole-cell patch clamp mode, apelin-13 (0.001-1 μM caused concentration-dependent inhibition of BK(Ca in VSM cells. Apelin-13 (0.1 µM significantly decreased BK(Ca current density from 71.25 ± 8.14 pA/pF to 44.52 ± 7.10 pA/pF (n=14 cells, P<0.05. This inhibitory effect of apelin-13 was confirmed by single channel recording in cell-attached patches, in which extracellular application of apelin-13 (0.1 µM decreased the open-state probability (NPo of BK(Ca channels in freshly isolated VSM cells. However, in inside-out patches, extracellular application of apelin-13 (0.1 µM did not alter the NPo of BK(Ca channels, suggesting that the inhibitory effect of apelin-13 on BKCa is not mediated by a direct action on BK(Ca. In whole cell patches, pretreatment of VSM cells with LY-294002, a PI3-kinase inhibitor, markedly attenuated the apelin-13-induced decrease in BK(Ca current density. In addition, treatment of arteries with apelin-13 (0.1 µM significantly increased the ratio of phosphorylated-Akt/total Akt, indicating that apelin-13 significantly increases PI3-kinase activity. Taken together, the data suggest that apelin-13 inhibits BK(Ca channel via a PI3-kinase-dependent signaling pathway in cerebral artery VSM cells, which may contribute to its regulatory action in the control of vascular tone.

  20. Rapid adaptation of the stimulatory effect of CO2 on brain norepinephrine metabolism.

    Science.gov (United States)

    Stone, E A

    1983-12-01

    The present study examined the effects of exposure of rats to elevated environmental levels of CO2 on norepinephrine metabolism in the hypothalamus and other regions of the brain. In confirmation of previous findings by others CO2 at 10 or 15% was found to elevate both dopa accumulation after dopa decarboxylase inhibition and norepinephrine utilization after tyrosine hydroxylase inhibition. These effects however were found to be transient occurring only during the first 30 min of 2.5 h exposure. In this regard CO2 differs from another form of stress, restraint which produces a sustained 2.5 h increase of dopa accumulation and NE accumulation. Restraint was also more effective than CO2 in depleting endogenous stores of hypothalamic NE. The factor responsible for the adaptation of the catecholamine response to CO2 was not identified although it was shown not to be hypothermia and it was reversed by a 2 h CO2-free recovery period.

  1. MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin

    International Nuclear Information System (INIS)

    Zhang, Zi-wei; Guo, Rui-wei; Lv, Jin-lin; Wang, Xian-mei; Ye, Jin-shan; Lu, Ni-hong; Liang, Xing; Yang, Li-xia

    2017-01-01

    Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis. - Highlights: • Suggesting a new mechanism of insulin-triggered VSMC functions. • Providing a new therapeutic strategies that target atherosclerosis in T2DM patients. • Providing a new strategies that target in-stent restenosis in T2DM patients.

  2. Surface smoothness

    DEFF Research Database (Denmark)

    Tummala, Sudhakar; Dam, Erik B.

    2010-01-01

    accuracy, such novel markers must therefore be validated against clinically meaningful end-goals such as the ability to allow correct diagnosis. We present a method for automatic cartilage surface smoothness quantification in the knee joint. The quantification is based on a curvature flow method used....... We demonstrate that the fully automatic markers eliminate the time required for radiologist annotations, and in addition provide a diagnostic marker superior to the evaluated semi-manual markers....

  3. MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling.

    Directory of Open Access Journals (Sweden)

    Jin Pan

    Full Text Available Abnormal proliferation of vascular smooth muscle cells (VSMCs contributes to the development of cardiovascular diseases. Studies have shown the great impact of microRNAs (miRNAs on the cell proliferation of VSMCs. This study examined the effects of miR-137 on the cell proliferation and migration of VSMCs and also explored the underlying molecular mechanisms. The mRNA and protein expression levels were determined by qRT-PCR and western blot assays, respectively. The CCK-8 assay, wound healing assay and transwell migration assay were performed to measure cell proliferation and migration of VSMCs. The miR-137-targeted 3'untranslated region of insulin-like growth factor-binding protein-5 (IGFBP-5 was confirmed by luciferase reporter assay. Platelet-derived growth factor-bb (PDGF-bb treatment enhanced cell proliferation and suppressed the expression of miR-137 in VSMCs. The gain-of-function and loss-of-function assays showed that overexpression of miR-137 suppressed the cell proliferation and migration, and also inhibited the expression of matrix genes of VSMCs; down-regulation of miR-137 had the opposite effects on VSMCs. Bioinformatics analysis and luciferase report assay results showed that IGFBP-5 was a direct target of miR-137, and miR-137 overexpression suppressed the IGFBP-5 expression and down-regulation of miR-137 increased the IGFBP-5 expression in VSMCs. PDGF-bb treatment also increased the IGFBP-5 mRNA expression. In addition, enforced expression of IGFBP-5 reversed the inhibitory effects of miR-137 on cell proliferation and migration of VSMCs. More importantly, overexpression of miR-137 also suppressed the activity of mTOR/STAT3 signaling in VSMCs. Taken together, the results suggest that miR-137 may suppress cell proliferation and migration of VSMCs via targeting IGFBP-5 and modulating mTOR/STAT3 signaling pathway.

  4. Intermedin inhibits norepinephrine-induced contraction of rat seminal vesicle

    Directory of Open Access Journals (Sweden)

    P.F. Wong

    2014-09-01

    Conclusion: The results demonstrated that the inhibitory action of IMD on NE-induced seminal vesicle contraction was mediated via the ADM receptor(s and the nitric oxide production pathway, partially by the IMD receptor, but not by the CGRP receptor and the cAMP-PKA pathway.

  5. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    Directory of Open Access Journals (Sweden)

    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  6. Interaction of antidepressants with the serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Sørensen, Lena; Andersen, Jacob; Thomsen, Mette

    2012-01-01

    The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used...

  7. The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

    Science.gov (United States)

    Chen, Zhengming; Yang, Ji; Skolnick, Phil

    The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

  8. Pituitary adenylate cyclase activating polypeptide induces vascular relaxation and inhibits non-vascular smooth muscle activity in the rabbit female genital tract

    DEFF Research Database (Denmark)

    Steenstrup, B R; Ottesen, B; Jørgensen, M

    1994-01-01

    In vitro effects of two bioactive forms of pituitary adenylate cyclase activating polypeptide (PACAP): PACAP-38 and PACAP-27 were studied on rabbit vascular and non-vascular smooth muscle. Segments of the ovarian artery and muscle strips from the fallopian tube were used. Two series of experiment...

  9. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint

    Directory of Open Access Journals (Sweden)

    Fitzgerald PJ

    2012-06-01

    Full Text Available Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: There is growing evidence that the neurotransmitter norepinephrine (NE and its sister molecule epinephrine (EPI (adrenaline affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically, and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body’s “fight or flight” response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically.Keywords: clonidine, guanfacine, aspirin, acetylcholine, epinephrine, adrenaline, sympathetic nervous system, parasympathetic nervous system, inflammation

  10. Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

    Science.gov (United States)

    Gelband, C H; Sumners, C; Lu, D; Raizada, M K

    1998-02-27

    The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

  11. Orienting of attention, pupil size, and the norepinephrine system.

    Science.gov (United States)

    Gabay, Shai; Pertzov, Yoni; Henik, Avishai

    2011-01-01

    This research examined a novel suggestion regarding the involvement of the locus coeruleus-norepinephrine (LC-NE) system in orienting reflexive (exogenous) attention. A common procedure for studying exogenous orienting of attention is Posner's cuing task. Importantly, one can manipulate the required level of target processing by changing task requirements, which, in turn, can elicit a different time course of inhibition of return (IOR). An easy task (responding to target location) produces earlier onset IOR, whereas a demanding task (responding to target identity) produces later onset IOR. Aston-Jones and Cohen (Annual Review of Neuroscience, 28, 403-450, 2005) presented a theory suggesting two different modes of LC activity: tonic and phasic. Accordingly, we suggest that in the more demanding task, the LC-NE system is activated in phasic mode, and in the easier task, it is activated in tonic mode. This, in turn, influences the appearance of IOR. We examined this suggestion by measuring participants' pupil size, which has been demonstrated to correlate with the LC-NE system, while they performed cuing tasks. We found a response-locked phasic dilation of the pupil in the discrimination task, as compared with the localization task, which may reflect different firing modes of the LC-NE system during the two tasks. We also demonstrated a correlation between pupil size at the time of cue presentation and magnitude of IOR.

  12. Stimulatory effects of neuronally released norepinephrine on renin release in vitro

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    Matsumura, Yasuo; Kawazoe, Shinka; Ichihara, Toshio; Shinyama, Hiroshi; Kageyama, Masaaki; Morimoto, Shiro (Osaka Univ. of Pharmaceutical Sciences (Japan))

    1988-10-01

    Extracellular high potassium inhibits renin release in vitro by increasing calcium concentrations in the juxtaglomerular cells. The authors found that the decreased response of renin release from rat kidney cortical slices in high potassium solution changed to a strikingly increased one in the presence of nifedipine at doses over 10{sup {minus}6} M. They then examined the stimulatory effect of extracellular high potassium in the presence of nifedipine on renin release. The enhancement of release was significantly suppressed either by propranolol or by metoprolol but not by prazosin. High potassium plus nifedipine-induced increase in renin release was markedly attenuated by renal denervation. The enhancing effect was not observed when the slices were incubated in calcium-free medium. Divalent cations such as Cd{sup 2+}, Co{sup 2+}, and Mn{sup 2+} blocked this enhancement in a concentration-dependent manner. High potassium elicited an increase in {sup 3}H efflux from the slices preloaded with ({sup 3}H)-norepinephrine. The increasing effect was not influenced by nifedipine but was abolished by the removal of extracellular calcium or by the addition of divalent cations. These observations suggest to us that the high potassium plus nifedipine-induced increase in renin release from the slices is mediated by norepinephrine derived from renal sympathetic nerves and that this neuronally released norepinephrine stimulates renin release via activation of {beta}-adrenoceptors.

  13. Relationships of Whole Blood Serotonin and Plasma Norepinephrine within Families.

    Science.gov (United States)

    Leventhal, Bennett L.; And Others

    1990-01-01

    This study of 47 families of autistic probands found that whole blood serotonin was positively correlated between autistic children and their mothers, fathers, and siblings, but plasma norepinephrine levels were not. (Author/JDD)

  14. TGF-beta1 inhibits Cx43 expression and formation of functional syncytia in cultured smooth muscle cells from human detrusor.

    Science.gov (United States)

    Neuhaus, Jochen; Heinrich, Marco; Schwalenberg, Thilo; Stolzenburg, Jens-Uwe

    2009-02-01

    Human detrusor smooth muscle cells (hBSMCs) are coupled by connexin 43 (Cx43)-positive gap junctions to form functional syncytia. Gap junctional communication likely is necessary for synchronised detrusor contractions and is supposed to be altered in voiding disturbances. Other authors have shown that the pleiotropic cytokine TGF-beta1 upregulates Cx43 expression in human aortic smooth muscle cells. In this study, we examined the TGF-beta1 effects on Cx43 expression in cultured hBSMCs. hBSMC cultures, established from patients undergoing cystectomy, were treated with recombinant human TGF-beta1. Cx43 expression was then examined by Western blotting, real-time PCR, and immunocytochemistry. Dye-injection experiments were used to study the size of functional syncytia. Dye-coupling experiments revealed stable formation of functional syncytia in passaged cell cultures (P1-P4). Stimulation with TGF-beta1 led to significant reduction of Cx43 immunoreactivity and coupling. Cx43 protein expression was significantly downregulated and Cx43 mRNA was only 30% of the control level. Interestingly, low phosphorylation species of Cx43 were particularly affected. Our experiments demonstrated a significant down regulation of connexin 43 by TGF-beta1 in cultured hBSMCs. These findings support the view that TGF-beta1 is involved in the pathophysiology of urinary bladder dysfunction.

  15. Muscle interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion

    DEFF Research Database (Denmark)

    Mortensen, Stefan P.; Gonzalez-Alonso, Jose; Nielsen, Jens Jung

    2009-01-01

    ATP and NE concentrations to gain insight into the interstitial and intravascular mechanisms by which ATP causes muscle vasodilation and sympatholysis. Leg hemodynamics and muscle interstitial nucleotide and norepinephrine (NE) concentrations were measured during: 1) femoral arterial ATP infusion (0......, respectively (Pcontracting muscle (Pmuscle, whereas interstitial NE concentrations increased similarly in both active...... and inactive muscles. These results suggest that the vasodilatory and sympatholytic effects of intraluminal ATP are mainly mediated via endothelial prinergic receptors. Intraluminal ATP and muscle contractions appear to modulate sympathetic nerve activity by inhibiting the effect of NE rather than blunting its...

  16. Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Christensen, N J; Ring-Larsen, H

    1989-01-01

    In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L[3H]norepinephrine ([3H]NE) for 75...... minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of [3H]NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver......-intestine extraction ratios of [3H]NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis...

  17. Divergent effects of norepinephrine, dopamine and substance P on the activation, differentiation and effector functions of human cytotoxic T lymphocytes

    Directory of Open Access Journals (Sweden)

    Niggemann Bernd

    2009-12-01

    Full Text Available Abstract Background Neurotransmitters are important regulators of the immune system, with very distinct and varying effects on different leukocyte subsets. So far little is known about the impact of signals mediated by neurotransmitters on the function of CD8+ T lymphocytes. Therefore, we investigated the influence of norepinephrine, dopamine and substance P on the key tasks of CD8+ T lymphocytes: activation, migration, extravasation and cytotoxicity. Results The activation of naïve CD8+ T lymphocytes by CD3/CD28 cross-linking was inhibited by norepinephrine and dopamine, which was caused by a downregulation of interleukin (IL-2 expression via Erk1/2 and NF-κB inhibition. Furthermore, all of the investigated neurotransmitters increased the spontaneous migratory activity of naïve CD8+ T lymphocytes with dopamine being the strongest inducer. In contrast, activated CD8+ T lymphocytes showed a reduced migratory activity in the presence of norepinephrine and substance P. With regard to extravasation we found norepinephrine to induce adhesion of activated CD8+ T cells: norepinephrine increased the interleukin-8 release from endothelium, which in turn had effect on the activated CXCR1+ CD8+ T cells. At last, release of cytotoxic granules from activated cells in response to CD3 cross-linking was not influenced by any of the investigated neurotransmitters, as we have analyzed by measuring the β-hexosamidase release. Conclusion Neurotransmitters are specific modulators of CD8+ T lymphocytes not by inducing any new functions, but by fine-tuning their key tasks. The effect can be either stimulatory or suppressive depending on the activation status of the cells.

  18. Histone Demethylase JMJD2A Inhibition Attenuates Neointimal Hyperplasia in the Carotid Arteries of Balloon-Injured Diabetic Rats via Transcriptional Silencing: Inflammatory Gene Expression in Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Hu Qi

    2015-09-01

    Full Text Available Background/Aims: Diabetic patients suffer from severe neointimal hyperplasia following angioplasty. The epigenetic abnormalities are increasingly considered to be relevant to the pathogenesis of diabetic cardiovascular complications. But the epigenetic mechanisms linking diabetes and coronary restenosis have not been fully elucidated. In this study, we explored the protective effect and underlying mechanisms of demethylases JMJD2A inhibition in balloon-injury induced neointimal formation in diabetic rats. Methods: JMJD2A inhibition was achieved by the chemical inhibitor 2,4-pyridinedicarboxylic acid (2,4-PDCA and small interfering RNA (siRNA. In vitro, we investigated the proliferation, migration and inflammation of rat vascular smooth muscle cells (VSMCs in response to high glucose (HG. In vivo, diabetic rats induced using high-fat diet and low-dose streptozotocin (35mg/kg underwent carotid artery balloon injury. Morphometric analysis was performed using hematein eosin and immumohistochemical staining. Chromatin Immunoprecipitation (ChIP was conducted to detect modification of H3K9me3 at inflammatory genes promoters. Results: The global JMJD2A was increased in HG-stimulated VSMCs and balloon-injured arteries of diabetic rats, accompanied by decreased H3K9me3. The inhibition of JMJD2A suppressed VSMCs proliferation, migration and inflammation induced by high glucose (HG in vitro. And JMJDA2A inhibition attenuated neointimal formation in balloon-injured diabetic rats. The underlying mechanisms were relevant to the restoration of H3K9me3 levels at the promoters of MCP-1 and IL-6, and then the suppressed expression of MCP-1 and IL-6. Conclusion: The JMJD2A inhibition significantly attenuated neointimal formation in balloon injured diabetic rats via the suppression of VSMCs proliferation, migration, and inflammation by restoring H3K9me3.

  19. Mir-22-3p Inhibits Arterial Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia by Targeting HMGB1 in Arteriosclerosis Obliterans

    Directory of Open Access Journals (Sweden)

    Shui-chuan Huang

    2017-08-01

    Full Text Available Background: Aberrant vascular smooth muscle cell (VSMC proliferation and migration contribute to the development of vascular pathologies, such as atherosclerosis and post-angioplasty restenosis. The aim of this study was to determine whether miR-22-3p plays a role in regulating human artery vascular smooth muscle cell (HASMC function and neointima formation. Methods: Quantitative real-time PCR (qRT-PCR and fluorescence in situ hybridization (FISH were used to detect miR-22-3p expression in human arteries. Cell Counting Kit-8 (CCK-8 and EdU assays were performed to assess cell proliferation, and transwell and wound closure assays were performed to assess cell migration. Moreover, luciferase reporter assays were performed to identify the target genes of miR-22-3p. Finally, a rat carotid artery balloon-injury model was used to determine the role of miR-22-3p in neointima formation. Results: MiR-22-3p expression was downregulated in arteriosclerosis obliterans (ASO arteries compared with normal arteries, as well as in platelet-derived growth factor-BB (PDGF-BB-stimulated HASMCs compared with control cells. MiR-22-3p overexpression had anti-proliferative and anti-migratory effects and dual-luciferase assay showed that high mobility group box-1 (HMGB1 is a direct target of miR-22-3p in HASMCs. Furthermore, miR-22-3p expression was negatively correlated with HMGB1 expression in ASO tissue specimens. Finally, LV-miR-22-3p-mediated miR-22-3p upregulation significantly suppressed neointimal hyperplasia specifically by reducing HMGB1 expression in vivo. Conclusions: Our results indicate that miR-22-3p is a key molecule in regulating HASMC proliferation and migration by targeting HMGB1 and that miR-22-3p and HMGB1 may be therapeutic targets in the treatment of human ASO.

  20. Dominant negative insulin-like growth factor-1 receptor inhibits neointimal formation through suppression of vascular smooth muscle cell migration and proliferation, and induction of apoptosis

    International Nuclear Information System (INIS)

    Lim, Hyun-Joung; Park, Hyun-Young; Ko, Young-Guk; Lee, Sea-Hyoung; Cho, Seung-Yeon; Lee, Eun Jig; Jameson, J. Larry; Jang, Yangsoo

    2004-01-01

    Blocking of the IGF-1 signaling pathway targeting the IGF-1 receptor (IGF-1R) provides a potential treatment strategy for restenosis. In this study, we have examined the effects of a dominant negative IGF-1R (IGF-1Rt) on primary rat VSMCs in vitro and on injured rat carotid artery in vivo. Ad/IGF-1Rt infection inhibited VSMC migration and proliferation, and it also induced apoptosis by inhibiting phosphorylation of Akt and phosphorylation of ERK1/2. Consistent with the anti-proliferative and apoptotic effects in vitro, the Ad/IGF-1Rt infection markedly reduced neointimal formation in carotid injury model. Ad/IGF-1Rt treated carotid arteries exhibited a suppressed proliferation index, PCNA expression, and also were stained positive for TUNEL assay. These results indicate that a dominant negative IGF-1R has the potential to reduce neointimal formation of injured rats' carotid arteries. The delivery of dominant negative IGF-1R by adenoviral or other vectors may provide a useful strategy for inhibiting restenosis after angioplasty

  1. Cyclic GMP alters Ca exchange in vascular smooth muscle

    International Nuclear Information System (INIS)

    Magliola, L.; Bailey, B.; Jones, A.W.

    1986-01-01

    Contraction and 42 K efflux from vascular smooth muscle stimulated either by norepinephrine (NE) or by K-depolarization is dependent on an increase in cytosolic Ca concentration. The purpose of this study was to determine if cyclic GMP (cGMP) inhibited these processes and if inhibition was secondary to the action of cGMP on Ca movements. Basal cGMP content of rat aorta was 1.2 fmol/mg wet wt. Sodium nitroprusside (NP) increased cGMP ∼2-fold at 1 nM and ∼750-fold at 1 μM with no effect on cAMP levels. A 5 min pretreatment with NP (1 μM) completely prevented tension development induced by 3 μM NE. The same concentration of NP also inhibited NE-stimulated 42 K and 45 Ca efflux > 90 and > 80%, respectively. Removal of NP in the continued presence of NE (3 μM) caused recovery of the 42 K efflux response to ∼75% of control with a half-time of ∼2.5 min. NP (1 μM) also caused a rapid relaxation of aorta contracted with 3 μM NE and a loss of the 42 K efflux response with half-times of 2-3 min. In contrast, 100 μM NP produced only a 50% inhibition of contraction induced by high K (55 mM). Also, NP (1 μM) inhibited K-stimulated 42 K efflux only ∼25%. These results demonstrate both a concentration- and a time-dependent relationship between increases in cGMP induced by NP and decreases in NE-stimulated contraction, 42 K and 45 Ca effluxes. They also indicate that the sensitivity of NE-induced contraction and 42 K efflux to NP is greater than that induced by high K. These studies suggest that cGMP modulates the control sites for Ca exchange in the plasma membrane and sarcoplasmic reticulum

  2. Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala

    Science.gov (United States)

    Sadowski, Renee N.; Canal, Clint E.; Gold, Paul E.

    2011-01-01

    When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 hr later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis. PMID:21453778

  3. Norepinephrine release in arteries of spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Zsoter, T.T.; Wolchinsky, C.; Lawrin, M.; Sirko, S.

    1982-01-01

    The role of the sympathetic nervous system in arterial hypertension cannot be properly evaluated until it is known about the activity in the vessels themselves. In this study researchers investigated the effect of transmural stimulation on the tail artery - labelled in vitro with 3 H-norepinephrine - of 7-9 week old spontaneously hypertensive rats (SHR) and Wistar Kyoto controls (WKR). Electrical stimulation using two frequencies (2 and 10 Hz) resulted in significantly more 3 H overflow in vessels from SHR than from WKR. With 10 Hz stimulation the fractional release was also greater. Column chromatographic analysis of 3 H overflow revealed that transmural stimulation in arteries of SHR enhanced mainly the release of norepinephrine and not of its metabolites. Significantly, an increased release of 3 H-norepinephrine on stimulation was observed in SHR before the full development of hypertension suggesting that it might be a cause rather than a consequence of high blood pressure

  4. Norepinephrine kinetics and dynamics in septic shock and trauma patients.

    Science.gov (United States)

    Beloeil, H; Mazoit, J-X; Benhamou, D; Duranteau, J

    2005-12-01

    There is considerable variability in the inter-patient response to norepinephrine. Pharmacokinetic studies of dopamine infusion in volunteers and in patients have also shown large variability. The purpose of this study was to define the pharmacokinetics of norepinephrine in septic shock and trauma patients. After Ethical Committee approval and written informed family consent, 12 patients with septic shock and 11 trauma patients requiring norepinephrine infusion were studied. Norepinephrine dose was increased in three successive steps of 0.1 mg kg(-1) min(-1) at 15-min intervals (20% maximum allowed increase in arterial pressure). Arterial blood was sampled before and at 0.5, 13, and 15 min after each infusion rate change and 30 s, 1, 2, 5, 10, and 15 min after return to baseline dosing. Norepinephrine was assayed by HPLC. The pharmacokinetics were modelled using NONMEM (one-compartment model). The effects of group, body weight (BW), gender and SAPS II (Simplified Acute Physiology Score II) [Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. J Am Med Assoc 1993; 270: 2957-63] patients score on clearance (CL) and volume of distribution (V) were tested. Group, gender, and BW did not influence CL or V. CL was negatively related to SAPS II. CL and T(1/2) varied from 3 litre min(-1) and 2 min, respectively, when SAPS II=20 to 0.9 litre min(-1) and 6.8 min when SAPS II=60. In trauma patients and in septic shock patients, norepinephrine clearance is negatively related to SAPS II.

  5. The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shuai [Beijing Institute of Respiratory Medicine, Beijing Chao-yang Hospital, Capital Medical University, 8 Gongti South Rd, Beijing (China); Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, 8 Gongti South Rd, Beijing (China); Zou, Lihui [Institute of Geriatrics, Beijing Hospital, 1 Dahua Rd, Beijing (China); National Clinical Research Center for Respiratory Diseases, 1 Dahua Rd, Beijing (China); Yang, Ting; Yang, Yuanhua; Zhai, Zhenguo [Beijing Institute of Respiratory Medicine, Beijing Chao-yang Hospital, Capital Medical University, 8 Gongti South Rd, Beijing (China); Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, 8 Gongti South Rd, Beijing (China); Xiao, Fei [Institute of Geriatrics, Beijing Hospital, 1 Dahua Rd, Beijing (China); National Clinical Research Center for Respiratory Diseases, 1 Dahua Rd, Beijing (China); Wang, Chen, E-mail: chenwangcjfh@163.com [Beijing Institute of Respiratory Medicine, Beijing Chao-yang Hospital, Capital Medical University, 8 Gongti South Rd, Beijing (China); Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, 8 Gongti South Rd, Beijing (China); National Clinical Research Center for Respiratory Diseases, 1 Dahua Rd, Beijing (China)

    2015-03-15

    Background: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. Objectives: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. Methods: After the transfection with PAI-2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured human PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. Results: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. Conclusions: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. - Highlights: • sGC activator BAY41-2272 up regulated PAI-2 in PASMCs, on the mRNA and protein level. • PAI-2 overexpression inhibits the proliferation and migration of human PASMCs. • PAI-2 overexpression promotes the apoptosis of human PASMCs. • sGC activator might alleviate the vascular remodeling in pulmonary hypertension.

  6. The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2

    International Nuclear Information System (INIS)

    Zhang, Shuai; Zou, Lihui; Yang, Ting; Yang, Yuanhua; Zhai, Zhenguo; Xiao, Fei; Wang, Chen

    2015-01-01

    Background: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. Objectives: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. Methods: After the transfection with PAI-2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured human PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. Results: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. Conclusions: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. - Highlights: • sGC activator BAY41-2272 up regulated PAI-2 in PASMCs, on the mRNA and protein level. • PAI-2 overexpression inhibits the proliferation and migration of human PASMCs. • PAI-2 overexpression promotes the apoptosis of human PASMCs. • sGC activator might alleviate the vascular remodeling in pulmonary hypertension

  7. Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

    Science.gov (United States)

    Dreyfus, Nicolas; Myers, Jason K; Badescu, Valentina O; de Frutos, Oscar; de la Puente, Maria Luz; Ding, Chunjin; Filla, Sandra A; Fynboe, Karsten; Gernert, Douglas L; Heinz, Beverly A; Hemrick-Luecke, Susan K; Johnson, Kirk W; Johnson, Michael P; López, Pilar; Love, Patrick L; Martin, Laura J; Masquelin, Thierry; McCoy, Michael J; Mendiola, Javier; Morrow, Denise; Muhlhauser, Mark; Pascual, Gustavo; Perun, Thomas J; Pfeifer, Lance A; Phebus, Lee A; Richards, Simon J; Rincón, Juan Antonio; Seest, Eric P; Shah, Jikesh; Shaojuan, Jia; Simmons, Rosa Maria A; Stephenson, Gregory A; Tromiczak, Eric G; Thompson, Linda K; Walter, Magnus W; Weber, Wayne W; Zarrinmayeh, Hamideh; Thomas, Craig E; Joshi, Elizabeth; Iyengar, Smriti; Johansson, Anette M

    2013-06-13

    The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

  8. Effect of tyrosine kinase blockade on norepinephrine-induced cytosolic calcium response in rat afferent arterioles

    DEFF Research Database (Denmark)

    Salomonsson, Max; Arendshorst, William J

    2004-01-01

    We used genistein (Gen) and tyrphostin 23 (Tyr-23) to evaluate the importance of tyrosine phosphorylation in norepinephrine (NE)-induced changes in intracellular free calcium concentration ([Ca(2+)](i)) in rat afferent arterioles. [Ca(2+)](i) was measured in microdissected arterioles using...... ratiometric photometry of fura 2 fluorescence. The control [Ca(2+)](i) response to NE (1 microM) consisted of a rapid initial peak followed by a plateau phase sustained above baseline. Pretreatment with the tyrosine kinase inhibitor Tyr-23 (50 microM, 10 min) caused a slow 40% increase in baseline [Ca(2+)](i...... of nifedipine and Tyr-23 were not additive. Nifedipine had no inhibitory effect after Tyr-23 pretreatment, indicating Tyr-23 inhibition of Ca(2+) entry. Another tyrosine kinase inhibitor, Gen (5 and 50 microM), did not affect baseline [Ca(2+)](i). High-dose Gen inhibited the peak and plateau response to NE...

  9. Effects of cocaine on [11C]norepinephrine and [11C]β-CIT uptake in the primate peripheral organs measured by PET

    International Nuclear Information System (INIS)

    Suhara, Tetsuya; Farde, L.; Halldin, C.; Karlsson, P.; Nagren, K.

    1996-01-01

    The toxic properties of cocaine are related to both the central and peripheral effects. To identify possible lethal mechanisms and the accumulation of cocaine in various organs, the effects of cocaine on [ 11 C] norepinephrine and cocaine congener [ 11 C]β-CIT uptake in Cynomolgus monkeys were measured by positron emission tomography (PET). Cocaine (5 mg/kg) noticeably inhibited [ 11 C] norepinephrine uptake in the heart. The uptake of [ 11 C]β-CIT in the heart and lung was reduced by pretreatment with cocaine. There was a significant uptake in the liver which was increased following cocaine pretreatment. The results of this study confirm that cocaine blocks the neuronal uptake of norepinephrine in sympathetic nerve terminals in the myocardium. The effect of cocaine on [ 11 C]β-CIT uptake indicates that the binding sites in the heart and lung are saturable, while the uptake mechanism in the liver is different from those of the heart and lung. (author)

  10. CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression

    Directory of Open Access Journals (Sweden)

    Ming-Horng Tsai

    2017-08-01

    Full Text Available Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9 induced migration of human aortic smooth muscle cells (HASMCs is the most common and basic pathological feature. Carbon monoxide (CO, a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2 on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed. Keywords: Angiotensin II, Carbon monoxide, Human aortic smooth muscle cell, Inflammation, Matrix metallopeptidase

  11. Inorganic phosphate inhibits sympathetic neurotransmission in canine saphenous veins

    International Nuclear Information System (INIS)

    Edoute, Y.; Vanhoutte, P.M.; Shepherd, J.T.

    1987-01-01

    Inorganic phosphate has been proposed as the initiator of metabolic vasodilatation in active skeletal muscle. The present study was primarily designed to determine if this substance has an inhibitory effect on adrenergic neurotransmission. Rings of canine saphenous veins were suspended for isometric tension recording in organ chambers. A comparison was made of the ability of inorganic phosphate (3 to 14 mM) to relax rings contracted to the same degree by electrical stimulation, exogenous norepinephrine, and prostaglandin F/sub 2α/. The relaxation during electrical stimulation was significantly greater at all concentrations of phosphate. In strips of saphenous veins previously incubated with [ 3 H]norepinephrine, the depression of the contractile response caused by phosphate during electrical stimulated was accompanied by a significant reduction in the overflow of labeled neurotransmitter. Thus inorganic phosphate inhibits sympathetic neurotransmission and hence may have a key role in the sympatholysis in the active skeletal muscles during exercise. By contrast, in this preparation, it has a modest direct relaxing action on the vascular smooth muscle

  12. [Spatial structure of the calixarene-aminophosphonic acids is important for their inhibition of the Na+,K(+)-ATPase activity in plasma membrane of smooth muscle cells].

    Science.gov (United States)

    Veklich, T O; Shkrabak, O A; Rodik, R V; Boĭko, V I; Kal'chenko, V I; Kosterin, S O

    2010-01-01

    It was found that calixarene C-107 (5,17-diamino(2-pyridyl)methylphosphono-11,23-di-tret-butyl-26,28-dihydroxy-25,27-dipropoxycalix[4]arene) could effectively reduce Na+,K(+)-ATPase activity of the myometrium cell plasmatic membranes (the value of the apparent constant of inhibition I0.5 was 33 +/- 4 nM) while it practically did not influence the "basal" Mg2(+)-ATPase activity of the same membrane. In comparative experiments, we have shown that the model calixarene C-150--the calixarene "scaffold" (26,28-dihydroxy-25,27-dipropoxycalix[4]arene), and the model compound M-3 (4-hydroxyaniline(2-pyridine)methylphosphonic acid)--a fragment of the calixarene C-107, had practically no influence on the enzymatic activities of Na+,K(+)-ATPase and Mg(2+)-ATPase over a wide range of concentrations. Hence, the influence of calixarene C-107 on Na+,K(+)-ATPase activity was caused by the joint action of two aminophosphonic substituents on the upper rim of the calixarene bowl. The isomer of calixarene C-107--calixarene C-160 (5,11-diamino(2-pyridyl)methylphosphono-17,23-di-tret-butyl-26,28-dihydroxy-25,27-dipropoxycalix[4]arene) also did not influence the Na+,K(+)-ATPase and Mg(2+)-ATPase activities of plasmatic membrane of myometrium cells. We carried out molecular modeling of calixarenes C-107 and C-160 and showed differences in interatomic distance between aminophosphonic substituents of mentioned calixarenes. We came to the conclusion that spatial structure of calixarene C-107, namely localization of two aminophosphonic substituents in 5,17 position of the upper rim of this calixarene, is crucial for inhibition of Na+,K(+)-ATPase activity. Using laser correlation spectroscopy it was found that the 100 microM solution of calixarene C-107 and 2.5% DMSO had microparticles with size range from 100 nm to 10 microm. Plasma membrane vesicles had average hydrodynamic diameter 401 +/- 17 nm, but after interaction of these vesicles with calixarene C-107 we have registered the creation of

  13. Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase

    NARCIS (Netherlands)

    Warren, C.M.; van den Brink, R.L.; Nieuwenhuis, S.; Bosch, J.A.

    It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy

  14. Arousal, exploration and the locus coeruleus-norepinephrine system

    NARCIS (Netherlands)

    Jepma, Marieke

    2011-01-01

    The studies described in this thesis address a range of topics related to arousal, exploration, temporal attention, and the locus coeruleus-norepinephrine (LC-NE) system. Chapters 2 and 3 report two studies that investigated a recent theory about the role of the LC-NE system in the regulation of the

  15. Radioenzymatic simultaneous determination of epinephrine and norepinephrine in plasma

    International Nuclear Information System (INIS)

    Mueller, T.

    1978-01-01

    The high-pressure liquid chromatography (= HPLC) was used in simultaneous determinations of a few pg epinephrine and norepinephrine. This separation procedure improves the efficiency when compared with the conventional thin-layer chromatographic methods (TLC) and allows routine assays in plasma. (orig.) [de

  16. Distinctive G Protein-Dependent Signaling by Protease-Activated Receptor 2 (PAR2 in Smooth Muscle: Feedback Inhibition of RhoA by cAMP-Independent PKA.

    Directory of Open Access Journals (Sweden)

    Wimolpak Sriwai

    Full Text Available We examined expression of protease-activated receptors 2 (PAR2 and characterized their signaling pathways in rabbit gastric muscle cells. The PAR2 activating peptide SLIGRL (PAR2-AP stimulated Gq, G13, Gi1, PI hydrolysis, and Rho kinase activity, and inhibited cAMP formation. Stimulation of PI hydrolysis was partly inhibited in cells expressing PAR2 siRNA, Gaq or Gai minigene and in cells treated with pertussis toxin, and augmented by expression of dominant negative regulator of G protein signaling (RGS4(N88S. Stimulation of Rho kinase activity was abolished by PAR-2 or Ga13 siRNA, and by Ga13 minigene. PAR2-AP induced a biphasic contraction; initial contraction was selectively blocked by the inhibitor of PI hydrolysis (U73122 or MLC kinase (ML-9, whereas sustained contraction was selectively blocked by the Rho kinase inhibitor (Y27632. PAR2-AP induced phosphorylation of MLC20, MYPT1 but not CPI-17. PAR2-AP also caused a decrease in the association of NF-kB and PKA catalytic subunit: the effect of PAR2-AP was blocked by PAR2 siRNA or phosphorylation-deficient RhoA (RhoA(S188A. PAR2-AP-induced degradation of IkBa and activation of NF-kB were abolished by the blockade of RhoA activity by Clostridium botulinum C3 exoenzyme suggesting RhoA-dependent activation of NF-kB. PAR2-AP-stimulated Rho kinase activity was significantly augmented by the inhibitors of PKA (myristoylated PKI, IKK2 (IKKIV or NF-kB (MG132, and in cells expressing dominant negative mutants of IKK (IKK(K44A, IkBa (IkBa (S32A/S36A or RhoA(S188A, suggesting feedback inhibition of Rho kinase activity via PKA derived from NF-kB pathway. PAR2-AP induced phosphorylation of RhoA and the phosphorylation was attenuated in cells expressing phosphorylation-deficient RhoA(S188A. Our results identified signaling pathways activated by PAR2 to mediate smooth muscle contraction and a novel pathway for feedback inhibition of PAR2-stimulated RhoA. The pathway involves activation of the NF-kB to

  17. 2′,3′-cAMP, 3′-AMP, and 2′-AMP inhibit human aortic and coronary vascular smooth muscle cell proliferation via A2B receptors

    Science.gov (United States)

    Ren, Jin; Gillespie, Delbert G.

    2011-01-01

    Rat vascular smooth muscle cells (VSMCs) from renal microvessels metabolize 2′,3′-cAMP to 2′-AMP and 3′-AMP, and these AMPs are converted to adenosine that inhibits microvascular VSMC proliferation via A2B receptors. The goal of this study was to test whether this mechanism also exists in VSMCs from conduit arteries and whether it is similarly expressed in human vs. rat VSMCs. Incubation of rat and human aortic VSMCs with 2′,3′-cAMP concentration-dependently increased levels of 2′-AMP and 3′-AMP in the medium, with a similar absolute increase in 2′-AMP vs. 3′-AMP. In contrast, in human coronary VSMCs, 2′,3′-cAMP increased 2′-AMP levels yet had little effect on 3′-AMP levels. In all cell types, 2′,3′-cAMP increased levels of adenosine, but not 5′-AMP, and 2′,3′-AMP inhibited cell proliferation. Antagonism of A2B receptors (MRS-1754), but not A1 (1,3-dipropyl-8-cyclopentylxanthine), A2A (SCH-58261), or A3 (VUF-5574) receptors, attenuated the antiproliferative effects of 2′,3′-cAMP. In all cell types, 2′-AMP, 3′-AMP, and 5′-AMP increased adenosine levels, and inhibition of ecto-5′-nucleotidase blocked this effect of 5′-AMP but not that of 2′-AMP nor 3′-AMP. Also, 2′-AMP, 3′-AMP, and 5′-AMP, like 2′,3′-cAMP, exerted antiproliferative effects that were abolished by antagonism of A2B receptors with MRS-1754. In conclusion, VSMCs from conduit arteries metabolize 2′,3′-cAMP to AMPs, which are metabolized to adenosine. In rat and human aortic VSMCs, both 2′-AMP and 3′-AMP are involved in this process, whereas, in human coronary VSMCs, 2′,3′-cAMP is mainly converted to 2′-AMP. Because adenosine inhibits VSMC proliferation via A2B receptors, local vascular production of 2′,3′-cAMP may protect conduit arteries from atherosclerosis. PMID:21622827

  18. Clonidine reduces norepinephrine and improves bone marrow function in a rodent model of lung contusion, hemorrhagic shock, and chronic stress.

    Science.gov (United States)

    Alamo, Ines G; Kannan, Kolenkode B; Ramos, Harry; Loftus, Tyler J; Efron, Philip A; Mohr, Alicia M

    2017-03-01

    Propranolol has been shown previously to restore bone marrow function and improve anemia after lung contusion/hemorrhagic shock. We hypothesized that daily clonidine administration would inhibit central sympathetic outflow and restore bone marrow function in our rodent model of lung contusion/hemorrhagic shock with chronic stress. Male Sprague-Dawley rats underwent 6 days of restraint stress after lung contusion/hemorrhagic shock during which the animals received clonidine (75 μg/kg) after the restraint stress. On postinjury day 7, we assessed urine norepinephrine, blood hemoglobin, plasma granulocyte colony stimulating factor, and peripheral blood mobilization of hematopoietic progenitor cells, as well as bone marrow cellularity and erythroid progenitor cell growth. The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased urine norepinephrine levels, improved bone marrow cellularity, restored erythroid progenitor colony growth, and improved hemoglobin (14.1 ± 0.6 vs 10.8 ± 0.6 g/dL). The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased hematopoietic progenitor cells mobilization and restored granulocyte colony stimulating factor levels. After lung contusion/hemorrhagic shock with chronic restraint stress, daily administration of clonidine restored bone marrow function and improved anemia. Alleviating chronic stress and decreasing norepinephrine is a key therapeutic target to improve bone marrow function after severe injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Norepinephrine as a Potential Aggravator of Symptomatic Cerebral Vasospasm: Two Cases and Argument for Milrinone Therapy

    Directory of Open Access Journals (Sweden)

    F. A. Zeiler

    2014-01-01

    Full Text Available Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140–150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130–140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.

  20. Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

    International Nuclear Information System (INIS)

    Peoples, R.W.

    1989-01-01

    Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of [ 3 H] norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 x 10 -5 -10 -3 M, enhanced potassium stimulated [ 3 H] norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of [ 3 H] norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA A receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA A agonist muscimol, 10 -4 M, mimicked the effect of GABA, but the GABA B agonist (±)baclofen, 10 -4 M, did not affect the release of [ 3 H] norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA A , but not GABA B , receptors. In contrast to the results that would be predicted for an event involving GABA A receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10 -8 and 10 -4 M. Thus these receptors may constitute a subclass of GABA A receptors. These results support a role of GABA uptake and GABA A receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat

  1. Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Peoples, R.W.

    1989-01-01

    Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of ({sup 3}H) norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 {times} 10{sup {minus}5}-10{sup {minus}3} M, enhanced potassium stimulated ({sup 3}H) norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of ({sup 3}H) norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA{sub A} receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA{sub A} agonist muscimol, 10{sup {minus}4} M, mimicked the effect of GABA, but the GABA{sub B} agonist ({plus minus})baclofen, 10{sup {minus}4} M, did not affect the release of ({sup 3}H) norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA{sub A}, but not GABA{sub B}, receptors. In contrast to the results that would be predicted for an event involving GABA{sub A} receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10{sup {minus}8} and 10{sup {minus}4} M. Thus these receptors may constitute a subclass of GABA{sub A} receptors. These results support a role of GABA uptake and GABA{sub A} receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat.

  2. Anti-CTGF single-chain variable fragment dimers inhibit human airway smooth muscle (ASM) cell proliferation by down-regulating p-Akt and p-mTOR levels.

    Science.gov (United States)

    Gao, Wei; Cai, Liting; Xu, Xudong; Fan, Juxiang; Xue, Xiulei; Yan, Xuejiao; Qu, Qinrong; Wang, Xihua; Zhang, Chen; Wu, Guoqiu

    2014-01-01

    Connective tissue growth factor (CTGF) contributes to airway smooth muscle (ASM) cell hyperplasia in asthma. Humanized single-chain variable fragment antibody (scFv) was well characterized as a CTGF antagonist in the differentiation of fibroblast into myofibroblast and pulmonary fibrosis in our previous studies. To further improve the bioactivity of scFv, we constructed a plasmid to express scFv-linker-matrilin-6×His fusion proteins that could self-assemble into the scFv dimers by disulfide bonds in matrilin under non-reducing conditions. An immunoreactivity assay demonstrated that the scFv dimer could highly bind to CTGF in a concentration-dependent manner. The MTT and EdU assay results revealed that CTGF (≥10 ng/mL) promoted the proliferation of ASM cells, and this effect was inhibited when the cells were treated with anti-CTGF scFv dimer. The western blot analysis results showed that increased phosphorylation of Akt and mTOR induced by CTGF could be suppressed by this scFv dimer. Based on these findings, anti-CTGF scFv dimer may be a potential agent for the prevention of airway remodeling in asthma.

  3. Gold Nanoparticles-Based Barcode Analysis for Detection of Norepinephrine.

    Science.gov (United States)

    An, Jeung Hee; Lee, Kwon-Jai; Choi, Jeong-Woo

    2016-02-01

    Nanotechnology-based bio-barcode amplification analysis offers an innovative approach for detecting neurotransmitters. We evaluated the efficacy of this method for detecting norepinephrine in normal and oxidative-stress damaged dopaminergic cells. Our approach use a combination of DNA barcodes and bead-based immunoassays for detecting neurotransmitters with surface-enhanced Raman spectroscopy (SERS), and provides polymerase chain reaction (PCR)-like sensitivity. This method relies on magnetic Dynabeads containing antibodies and nanoparticles that are loaded both with DNA barcords and with antibodies that can sandwich the target protein captured by the Dynabead-bound antibodies. The aggregate sandwich structures are magnetically separated from the solution and treated to remove the conjugated barcode DNA. The DNA barcodes are then identified by SERS and PCR analysis. The concentration of norepinephrine in dopaminergic cells can be readily detected using the bio-barcode assay, which is a rapid, high-throughput screening tool for detecting neurotransmitters.

  4. Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish.

    Science.gov (United States)

    Singh, Chanpreet; Oikonomou, Grigorios; Prober, David A

    2015-09-16

    Pharmacological studies in mammals suggest that norepinephrine (NE) plays an important role in promoting arousal. However, the role of endogenous NE is unclear, with contradicting reports concerning the sleep phenotypes of mice lacking NE due to mutation of dopamine β-hydroxylase (dbh). To investigate NE function in an alternative vertebrate model, we generated dbh mutant zebrafish. In contrast to mice, these animals exhibit dramatically increased sleep. Surprisingly, despite an increase in sleep, dbh mutant zebrafish have a reduced arousal threshold. These phenotypes are also observed in zebrafish treated with small molecules that inhibit NE signaling, suggesting that they are caused by the lack of NE. Using genetic overexpression of hypocretin (Hcrt) and optogenetic activation of hcrt-expressing neurons, we also find that NE is important for Hcrt-induced arousal. These results establish a role for endogenous NE in promoting arousal and indicate that NE is a critical downstream effector of Hcrt neurons.

  5. Effects of cadmium on the uptake of dopamine and norepinephrine in rat brain synaptosomes

    International Nuclear Information System (INIS)

    Anon.

    1986-01-01

    Cadmium (Cd) a known environmental contaminant is neurotoxic. Kinetics of cadmium inhibition indicate that the metal may compete with ATP and Na + sites on Na + -K + ATPase in rat brain synaptosomes. Uptake and release processes of catecholamines into the central nervous system are dependent on membrane bound Na + -K + ATPase. It is suggested that the uptake and release processes of dopamine (DA) and norepinephrine (NE) in neurons are energy utilizing and hence are dependent on active ion transport. If the two aforementioned mechanisms are truly interdependent, then any alteration caused by a toxin to either of the above two mechanisms should also cause a parallel change in the other. The purpose of this study was to examine in vitro effects of cadmium chloride on the uptake of DA and NE and the activity of ATPase in the rat brain synaptosome

  6. Mechanisms of immune regulation by norepinephrine and cholera toxin

    International Nuclear Information System (INIS)

    Campbell, K.S.

    1988-01-01

    Norepinephrine has previously been demonstrated by this laboratory to potentiate the in vitro T-dependent antibody response through the stimulation of β-adrenergic receptors. The role of β-adrenergic receptor subtypes in norepinephrine-induced potentiation of the antibody responses was examined with selective β-adrenergic antagonists. The antagonists were metoprolol (β 1 -selective), ICI 118-551 (β 2 -selective), and propranolol (β-non-selective). Both propranolol and ICI 118-551 blocked norepinephrine-induced potentiation of the antibody response, but metoprolol was ineffective. Receptor binding competition of antagonists with the radioligant, [ 3 H]CGP-12177 was examined and results were analyzed with the computer program, LIGAND. Competition by ICI 118-551 identified 75% β 2 - and 25% β 1 -adrenergic receptors on splenic mononuclear cells. Enriched T lymphocytes exhibited 75% β 2 -adrenergic receptors, while enriched B lymphocytes contained 90% β 2 -adrenergic receptors as identified by ICI 118-551. Greater than twice as many total receptors were identified on B lymphocytes than T lymphocytes. A T cell lymphoma contained about 60% β 2 -receptors, while 100% were β 2 receptors on a B cell lymphoma, as assessed by ICI 118-551. Results support a heterogeneous β-adrenergic receptor population on T lymphocytes and a more homogeneous β 2 -population on B lymphocytes

  7. Mechanisms of immune regulation by norepinephrine and cholera toxin

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, K.S.

    1988-01-01

    Norepinephrine has previously been demonstrated by this laboratory to potentiate the in vitro T-dependent antibody response through the stimulation of {beta}-adrenergic receptors. The role of {beta}-adrenergic receptor subtypes in norepinephrine-induced potentiation of the antibody responses was examined with selective {beta}-adrenergic antagonists. The antagonists were metoprolol ({beta}{sub 1}-selective), ICI 118-551 ({beta}{sub 2}-selective), and propranolol ({beta}-non-selective). Both propranolol and ICI 118-551 blocked norepinephrine-induced potentiation of the antibody response, but metoprolol was ineffective. Receptor binding competition of antagonists with the radioligant, ({sup 3}H)CGP-12177 was examined and results were analyzed with the computer program, LIGAND. Competition by ICI 118-551 identified 75% {beta}{sub 2}- and 25% {beta}{sub 1}-adrenergic receptors on splenic mononuclear cells. Enriched T lymphocytes exhibited 75% {beta}{sub 2}-adrenergic receptors, while enriched B lymphocytes contained 90% {beta}{sub 2}-adrenergic receptors as identified by ICI 118-551. Greater than twice as many total receptors were identified on B lymphocytes than T lymphocytes. A T cell lymphoma contained about 60% {beta}{sub 2}-receptors, while 100% were {beta}{sub 2} receptors on a B cell lymphoma, as assessed by ICI 118-551. Results support a heterogeneous {beta}-adrenergic receptor population on T lymphocytes and a more homogeneous {beta}{sub 2}-population on B lymphocytes.

  8. MicroRNA-20b-5p inhibits platelet-derived growth factor-induced proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3.

    Science.gov (United States)

    Tang, Jin; Luo, Lingying

    2018-06-01

    Pediatric asthma is still a health threat to the pediatric population in recent years. The airway remodeling induced by abnormal airway smooth muscle (ASM) cell proliferation is an important cause of asthma. MicroRNAs (miRNAs) are important regulators of ASM cell proliferation. Numerous studies have reported that miR-20b-5p is a critical regulator for cell proliferation. However, whether miR-20b-5p is involved in regulating ASM cell proliferation remains unknown. In this study, we aimed to investigate the potential role of miR-20b-5p in regulating the proliferation of fetal ASM cell induced by platelet-derived growth factor (PDGF). Here, we showed that miR-20b-5p was significantly decreased in fetal ASM cells treated with PDGF. Biological experiments showed that the overexpression of miR-20b-5p inhibited the proliferation while miR-20b-5p inhibition markedly promoted the proliferation of fetal ASM cells. Bioinformatics analysis and luciferase reporter assay showed that miR-20b-5p directly targeted the 3'-UTR of signal transducer and activator of transcription 3 (STAT3). Further data showed that miR-20b-5p negatively regulated the expression of STAT3 in fetal ASM cells. Moreover, miR-20b-5p regulates the transcriptional activity of STAT3 in fetal ASM cells. Overexpression of STAT3 reversed the inhibitory effect of miR-20b-5p overexpression on fetal ASM cell proliferation while the knockdown of STAT3 abrogated the promoted effect of miR-20b-5p inhibition on fetal ASM cell proliferation. Overall, our results show that miR-20b-5p impedes PDGF-induced proliferation of fetal ASM cells through targeting STAT3. Our study suggests that miR-20b-5p may play an important role in airway remodeling during asthma and suggests that miR-20b-5p may serve as a potential therapeutic target for pediatric asthma. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  9. Bayesian Exponential Smoothing.

    OpenAIRE

    Forbes, C.S.; Snyder, R.D.; Shami, R.S.

    2000-01-01

    In this paper, a Bayesian version of the exponential smoothing method of forecasting is proposed. The approach is based on a state space model containing only a single source of error for each time interval. This model allows us to improve current practices surrounding exponential smoothing by providing both point predictions and measures of the uncertainty surrounding them.

  10. Smooth polyhedral surfaces

    KAUST Repository

    Gü nther, Felix; Jiang, Caigui; Pottmann, Helmut

    2017-01-01

    Polyhedral surfaces are fundamental objects in architectural geometry and industrial design. Whereas closeness of a given mesh to a smooth reference surface and its suitability for numerical simulations were already studied extensively, the aim of our work is to find and to discuss suitable assessments of smoothness of polyhedral surfaces that only take the geometry of the polyhedral surface itself into account. Motivated by analogies to classical differential geometry, we propose a theory of smoothness of polyhedral surfaces including suitable notions of normal vectors, tangent planes, asymptotic directions, and parabolic curves that are invariant under projective transformations. It is remarkable that seemingly mild conditions significantly limit the shapes of faces of a smooth polyhedral surface. Besides being of theoretical interest, we believe that smoothness of polyhedral surfaces is of interest in the architectural context, where vertices and edges of polyhedral surfaces are highly visible.

  11. Smooth polyhedral surfaces

    KAUST Repository

    Günther, Felix

    2017-03-15

    Polyhedral surfaces are fundamental objects in architectural geometry and industrial design. Whereas closeness of a given mesh to a smooth reference surface and its suitability for numerical simulations were already studied extensively, the aim of our work is to find and to discuss suitable assessments of smoothness of polyhedral surfaces that only take the geometry of the polyhedral surface itself into account. Motivated by analogies to classical differential geometry, we propose a theory of smoothness of polyhedral surfaces including suitable notions of normal vectors, tangent planes, asymptotic directions, and parabolic curves that are invariant under projective transformations. It is remarkable that seemingly mild conditions significantly limit the shapes of faces of a smooth polyhedral surface. Besides being of theoretical interest, we believe that smoothness of polyhedral surfaces is of interest in the architectural context, where vertices and edges of polyhedral surfaces are highly visible.

  12. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Energy Technology Data Exchange (ETDEWEB)

    Matthew, E.; Parfitt, A.G.; Sugden, D.; Engelhardt, D.L.; Zimmerman, E.A.; Klein, D.C.

    1984-02-01

    Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.

  13. Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study [ISRCTN70707830

    Directory of Open Access Journals (Sweden)

    Casanova Jose-Miguel

    2002-01-01

    Full Text Available Abstract Background Fibromyalgia syndrome displays sympathetically maintained pain features such as frequent post-traumatic onset and stimuli-independent pain accompanied by allodynia and paresthesias. Heart rate variability studies showed that fibromyalgia patients have changes consistent with ongoing sympathetic hyperactivity. Norepinephrine-evoked pain test is used to assess sympathetically maintained pain syndromes. Our objective was to define if fibromyalgia patients have norepinephrine-evoked pain. Methods Prospective double blind controlled study. Participants: Twenty FM patients, and two age/sex matched control groups; 20 rheumatoid arthritis patients and 20 healthy controls. Ten micrograms of norepinephrine diluted in 0.1 ml of saline solution were injected in a forearm. The contrasting substance, 0.1 ml of saline solution alone, was injected in the opposite forearm. Maximum local pain elicited during the 5 minutes post-injection was graded on a visual analog scale (VAS. Norepinephrine-evoked pain was diagnosed when norepinephrine injection induced greater pain than placebo injection. Intensity of norepinephrine-evoked pain was calculated as the difference between norepinephrine minus placebo-induced VAS scores. Results Norepinephrine-evoked pain was seen in 80 % of FM patients (95% confidence intervals 56.3 – 94.3%, in 30 % of rheumatoid arthritis patients and in 30 % of healthy controls (95% confidence intervals 11.9 – 54.3 (p Conclusions Fibromyalgia patients have norepinephrine-evoked pain. This finding supports the hypothesis that fibromyalgia may be a sympathetically maintained pain syndrome.

  14. Effect of pinacidil on norepinephrine- and potassium-induced contractions and membrane potential in rat and human resistance vessels and in rat aorta

    International Nuclear Information System (INIS)

    Videbaek, L.M.; Aalkjaer, C.; Mulvany, M.J.

    1988-01-01

    The effect of pinacidil on contractile responses to norepinephrine, potassium, and membrane potential was examined in rat and human resistance vessels. In some experiments rat aorta was also used. Pinacidil (0.1-30 microM) caused a concentration-dependent relaxation of norepinephrine-induced contractions in all vessels studied. In the same concentration range, pinacidil had only little effect on potassium (125 mM) activated rat mesenteric and femoral resistance vessels. In denervated rat mesenteric resistance vessels, a depolarization with potassium (125 mM) before superimposing a norepinephrine tone markedly diminished the effect of pinacidil. In resting rat mesenteric resistance vessels, pinacidil (1-10 microM) caused a hyperpolarization of 10-15 mV. In rat aorta, pinacidil (10 microM) caused a significant (p less than 0.001) increase in 86 Rb+ efflux rate constant whereas 1 microM had no effect. The results of these experiments indicate that the vasodilating effect may be caused by a hyperpolarization of the vascular smooth muscle cell membrane

  15. Smoothness of limit functors

    Indian Academy of Sciences (India)

    Abstract. Let S be a scheme. Assume that we are given an action of the one dimen- sional split torus Gm,S on a smooth affine S-scheme X. We consider the limit (also called attractor) subfunctor Xλ consisting of points whose orbit under the given action. 'admits a limit at 0'. We show that Xλ is representable by a smooth ...

  16. Myocardial imaging with a radioiodinated norepinephrine storage analog

    International Nuclear Information System (INIS)

    Wieland, D.M.; Brown, L.E.; Rogers, W.L.; Worthington, K.C.; Wu, J.L.; Clinthorne, N.H.; Otto, C.A.; Swanson, D.P.; Beierwaltes, W.H.

    1981-01-01

    Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug guanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norepinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention

  17. Norepinephrine accumulation by the rat caudal artery in the presence of hypertensive plasma

    International Nuclear Information System (INIS)

    Freas, W.; Thompson, D.A.; Hart, J.L.; Muldoon, S.M.

    1986-01-01

    We have partially isolated endogenous factors from canine plasma which inhibit 3 H-norepinephrine (NE) accumulation by the canine saphenous vein. The purpose of this study is to determine if these circulating factors may account for the observed differences in 3 H-NE uptake by hypertensive and normotensive blood vessels. Three models of hypertension were examined in this study. Blood vessels were compared from SHR and WKY rats, deoxycorticosterone acetate (DOCA) and control rats, and reduced renal mass (RRM) and control rats. There was no significant difference in 3 H-NE accumulation between blood vessels obtained from RRM and paired control rats. However, both the SHR and DOCA hypertensive caudal arteries and aorta accumulated significantly more 3 H-NE than their corresponding control tissues. There was not a significant change in 3 H-NE accumulation between hypertensive and control vena cava and mesenteric arteries. Normotensive and hypertensive plasma inhibited 3 H-NE accumulation by the rat caudal artery. However, there was not a correlation between blood pressure of plasma donor rats and accumulation of 3 H-NE. Therefore, although there are differences in 3 H-NE accumulation between hypertensive and normotensive blood vessels, plasma does not contain a factor responsible for this observed difference

  18. Synthesis and structure-distribution study of radioiodinated norepinephrine storage analogs

    Energy Technology Data Exchange (ETDEWEB)

    Wieland, D.M.; Inbasekaran, M.; Brown, L.E.; Marsh, D.D.; Beierwaltes, W.H. (Michigan Univ., Ann Arbor (USA). Medical Center)

    Unlabelled analogs of norepinephrine have been synthesised and then labelled with /sup 125/I in an attempt to find an agent with heart uptake and neuronal specificity greater than metaiodobenzylguanidine (MIBG). The analogs of norepinephrine were injected intravenously into dogs and showed a heart concentration similar to MIBG. Neuronal specificity of some analogs is being evaluated in rat heart.

  19. Synthesis and structure-distribution study of radioiodinated norepinephrine storage analogs

    International Nuclear Information System (INIS)

    Wieland, D.M.; Inbasekaran, M.; Brown, L.E.; Marsh, D.D.; Beierwaltes, W.H.

    1982-01-01

    Unlabelled analogs of norepinephrine have been synthesised and then labelled with 125 I in an attempt to find an agent with heart uptake and neuronal specificity greater than metaiodobenzylguanidine (MIBG). The analogs of norepinephrine were injected intravenously into dogs and showed a heart concentration similar to MIBG. Neuronal specificity of some analogs is being evaluated in rat heart. (U.K.)

  20. Norepinephrine spillover from skeletal muscle during exercise in humans

    DEFF Research Database (Denmark)

    Savard, G K; Richter, Erik; Strange, S

    1989-01-01

    The purpose of this study was to determine the effect of increasing muscle mass involvement in dynamic exercise on both sympathetic nervous activation and local hemodynamic variables of individual active and inactive skeletal muscle groups. Six male subjects performed 15-min bouts of one...... legs, with a steeper rise occurring approximately 70% VO2max. These increases were not associated with any significant changes in leg blood flow or leg vascular conductance at the exercise intensities examined. These results suggest that, as the total active muscle mass increases, the rise...... in both legs. Arterial and venous plasma concentrations of norepinephrine (NE) and epinephrine were analyzed, and the calculated NE spillover was used as an index of sympathetic nervous activity to the limb. NE spillover increased gradually both in the resting, and to a larger extent in the exercising...

  1. Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock.

    Science.gov (United States)

    Su, Fuhong; Huang, Hongchuan; Akieda, Kazuki; Occhipinti, Giovanna; Donadello, Katia; Piagnerelli, Michael; De Backer, Daniel; Vincent, Jean-Louis

    2010-09-01

    Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.

  2. Role of phosphatidylinositol 3-kinase in angiotensin II regulation of norepinephrine neuromodulation in brain neurons of the spontaneously hypertensive rat.

    Science.gov (United States)

    Yang, H; Raizada, M K

    1999-04-01

    Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin II (Ang II) involves activation of the Ras-Raf-MAP kinase signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only partially responsible for this heightened action of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves activation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY and SHR brain neurons and was accompanied by its translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. Inhibition of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40-50% attenuation of the Ang II-induced increase in norepinephrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [3H]-NE uptake in the SHR neuron. In contrast, inhibition of MAP kinase completely attenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it caused only a 45% decrease in the SHR neuron. However, an additive attenuation was observed when both kinases of the SHR neurons were inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons. This stimulation was 30% higher and lasted longer in the SHR neuron compared with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase-PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, this study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.

  3. Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart

    International Nuclear Information System (INIS)

    Farde, L.; Halldin, C.; Naagren, K.; Suhara, Tetsuya; Karlsson, P.; Schoeps, K.O.; Swahn, C.G.; Bone, D.

    1994-01-01

    (-)-Norepinephrine is the predominant neurotransmitter of the sympathetic innervation of the heart. Racemic norepinephrine was labelled with carbon-11 and injected i.v. into Cynomolgus monkeys. Five minutes after injection there was a more than tenfold higher radioactivity in the heart than in adjacent tissue. Pretreatment with the norepinephrine reuptake inhibitor desipramine reduced the uptake by more than 80%. The high specific uptake of racemic [ 11 C]norepinephrine indicates that enatiomerically pure(-)-[ 11 C]norepinephrine has promising potential for detailed mapping of the sympathetic innervation of the human myocardium. (orig.)

  4. Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart

    Energy Technology Data Exchange (ETDEWEB)

    Farde, L [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Halldin, C [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Naagren, K [Turku Univ., Cyclotron/PET Center (Finland); Suhara, Tetsuya [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Karlsson, P [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Schoeps, K O [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Swahn, C G [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden); Bone, D [Dept. of Clinical Neuroscience, Karolinska Inst., Stockholm (Sweden)

    1994-04-01

    (-)-Norepinephrine is the predominant neurotransmitter of the sympathetic innervation of the heart. Racemic norepinephrine was labelled with carbon-11 and injected i.v. into Cynomolgus monkeys. Five minutes after injection there was a more than tenfold higher radioactivity in the heart than in adjacent tissue. Pretreatment with the norepinephrine reuptake inhibitor desipramine reduced the uptake by more than 80%. The high specific uptake of racemic [[sup 11]C]norepinephrine indicates that enatiomerically pure(-)-[[sup 11]C]norepinephrine has promising potential for detailed mapping of the sympathetic innervation of the human myocardium. (orig.)

  5. Revealed smooth nontransitive preferences

    DEFF Research Database (Denmark)

    Keiding, Hans; Tvede, Mich

    2013-01-01

    In the present paper, we are concerned with the behavioural consequences of consumers having nontransitive preference relations. Data sets consist of finitely many observations of price vectors and consumption bundles. A preference relation rationalizes a data set provided that for every observed...... consumption bundle, all strictly preferred bundles are more expensive than the observed bundle. Our main result is that data sets can be rationalized by a smooth nontransitive preference relation if and only if prices can normalized such that the law of demand is satisfied. Market data sets consist of finitely...... many observations of price vectors, lists of individual incomes and aggregate demands. We apply our main result to characterize market data sets consistent with equilibrium behaviour of pure-exchange economies with smooth nontransitive consumers....

  6. Generalizing smooth transition autoregressions

    DEFF Research Database (Denmark)

    Chini, Emilio Zanetti

    We introduce a variant of the smooth transition autoregression - the GSTAR model - capable to parametrize the asymmetry in the tails of the transition equation by using a particular generalization of the logistic function. A General-to-Specific modelling strategy is discussed in detail, with part......We introduce a variant of the smooth transition autoregression - the GSTAR model - capable to parametrize the asymmetry in the tails of the transition equation by using a particular generalization of the logistic function. A General-to-Specific modelling strategy is discussed in detail......, with particular emphasis on two different LM-type tests for the null of symmetric adjustment towards a new regime and three diagnostic tests, whose power properties are explored via Monte Carlo experiments. Four classical real datasets illustrate the empirical properties of the GSTAR, jointly to a rolling...

  7. Smooth Phase Interpolated Keying

    Science.gov (United States)

    Borah, Deva K.

    2007-01-01

    Smooth phase interpolated keying (SPIK) is an improved method of computing smooth phase-modulation waveforms for radio communication systems that convey digital information. SPIK is applicable to a variety of phase-shift-keying (PSK) modulation schemes, including quaternary PSK (QPSK), octonary PSK (8PSK), and 16PSK. In comparison with a related prior method, SPIK offers advantages of better performance and less complexity of implementation. In a PSK scheme, the underlying information waveform that one seeks to convey consists of discrete rectangular steps, but the spectral width of such a waveform is excessive for practical radio communication. Therefore, the problem is to smooth the step phase waveform in such a manner as to maintain power and bandwidth efficiency without incurring an unacceptably large error rate and without introducing undesired variations in the amplitude of the affected radio signal. Although the ideal constellation of PSK phasor points does not cause amplitude variations, filtering of the modulation waveform (in which, typically, a rectangular pulse is converted to a square-root raised cosine pulse) causes amplitude fluctuations. If a power-efficient nonlinear amplifier is used in the radio communication system, the fluctuating-amplitude signal can undergo significant spectral regrowth, thus compromising the bandwidth efficiency of the system. In the related prior method, one seeks to solve the problem in a procedure that comprises two major steps: phase-value generation and phase interpolation. SPIK follows the two-step approach of the related prior method, but the details of the steps are different. In the phase-value-generation step, the phase values of symbols in the PSK constellation are determined by a phase function that is said to be maximally smooth and that is chosen to minimize the spectral spread of the modulated signal. In this step, the constellation is divided into two groups by assigning, to information symbols, phase values

  8. Anti-smooth muscle antibody

    Science.gov (United States)

    ... gov/ency/article/003531.htm Anti-smooth muscle antibody To use the sharing features on this page, please enable JavaScript. Anti-smooth muscle antibody is a blood test that detects the presence ...

  9. Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory.

    Science.gov (United States)

    Mather, Mara; Clewett, David; Sakaki, Michiko; Harley, Carolyn W

    2016-01-01

    Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate "NE hotspots." At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.

  10. Selective binding of 2-[125I]iodo-nisoxetine to norepinephrine transporters in the brain

    International Nuclear Information System (INIS)

    Kung, M.-P.; Choi, Seok-Rye; Hou, Catherine; Zhuang, Z.-P.; Foulon, Catherine; Kung, Hank F.

    2004-01-01

    A radioiodinated ligand, (R)-N-methyl-(2-[ 125 I]iodo-phenoxy)-3-phenylpropylamine, [ 125 I]2-INXT, targeting norepinephrine transporters (NET), was successfully prepared. A no-carrier-added product, [ 125 I]2-INXT, displayed a saturable binding with a high affinity (K d =0.06 nM) in the homogenates prepared from rat cortical tissues as well as from LLC-PK 1 cells expressing NET. A relatively low number of binding sties (B max =55 fmol/mg protein) measured with [ 125 I]2-INXT in rat cortical homogenates is consistent with the value reported for a known NET ligand, [ 3 H]nisoxetine. Competition studies with various compounds on [ 125 I]2-INXT binding clearly confirmed the pharmacological specificity and selectivity for NET binding sites. Following a tail-vein injection of [ 125 I]2-INXT in rats, a good initial brain uptake was observed (0.56% dose at 2 min) followed by a slow washout from the brain (0.2% remained at 3 hours post-injection). The hypothalamus (a NET-rich region) to striatum (a region devoid of NET) ratio was 1.5 at 3 hours post-i.v. injection. Pretreatment of rats with nisoxetine significantly inhibited the uptake of [ 125 I]2-INXT (70-100% inhibition) in locus coeruleus, hypothalamus and raphe nuclei, regions known to have a high density of NET; whereas escitalopram, a serotonin transporter ligand, did not show a similar effect. Ex vivo autoradiography of rat brain sections of [ 125 I]2-INXT (at 3 hours after an i.v. injection) displayed an excellent regional brain localization pattern corroborated to the specific NET distribution in the brain. The specific brain localization was significantly reduced by a dose of nisoxetine pretreatment. Taken together, the data suggest that [ 123 I]2-INXT may be useful for mapping NET binding sites in the brain

  11. Norepinephrine storage, distribution, and release in diabetic cardiomyopathy

    International Nuclear Information System (INIS)

    Ganguly, P.K.; Beamish, R.E.; Dhalla, K.S.; Innes, J.R.; Dhalla, N.S.

    1987-01-01

    The ability of hearts to store, distribute, and release norepinephrine (NE) was investigated in rats 8 wk after the induction of diabetes by an injection of streptozotocin. Chronic diabetes was associated with increased content and concentration of NE in heart and in other tissues such as kidney, brain, and spleen. Reserpine or tyramine treatment resulted in depletion of endogenous cardiac NE in control and diabetic rats. The depletion of NE stores at different times after a dose of reserpine was greater in diabetic hearts. On the other hand, NE stores in diabetic hearts were less sensitive than control hearts to low doses of tyramine but were more sensitive to high doses. The uptake of [ 3 H]NE was greater in diabetic hearts in isolated perfused preparations. In comparison with the control values, diabetic hearts showed a decrease in [ 3 H]NE in the granular fraction and an increase in the supernatant fraction. Diabetic hearts also showed an accelerated spontaneous release of [ 3 H]NE. The increased cardiac NE and the uptake and release of NE in diabetic animals were reversible upon treatment with insulin. These results are consistent with the view that sympathetic activity is increased in diabetic cardiomyopathy and indicate that cardiac NE in diabetic rats is maintained at a higher level partly due to an increased uptake of released NE by adrenergic nerve terminals

  12. Subcellular localization of the antidepressant-sensitive norepinephrine transporter

    Directory of Open Access Journals (Sweden)

    Winder Danny G

    2009-06-01

    Full Text Available Abstract Background Reuptake of synaptic norepinephrine (NE via the antidepressant-sensitive NE transporter (NET supports efficient noradrenergic signaling and presynaptic NE homeostasis. Limited, and somewhat contradictory, information currently describes the axonal transport and localization of NET in neurons. Results We elucidate NET localization in brain and superior cervical ganglion (SCG neurons, aided by a new NET monoclonal antibody, subcellular immunoisolation techniques and quantitative immunofluorescence approaches. We present evidence that axonal NET extensively colocalizes with syntaxin 1A, and to a limited degree with SCAMP2 and synaptophysin. Intracellular NET in SCG axons and boutons also quantitatively segregates from the vesicular monoamine transporter 2 (VMAT2, findings corroborated by organelle isolation studies. At the surface of SCG boutons, NET resides in both lipid raft and non-lipid raft subdomains and colocalizes with syntaxin 1A. Conclusion Our findings support the hypothesis that SCG NET is segregated prior to transport from the cell body from proteins comprising large dense core vesicles. Once localized to presynaptic boutons, NET does not recycle via VMAT2-positive, small dense core vesicles. Finally, once NET reaches presynaptic plasma membranes, the transporter localizes to syntaxin 1A-rich plasma membrane domains, with a portion found in cholera toxin-demarcated lipid rafts. Our findings indicate that activity-dependent insertion of NET into the SCG plasma membrane derives from vesicles distinct from those that deliver NE. Moreover, NET is localized in presynaptic membranes in a manner that can take advantage of regulatory processes targeting lipid raft subdomains.

  13. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    International Nuclear Information System (INIS)

    Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

    1987-01-01

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 μM) stimulates increased neuronal [ 3 H]NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal [ 3 H]DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism

  14. Epinephrine in the heart: uptake and release, but no facilitation of norepinephrine release

    NARCIS (Netherlands)

    Th.W. Lameris (Thomas); P.A. de Zeeuw (Sandra); D.J.G.M. Duncker (Dirk); W. Tietge; G. Alberts; F. Boomsma (Frans); P.D. Verdouw (Pieter); A.H. van den Meiracker (Anton)

    2002-01-01

    textabstractBACKGROUND: Several studies have suggested that epinephrine augments the release of norepinephrine from sympathetic nerve terminals through stimulation of presynaptic receptors, but evidence pertaining to this mechanism in the heart is scarce and conflicting. Using

  15. Kinetics of the norepinephrine analog [76Br]-meta-bromobenzylguanidine in isolated working rat heart

    International Nuclear Information System (INIS)

    Raffel, David; Loc'h, Christian; Mardon, Karine; Maziere, Bernard; Syrota, Andre

    1998-01-01

    A related set of kinetic studies of the norepinephrine analog [ 76 Br]-meta-bromobenzylguanidine (MBBG) were performed with an isolated working rat heart preparation. A series of constant infusion studies over a wide range of MBBG concentrations allowed estimation of the Michaelis-Menten constants for transport by the neuronal norepinephrine transporter (uptake 1 ) and the extraneuronal uptake system (uptake 2 ). Pharmacological blocking studies with inhibitors of uptake 1 , uptake 2 and vesicular uptake were performed to delineate the relative importance of these norepinephrine handling mechanisms on the kinetics of MBBG in the rat heart. Bolus injection studies were done to assess the ability of compartmental modeling techniques to characterize the kinetics of MBBG. These studies demonstrate that MBBG shares many of the same uptake mechanisms as norepinephrine in the rat heart. PET imaging studies with MBBG would be useful for assessing sympathetic nerve status in the living human heart

  16. Effect of atropine, norepinephrine and phenylephrine on cerebral oxygenation and cardiac output during anesthesia.

    NARCIS (Netherlands)

    Kalmar, A.F.; Poterman, Marieke; Mooyaart, E.A.; Struys, Michel; Scheeren, Thomas

    2012-01-01

    Background:  Induction of general anesthesia often induces unwanted hypotension which is commonly treated with vasoactive medication to restore an appropriate blood pressure. Phenylephrine, norepinephrine and atropine are commonly used agents for this purpose with different physiological effects.

  17. Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects?

    DEFF Research Database (Denmark)

    Brassard, P.; Seifert, T.; Secher, Niels H.

    2009-01-01

    BACKGROUND: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion of norep......BACKGROUND: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion...... of norepinephrine on cerebral oxygenation in healthy subjects. METHODS: Three doses of norepinephrine (0.05, 0.1, and 0.15 microg kg(-1) min(-1) for 20 min each) were infused in nine healthy subjects [six males; 26 (6) yr, mean (SD)]. MAP, cerebral oxygenation characterized by frontal lobe oxygenation (Sc(O2...

  18. Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population.

    Science.gov (United States)

    Ham, Byung-Joo; Choi, Myoung-Jin; Lee, Heon-Jeong; Kang, Rhee-Hun; Lee, Min-Soo

    2005-06-01

    It is well established that approximately 50% of the variance in personality traits is genetic. The goal of this study was to investigate a relationship between personality traits and the T-182C polymorphism in the norepinephrine transporter gene. The participants included 115 healthy adults with no history of psychiatric disorders and other physical illness during the past 6 months. All participants were tested with the Temperament and Character Inventory and genotyped norepinephrine transporter gene polymorphism. Differences on the Temperament and Character Inventory dimensions among three groups were examined with one-way analysis of variance. Our study suggests that the norepinephrine transporter T-182C gene polymorphism is associated with reward dependence in Koreans, but the small number of study participants and their sex and age heterogeneity limits generalization of our results. Further studies are necessary with a larger number of homogeneous participants to confirm whether the norepinephrine transporter gene is related to personality traits.

  19. Smooth functors vs. differential forms

    NARCIS (Netherlands)

    Schreiber, U.; Waldorf, K.

    2011-01-01

    We establish a relation between smooth 2-functors defined on the path 2-groupoid of a smooth manifold and differential forms on this manifold. This relation can be understood as a part of a dictionary between fundamental notions from category theory and differential geometry. We show that smooth

  20. Why we forget our dreams: Acetylcholine and norepinephrine in wakefulness and REM sleep.

    Science.gov (United States)

    Becchetti, Andrea; Amadeo, Alida

    2016-01-01

    The ascending fibers releasing norepinephrine and acetylcholine are highly active during wakefulness. In contrast, during rapid-eye-movement sleep, the neocortical tone is sustained mainly by acetylcholine. By comparing the different physiological features of the norepinephrine and acetylcholine systems in the light of the GANE (glutamate amplifies noradrenergic effects) model, we suggest how to interpret some functional differences between waking and rapid-eye-movement sleep.

  1. Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion

    DEFF Research Database (Denmark)

    Wemmelund, Kristian Borup; Ringgård, Viktor Kromann; Vistisen, Simon Tilma

    2017-01-01

    BACKGROUND: Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic d...... global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE....

  2. Dopamine versus norepinephrine in the treatment of cardiogenic shock: A PRISMA-compliant meta-analysis.

    Science.gov (United States)

    Rui, Qing; Jiang, Yufeng; Chen, Min; Zhang, Nannan; Yang, Huajia; Zhou, Yafeng

    2017-10-01

    Guidelines recommend that norepinephrine (NA) should be used to reach the target mean arterial pressure (MAP) during cardiogenic shock (CS), rather than epinephrine and dopamine (DA). However, there has actually been few studies on comparing norepinephrine with dopamine and their results conflicts. These studies raise a heat discussion. This study aimed to validate the effectiveness of norepinephrine for treating CS in comparison with dopamine. We performed a meta-analysis of randomized controlled trials (RCTs) to assess pooled estimates of risk ratio (RR) and 95% confidence interval (CI) for 28-day mortality, incidence of arrhythmic events, gastrointestinal reaction, and some indexes after treatment. Compared with dopamine, patients receiving norepinephrine had a lower 28-day mortality (RR 1.611 [95% CI 1.219-2.129]; P dopamine in 2 subgroups. Our analysis revealed that norepinephrine was associated with a lower 28-day mortality, a lower risk of arrhythmic events, and gastrointestinal reaction. No matter whether CS is caused by coronary heart disease or not, norepinephrine is superior to dopamine for correcting CS on the 28-day mortality.

  3. Exponential smoothing weighted correlations

    Science.gov (United States)

    Pozzi, F.; Di Matteo, T.; Aste, T.

    2012-06-01

    In many practical applications, correlation matrices might be affected by the "curse of dimensionality" and by an excessive sensitiveness to outliers and remote observations. These shortcomings can cause problems of statistical robustness especially accentuated when a system of dynamic correlations over a running window is concerned. These drawbacks can be partially mitigated by assigning a structure of weights to observational events. In this paper, we discuss Pearson's ρ and Kendall's τ correlation matrices, weighted with an exponential smoothing, computed on moving windows using a data-set of daily returns for 300 NYSE highly capitalized companies in the period between 2001 and 2003. Criteria for jointly determining optimal weights together with the optimal length of the running window are proposed. We find that the exponential smoothing can provide more robust and reliable dynamic measures and we discuss that a careful choice of the parameters can reduce the autocorrelation of dynamic correlations whilst keeping significance and robustness of the measure. Weighted correlations are found to be smoother and recovering faster from market turbulence than their unweighted counterparts, helping also to discriminate more effectively genuine from spurious correlations.

  4. Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia.

    Directory of Open Access Journals (Sweden)

    Qijun Jiang

    Full Text Available OBJECTIVE: During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells (EPCs mobilization was enhanced with an increase of sympathetic nerve activity and norepinephrine (NE secretion, yet the cellular and molecular mechanisms involved in the effects of NE on EPCs has less been investigated. METHODS AND RESULTS: EPCs from BMs, peripheral circulation and spleens, the VEGF concentration in BM, skeletal muscle, peripheral circulation and spleen and angiogenesis in ischemic gastrocnemius were quantified in mice with hindlimbs ischemia. Systemic treatment of NE significantly increased EPCs number in BM, peripheral circulation and spleen, VEGF concentration in BM and skeletal muscle and angiogenesis in ischemic gastrocnemius in mice with hind limb ischemia, but did not affair VEGF concentration in peripheral circulation and spleen. EPCs isolated from healthy adults were cultured with NE in vitro to evaluate proliferation potential, migration capacity and phosphorylations of Akt and eNOS signal moleculars. Treatment of NE induced a significant increase in number of EPCs in the S-phase in a dose-dependent manner, as well as migrative activity of EPCs in vitro (p<0.05. The co-treatment of Phentolamine, I127, LY294002 and L-NAME with NE blocked the effects of NE on EPCs proliferation and migration. Treatment with NE significantly increased phosphorylation of Akt and eNOS of EPCs. Addition of phentolamine and I127 attenuated the activation of Akt/eNOS pathway, but metoprolol could not. Pretreatment of mice with either Phentolamine or I127 significantly attenuated the effects of NE on EPCs in vivo, VEGF concentration in BM, skeletal muscle and angiogenesis in ischemic gastrocnemius, but Metoprolol did not. CONCLUSION: These results unravel that sympathetic nervous system regulate EPCs mobilization and their pro-angiogenic capacity via α adrenoceptor

  5. Norepinephrine metabolism in humans. Kinetic analysis and model

    International Nuclear Information System (INIS)

    Linares, O.A.; Jacquez, J.A.; Zech, L.A.; Smith, M.J.; Sanfield, J.A.; Morrow, L.A.; Rosen, S.G.; Halter, J.B.

    1987-01-01

    The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [ 3 H]NE infusion and postinfusion plasma disappearance of [ 3 H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [ 3 H]NE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P less than 0.01) and upright (r = 0.90-0.98, all P less than 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87 +/- 0.08 vs. 3.25 +/- 0.2 micrograms/min per m2, P less than 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5 +/- 0.6 vs. 4.7 +/- 0.3 liters, P less than 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80 +/- 0.11 vs. 1.21 +/- 0.08 liters/min per m2, P less than 0.001). We conclude that a two-compartment model is the minimal model that can accurately describe the kinetics of distribution and metabolism of NE in humans

  6. Norepinephrine is coreleased with serotonin in mouse taste buds.

    Science.gov (United States)

    Huang, Yijen A; Maruyama, Yutaka; Roper, Stephen D

    2008-12-03

    ATP and serotonin (5-HT) are neurotransmitters secreted from taste bud receptor (type II) and presynaptic (type III) cells, respectively. Norepinephrine (NE) has also been proposed to be a neurotransmitter or paracrine hormone in taste buds. Yet, to date, the specific stimulus for NE release in taste buds is not well understood, and the identity of the taste cells that secrete NE is not known. Chinese hamster ovary cells were transfected with alpha(1A) adrenoceptors and loaded with fura-2 ("biosensors") to detect NE secreted from isolated mouse taste buds and taste cells. Biosensors responded to low concentrations of NE (>or=10 nm) with a reliable fura-2 signal. NE biosensors did not respond to stimulation with KCl or taste compounds. However, we recorded robust responses from NE biosensors when they were positioned against mouse circumvallate taste buds and the taste buds were stimulated with KCl (50 mm) or a mixture of taste compounds (cycloheximide, 10 microm; saccharin, 2 mm; denatonium, 1 mm; SC45647, 100 microm). NE biosensor responses evoked by stimulating taste buds were reversibly blocked by prazosin, an alpha(1A) receptor antagonist. Together, these findings indicate that taste bud cells secrete NE when they are stimulated. We isolated individual taste bud cells to identify the origin of NE release. NE was secreted only from presynaptic (type III) taste cells and not receptor (type II) cells. Stimulus-evoked NE release depended on Ca(2+) in the bathing medium. Using dual biosensors (sensitive to 5-HT and NE), we found all presynaptic cells secrete 5-HT and 33% corelease NE with 5-HT.

  7. Smooth functions statistics

    International Nuclear Information System (INIS)

    Arnold, V.I.

    2006-03-01

    To describe the topological structure of a real smooth function one associates to it the graph, formed by the topological variety, whose points are the connected components of the level hypersurface of the function. For a Morse function, such a graph is a tree. Generically, it has T triple vertices, T + 2 endpoints, 2T + 2 vertices and 2T + 1 arrows. The main goal of the present paper is to study the statistics of the graphs, corresponding to T triple points: what is the growth rate of the number φ(T) of different graphs? Which part of these graphs is representable by the polynomial functions of corresponding degree? A generic polynomial of degree n has at most (n - 1) 2 critical points on R 2 , corresponding to 2T + 2 = (n - 1) 2 + 1, that is to T = 2k(k - 1) saddle-points for degree n = 2k

  8. Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

    Science.gov (United States)

    Erickson, Susan L.; Gandhi, Anjalika R.; Asafu-Adjei, Josephine K.; Sampson, Allan R.; Miner, LeeAnn; Blakely, Randy D.; Sesack, Susan R.

    2011-01-01

    Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance. PMID:21208501

  9. Reserpine-induced reduction in norepinephrine transporter function requires catecholamine storage vesicles.

    Science.gov (United States)

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5min decreased [(3)H]NE uptake capacity, an effect characterized by a robust decrease in the V(max) of the transport of [(3)H]NE. As expected, reserpine did not displace the binding of [(3)H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [(3)H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [(3)H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca(2+)/Ca(2+)-calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [(3)H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, alpha-methyl-p-tyrosine, increased [(3)H]NE uptake and eliminated the inhibitory effects of reserpine on [(3)H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca(2+)-independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Harsing, L.G. Jr.; Vizi, E.S. (Institute of Experimental Medicine, Budapest (Hungary))

    1991-01-01

    Cerebral cortex slices from the rat were loaded with (3H)norepinephrine ((3H)NE) and superfused in order to measure the release of radioactivity at rest and in response to electrical stimulation. The (-)-isomer and the (+)-isomer of CH-38083 (7,8-(methylenedioxy)-14- alpha-hydroxyalloberbane HCl), a selective alpha-2-adrenoceptor antagonist with an alloberbane skeleton, increased the electrically induced release of (3H)NE in a concentration-dependent manner, and a similar effect was observed with racemic CH-38083 and idazoxan. The stereoisomers of CH-38083 applied in a concentration range of 10(-8) to 10(-6) mol/l were equipotent in facilitating stimulation-evoked (3H)NE release: concentrations needed to enhance tritium outflow by 50% were 1.3 X 10(-7) mol/l for (-)-CH-38083 and 1.4 X 10(-7) mol/l for (+)-CH-38083. Exogenous NE decreased the electrically stimulated release of (3H)NE, and the stereoisomers of CH-38083 antagonized this inhibition with different potencies: the dissociation constant (KB) values for (-)-isomer and for (+)-isomer of CH-38083 were 14.29 and 97.18 nmol/l. These data indicate that presynaptic alpha-2 adrenoceptors that are available for NE released from axon terminals do not show stereospecificity toward enantiomers of CH-38083, whereas those that are occupied by exogenous NE are much more sensitive toward (-)-CH-38083. The alpha-1 adrenoceptor antagonist prazosin also differentiated between the alpha-2 adrenoceptor subtypes: prazosin (10(-6) mol/l) did not alter the increase of electrically induced (3H)NE release evoked by (-)- and (+)-CH-38083; however, in its presence, the stereoisomers of CH-38083 failed to antagonize the inhibitory effect of exogenous NE on its own release.

  11. Neurotensin releases norepinephrine differentially from perfused hypothalamus of sated and fasted rat

    International Nuclear Information System (INIS)

    Lee, T.F.; Rezvani, A.H.; Hepler, J.R.; Myers, R.D.

    1987-01-01

    The central injection of neurotensin (NT) has been reported to attenuate the intake of food in the fasted animal. To determine whether endogenous norepinephrine (NE) is involved in the satiating effect of NT, the in vivo activity of NE in circumscribed sites in the hypothalamus of the unanesthetized rat was examined. Bilateral guide tubes for push-pull perfusion were implanted stereotaxically to rest permanently above one of several intended sites of perfusion, which included the paraventricular nucleus (PVN), ventromedial nucleus (VMN), and the lateral hypothalamic (LH) area. After endogenous stores of NE at a specific hypothalamic locus were radiolabeled by microinjection of 0.02-0.5 μCi of [ 3 H]NE, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 μl/min over successive intervals of 5.0 min. When 0.05 or 0.1 μg/μl NT was added to the perfusate, the peptide served either to enhance or educe the local release of NE at 50% of the sites of perfusion. In these experiments, the circumscribed effect of NT on the characteristics of catecholamine efflux depended entirely on the state of hunger or satiety of the rat. That is, when NT was perfused in the fully satiated rat, NE release was augmented within the PVn or VMN; conversely, NE release was inhibited in the LH. in the animal fasted for 18-22 h, NT exerted an opposite effect on the activity of NE within the same anatomical loci in that the efflux of NE was enhanced in the LH but attenuated or unaffected in the PVN or VMN. Taken together, these observations provide experimental support for the view-point that NT could act as a neuromodulator of the activity of hypothalamic noradrenergic neurons that are thought to play a functional role in the regulation of food intake

  12. Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems

    Science.gov (United States)

    More, Swati S.; Itsara, Melissa; Yang, Xiaodong; Geier, Ethan G.; Tadano, Michelle K.; Seo, Youngho; VanBrocklin, Henry F.; Weiss, William A.; Mueller, Sabine; Haas-Kogan, Daphne A.; DuBois, Steven G.; Matthay, Katherine K.; Giacomini, Kathleen M.

    2011-01-01

    Purpose Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with 131I-metaiodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET). Experimental Design In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for 131I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on 123I-MIBG biodistribution. Results Preincubation of NB cell lines, Kelly and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four-fold and 2.5 fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pre-treated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on 123I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat treated (0.062 ± 0.011 μCi/(mg tissue-dose injected)) versus untreated mice (0.022 ± 0.003 μCi/(mg tissue-dose injected); p vorinostat treatment can enhance NB therapy with 131I-MIBG. PMID:21421857

  13. Classification of smooth Fano polytopes

    DEFF Research Database (Denmark)

    Øbro, Mikkel

    A simplicial lattice polytope containing the origin in the interior is called a smooth Fano polytope, if the vertices of every facet is a basis of the lattice. The study of smooth Fano polytopes is motivated by their connection to toric varieties. The thesis concerns the classification of smooth...... Fano polytopes up to isomorphism. A smooth Fano -polytope can have at most vertices. In case of vertices an explicit classification is known. The thesis contains the classification in case of vertices. Classifications of smooth Fano -polytopes for fixed exist only for . In the thesis an algorithm...... for the classification of smooth Fano -polytopes for any given is presented. The algorithm has been implemented and used to obtain the complete classification for ....

  14. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.

    Directory of Open Access Journals (Sweden)

    Yu-Ting Liao

    Full Text Available Enterovirus 71 (EV71 infections may be associated with neurological complications, including brainstem encephalitis (BE. Severe EV71 BE may be complicated with autonomic nervous system (ANS dysregulation and/or pulmonary edema (PE. ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release.The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines.Plasma levels of norepinephrine (NE and epinephrine (EP in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP.The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE.The plasma levels of NE and EP elevated in EV71-infected patients with ANS

  15. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.

    Science.gov (United States)

    Liao, Yu-Ting; Wang, Shih-Min; Wang, Jen-Ren; Yu, Chun-Keung; Liu, Ching-Chuan

    2015-01-01

    Enterovirus 71 (EV71) infections may be associated with neurological complications, including brainstem encephalitis (BE). Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema (PE). ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release. The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines. Plasma levels of norepinephrine (NE) and epinephrine (EP) in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs) on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs) were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP. The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE. The plasma levels of NE and EP elevated in EV71-infected patients with ANS dysregulation and

  16. Norepinephrine transporter function and desipramine: residual drug effects versus short-term regulation.

    Science.gov (United States)

    Ordway, Gregory A; Jia, Weihong; Li, Jing; Zhu, Meng-Yang; Mandela, Prashant; Pan, Jun

    2005-04-30

    Previous research has shown that exposure of norepinephrine transporter (NET)-expressing cells to desipramine (DMI) downregulates the norepinephrine transporter, although changes in the several transporter parameters do not demonstrate the same time course. Exposures to desipramine for effects of residual desipramine on norepinephrine transporter binding and uptake were re-evaluated following exposures of PC12 cells to desipramine using different methods to remove residual drug. Using a method that minimizes residual drug, exposure of intact PC12 cells to desipramine for 4h had no effect on uptake capacity or [(3)H]nisoxetine binding to the norepinephrine transporter, while exposures for > or =16 h reduced uptake capacity. Desipramine-induced reductions in binding to the transporter required >24 h or greater periods of desipramine exposure. This study confirms that uptake capacity of the norepinephrine transporter is reduced earlier than changes in radioligand binding, but with a different time course than originally shown. Special pre-incubation procedures are required to abolish effects of residual transporter inhibitor when studying inhibitor-induced transporter regulation.

  17. SmoothMoves : Smooth pursuits head movements for augmented reality

    NARCIS (Netherlands)

    Esteves, Augusto; Verweij, David; Suraiya, Liza; Islam, Rasel; Lee, Youryang; Oakley, Ian

    2017-01-01

    SmoothMoves is an interaction technique for augmented reality (AR) based on smooth pursuits head movements. It works by computing correlations between the movements of on-screen targets and the user's head while tracking those targets. The paper presents three studies. The first suggests that head

  18. Selective binding of 2-[{sup 125}I]iodo-nisoxetine to norepinephrine transporters in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Kung, M.-P.; Choi, Seok-Rye; Hou, Catherine; Zhuang, Z.-P.; Foulon, Catherine; Kung, Hank F. E-mail: kunghf@sunmac.spect.upenn.edu

    2004-07-01

    A radioiodinated ligand, (R)-N-methyl-(2-[{sup 125}I]iodo-phenoxy)-3-phenylpropylamine, [{sup 125}I]2-INXT, targeting norepinephrine transporters (NET), was successfully prepared. A no-carrier-added product, [{sup 125}I]2-INXT, displayed a saturable binding with a high affinity (K{sub d}=0.06 nM) in the homogenates prepared from rat cortical tissues as well as from LLC-PK{sub 1} cells expressing NET. A relatively low number of binding sties (B{sub max}=55 fmol/mg protein) measured with [{sup 125}I]2-INXT in rat cortical homogenates is consistent with the value reported for a known NET ligand, [{sup 3}H]nisoxetine. Competition studies with various compounds on [{sup 125}I]2-INXT binding clearly confirmed the pharmacological specificity and selectivity for NET binding sites. Following a tail-vein injection of [{sup 125}I]2-INXT in rats, a good initial brain uptake was observed (0.56% dose at 2 min) followed by a slow washout from the brain (0.2% remained at 3 hours post-injection). The hypothalamus (a NET-rich region) to striatum (a region devoid of NET) ratio was 1.5 at 3 hours post-i.v. injection. Pretreatment of rats with nisoxetine significantly inhibited the uptake of [{sup 125}I]2-INXT (70-100% inhibition) in locus coeruleus, hypothalamus and raphe nuclei, regions known to have a high density of NET; whereas escitalopram, a serotonin transporter ligand, did not show a similar effect. Ex vivo autoradiography of rat brain sections of [{sup 125}I]2-INXT (at 3 hours after an i.v. injection) displayed an excellent regional brain localization pattern corroborated to the specific NET distribution in the brain. The specific brain localization was significantly reduced by a dose of nisoxetine pretreatment. Taken together, the data suggest that [{sup 123}I]2-INXT may be useful for mapping NET binding sites in the brain.

  19. Smoothness in Binomial Edge Ideals

    Directory of Open Access Journals (Sweden)

    Hamid Damadi

    2016-06-01

    Full Text Available In this paper we study some geometric properties of the algebraic set associated to the binomial edge ideal of a graph. We study the singularity and smoothness of the algebraic set associated to the binomial edge ideal of a graph. Some of these algebraic sets are irreducible and some of them are reducible. If every irreducible component of the algebraic set is smooth we call the graph an edge smooth graph, otherwise it is called an edge singular graph. We show that complete graphs are edge smooth and introduce two conditions such that the graph G is edge singular if and only if it satisfies these conditions. Then, it is shown that cycles and most of trees are edge singular. In addition, it is proved that complete bipartite graphs are edge smooth.

  20. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Antonio Paulo Nassar Junior

    Full Text Available BACKGROUND: Hepatorenal syndrome (HRS is a severe and progressive functional renal failure occurring in patients with cirrhosis and ascites. Terlipressin is recognized as an effective treatment of HRS, but it is expensive and not widely available. Norepinephrine could be an effective alternative. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of norepinephrine compared to terlipressin in the management of HRS. METHODS: We searched the Medline, Embase, Scopus, CENTRAL, Lilacs and Scielo databases for randomized trials of norepinephrine and terlipressin in the treatment of HRS up to January 2014. Two reviewers collected data and assessed the outcomes and risk of bias. The primary outcome was the reversal of HRS. Secondary outcomes were mortality, recurrence of HRS and adverse events. RESULTS: Four studies comprising 154 patients were included. All trials were considered to be at overall high risk of bias. There was no difference in the reversal of HRS (RR = 0.97, 95% CI = 0.76 to 1.23, mortality at 30 days (RR = 0.89, 95% CI = 0.68 to 1.17 and recurrence of HRS (RR = 0.72; 95% CI = 0.36 to 1.45 between norepinephrine and terlipressin. Adverse events were less common with norepinephrine (RR = 0.36, 95% CI = 0.15 to 0.83. CONCLUSIONS: Norepinephrine seems to be an attractive alternative to terlipressin in the treatment of HRS and is associated with less adverse events. However, these findings are based on data extracted from only four small studies.

  1. Smooth quantile normalization.

    Science.gov (United States)

    Hicks, Stephanie C; Okrah, Kwame; Paulson, Joseph N; Quackenbush, John; Irizarry, Rafael A; Bravo, Héctor Corrada

    2018-04-01

    Between-sample normalization is a critical step in genomic data analysis to remove systematic bias and unwanted technical variation in high-throughput data. Global normalization methods are based on the assumption that observed variability in global properties is due to technical reasons and are unrelated to the biology of interest. For example, some methods correct for differences in sequencing read counts by scaling features to have similar median values across samples, but these fail to reduce other forms of unwanted technical variation. Methods such as quantile normalization transform the statistical distributions across samples to be the same and assume global differences in the distribution are induced by only technical variation. However, it remains unclear how to proceed with normalization if these assumptions are violated, for example, if there are global differences in the statistical distributions between biological conditions or groups, and external information, such as negative or control features, is not available. Here, we introduce a generalization of quantile normalization, referred to as smooth quantile normalization (qsmooth), which is based on the assumption that the statistical distribution of each sample should be the same (or have the same distributional shape) within biological groups or conditions, but allowing that they may differ between groups. We illustrate the advantages of our method on several high-throughput datasets with global differences in distributions corresponding to different biological conditions. We also perform a Monte Carlo simulation study to illustrate the bias-variance tradeoff and root mean squared error of qsmooth compared to other global normalization methods. A software implementation is available from https://github.com/stephaniehicks/qsmooth.

  2. Whole body clearance of norepinephrine. The significance of arterial sampling and of surgical stress

    DEFF Research Database (Denmark)

    Hilsted, J; Christensen, N J; Madsbad, S

    1983-01-01

    The whole body clearance of norepinephrine (NE) was measured in seven patients pre- and postoperatively. L[(3)H]NE was infused intravenously for 90 min and steady-state concentrations of L[(3)H]NE were measured at 75 and 90 min in both arterial and peripheral venous blood. Preoperatively, in the ......The whole body clearance of norepinephrine (NE) was measured in seven patients pre- and postoperatively. L[(3)H]NE was infused intravenously for 90 min and steady-state concentrations of L[(3)H]NE were measured at 75 and 90 min in both arterial and peripheral venous blood. Preoperatively...

  3. Time dependent changes in myocardial norepinephrine concentration and adrenergic receptor density following X-irradiation of the rat heart

    NARCIS (Netherlands)

    Franken, N. A.; van der Laarse, A.; Bosker, F. J.; Reynart, I. W.; van Ravels, F. J.; Strootman, E.; Wondergem, J.

    1992-01-01

    The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine

  4. Effects of Methylphenidate and Atomoxetine on Cortical Inhibition in ADHD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-09-01

    Full Text Available The effects of methylphenidate (MPH, a psychostimulant, and atomoxetine (ATX, a selective norepinephrine reuptake inhibitor, on short interval-cortical inhibition (SICI were measured in motor cortex with transcranial magnetic stimulation, in a study at Cincinnati Children’s Medical Center, OH, and other centers.

  5. α2-Adrenergic regulation of galanin and norepinephrine release from canine pancreas

    NARCIS (Netherlands)

    Scheurink, Anton J.W.; Mundinger, Thomas O.; Dunning, Beth E.; Veith, Richard C.; Taborsky, Jr.

    1992-01-01

    We found previously that electrical stimulation of the mixed autonomic pancreatic nerves (MPNS) in anesthesized dogs elicits marked and rapid increases of pancreatic output of both norepinephrine (NE) and galanin, and on that basis hypothesized a role for galanin as a sympathetic cotransmitter in

  6. The conversion of dopamine to epinephrine and nor-epinephrine is ...

    African Journals Online (AJOL)

    Tyrosine is a conditionally non-essential large neutral amino acid and the precursor of the neurotransmitters dopamine, nor-epinephrine and epinephrine. Ante-mortem stress experienced by an animal may be influenced by amino acids that provide substrates for neurotransmitter synthesis. The Nguni type cattle showed ...

  7. Effects of surgical stress and insulin on cardiovascular function and norepinephrine kinetics

    DEFF Research Database (Denmark)

    Christensen, N J; Hilsted, J; Hegedüs, Laszlo

    1984-01-01

    In resting supine subjects the whole-body clearance of norepinephrine (NE) based on arterial and venous sampling averaged 1.4 and 2.5 liters/min, respectively (P less than 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The calculation of plasma NE...

  8. Fluctuating Estrogen and Progesterone Receptor Expression in Brainstem Norepinephrine Neurons through the Rat Estrous Cycle

    NARCIS (Netherlands)

    Haywood, S.A.; Simonian, S.X.; Beek, van der E.M.; Bicknell, R.J.; Herbison, A.E.

    1999-01-01

    Norepinephrine (NE) neurons within the nucleus tractus solitarii (NTS; A2 neurons) and ventrolateral medulla (A1 neurons) represent gonadal steroid-dependent components of several neural networks regulating reproduction. Previous studies have shown that both A1 and A2 neurons express estrogen

  9. Effects of norepinephrine on tissue perfusion in a sheep model of intra-abdominal hypertension

    NARCIS (Netherlands)

    Ferrara, Gonzalo; Kanoore Edul, Vanina S.; Caminos Eguillor, Juan F.; Martins, Enrique; Canullán, Carlos; Canales, Héctor S.; Ince, Can; Estenssoro, Elisa; Dubin, Arnaldo

    2015-01-01

    The aim of the study was to describe the effects of intra-abdominal hypertension (IAH) on regional and microcirculatory intestinal blood flow, renal blood flow, and urine output, as well as their response to increases in blood pressure induced by norepinephrine. This was a pilot, controlled study,

  10. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study

    NARCIS (Netherlands)

    Dubin, Arnaldo; Pozo, Mario O.; Casabella, Christian A.; Palizas, Fernando; Murias, Gaston; Moseinco, Miriam C.; Kanoore Edul, Vanina S.; Estenssoro, Elisa; Ince, Can

    2009-01-01

    Introduction Our goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation. Methods Twenty septic shock patients were prospectively studied in two teaching intensive care units. The patients were

  11. Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects?

    DEFF Research Database (Denmark)

    Brassard, P.; Seifert, T.; Secher, Niels H.

    2009-01-01

    BACKGROUND: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion of norep......BACKGROUND: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion...... of norepinephrine on cerebral oxygenation in healthy subjects. METHODS: Three doses of norepinephrine (0.05, 0.1, and 0.15 microg kg(-1) min(-1) for 20 min each) were infused in nine healthy subjects [six males; 26 (6) yr, mean (SD)]. MAP, cerebral oxygenation characterized by frontal lobe oxygenation (Sc(O2...... infused at 0.1 microg kg(-1) min(-1) [Sc(O2): 78 (75-94) to 69 (61-83)%; P

  12. The norepinephrine transporter gene is a candidate gene for panic disorder

    DEFF Research Database (Denmark)

    Buttenschøn, Henriette Nørmølle; Kristensen, A S; Buch, H N

    2011-01-01

    Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis...

  13. The norepinephrine transporter in attention-deficit/hyperactivity disorder investigated with positron emission tomography.

    Science.gov (United States)

    Vanicek, Thomas; Spies, Marie; Rami-Mark, Christina; Savli, Markus; Höflich, Anna; Kranz, Georg S; Hahn, Andreas; Kutzelnigg, Alexandra; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Volkow, Nora D; Kasper, Siegfried; Lanzenberger, Rupert

    2014-12-01

    Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system's contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD. To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls. Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups. The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest). We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41sex nor smoking status influenced NET availability. We determined a significant negative correlation between age and NET availability in the thalamus (R2=0.29; P<.01 corrected) and midbrain with pons, including the locus coeruleus (R2=0.18; P<.01 corrected), which corroborates prior findings of a

  14. The Norepinephrine Transporter in Attention-Deficit/Hyperactivity Disorder Investigated With Positron Emission Tomography

    Science.gov (United States)

    Rami-Mark, Christina; Savli, Markus; Höflich, Anna; Kranz, Georg S.; Hahn, Andreas; Kutzelnigg, Alexandra; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Volkow, Nora D.; Kasper, Siegfried; Lanzenberger, Rupert

    2015-01-01

    IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system’s contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD. OBJECTIVE To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls. DESIGN, SETTING, AND PARTICIPANTS Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups. MAIN OUTCOMES AND MEASURES The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest). RESULTS We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41 < 0.01; P = .96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined

  15. The small GTPase Rac1 is required for smooth muscle contraction

    DEFF Research Database (Denmark)

    Rahman, Awahan; Davis, Benjamin; Lövdahl, Cecilia

    2014-01-01

    The role of the small GTP-binding protein Rac1 in smooth muscle contraction was examined using small molecule inhibitors (EHT1864, NSC23766) and a novel smooth muscle-specific, conditional, Rac1 knockout mouse strain. EHT1864, which affects nucleotide binding and inhibits Rac1 activity, concentra...

  16. Vinpocetine Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells.

    Directory of Open Access Journals (Sweden)

    Yun-Yun Ma

    Full Text Available Vascular calcification is an active process of osteoblastic differentiation of vascular smooth muscle cells; however, its definite mechanism remains unknown. Vinpocetine, a derivative of the alkaloid vincamine, has been demonstrated to inhibit the high glucose-induced proliferation of vascular smooth muscle cells; however, it remains unknown whether vinpocetine can affect the osteoblastic differentiation of vascular smooth muscle cells. We hereby investigated the effect of vinpocetine on vascular calcification using a beta-glycerophosphate-induced cell model. Our results showed that vinpocetine significantly reduced the osteoblast-like phenotypes of vascular smooth muscle cells including ALP activity, osteocalcin, collagen type I, Runx2 and BMP-2 expression as well as the formation of mineralized nodule. Vinpocetine, binding to translocation protein, induced phosphorylation of extracellular signal-related kinase and Akt and thus inhibited the translocation of nuclear factor-kappa B into the nucleus. Silencing of translocator protein significantly attenuated the inhibitory effect of vinpocetine on osteoblastic differentiation of vascular smooth muscle cells. Taken together, vinpocetine may be a promising candidate for the clinical therapy of vascular calcification.

  17. Vitamin K2 can suppress the expression of Toll-like receptor 2 (TLR2) and TLR4, and inhibit calcification of aortic intima in ApoE-/- mice as well as smooth muscle cells.

    Science.gov (United States)

    Wang, Zhaojun; Wang, Zhongqun; Zhu, Jie; Long, Xinguang; Yan, Jinchuan

    2018-02-01

    Background and objectives Vascular calcification is a common complication in atherosclerosis. Accumulating evidence showed that Toll-like receptors (TLRs) mediate pro-inflammatory and atherosclerosis. Recent studies demonstrated that vascular calcification is one of the detrimental effects of vitamin K (Vit K) antagonists. However, the effects of Vit K on the expression of TLR2 and 4 and intimal calcification in artery remained unidentified. Methods and results Eighteen ApoE -/- mice were randomly divided into model group, Vit K-treated group, and control group. The mice of model and Vit K-treated group were fed with high-fat diet, while control group mice were fed with normal diet. Mice of Vit K-treated group were administered orally with vitamin K2 (40 mg.kg -1 .day -1 ) for 12 weeks. Twelve weeks later the aortic sections of mice were acquired and stained with hematoxylin and eosin and von Kossa, respectively. Calcium content and activity of alkaline phosphatase (ALP) at aortic tissues were measured. The expression levels of TLR2 and TLR4 in aorta sections were detected by immunohistochemisty and RT-PCR, respectively. The effects of Vit K on cellular calcification were further studied in A7r5 SMCs. Results demonstrated that high-fat diet induced typical atherosclerosis with intimal calcification in ApoE -/- mice, while in Vit K-treated group atherosclerosis and calcium deposits were not serious; Vit K2 also inhibited cellular calcification in A7r5 SMCs. Quantitative analysis showed that calcium and ALP activity at aortic tissues in the Vit K-treated mice were significantly lower than that of the model group ( P < 0.01); Compared to the control group, the expression levels of TLR2 and TLR4 in the model group were significantly higher ( P < 0.05), while in Vit K-treated group the levels of TLR2 and 4 were significantly lower than that in the model group. Furthermore, the content of calcium was positively related to the expression levels of TLR2 and TLR4

  18. Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress through Modulation of Locus Coeruleus-Norepinephrine System.

    Science.gov (United States)

    Ding, Xiu-Fang; Zhao, Xiao-Hua; Tao, Yang; Zhong, Wei-Chao; Fan, Qin; Diao, Jian-Xin; Liu, Yuan-Liang; Chen, Yu-Yao; Chen, Jia-Xu; Lv, Zhi-Ping

    2014-01-01

    Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE) concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly increased compared to the control group. But XYS-treated group displayed a significantly decreased in NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE neurons activity.

  19. Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats

    Science.gov (United States)

    Bradshaw, Sarah E.; Agster, Kara L.; Waterhouse, Barry D.; McGaughy, Jill A.

    2016-01-01

    Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct subregions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. PMID:26774596

  20. Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans

    DEFF Research Database (Denmark)

    Astrup, A; Andersen, T; Christensen, N J

    1990-01-01

    A reduced thermic response and an impaired activation of the sympathetic nervous system (SNS) has been reported after oral glucose in human obesity. It is, however, not known whether the reduced SNS activity returns to normal along with weight reduction. The thermic effect of glucose was lower...... in eight obese patients than in matched control subjects (1.7% vs 9.2%, p less than 0.002). The increase in arterial norepinephrine after glucose was also blunted in the obese patients. After a 30-kg weight loss their glucose and lipid profiles were markedly improved but the thermic effect of glucose...... was still lower than that of the control subjects (4.2%, p less than 0.001). The glucose-induced arterial norepinephrine response remained diminished in the reduced obese patients whereas the changes in plasma epinephrine were similar in all three groups. The results suggest that a defective SNS may...

  1. Analytical Strategies for the Determination of Norepinephrine Reuptake Inhibitors in Pharmaceutical Formulations and Biological Fluids.

    Science.gov (United States)

    Saka, Cafer

    2016-01-01

    Norepinephrine reuptake inhibitors (NRIs) are a class of antidepressant drugs that act as reuptake inhibitors for the neurotransmitters norepinephrine and epinephrine. The present review provides an account of analytical methods published in recent years for the determination of NRI drugs. NRIs are atomoxetine, reboxetine, viloxazine and maprotiline. NRIs with less activity at other sites are mazindol, bupropion, tapentadol, and teniloxazine. This review focuses on the analytical methods including chromatographic, spectrophotometric, electroanalytical, and electrophoresis techniques for NRI analysis from pharmaceutical formulations and biological samples. Among all of the published methods, liquid chromatography with UV-vis or MS-MS detection is the most popular technique. The most the common sample preparation techniques in the analytical methods for NRIs include liquid-liquid extraction and solid-phase extraction. Besides the analytical methods for single components, some of the simultaneous determinations are also included in this review.

  2. Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

    Science.gov (United States)

    Cases, Olivier; Grimsby, Joseph; Gaspar, Patricia; Chen, Kevin; Pournin, Sandrine; Müller, Ulrike; Aguet, Michel; Babinet, Charles; Shih, Jean Chen; De Maeyer, Edward

    2010-01-01

    Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males. PMID:7792602

  3. Regulation of the fear network by mediators of stress: Norepinephrine alters the balance between Cortical and Subcortical afferent excitation of the Lateral Amygdala

    Directory of Open Access Journals (Sweden)

    Luke R Johnson

    2011-05-01

    Full Text Available Pavlovian auditory fear conditioning crucially involves the integration of information about and acoustic conditioned stimulus (CS and an aversive unconditioned stimulus (US in the lateral nucleus of the amygdala (LA. The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE, regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased towards the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance towards the faster but more primitive subcortical input.

  4. Iatrogenic Takotsubo Cardiomyopathy Secondary to Norepinephrine by Continuous Infusion for Shock

    OpenAIRE

    Alfredo Vieira; Bárbara Batista; Tiago Tribolet de Abreu

    2018-01-01

    Takotsubo cardiomyopathy is a condition characterized by transient left ventricular systolic and diastolic dysfunction, with a possible direct causal role of catecholamine in its pathophysiology. We present a case of a woman with shock and adrenal insufficiency in whom Takotsubo cardiomyopathy developed after treatment with norepinephrine. This case confirms the direct causal role of catecholamine in the pathophysiology of Takotsubo cardiomyopathy. An 82-year-old woman presented with asthenia...

  5. Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Andersen, Jacob; Kristensen, Anders Skov; Bang-Andersen, Benny

    2009-01-01

    The biogenic monoamine transporters are integral membrane proteins that perform active transport of extracellular dopamine, serotonin and norepinephrine into cells. These transporters are targets for therapeutic agents such as antidepressants, as well as addictive substances such as cocaine...... and amphetamine. Seminal advances in the understanding of the structure and function of this transporter family have recently been accomplished by structural studies of a bacterial transporter, as well as medicinal chemistry and pharmacological studies of mammalian transporters. This feature article focuses...

  6. HSP20 phosphorylation and airway smooth muscle relaxation

    Directory of Open Access Journals (Sweden)

    Mariam Ba

    2009-06-01

    Full Text Available Mariam Ba1, Cherie A Singer1, Manoj Tyagi2, Colleen Brophy3, Josh E Baker4, Christine Cremo4, Andrew Halayko5, William T Gerthoffer21Department of Pharmacology, University of Nevada School of Medicine, Reno, NV, USA; 2Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, USA; 3Harrington Department of Biochemistry, Arizona State University, Tempe, AZ, USA; 4Department of Biochemistry and Molecular Biology, University of Nevada, Reno, NV, USA; 5Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg, MB, CanadaAbstract: HSP20 (HSPB6 is a small heat shock protein expressed in smooth muscles that is hypothesized to inhibit contraction when phosphorylated by cAMP-dependent protein kinase. To investigate this hypothesis in airway smooth muscle (ASM we showed that HSP20 was constitutively expressed as well as being inducible in cultured hASM cells by treatment with 1 µM isoproterenol or 10 µM salmeterol. In contrast, a mixture of proinflammatory mediators (interleukin-1β, tumor necrosis factor α, and interferon γ inhibited expression of HSP20 by about 50% in 48 hours. To determine whether phosphorylation of HSP20 is sufficient to induce relaxation, canine tracheal smooth muscle was treated with a cell permeant phosphopeptide that mimics the phosphorylation of HSP20. The HSP20 phosphopeptide antagonized carbacholinduced contraction by 60% with no change in myosin light chain phosphorylation. Recombinant full length HSP20 inhibited skeletal actin binding to smooth muscle myosin subfragment 1 (S1, and recombinant cell permeant TAT-HSP20 S16D mutant reduced F-actin filaments in cultured hASM cells. Carbachol stimulation of canine tracheal smooth muscle tissue caused redistribution of HSP20 from large macromolecular complexes (200–500 kDa to smaller complexes (<60 kDa. The results are consistent with HSP20 expression and macromolecular structure being dynamically regulated in airway

  7. Differential effects of phenylephrine and norepinephrine on peripheral tissue oxygenation during general anaesthesia : A randomised controlled trial

    NARCIS (Netherlands)

    Poterman, Marieke; Vos, Jaap Jan; Vereecke, Hugo E. M.; Struys, Michel M. R. F.; Vanoverschelde, Henk; Scheeren, Thomas W. L.; Kalmar, Alain F.

    BACKGROUND Phenylephrine and norepinephrine are two vasopressors commonly used to counteract anaesthesia-induced hypotension. Their dissimilar working mechanisms may differentially affect the macro and microcirculation, and ultimately tissue oxygenation. OBJECTIVES We investigated the differential

  8. Non-smooth dynamical systems

    CERN Document Server

    2000-01-01

    The book provides a self-contained introduction to the mathematical theory of non-smooth dynamical problems, as they frequently arise from mechanical systems with friction and/or impacts. It is aimed at applied mathematicians, engineers, and applied scientists in general who wish to learn the subject.

  9. Panel Smooth Transition Regression Models

    DEFF Research Database (Denmark)

    González, Andrés; Terasvirta, Timo; Dijk, Dick van

    We introduce the panel smooth transition regression model. This new model is intended for characterizing heterogeneous panels, allowing the regression coefficients to vary both across individuals and over time. Specifically, heterogeneity is allowed for by assuming that these coefficients are bou...

  10. Smoothing type buffer memory device

    International Nuclear Information System (INIS)

    Podorozhnyj, D.M.; Yashin, I.V.

    1990-01-01

    The layout of the micropower 4-bit smoothing type buffer memory device allowing one to record without counting the sequence of input randomly distributed pulses in multi-channel devices with serial poll, is given. The power spent by a memory cell for one binary digit recording is not greater than 0.15 mW, the device dead time is 10 mus

  11. Covariances of smoothed observational data

    Czech Academy of Sciences Publication Activity Database

    Vondrák, Jan; Čepek, A.

    2000-01-01

    Roč. 40, 5-6 (2000), s. 42-44 ISSN 1210-2709 R&D Projects: GA ČR GA205/98/1104 Institutional research plan: CEZ:AV0Z1003909 Keywords : digital filter * smoothing * estimation of uncertainties Subject RIV: BN - Astronomy, Celestial Mechanics, Astrophysics

  12. Income smoothing by Dutch hospitals

    NARCIS (Netherlands)

    Boterenbrood, D.R.

    2014-01-01

    Research indicates that hospitals manage their earnings. However, these findings might be influenced by methodological issues. In this study, I exploit specific features of Dutch hospitals to study income smoothing while limiting these methodological issues. The managers of Dutch hospitals have the

  13. Norepinephrine remains increased in the six-minute walking test after heart transplantation

    Directory of Open Access Journals (Sweden)

    Guilherme Veiga Guimarães

    2010-01-01

    Full Text Available OBJECTIVE: We sought to evaluate the neurohormonal activity in heart transplant recipients and compare it with that in heart failure patients and healthy subjects during rest and just after a 6-minute walking test. INTRODUCTION: Despite the improvements in quality of life and survival provided by heart transplantation, the neurohormonal profile is poorly described. METHODS: Twenty heart transplantation (18 men, 49±11 years and 8.5±3.3 years after transplantation, 11 heart failure (8 men, 43±10 years, and 7 healthy subjects (5 men 39±8 years were included in this study. Blood samples were collected immediately before and during the last minute of the exercise. RESULTS: During rest, patients' norepinephrine plasma level (659±225 pg/mL was higher in heart transplant recipients (463±167 pg/mL and heathy subjects (512±132, p<0.05. Heart transplant recipient's norepinephrine plasma level was not different than that of healthy subjects. Just after the 6-minute walking test, the heart transplant recipient's norepinephrine plasma level (1248±692 pg/mL was not different from that of heart failure patients (1174±653 pg/mL. Both these groups had a higher level than healthy subjects had (545±95 pg/mL, p<0.05. CONCLUSION: Neurohormonal activity remains increased after the 6-minute walking test after heart transplantation.

  14. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension.

    Science.gov (United States)

    Tourneux, Pierre; Rakza, Thameur; Bouissou, Antoine; Krim, Gérard; Storme, Laurent

    2008-09-01

    To evaluate the respiratory and the pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension (PPHN)-induced cardiac dysfunction. Inclusion criteria were: 1) Newborn infants >35 weeks gestational age; 2) PPHN treated with inhaled nitric oxide; and 3) symptoms of circulatory failure despite adequate fluid resuscitation. Lung function and pulmonary hemodynamic variables assessed with Doppler echocardiography were recorded prospectively before and after starting norepinephrine. Eighteen newborns were included (gestational age: 37 +/- 3 weeks; birth weight: 2800 +/- 700 g). After starting norepinephrine, systemic pressure and left ventricular output increased respectively from 33 +/- 4 mm Hg to 49 +/- 4 mm Hg and from 172 +/- 79 mL/kg/min to 209+/-90 mL/kg/min (P ventilatory variables have not been changed, the post-ductal transcutaneous arterial oxygen saturation increased from 89% +/- 1% to 95% +/- 4%, whereas the oxygen need decreased from 51% +/- 24% to 41% +/- 20% (P newborn infants with PPHN through a decrease in pulmonary/systemic artery pressure ratio and improved cardiac performance.

  15. Poly(norepinephrine)-coated open tubular column for the separation of proteins and recombination human erythropoietin by capillary electrochromatography.

    Science.gov (United States)

    Xiao, Xue; Zhang, Yamin; Wu, Jia; Jia, Li

    2017-12-01

    Recombinant human erythropoietin is an important therapeutic protein with high economic interest due to the benefits provided by its clinical use for the treatment of anemias associated with chronic renal failure and chemotherapy. In this work, a poly(norepinephrine)-coated open tubular column was successfully prepared based on the self-polymerization of norepinephrine under mild alkaline condition, the favorable film forming and easy adhesive properties of poly(norepinephrine). The poly(norepinephrine) coating was characterized by scanning electron microscopy and measurement of the electro-osmotic flow. The thickness of the coating was about 431 nm. The electrochromatographic performance of the poly(norepinephrine)-coated open tubular column was evaluated by separation of proteins. Some basic and acidic proteins including two variants of bovine serum albumin and two variants of β-lactoglobulin achieved separation in the poly(norepinephrine)-coated open tubular column. More importantly, the column demonstrated separation ability for the glycoforms of recombinant human erythropoietin. In addition, the column demonstrated good repeatability with the run-to-run, day-to-day, and column-to-column relative standard deviations of migration times of proteins less than 3.40%. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion.

    Science.gov (United States)

    Wemmelund, Kristian Borup; Ringgård, Viktor Kromann; Vistisen, Simon Tilma; Hyldebrandt, Janus Adler; Sloth, Erik; Juhl-Olsen, Peter

    2017-09-11

    Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 μg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values  0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

  17. ASIC proteins regulate smooth muscle cell migration.

    Science.gov (United States)

    Grifoni, Samira C; Jernigan, Nikki L; Hamilton, Gina; Drummond, Heather A

    2008-03-01

    The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated that Epithelial Na(+)Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration; however, the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence individual ASIC expression and determine the importance of ASIC proteins in wound healing and chemotaxis (PDGF-bb)-initiated migration. We found ASIC1, ASIC2, and ASIC3, but not ASIC4, expression in A10 cells. ASIC1, ASIC2, and ASIC3 siRNA molecules significantly suppressed expression of their respective proteins compared to non-targeting siRNA (RISC) transfected controls by 63%, 44%, and 55%, respectively. Wound healing was inhibited by 10, 20, and 26% compared to RISC controls following suppression of ASIC1, ASIC2, and ASIC3, respectively. Chemotactic migration was inhibited by 30% and 45%, respectively, following suppression of ASIC1 and ASIC3. ASIC2 suppression produced a small, but significant, increase in chemotactic migration (4%). Our data indicate that ASIC expression is required for normal migration and may suggest a novel role for ASIC proteins in cellular migration.

  18. Relaxation of soman-induced contracture of airway smooth muscle in vitro. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Filbert, M.G.; Moore, D.H.; Adler, M.

    1992-12-31

    A possible role for beta-adrenergic agonists in the management of bronchoconstriction resulting from exposure to anticholinesterase compounds was investigated in vitro in canine tracheal smooth muscle. Norepinephrine, salbutamol and isoproterenol produced partial relaxation of soman-induced contractures. However, the relaxation induced was not sustained; muscle tensions returned to pretreatment levels within minutes despite the continued presence of beta-agonists. Increasing cAMP levels with the non beta-agonist bronchodilators such as thoophylline, a phosphodiesterase inhibitor, or forskolin, a specific stimulator of adenylate cyclase, resulted in more complete and longer lasting relaxation, suggesting that beta-adrenoceptor desensitization may contribute to the failure by beta-agonists to produce sustained relaxation. Nerve agents, Soman, Toxicity, Airway smooth muscle, In vitro, Physiology, Effects.

  19. Exchange rate smoothing in Hungary

    OpenAIRE

    Karádi, Péter

    2005-01-01

    The paper proposes a structural empirical model capable of examining exchange rate smoothing in the small, open economy of Hungary. The framework assumes the existence of an unobserved and changing implicit exchange rate target. The central bank is assumed to use interest rate policy to obtain this preferred rate in the medium term, while market participants are assumed to form rational expectations about this target and influence exchange rates accordingly. The paper applies unobserved varia...

  20. Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil.

    Science.gov (United States)

    Phelps, Laura E; Peuler, Jacob D

    2010-01-01

    Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARalpha). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPAR alpha may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 microM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 microM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or

  1. Smooth surfaces from rational bilinear patches

    KAUST Repository

    Shi, Ling; Wang, Jun; Pottmann, Helmut

    2014-01-01

    Smooth freeform skins from simple panels constitute a challenging topic arising in contemporary architecture. We contribute to this problem area by showing how to approximate a negatively curved surface by smoothly joined rational bilinear patches

  2. Sodium pump activity and calcium relaxation in vascular smooth muscle of deoxycorticosterone acetate-salt rats

    International Nuclear Information System (INIS)

    Soltis, E.E.; Field, F.P.

    1986-01-01

    The Na + -K + pump activity was determined in femoral arterial smooth muscle from deoxycorticosterone acetate (DOCA)-salt hypertensive rats using potassium relaxation and ouabain-sensitive 86 Rb uptake as indices. The membrane-stabilizing effect of calcium and its relation to Na + -K + pump activity also were examined. Femoral arteries from DOCA-salt rats exhibited a greater relaxation in response to potassium addition after contraction with norepinephrine in a low potassium (0.6 mM) Krebs solution. The concentration of potassium required to produce a 50% relaxation was significantly less in DOCA-salt rats. Ouabain-sensitive 86 Rb uptake was significantly greater at 3, 10, and 20 minutes of 86 Rb incubation in femoral arteries from DOCA-salt rats. Linear regression analysis revealed a significant correlation between the uptake of 86 Rb and time of incubation in both control and DOCA-salt rats. A significant difference in the slopes of the regression lines showed that the rate of uptake was greater in DOCA-salt rats. No difference was observed in ouabain-insensitive 86 Rb uptake. A dose-dependent relaxation in response to increasing concentrations of calcium following contraction to norepinephrine was observed in femoral arteries from control and DOCA-salt rats. The relaxation was directly dependent on the level of extracellular potassium and was blocked by ouabain. Femoral arteries from DOCA-salt rats relaxed to a significantly greater extent in response to calcium at each level of potassium when compared with controls. These results provide further evidence for an increase in Na + -K + pump activity in vascular smooth muscle from DOCA-salt hypertensive rats

  3. Calcium dynamics in vascular smooth muscle

    OpenAIRE

    Amberg, Gregory C.; Navedo, Manuel F.

    2013-01-01

    Smooth muscle cells are ultimately responsible for determining vascular luminal diameter and blood flow. Dynamic changes in intracellular calcium are a critical mechanism regulating vascular smooth muscle contractility. Processes influencing intracellular calcium are therefore important regulators of vascular function with physiological and pathophysiological consequences. In this review we discuss the major dynamic calcium signals identified and characterized in vascular smooth muscle cells....

  4. multiscale smoothing in supervised statistical learning

    Indian Academy of Sciences (India)

    Optimum level of smoothing is chosen based on the entire training sample, while a good choice of smoothing parameter may also depend on the observation to be classified. One may like to assess the strength of evidence in favor of different competing class at different scale of smoothing. In allows only one single ...

  5. A SAS IML Macro for Loglinear Smoothing

    Science.gov (United States)

    Moses, Tim; von Davier, Alina

    2011-01-01

    Polynomial loglinear models for one-, two-, and higher-way contingency tables have important applications to measurement and assessment. They are essentially regarded as a smoothing technique, which is commonly referred to as loglinear smoothing. A SAS IML (SAS Institute, 2002a) macro was created to implement loglinear smoothing according to…

  6. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo, E-mail: pompeo.volpe@unipd.it

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α{sub 1}-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy.

  7. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    International Nuclear Information System (INIS)

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo

    2013-01-01

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α 1 -adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy

  8. Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles

    OpenAIRE

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A.

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5 min decreased [3H]NE uptake capacity, an effect characterized by a robust decrease in the Vmax of the transport of [3H]NE. As expected, res...

  9. Synthesis and biological evaluation of trans-3-phenyl-1-indanamines as potential norepinephrine transporter imaging agents

    International Nuclear Information System (INIS)

    McConathy, Jonathan; Owens, Michael J.; Kilts, Clinton D.; Malveaux, Eugene J.; Votaw, John R.; Nemeroff, Charles B.; Goodman, Mark M.

    2005-01-01

    The development of radioligands suitable for studying the central nervous system (CNS) norepinephrine transporter (NET) in vivo will provide important new tools for examining the pathophysiology and pharmacotherapy of a variety of neuropsychiatric disorders including major depression. Towards this end, a series of trans-3-phenyl-1-indanamine derivatives were prepared and evaluated in vitro. The biological properties of the most promising compound, [ 11 C]3-BrPA, were investigated in rat biodistribution and nonhuman primate PET studies. Despite high in vitro affinity for the human NET, the uptake of [ 11 C]3-BrPA in the brain and the heart was not displaceable with pharmacological doses of NET antagonists

  10. Consensus statement and research needs: the role of dopamine and norepinephrine in depression and antidepressant treatment.

    Science.gov (United States)

    Nutt, David J; Baldwin, David S; Clayton, Anita H; Elgie, Rodney; Lecrubier, Yves; Montejo, Angel L; Papakostas, George I; Souery, Daniel; Trivedi, Madhukar H; Tylee, Andre

    2006-01-01

    During a special session, the faculty identified several specific areas related to the role of dopamine and norepinephrine in depression and antidepressant treatment that either warrant the clinician's attention or are in need of more research. Areas of interest include fatigue and lethargy in depression, treatment strategies for treatment-resistant depression, the somatic presentation of depression, neurobiology of fatigue and its role in determining treatment, symptom rating scales, and sexual side effects. In addition, the faculty discussed the importance of patient psychoeducation and self-management as well as the ways in which disease models of depression affect treatment.

  11. Comparison of some nonlinear smoothing methods

    International Nuclear Information System (INIS)

    Bell, P.R.; Dillon, R.S.

    1977-01-01

    Due to the poor quality of many nuclear medicine images, computer-driven smoothing procedures are frequently employed to enhance the diagnostic utility of these images. While linear methods were first tried, it was discovered that nonlinear techniques produced superior smoothing with little detail suppression. We have compared four methods: Gaussian smoothing (linear), two-dimensional least-squares smoothing (linear), two-dimensional least-squares bounding (nonlinear), and two-dimensional median smoothing (nonlinear). The two dimensional least-squares procedures have yielded the most satisfactorily enhanced images, with the median smoothers providing quite good images, even in the presence of widely aberrant points

  12. Smooth random change point models.

    Science.gov (United States)

    van den Hout, Ardo; Muniz-Terrera, Graciela; Matthews, Fiona E

    2011-03-15

    Change point models are used to describe processes over time that show a change in direction. An example of such a process is cognitive ability, where a decline a few years before death is sometimes observed. A broken-stick model consists of two linear parts and a breakpoint where the two lines intersect. Alternatively, models can be formulated that imply a smooth change between the two linear parts. Change point models can be extended by adding random effects to account for variability between subjects. A new smooth change point model is introduced and examples are presented that show how change point models can be estimated using functions in R for mixed-effects models. The Bayesian inference using WinBUGS is also discussed. The methods are illustrated using data from a population-based longitudinal study of ageing, the Cambridge City over 75 Cohort Study. The aim is to identify how many years before death individuals experience a change in the rate of decline of their cognitive ability. Copyright © 2010 John Wiley & Sons, Ltd.

  13. Calcium signaling in smooth muscle.

    Science.gov (United States)

    Hill-Eubanks, David C; Werner, Matthias E; Heppner, Thomas J; Nelson, Mark T

    2011-09-01

    Changes in intracellular Ca(2+) are central to the function of smooth muscle, which lines the walls of all hollow organs. These changes take a variety of forms, from sustained, cell-wide increases to temporally varying, localized changes. The nature of the Ca(2+) signal is a reflection of the source of Ca(2+) (extracellular or intracellular) and the molecular entity responsible for generating it. Depending on the specific channel involved and the detection technology employed, extracellular Ca(2+) entry may be detected optically as graded elevations in intracellular Ca(2+), junctional Ca(2+) transients, Ca(2+) flashes, or Ca(2+) sparklets, whereas release of Ca(2+) from intracellular stores may manifest as Ca(2+) sparks, Ca(2+) puffs, or Ca(2+) waves. These diverse Ca(2+) signals collectively regulate a variety of functions. Some functions, such as contractility, are unique to smooth muscle; others are common to other excitable cells (e.g., modulation of membrane potential) and nonexcitable cells (e.g., regulation of gene expression).

  14. Major vault protein in cardiac and smooth muscle.

    Science.gov (United States)

    Shults, Nataliia V; Das, Dividutta; Suzuki, Yuichiro J

    Major vault protein (MVP) is the major component of the vault particle whose functions are not well understood. One proposed function of the vault is to serve as a mechanism of drug transport, which confers drug resistance in cancer cells. We show that MVP can be found in cardiac and smooth muscle. In human airway smooth muscle cells, knocking down MVP was found to cause cell death, suggesting that MVP serves as a cell survival factor. Further, our laboratory found that MVP is S-glutathionylated in response to ligand/receptor-mediated cell signaling. The S-glutathionylation of MVP appears to regulate protein-protein interactions between MVP and a protein called myosin heavy chain 9 (MYH9). Through MYH9 and Vsp34, MVP may form a complex with Beclin-1 that regulates autophagic cell death. In pulmonary vascular smooth muscle, proteasome inhibition promotes the ubiquitination of MVP, which may function as a mechanism of proteasome inhibition-mediated cell death. Investigating the functions and the regulatory mechanisms of MVP and vault particles is an exciting new area of research in cardiovascular/pulmonary pathophysiology.

  15. Aerobic metabolism on muscle contraction in porcine gastric smooth muscle.

    Science.gov (United States)

    Kanda, Hidenori; Kaneda, Takeharu; Nagai, Yuta; Urakawa, Norimoto; Shimizu, Kazumasa

    2018-05-18

    Exposure to chronic hypoxic conditions causes various gastric diseases, including gastric ulcers. It has been suggested that gastric smooth muscle contraction is associated with aerobic metabolism. However, there are no reports on the association between gastric smooth muscle contraction and aerobic metabolism, and we have investigated this association in the present study. High K + - and carbachol (CCh)-induced muscle contractions involved increasing O 2 consumption. Aeration with N 2 (hypoxia) and NaCN significantly decreased high K + - and CCh-induced muscle contraction and O 2 consumption. In addition, hypoxia and NaCN significantly decreased creatine phosphate (PCr) contents in the presence of high K + . Moreover, decrease in CCh-induced contraction and O 2 consumption was greater than that of high K + . Our results suggest that hypoxia and NaCN inhibit high K + - and CCh-induced contractions in gastric fundus smooth muscles by decreasing O 2 consumption and intracellular PCr content. However, the inhibition of CCh-induced muscle contraction was greater than that of high K + -induced muscle contraction.

  16. Increased norepinephrine release from dog pulmonary artery caused by nitrous oxide

    International Nuclear Information System (INIS)

    Rorie, D.K.; Tyce, G.M.; Sill, J.C.

    1986-01-01

    The effects of nitrous oxide on the release and metabolism of norepinephrine (NE) at neuroeffector junctions in dog pulmonary artery were examined. Helical strips of artery were incubated in Krebs-Ringer solution containing L-( 3 H)NE and mounted for superfusion. The arterial strips were studied in the presence of 95% oxygen-5% carbon dioxide, 70% nitrogen-30% oxygen, or 70% nitrous oxide-30% oxygen. During the 60 min of each experiment, five samples of superfusion fluid were collected for analysis and the effluxes of ( 3 H)NE and its radiolabeled metabolites were measured before and during electrical stimulation and during recovery from stimulation. ( 3 H)Norepinephrine was separated from its metabolites in the superfusate and in extracts of artery by column chromatography and quantitated by liquid scintillation spectrometry. Nitrous oxide significantly increased the fractional loss of total radioactivity and the amount of NE in the superfusate both during resting conditions and during stimulation. Nitrous oxide had no effect on the proportions of radioactivity among metabolites of NE in the superfusate or on the profile of NE metabolites remaining in the tissue after experimentation. These findings are consistent with increased NE release as a direct effect of nitrous oxide on nerve endings

  17. Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

    Science.gov (United States)

    Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

    2017-08-01

    Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Spatiotemporal norepinephrine mapping using a high-density CMOS microelectrode array.

    Science.gov (United States)

    Wydallis, John B; Feeny, Rachel M; Wilson, William; Kern, Tucker; Chen, Tom; Tobet, Stuart; Reynolds, Melissa M; Henry, Charles S

    2015-10-21

    A high-density amperometric electrode array containing 8192 individually addressable platinum working electrodes with an integrated potentiostat fabricated using Complementary Metal Oxide Semiconductor (CMOS) processes is reported. The array was designed to enable electrochemical imaging of chemical gradients with high spatiotemporal resolution. Electrodes are arranged over a 2 mm × 2 mm surface area into 64 subarrays consisting of 128 individual Pt working electrodes as well as Pt pseudo-reference and auxiliary electrodes. Amperometric measurements of norepinephrine in tissue culture media were used to demonstrate the ability of the array to measure concentration gradients in complex media. Poly(dimethylsiloxane) microfluidics were incorporated to control the chemical concentrations in time and space, and the electrochemical response at each electrode was monitored to generate electrochemical heat maps, demonstrating the array's imaging capabilities. A temporal resolution of 10 ms can be achieved by simultaneously monitoring a single subarray of 128 electrodes. The entire 2 mm × 2 mm area can be electrochemically imaged in 64 seconds by cycling through all subarrays at a rate of 1 Hz per subarray. Monitoring diffusional transport of norepinephrine is used to demonstrate the spatiotemporal resolution capabilities of the system.

  19. Anxiety-induced plasma norepinephrine augmentation increases reactive oxygen species formation by monocytes in essential hypertension.

    Science.gov (United States)

    Yasunari, Kenichi; Matsui, Tokuzo; Maeda, Kensaku; Nakamura, Munehiro; Watanabe, Takanori; Kiriike, Nobuo

    2006-06-01

    An association between anxiety and depression and increased blood pressure (BP) and cardiovascular disease risk has not been firmly established. We examined the hypothesis that anxiety and depression lead to increased plasma catecholamines and to production of reactive oxygen species (ROS) by mononuclear cells (MNC) in hypertensive individuals. We also studied the role of BP in this effect. In Protocol 1, a cross-sectional study was performed in 146 hypertensive patients to evaluate whether anxiety and depression affect BP and ROS formation by MNC through increasing plasma catecholamines. In Protocol 2, a 6-month randomized controlled trial using a subtherapeutic dose of the alpha(1)-adrenergic receptor antagonist doxazosin (1 mg/day) versus placebo in 86 patients with essential hypertension was performed to determine whether the increase in ROS formation by MNC was independent of BP. In Protocol 1, a significant relationship was observed between the following: trait anxiety and plasma norepinephrine (r = 0.32, P anxiety may increase plasma norepinephrine and increase ROS formation by MNC independent of BP in hypertensive patients.

  20. Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria.

    Science.gov (United States)

    Boyanova, Lyudmila

    2017-04-01

    Microbial endocrinology is a relatively new research area that already encompasses the anaerobes. Stress hormones, epinephrine and norepinephrine, can affect the growth of anaerobic bacteria such as Fusobacterium nucleatum, Prevotella spp., Porhyromonas spp., Tanerella forsythia and Propionibacterium acnes and can increase virulence gene expression, iron acquisition and many virulence factors of some anaerobic species such as Clostridium perfringens, Porphyromonas gingivalis and Brachyspira pilosicoli. Epinephrine and norepinephrine effects can lead to a growth increase or decrease, or no effect on the growth of the anaerobes. The effects are species-specific and perhaps strain-specific. Discrepancies in the results of some studies can be due to the different methods and media used, catecholamine concentrations, measurement techniques and the low number of strains tested. Biological effects of the stress hormones on the anaerobes may range from halitosis and a worsening of periodontal diseases to tissue damages and atherosclerotic plaque ruptures. Optimizations of the research methods and a detailed assessment of the catecholamine effects in conditions mimicking those in affected organs and tissues, as well as the effects on the quorum sensing and virulence of the anaerobes and the full spectrum of biological consequences of the effects are interesting topics for further evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Energetic Surface Smoothing of Complex Metal-Oxide Thin Films

    International Nuclear Information System (INIS)

    Willmott, P.R.; Herger, R.; Schlepuetz, C.M.; Martoccia, D.; Patterson, B.D.

    2006-01-01

    A novel energetic smoothing mechanism in the growth of complex metal-oxide thin films is reported from in situ kinetic studies of pulsed laser deposition of La 1-x Sr x MnO 3 on SrTiO 3 , using x-ray reflectivity. Below 50% monolayer coverage, prompt insertion of energetic impinging species into small-diameter islands causes them to break up to form daughter islands. This smoothing mechanism therefore inhibits the formation of large-diameter 2D islands and the seeding of 3D growth. Above 50% coverage, islands begin to coalesce and their breakup is thereby suppressed. The energy of the incident flux is instead rechanneled into enhanced surface diffusion, which leads to an increase in the effective surface temperature of ΔT≅500 K. These results have important implications on optimal conditions for nanoscale device fabrication using these materials

  2. Effect of etorphine on the spontaneous and field stimulation-mediated release of norepinephrine and total tritium from perfused guinea pig hearts

    International Nuclear Information System (INIS)

    Anon.

    1986-01-01

    Isolated guinea pig hearts were prelabeled with 3 H-norepinephrine ( 3 H-NE) and perfused with modified Krebs-bicarbonate solution at 37 0 C. Spontaneous release of total 3 H and field stimulation-mediated (supramax. V., 1 Hz, 2 msec duration for a total of 60 pulses) overflow of NE and 3 H-NE were measured in the absence or presence of etorphine. Etorphine (0.1 - 100 μM) was added to the perfusion fluid 15 min. before the stimulation. To study the effect of etorphine on spontaneous release of total 3 H, etorphine was added cumulatively without stimulation. Etorphine (1.0 - 100 μM) caused a significant decrease in the stimulation-mediated overflow of NE and the inhibition was dose-related. The overflow of NE was 5.1 +/- 0.3 ng in the absence and 4.0 +/- 0.2 ng in the presence of etorphine (1.0 μM). Low concentrations of etorphine (0.1 - 1.0 μM) had no effect on the spontaneous release of total 3 H while 10 μM and 100 μM caused a 3 and 6-fold increase respectively. The results show that etorphine inhibited neuronal release of NE at a dose which had no effect on spontaneous release. It is suggested that opiate receptors might be involved in the prejunctional modulation of the release of NE in the guinea pig heart

  3. Lensing smoothing of BAO wiggles

    Energy Technology Data Exchange (ETDEWEB)

    Dio, Enea Di, E-mail: enea.didio@oats.inaf.it [INAF—Osservatorio Astronomico di Trieste, Via G.B. Tiepolo 11, I-34143 Trieste (Italy)

    2017-03-01

    We study non-perturbatively the effect of the deflection angle on the BAO wiggles of the matter power spectrum in real space. We show that from redshift z ∼2 this introduces a dispersion of roughly 1 Mpc at BAO scale, which corresponds approximately to a 1% effect. The lensing effect induced by the deflection angle, which is completely geometrical and survey independent, smears out the BAO wiggles. The effect on the power spectrum amplitude at BAO scale is about 0.1 % for z ∼2 and 0.2 % for z ∼4. We compare the smoothing effects induced by the lensing potential and non-linear structure formation, showing that the two effects become comparable at z ∼ 4, while the lensing effect dominates for sources at higher redshifts. We note that this effect is not accounted through BAO reconstruction techniques.

  4. Radial smoothing and closed orbit

    International Nuclear Information System (INIS)

    Burnod, L.; Cornacchia, M.; Wilson, E.

    1983-11-01

    A complete simulation leading to a description of one of the error curves must involve four phases: (1) random drawing of the six set-up points within a normal population having a standard deviation of 1.3 mm; (b) random drawing of the six vertices of the curve in the sextant mode within a normal population having a standard deviation of 1.2 mm. These vertices are to be set with respect to the axis of the error lunes, while this axis has as its origins the positions defined by the preceding drawing; (c) mathematical definition of six parabolic curves and their junctions. These latter may be curves with very slight curvatures, or segments of a straight line passing through the set-up point and having lengths no longer than one LSS. Thus one gets a mean curve for the absolute errors; (d) plotting of the actually observed radial positions with respect to the mean curve (results of smoothing)

  5. Doing smooth pursuit paradigms in Windows 7

    DEFF Research Database (Denmark)

    Wilms, Inge Linda

    predict strengths or deficits in perception and attention. However, smooth pursuit movements have been difficult to study and very little normative data is available for smooth pursuit performance in children and adults. This poster describes the challenges in setting up a smooth pursuit paradigm...... in Windows 7 with live capturing of eye movements using a Tobii TX300 eye tracker. In particular, the poster describes the challenges and limitations created by the hardware and the software...

  6. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

    Science.gov (United States)

    Dienel, Gerald A; Cruz, Nancy F

    2016-07-01

    Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain

  7. Income and Consumption Smoothing among US States

    DEFF Research Database (Denmark)

    Sørensen, Bent; Yosha, Oved

    within regions but not between regions. This suggests that capital markets transcend regional barriers while credit markets are regional in their nature. Smoothing within the club of rich states is accomplished mainly via capital markets whereas consumption smoothing is dominant within the club of poor...... states. The fraction of a shock to gross state products smoothed by the federal tax-transfer system is the same for various regions and other clubs of states. We calculate the scope for consumption smoothing within various regions and clubs, finding that most gains from risk sharing can be achieved...

  8. Mass spectrometric measurements of norepinephrine synthesis in man from infusion of stable isotope-labelled L-threo-3,4-dihydroxyphenylserine

    International Nuclear Information System (INIS)

    Suzuki, T.; Sakoda, S.; Ueji, M.; Kishimoto, S.

    1985-01-01

    The kinetics of stable isotope-labelled L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), an immediate precursor of (-)-norepinephrine, was studied to investigate the pharmacologic mechanism of its therapeutic effect on orthostatic hypotension in familial amyloid polyneuropathy (FAP) and on akinesia and freezing in parkinsonism. [ 13 C,D]-L-threo-DOPS was synthesized, and 100 mg of the compound was infused for 2 h into two normal subjects, two FAP patients and two patients with the degenerative diseases of the central nervous system. Labelled and endogenous norepinephrine in urine and plasma was assayed simultaneously by gas chromatography/mass spectrometry. The results indicate that the increase in norepinephrine in biological fluids after administration of L-threo-DOPS is attributable mostly to norepinephrine derived from L-threo-DOPS, not to pre-formed endogenous norepinephrine released by L-threo-DOPS

  9. Noise stimulation decreases the concentration of norepinephrine in the rat cochlea.

    Science.gov (United States)

    Vicente-Torres, M A; Gil-Loyzaga, P

    1999-05-14

    The present study was designed to analyze, by using high performance liquid chromatography (HPLC), the effect of acoustic stimulation on the cochlear concentration of norepinephrine (NE). Independently of the rat strain (Long-Evans or Wistar strains), NE concentration decreased about 18% when animals were exposed to white noise (90 dB SPL for 1 h). The same decrease was observed in animals perfused by aortic pathway to remove the blood, indicating that this decrease corresponds exclusively to a neurophysiological process. In fact, these findings could indicate that noise stimulation is involved in the NE release from sympathetic fibers innervating the cochlea. This likely release of NE supports that sympathetic fibers play a functional role in cochleae exposed to noisy situations.

  10. Blood ketone response to norepinephrine-induced free fatty acid in diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Blackard, W G; Omori, Yoshiaki

    1963-04-18

    During 90-minute norepinephrine infusions, blood free fatty acid and ketone responses of Japanese nondiabetic and diabetic subjects were determined. Nonobese diabetic subjects with and without fasting hyperglycemia demonstrated significantly greater blood ketone elevations than nondiabetics. An inverse correlation between obesity and blood ketone response to nonrepinephrine was observed in diabetics. This correlation could not be attributed to varying degrees of fasting hyperglycemia or free fatty acid elevation. Nonobese diabetics with mild fasting hyperglycemia (90 to 150 mg%) exhibited an unexpected greater increase in blood ketones than nonobese diabetics with moderate fasting hyperglycemia (150 to 250 mg%). Differences in free fatty acid elevations were not responsible for this apparent paradox. The magnitude of the hyperketonemic response, though dependent on free fatty elevation, seemed more sensitive to the degree of obesity and the fasting blood glucose level. Fractional ketone body measurements attributed the blood ketone elevations predominantly to ..beta..-hydroxybutyric acid increases. 43 references, 6 figures, 1 table.

  11. Effects of Aroclor 1254 on dopamine and norepinephrine concentrations in pheochromocytoma (PC-12) cells

    International Nuclear Information System (INIS)

    Seegal, R.F.; Brosch, K.; Bush, B.; Ritz, M.; Shain, W.

    1990-01-01

    Pheochromocytoma (PC-12) cells synthesize, store, release and metabolize dopamine (DA) and norepinephrine (NE) in a manner analogous to that observed in the mammalian central nervous system. These cells were used to develop and validate an alternate method to animal testing to assess the effects of a complex environmental mixture of polychlorinated biphenyls (Aroclor 1254) on cellular catecholamine function. Aroclor 1254, at concentrations of 1 to 100 ppm, significantly decreased cellular catecholamine concentrations after 6 hrs. Exposure at 100 ppm for periods of less than an hr increased cellular catecholamine concentrations while longer exposure times (i.e., 1 to 24 hr) decreased cellular catecholamine concentrations. This in vitro depletion of catecholamines is similar to that seen in vivo. Thus, PC-12 cells may be useful for neurochemical evaluation of neurotoxicants with particular reference to effects on catecholaminergic systems

  12. Lack of effect of norepinephrine on cranial haemodynamics and headache in healthy volunteers

    DEFF Research Database (Denmark)

    Lindholt, M; Petersen, K A; Tvedskov, J F

    2009-01-01

    Stress is a provoking factor for both tension-type headache and migraine attacks. In the present single-blind study, we investigated if stress induced by norepinephrine (NE) could elicit delayed headache in 10 healthy subjects and recorded the cranial arterial responses. NE at a dose of 0...... no changes in these arterial parameters after NE. In both treatment groups three subjects developed delayed headaches. Thus, stress by NE infusion did not result in delayed headache........025 microg kg(-1) min(-1) or placebo was infused for 90 min and the headache was followed for 14 h. Blood flow velocity in the middle cerebral artery (measured with transcranial Doppler) and diameters of the temporal artery and the radial artery (measured with ultrasound) were followed for 2 h. There were...

  13. The role of dopamine and norepinephrine in depression and antidepressant treatment.

    Science.gov (United States)

    Nutt, David J

    2006-01-01

    Most antidepressants in use today are descendants of the monoamine oxidase inhibitor iproniazid and the tricyclic agent imipramine. These agents were both originally developed for other indications but then were serendipitously determined to have antidepressant effects. Elucidation of the mechanisms of action of these first antidepressants, along with those of reserpine and amphetamine, led to the monoamine theories of depression. Through the past several decades, approaches undertaken to clarify the roles of the neurotransmitters norepinephrine, dopamine, and serotonin in depression have included animal studies, human biological and postmortem studies, inferences drawn from antidepressant drug actions, and challenge or depletion studies; most recently, brain imaging studies have proved to be especially informative. This research has identified novel potential targets, with the goal of developing new antidepressant drugs with better efficacy and faster onset of action than current "gold-standard" treatments.

  14. Cerebellar Norepinephrine Modulates Learning of Delay Classical Eyeblink Conditioning: Evidence for Post-Synaptic Signaling via PKA

    Science.gov (United States)

    Fister, Mathew; Bickford, Paula C.; Cartford, M. Claire; Samec, Amy

    2004-01-01

    The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no studies have shown a direct involvement of…

  15. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies

    NARCIS (Netherlands)

    Ruhe, H. G.; Mason, N. S.; Schene, A. H.

    2007-01-01

    Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine

  16. Poincaré plot width, morning urine norepinephrine levels, and autonomic imbalance in children with obstructive sleep apnea.

    Science.gov (United States)

    Chaidas, Konstantinos; Tsaoussoglou, Marina; Theodorou, Emmanouel; Lianou, Loukia; Chrousos, George; Kaditis, Athanasios G

    2014-08-01

    Obstructive sleep apnea (OSA) in childhood is accompanied by sympathetic overflow unopposed by the parasympathetic tone. Complex methods like power spectral analysis of heart rate variability have been applied to study this imbalance. In this report, width of Poincaré scattergram of the R-R interval (parasympathetic tone) and morning urine norepinephrine concentration (sympathetic activity) were used to assess autonomic imbalance. Poincaré plot was obtained from the electrocardiographic channel of nocturnal polysomnography and its width was measured, and norepinephrine-to-creatinine concentration ratio was calculated in morning urine specimen. Twenty children with obstructive sleep apnea and moderate-to-severe nocturnal hypoxemia (oxygen saturation of hemoglobin [SpO(2)] nadir plot width (318.7 ± 139.3 ms) and higher ln-transformed urine norepinephrine-to-creatinine ratio (4.5 ± 0.6) than control subjects (484.2 ± 104.4 ms and 3.8 ± 0.4, respectively; P plot width (P = 0.02). Subjects with obstructive sleep apnea and moderate-to-severe nocturnal hypoxemia have enhanced sympathetic activity and reduced parasympathetic drive. Poincaré plot width and urine norepinephrine levels are simple measures of autonomic imbalance in pediatric obstructive sleep apnea. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. The role of serotonin and norepinephrine in sleep-waking activity.

    Science.gov (United States)

    Morgane, P J; Stern, W C

    1975-11-01

    A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.

  18. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells

    International Nuclear Information System (INIS)

    Yang, R.; Lin, Q.; Gao, H.B.; Zhang, P.

    2014-01-01

    In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5′-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression

  19. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, R.; Lin, Q.; Gao, H.B.; Zhang, P. [Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai (China)

    2014-02-17

    In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5′-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.

  20. Norepinephrine and dopamine increase motility, biofilm formation and virulence of Vibrio harveyi

    Directory of Open Access Journals (Sweden)

    Qian eYang

    2014-11-01

    Full Text Available Vibrio harveyi is one of the major pathogens of aquatic organisms, affecting both vertebrates and invertebrates, and causes important losses in the aquaculture industry. In order to develop novel methods to control disease caused by this pathogen, we need to obtain a better understanding of pathogenicity mechanisms. Sensing of catecholamines increases both growth and production of virulence-related factors in pathogens of terrestrial animals and humans. However, at this moment, knowledge on the impact of catecholamines on the virulence of pathogens of aquatic organisms is lacking. In the present study, we report that in V. harveyi, norepinephrine and dopamine increased growth in serum-supplemented medium, siderophore production, swimming motility and expression of genes involved in flagellar motility, biofilm formation, and exopolysaccharide production. Consistent with this, pretreatment of V. harveyi with catecholamines prior to inoculation into the rearing water resulted in significantly decreased survival of gnotobiotic brine shrimp larvae, when compared to larvae challenged with untreated V. harveyi. Further, norepinephrine-induced effects could be neutralized by α-adrenergic antagonists or by the bacterial catecholamine receptor antagonist LED209, but not by β-adrenergic or dopaminergic antagonists. Dopamine-induced effects could be neutralized by dopaminergic antagonists or LED209, but not by adrenergic antagonists. Together, our results indicate that catecholamine sensing increases the success of transmission of V. harveyi and that interfering with catecholamine sensing might be an interesting strategy to control vibriosis in aquaculture. We hypothesise that upon tissue and/or hemocyte damage during infection, pathogens come into contact with elevated catecholamine levels, and that this stimulates the expression of virulence factors that are required to colonize a new host.

  1. Isolating the Norepinephrine Pathway Comparing Lithium in Bipolar Patients to SSRIs in Depressive Patients

    Directory of Open Access Journals (Sweden)

    Andy R. Eugene

    2015-07-01

    Full Text Available Introduction: The purpose of this investigatory neuroimaging analysis was done to better understand the pharmacodynamics of Lithium by isolating the norepinephrine pathway in the brain. To accomplish this, we compared patients with Bipolar Disorder treated with Lithium to patients diagnosed with Major Depression or Depressive Disorder who are treated with Selective Serotonin Reuptake Inhibitors (SSRIs.Methodology: We used Standardized Low Resolution Brain Electrotomography to calculate the whole brain, voxel-by-voxel, unpaired t-tests Statistical non-Parametric Maps. For our first electrophysiological neuroimaging investigation, we compared 46 patients (average age = 34 ± 16.5 diagnosed with Bipolar Affective Disorder to three patient groups all diagnosed with Major Depression or Depressive Episode. The first is with 48 patients diagnosed with Major Depression or Depressive Episode (average age = 49 ± 12.9, the second to 16 male depressive patients (average age = 45 ± 15.1, and the final comparison to 32 depressive females (average age = 50 ± 11.7.Results: The results of sLORETA three-dimensional statistical non-parametric maps illustrated that Lithium influenced an increase in neurotransmission in the right Superior TemporalGyrus (t=1.403, p=0.00780, Fusiform Gyrus (t=1.26, and Parahippocampal Gyrus (t=1.29.Moreover, an increased in neuronal function was found was also identified at the Cingulate Gyrus(t=1.06, p=0.01200.Conclusion: We are proposing a translational clinical biological marker for patients diagnosed with Bipolar Disorder to guide physicians during the course of Lithium therapy and have identified neuroanatomical structures influenced by norepinephrine.

  2. Smooth horizons and quantum ripples

    International Nuclear Information System (INIS)

    Golovnev, Alexey

    2015-01-01

    Black holes are unique objects which allow for meaningful theoretical studies of strong gravity and even quantum gravity effects. An infalling and a distant observer would have very different views on the structure of the world. However, a careful analysis has shown that it entails no genuine contradictions for physics, and the paradigm of observer complementarity has been coined. Recently this picture was put into doubt. In particular, it was argued that in old black holes a firewall must form in order to protect the basic principles of quantum mechanics. This AMPS paradox has already been discussed in a vast number of papers with different attitudes and conclusions. Here we want to argue that a possible source of confusion is the neglect of quantum gravity effects. Contrary to widespread perception, it does not necessarily mean that effective field theory is inapplicable in rather smooth neighbourhoods of large black hole horizons. The real offender might be an attempt to consistently use it over the huge distances from the near-horizon zone of old black holes to the early radiation. We give simple estimates to support this viewpoint and show how the Page time and (somewhat more speculative) scrambling time do appear. (orig.)

  3. Smooth horizons and quantum ripples

    Energy Technology Data Exchange (ETDEWEB)

    Golovnev, Alexey [Saint Petersburg State University, High Energy Physics Department, Saint-Petersburg (Russian Federation)

    2015-05-15

    Black holes are unique objects which allow for meaningful theoretical studies of strong gravity and even quantum gravity effects. An infalling and a distant observer would have very different views on the structure of the world. However, a careful analysis has shown that it entails no genuine contradictions for physics, and the paradigm of observer complementarity has been coined. Recently this picture was put into doubt. In particular, it was argued that in old black holes a firewall must form in order to protect the basic principles of quantum mechanics. This AMPS paradox has already been discussed in a vast number of papers with different attitudes and conclusions. Here we want to argue that a possible source of confusion is the neglect of quantum gravity effects. Contrary to widespread perception, it does not necessarily mean that effective field theory is inapplicable in rather smooth neighbourhoods of large black hole horizons. The real offender might be an attempt to consistently use it over the huge distances from the near-horizon zone of old black holes to the early radiation. We give simple estimates to support this viewpoint and show how the Page time and (somewhat more speculative) scrambling time do appear. (orig.)

  4. Local Transfer Coefficient, Smooth Channel

    Directory of Open Access Journals (Sweden)

    R. T. Kukreja

    1998-01-01

    Full Text Available Naphthalene sublimation technique and the heat/mass transfer analogy are used to determine the detailed local heat/mass transfer distributions on the leading and trailing walls of a twopass square channel with smooth walls that rotates about a perpendicular axis. Since the variation of density is small in the flow through the channel, buoyancy effect is negligible. Results show that, in both the stationary and rotating channel cases, very large spanwise variations of the mass transfer exist in he turn and in the region immediately downstream of the turn in the second straight pass. In the first straight pass, the rotation-induced Coriolis forces reduce the mass transfer on the leading wall and increase the mass transfer on the trailing wall. In the turn, rotation significantly increases the mass transfer on the leading wall, especially in the upstream half of the turn. Rotation also increases the mass transfer on the trailing wall, more in the downstream half of the turn than in the upstream half of the turn. Immediately downstream of the turn, rotation causes the mass transfer to be much higher on the trailing wall near the downstream corner of the tip of the inner wall than on the opposite leading wall. The mass transfer in the second pass is higher on the leading wall than on the trailing wall. A slower flow causes higher mass transfer enhancement in the turn on both the leading and trailing walls.

  5. Effects of α2A Adrenoceptors on Norepinephrine Secretion from the Locus Coeruleus during Chronic Stress-Induced Depression

    Directory of Open Access Journals (Sweden)

    Hong-ping Huang

    2017-05-01

    Full Text Available Chronic stressors can often lead to the development of psychological disorders, such as depression and anxiety. The locus coeruleus (LC is a stress sensitive brain region located in the pons, with noradrenergic neurons that project to the hypothalamus, especially the paraventricular nucleus (PVN of the hypothalamus. The purpose of this paper is to better understand how alpha 2A-adrenoceptors (α2A-ARs and LC-hypothalamus noradrenergic system participate in the pathophysiological mechanism of depression. In vivo norepinephrine (NE release in the PVN triggered by electrical stimulation in the LC was detected with carbon fiber electrodes in depression model of rats induced by chronic unpredictable mild stress (CUMS. Also, the extracellular level of NE in the PVN was measured by microdialysis in vivo without any stimulation in the LC. The alpha 2-adrenoceptor (α2-AR antagonist yohimbine and α2A-ARs antagonist BRL-44408 maleate were systemically administered to rats to determine the effects of α2A-ARs on NE release in the PVN. The peak value of elicited NE release signals in the PVN induced by electrical stimulation in the LC in the CUMS rats were lower than that in the control rats. The extracellular levels of NE in the PVN of the CUMS rats were significantly less than that of the control rats. Intraperitoneal injection of yohimbine or BRL-44408 maleate significantly potentiated NE release in the PVN of the CUMS rats. The CUMS significantly increased protein expression levels of α2A-AR in the hypothalamus, and BRL-44408 maleate significantly reversed the increase of α2A-AR protein expression levels in the CUMS rats. Our results suggest that the CUMS could significantly facilitate the effect of α2-adrenoceptor-mediated presynaptic inhibition and decrease the release of NE in the PVN from LC. Blockade of the inhibitory action of excessive α2A-adrenergic receptors in the CUMS rats could increase the level of NE in the PVN, which is effective in

  6. Meta-iodobenzylguanidine inhibits complex I and III of the respiratory chain in the human cell line Molt-4

    NARCIS (Netherlands)

    Cornelissen, J.; Wanders, R. J.; van Gennip, A. H.; van den Bogert, C.; Voûte, P. A.; van Kuilenburg, A. B.

    1995-01-01

    In this paper we report the effects of meta-iodobenzylguanidine (MIBG), a structural analogue of norepinephrine, on cell proliferation and several parameters related to mitochondrial respiration in Molt-4 cells. In micromolar concentrations, MIBG completely inhibited the proliferation of Molt-4

  7. Smoothed Analysis of Local Search Algorithms

    NARCIS (Netherlands)

    Manthey, Bodo; Dehne, Frank; Sack, Jörg-Rüdiger; Stege, Ulrike

    2015-01-01

    Smoothed analysis is a method for analyzing the performance of algorithms for which classical worst-case analysis fails to explain the performance observed in practice. Smoothed analysis has been applied to explain the performance of a variety of algorithms in the last years. One particular class of

  8. Assessment of smoothed spectra using autocorrelation function

    International Nuclear Information System (INIS)

    Urbanski, P.; Kowalska, E.

    2006-01-01

    Recently, data and signal smoothing became almost standard procedures in the spectrometric and chromatographic methods. In radiometry, the main purpose to apply smoothing is minimisation of the statistical fluctuation and avoid distortion. The aim of the work was to find a qualitative parameter, which could be used, as a figure of merit for detecting distortion of the smoothed spectra, based on the linear model. It is assumed that as long as the part of the raw spectrum removed by the smoothing procedure (v s ) will be of random nature, the smoothed spectrum can be considered as undistorted. Thanks to this feature of the autocorrelation function, drifts of the mean value in the removed noise vs as well as its periodicity can be more easily detected from the autocorrelogram than from the original data

  9. Mediators on human airway smooth muscle.

    Science.gov (United States)

    Armour, C; Johnson, P; Anticevich, S; Ammit, A; McKay, K; Hughes, M; Black, J

    1997-01-01

    1. Bronchial hyperresponsiveness in asthma may be due to several abnormalities, but must include alterations in the airway smooth muscle responsiveness and/or volume. 2. Increased responsiveness of airway smooth muscle in vitro can be induced by certain inflammatory cell products and by induction of sensitization (atopy). 3. Increased airway smooth muscle growth can also be induced by inflammatory cell products and atopic serum. 4. Mast cell numbers are increased in the airways of asthmatics and, in our studies, in airway smooth muscle that is sensitized and hyperresponsive. 5. We propose that there is a relationship between mast cells and airway smooth muscle cells which, once an allergic process has been initiated, results in the development of critical features in the lungs in asthma.

  10. Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death

    Directory of Open Access Journals (Sweden)

    Daniel Herrmann

    2014-09-01

    Conclusions: Honokiol inhibits smooth muscle contraction in the human prostate, and induces cell death in cultured stromal cells. Because prostate smooth muscle tone and prostate growth may cause LUTS, it appears possible that honokiol improves voiding symptoms.

  11. Smooth halos in the cosmic web

    International Nuclear Information System (INIS)

    Gaite, José

    2015-01-01

    Dark matter halos can be defined as smooth distributions of dark matter placed in a non-smooth cosmic web structure. This definition of halos demands a precise definition of smoothness and a characterization of the manner in which the transition from smooth halos to the cosmic web takes place. We introduce entropic measures of smoothness, related to measures of inequality previously used in economy and with the advantage of being connected with standard methods of multifractal analysis already used for characterizing the cosmic web structure in cold dark matter N-body simulations. These entropic measures provide us with a quantitative description of the transition from the small scales portrayed as a distribution of halos to the larger scales portrayed as a cosmic web and, therefore, allow us to assign definite sizes to halos. However, these ''smoothness sizes'' have no direct relation to the virial radii. Finally, we discuss the influence of N-body discreteness parameters on smoothness

  12. Smooth halos in the cosmic web

    Energy Technology Data Exchange (ETDEWEB)

    Gaite, José, E-mail: jose.gaite@upm.es [Physics Dept., ETSIAE, IDR, Universidad Politécnica de Madrid, Pza. Cardenal Cisneros 3, E-28040 Madrid (Spain)

    2015-04-01

    Dark matter halos can be defined as smooth distributions of dark matter placed in a non-smooth cosmic web structure. This definition of halos demands a precise definition of smoothness and a characterization of the manner in which the transition from smooth halos to the cosmic web takes place. We introduce entropic measures of smoothness, related to measures of inequality previously used in economy and with the advantage of being connected with standard methods of multifractal analysis already used for characterizing the cosmic web structure in cold dark matter N-body simulations. These entropic measures provide us with a quantitative description of the transition from the small scales portrayed as a distribution of halos to the larger scales portrayed as a cosmic web and, therefore, allow us to assign definite sizes to halos. However, these ''smoothness sizes'' have no direct relation to the virial radii. Finally, we discuss the influence of N-body discreteness parameters on smoothness.

  13. Experimental investigation of smoothing by spectral dispersion

    International Nuclear Information System (INIS)

    Regan, Sean P.; Marozas, John A.; Kelly, John H.; Boehly, Thomas R.; Donaldson, William R.; Jaanimagi, Paul A.; Keck, Robert L.; Kessler, Terrance J.; Meyerhofer, David D.; Seka, Wolf

    2000-01-01

    Measurements of smoothing rates for smoothing by spectral dispersion (SSD) of high-power, solid-state laser beams used for inertial confinement fusion (ICF) research are reported. Smoothing rates were obtained from the intensity distributions of equivalent target plane images for laser pulses of varying duration. Simulations of the experimental data with the known properties of the phase plates and the frequency modulators are in good agreement with the experimental data. These results inspire confidence in extrapolating to higher bandwidths and other SSD configurations that may be suitable for ICF experiments and ultimately for direct-drive laser-fusion ignition. (c) 2000 Optical Society of America

  14. Bifurcations of non-smooth systems

    Science.gov (United States)

    Angulo, Fabiola; Olivar, Gerard; Osorio, Gustavo A.; Escobar, Carlos M.; Ferreira, Jocirei D.; Redondo, Johan M.

    2012-12-01

    Non-smooth systems (namely piecewise-smooth systems) have received much attention in the last decade. Many contributions in this area show that theory and applications (to electronic circuits, mechanical systems, …) are relevant to problems in science and engineering. Specially, new bifurcations have been reported in the literature, and this was the topic of this minisymposium. Thus both bifurcation theory and its applications were included. Several contributions from different fields show that non-smooth bifurcations are a hot topic in research. Thus in this paper the reader can find contributions from electronics, energy markets and population dynamics. Also, a carefully-written specific algebraic software tool is presented.

  15. Evaluation of radioiodinated (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine as a radioligand for imaging of norepinephrine transporter in the heart

    Energy Technology Data Exchange (ETDEWEB)

    Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan)], E-mail: ykiyono@u-fukui.ac.jp; Sugita, Taku [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Ueda, Masashi [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kawashima, Hidekazu [Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kanegawa, Naoki; Kuge, Yuji [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Fujibayashi, Yasuhisa [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Saji, Hideo [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2008-02-15

    Introduction: The norepinephrine transporter (NET) is located presynaptically on noradrenergic nerve terminals and plays a critical role in the regulation of the synaptic norepinephrine (NE) concentration via the reuptake of NE. Changes in NET have been recently reported in several cardiac failures. Therefore, a NET-specific radioligand is useful for in vivo assessment of changes in NET density in various cardiac disorders. Recently, we developed a radioiodinated reboxetine analogue, (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine ((S,S)-IPBM), for NET imaging. In the current study, we assessed the applicability of radioiodinated (S,S)-IPBM to NET imaging in the heart. Methods: The NET affinity and selectivity were measured from the ability to displace specific [{sup 3}H]nisoxetine and (S,S)-[{sup 125}I]IPBM binding to rat heart membrane, respectively. To evaluate the distribution of (S,S)-[{sup 125}I]IPBM in vivo, biodistribution experiment was performed in rats. With the use of several monoamine transporter binding agents, pharmacological blocking experiments were performed in rats. Results: In vitro binding assays showed that the affinity of (S,S)-IPBM to NET was similar to those of the well-known NET-specific binding agents, nisoxetine and desipramine. Furthermore, (S,S)-[{sup 125}I]IPBM binding was inhibited by nisoxetine and desipramine, but not by dopamine or serotonin transporter binding agents. These data indicated that (S,S)-IPBM had high affinity and selectivity for NET in vitro. Biodistribution studies in rats showed rapid and high uptake of (S,S)-[{sup 125}I]IPBM by the heart and rapid clearance from the blood. The heart-to-blood ratio was 31.9 at 180 min after the injection. The administration of nisoxetine and desipramine decreased (S,S)-[{sup 125}I]IPBM accumulation in the heart, but injection of fluoxetine and GBR12909 had little influence. Conclusions: Radioiodinated (S,S)-IPBM is a potential radioligand for NET imaging in the heart.

  16. Rac1 modulates G-protein-coupled receptor-induced bronchial smooth muscle contraction.

    Science.gov (United States)

    Sakai, Hiroyasu; Kai, Yuki; Sato, Ken; Ikebe, Mitsuo; Chiba, Yohihiko

    2018-01-05

    Increasing evidence suggests a functional role of RhoA/Rho-kinase signalling as a mechanism for smooth muscle contraction; however, little is known regarding the roles of Rac1 and other members of the Rho protein family. This study aimed to examine whether Rac1 modulates bronchial smooth muscle contraction. Ring preparations of bronchi isolated from rats were suspended in an organ bath, and isometric contraction of circular smooth muscle was measured. Immunoblotting was used to examine myosin light chain phosphorylation in bronchial smooth muscle. Our results demonstrated that muscle contractions induced by carbachol (CCh) and endothelin-1 (ET-1) were inhibited by EHT1864, a selective Rac1 inhibitor, and NSC23766, a selective inhibitor of Rac1-specific guanine nucleotide exchange factors. Similarly, myosin light chain and myosin phosphatase target subunit 1 (MYPT1) at Thr853 phosphorylation induced by contractile agonist were inhibited with Rac1 inhibition. However, contractions induced by high K + , calyculin A (a potent protein phosphatase inhibitor) and K + /PDBu were not inhibited by these Rac1 inhibitors. Interestingly, NaF (a G-protein activator)-induced contractions were inhibited by EHT1864 but not by NSC23766. We next examined the effects of a trans-acting activator of transcription protein transduction domain (PTD) fusion protein with Rac1 (PTD-Rac1) on muscle contraction. The constitutively active form of PTD-Rac1 directly induced force development and contractions were abolished by EHT1864. These results suggest that Rac1, activated by G protein-coupled receptor agonists, such as CCh and ET-1, may induce myosin light chain and MYPT phosphorylation and modulate the contraction of bronchial smooth muscle. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Optimal Smoothing in Adaptive Location Estimation

    OpenAIRE

    Mammen, Enno; Park, Byeong U.

    1997-01-01

    In this paper higher order performance of kernel basedadaptive location estimators are considered. Optimalchoice of smoothing parameters is discussed and it isshown how much is lossed in efficiency by not knowingthe underlying translation density.

  18. Smooth surfaces from rational bilinear patches

    KAUST Repository

    Shi, Ling

    2014-01-01

    Smooth freeform skins from simple panels constitute a challenging topic arising in contemporary architecture. We contribute to this problem area by showing how to approximate a negatively curved surface by smoothly joined rational bilinear patches. The approximation problem is solved with help of a new computational approach to the hyperbolic nets of Huhnen-Venedey and Rörig and optimization algorithms based on it. We also discuss its limits which lie in the topology of the input surface. Finally, freeform deformations based on Darboux transformations are used to generate smooth surfaces from smoothly joined Darboux cyclide patches; in this way we eliminate the restriction to surfaces with negative Gaussian curvature. © 2013 Elsevier B.V.

  19. Smooth embeddings with Stein surface images

    OpenAIRE

    Gompf, Robert E.

    2011-01-01

    A simple characterization is given of open subsets of a complex surface that smoothly perturb to Stein open subsets. As applications, complex 2-space C^2 contains domains of holomorphy (Stein open subsets) that are exotic R^4's, and others homotopy equivalent to the 2-sphere but cut out by smooth, compact 3-manifolds. Pseudoconvex embeddings of Brieskorn spheres and other 3-manifolds into complex surfaces are constructed, as are pseudoconcave holomorphic fillings (with disagreeing contact and...

  20. Some splines produced by smooth interpolation

    Czech Academy of Sciences Publication Activity Database

    Segeth, Karel

    2018-01-01

    Roč. 319, 15 February (2018), s. 387-394 ISSN 0096-3003 R&D Projects: GA ČR GA14-02067S Institutional support: RVO:67985840 Keywords : smooth data approximation * smooth data interpolation * cubic spline Subject RIV: BA - General Mathematics OBOR OECD: Applied mathematics Impact factor: 1.738, year: 2016 http://www.sciencedirect.com/science/article/pii/S0096300317302746?via%3Dihub

  1. Some splines produced by smooth interpolation

    Czech Academy of Sciences Publication Activity Database

    Segeth, Karel

    2018-01-01

    Roč. 319, 15 February (2018), s. 387-394 ISSN 0096-3003 R&D Projects: GA ČR GA14-02067S Institutional support: RVO:67985840 Keywords : smooth data approximation * smooth data interpolation * cubic spline Subject RIV: BA - General Mathematics OBOR OECD: Applied mathematics Impact factor: 1.738, year: 2016 http://www. science direct.com/ science /article/pii/S0096300317302746?via%3Dihub

  2. Optimal Smooth Consumption and Annuity Design

    DEFF Research Database (Denmark)

    Bruhn, Kenneth; Steffensen, Mogens

    2013-01-01

    We propose an optimization criterion that yields extraordinary consumption smoothing compared to the well known results of the life-cycle model. Under this criterion we solve the related consumption and investment optimization problem faced by individuals with preferences for intertemporal stabil...... stability in consumption. We find that the consumption and investment patterns demanded under the optimization criterion is in general offered as annuity benefits from products in the class of ‘Formula Based Smoothed Investment-Linked Annuities’....

  3. Reference intervals and variation for urinary epinephrine, norepinephrine and cortisol in healthy men and women in Denmark

    DEFF Research Database (Denmark)

    Hansen, Åse Marie; Garde, A H; Christensen, J M

    2001-01-01

    Reference intervals for urinary epinephrine, norepinephrine and cortisol in 120 healthy individuals performing their routine work were established according to the International Union of Pure and Applied Chemistry (IUPAC) and the International Federation of Clinical Chemistry and Laboratory...... Medicine (IFCC) for use in the risk assessment of exposure to occupational stress. Reference intervals were established for three different times of the day: in morning samples (05.45-07.15) the limit of detection (LOD) was 2.10 micromol epinephrine/mol creatinine (82 women) and 2.86 micromol epinephrine....../mol creatinine (37 men), and the reference interval was 3.6-29.1 micromol norepinephrine/mol creatinine and 2.3-52.8 micromol cortisol/mol creatinine (119 women and men); in afternoon samples (15.30-18.30) the reference interval was 0.64-10.8 micromol epinephrine/mol creatinine (82 women), 1.20-11.2 micromol...

  4. Increased release of norepinephrine and dopamine from canine kidney during bilateral carotid occlusion

    International Nuclear Information System (INIS)

    Bradley, T.; Hjemdahl, P.; DiBona, G.F.

    1987-01-01

    The renal overflow of norepinephrine (NE) and dopamine (DA) to plasma from the innervated kidney was studied at rest and during sympathetic nervous system activation by bilateral carotid artery occlusion (BCO) in vagotomized dogs under barbiturate or barbiturate/nitrous oxide anesthesia. BCO elevated arterial pressure and the arterial plasma concentration of NE, DA, and epinephrine (Epi). Renal vascular resistance (renal arterial pressure kept constant) increased by 15 +/- 7% and the net renal venous outflows (renal veno-arterial concentration difference x renal plasma flow) of NE and DA were enhanced. To obtain more correct estimates of the renal contribution to the renal venous catecholamine outflow, they corrected for the renal extraction of arterial catecholamines, assessed as the extractions of [ 3 H]NE, [ 3 H]DA, or endogenous Epi. The [ 3 H]NE corrected renal NE overflow to plasma increased from 144 +/- 40 to 243 +/- 64 pmol-min -1 during BCO, which, when compared with a previous study of the [ 3 H]NE corrected renal NE overflow to plasma evoked by electrical renal nerve stimulation, corresponds to a 40% increase in nerve impulse frequency from ∼ 0.6 Hz. If the renal catecholamine extraction was not taken into account the effect of BCO was underestimated. The renal DA overflow to plasma was about one-fifth of the NE overflow both at rest and during BCO, indicating that there was no preferential activation of noradrenergic or putative dopaminergic nerves by BCO

  5. Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

    Science.gov (United States)

    Jacob, G.; Shannon, J. R.; Costa, F.; Furlan, R.; Biaggioni, I.; Mosqueda-Garcia, R.; Robertson, R. M.; Robertson, D.

    1999-01-01

    BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, Pheart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, Pheart rate was similar in both groups. CONCLUSIONS: The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.

  6. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

    Science.gov (United States)

    Dahl, D; Sarvey, J M

    1989-01-01

    The study presented here indicates that norepinephrine (NE) selectively induces long-lasting modifications of synaptically mediated responses in the dentate gyrus of the rat hippocampal slice. A low concentration of NE (1.0 microM; in the presence of 50 microM phentolamine, an alpha-adrenergic antagonist) or a 1.0 microM concentration of the specific beta-adrenergic agonist isoproterenol induced long-lasting pathway-specific alterations of granule cell electrophysiological responses. Excitatory postsynaptic potentials and population spikes evoked by stimulation of the medial perforant pathway (PP) were potentiated for more than 45 min. In contrast, responses to lateral PP stimulation were depressed for the same period. Both potentiation and depression were blocked by the beta-adrenergic antagonist propranolol (1.0 microM). These results indicate that NE can act differentially on projections to the dentate gyrus arising in the entorhinal cortex. Such selective persistent modifications of cortical circuits may be involved in processes in the mammalian brain underlying attention, learning, and memory. PMID:2734319

  7. The Role of L-type Calcium Channels in Olfactory Learning and Its Modulation by Norepinephrine

    Directory of Open Access Journals (Sweden)

    Abhinaba Ghosh

    2017-12-01

    Full Text Available L type calcium channels (LTCCs are prevalent in different systems and hold immense importance for maintaining/performing selective functions. In the nervous system, CaV1.2 and CaV1.3 are emerging as critical modulators of neuronal functions. Although the general role of these calcium channels in modulating synaptic plasticity and memory has been explored, their role in olfactory learning is not well understood. In this review article we first discuss the role of LTCCs in olfactory learning especially focusing on early odor preference learning in neonate rodents, presenting evidence that while NMDARs initiate stimulus-specific learning, LTCCs promote protein-synthesis dependent long-term memory (LTM. Norepinephrine (NE release from the locus coeruleus (LC is essential for early olfactory learning, thus noradrenergic modulation of LTCC function and its implication in olfactory learning is discussed here. We then address the differential roles of LTCCs in adult learning and learning in aged animals.

  8. Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex.

    Science.gov (United States)

    Schmidt, Karl T; Schroeder, Jason P; Foster, Stephanie L; Squires, Katherine; Smith, Brilee M; Pitts, Elizabeth G; Epstein, Michael P; Weinshenker, David

    2017-06-01

    Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Norepinephrine metabolism in man using deuterium labeling: turnover 4-hydroxy-3-methoxymandelic acid

    Energy Technology Data Exchange (ETDEWEB)

    Mardh, G.; Sjoequist, B.; Anggard, E.

    1982-06-01

    4-Hydroxy-3-methoxymandelic acid (HMMA; VMA) labeled with three deuterium atoms was used to study the turnover and fate of HMMA following intravenous injection. Five healthy men were given a pulse dose of 5.0 mumol of labeled HMMA. Plasma and urinary levels of both endogenous and labeled HMMA were subsequently followed by gas chromatography-mass spectrometry using selected ion detection. The kinetic parameters were determined both with and without compensation for the pool expansion caused by the injection of labeled HMMA. The urinary recovery of labeled HMMA was 85 +/- 10% (mean +/- SD). No conversion of HMMA to 4-hydroxy-3-methoxyphenyl glycol (HMPG) occurred. The biological half-life of HMMA was 0.54 +/- 0.22 h. The apparent volume of distribution was 0.36 +/- 0.11 L/kg. The production rate or body turnover was 1.27 +/- 0.51 mumol HMMA/h and urinary excretion rate was 0.82 +/- 0.22 mumol/h. These results show that HMMA is turnover over rapidly in a relatively small volume of distribution and that, unlike HMPG, it is an end metabolite of norepinephrine in man.

  10. A locus coeruleus-norepinephrine account of individual differences in working memory capacity and attention control.

    Science.gov (United States)

    Unsworth, Nash; Robison, Matthew K

    2017-08-01

    Studies examining individual differences in working memory capacity (WMC) have suggested that low WMC individuals have particular deficits in attention control processes compared to high WMC individuals. In the current article we suggest that part of the WMC-attention control relation is due to variation in the functioning of the locus coeruleus-norepinephrine system (LC-NE). Specifically, we suggest that because of dysregulation of LC-NE functioning, the fronto-parietal control network for low WMC individuals is only weakly activated, resulting in greater default-mode network activity (and greater mind-wandering) for low WMC individuals compared to high WMC individuals. This results in disrupted attention control and overall more erratic performance (more lapses of attention) for low WMC individuals than for high WMC individuals. This framework is used to examine previous studies of individual differences in WMC and attention control, and new evidence is examined on the basis of predictions of the framework to pupillary responses as an indirect marker of LC-NE functioning.

  11. Effects of estradiol on norepinephrine and prostaglandin efflux in medial basal hypothalamus of ovariectomized rats

    International Nuclear Information System (INIS)

    Cardinali, D.P.; Fernandez Pardal, J.; Gimeno, M.F.; Gimeno, A.L.

    1982-01-01

    The spontaneous and K + -stimulated efflux of norepinephrine (NE) and the release of PGE 2 and PGF 2 α were examined in medial basal hypothalamus (MBH) of ovariectomized rats killed before and during the LH release that follows estradiol treatment. As compared to vehicle-treated, ovariectomized rats, estradiol-primed rats exhibited a 60% more increase in K + -stimulated 3 H-overflow of MBH slices preloaded with 3 H-NE at morning hours (1000 hours). Estradiol treatment did not result in further increase of K + -induced 3 H release from MBH slices at the time of LH release (1700 hours), nor affected labelled NE release in occipital cortex slices. A significant difference between K + -stimulated NE release of vehicle-treated spayed rats killed at 1000 and 1700 hours was observed, the latter showing 54% more release upon stimulus. PGE 2 efflux was time-dependent being highest at the evening in both vehicle- and estradiol-treated animals. The MBH of estrogenized rats released significantly more PGE 2 at the evening as compared to the controls. The release of PGF 2 α remained essentially unchanged regardless of estradiol treatment or time of day. The present results offer additional support to the involvement of MBH catecholamines and prostaglandins in the mechanism of LH secretion in the rat. (author)

  12. Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress.

    Science.gov (United States)

    Bangasser, Debra A; Wiersielis, Kimberly R; Khantsis, Sabina

    2016-06-15

    Women are more likely than men to suffer from post-traumatic stress disorder (PTSD) and major depression. In addition to their sex bias, these disorders share stress as an etiological factor and hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by stress could help explain increased vulnerability to these disorders in women. Here we review preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE) arousal system. First, we detail how structural sex differences in the LC can bias females towards increased arousal in response to emotional events. Second, we highlight studies demonstrating that estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC neuronal sensitivity to CRF in females compared to males. This effect could translate into hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression. The implications of these sex differences for the treatment of stress-related psychiatric disorders are discussed. Moreover, the value of using information regarding biological sex differences to aid in the development of novel pharmacotherapies to better treat men and women with PTSD and depression is also highlighted. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Plasma levels of norepinephrine during the periovulatory period in normal women

    International Nuclear Information System (INIS)

    Badano, A.R.; Nagle, C.A.; Casas, P.R.F.; Miechi, H.; Mirkin, A.; Turner, D.E.; Aparicio, N.; Rosner, J.M.

    1978-01-01

    Eleven normally cycling women in whom laparotomy was indicated for benign gynecologic pathology were studied. Surgery was performed on day 0 (expected day of ovulation). Blood samples were drawn daily from day -8 to day -4, and every 8 hours from day -3 to day +2; estradiol (E 2 ), progesterone (P), norepinephrine (NE), and LH were determined by RIA. Ovulation was certified by ovarian visualization and biopsy during laparotomy. In nine ovulatory patients mean E 2 peak was found 48 hours before LH peak. Mean NE levels showed minimal variations until 48 hours before LH peak; 8 hours after E 2 peak mean NE values increased significantly, fell 8 hours later, and rose immediately again, reaching maximal levels 24 hours after E 2 peak. These values remained high until 16 hours before the LH peak and decreased gradully, thereafter reaching basal levels 32 hours after LH peak. Two anovulatory patients showed an atypical pattern of ovarian steroids and LH secretion and NE showed large variations without any correlation with estradiol or LH levels. This study confirms previous findings in women and experimental work in animals regarding the existence of a noradrenergic trigger mechanism to the LH ovulatory discharge

  14. A microelectrode array electrodeposited with reduced graphene oxide and Pt nanoparticles for norepinephrine and electrophysiological recordings

    Science.gov (United States)

    Wang, Li; Song, Yilin; Zhang, Yu; Xu, Shengwei; Xu, Huiren; Wang, Mixia; Wang, Yang; Cai, Xinxia

    2017-11-01

    Norepinephrine (NE), a common neurotransmitter released by locus coeruleus neurons, plays an essential role in the communication mechanism of the mammalian nervous system. In this work, a microelectrode array (MEA) was fabricated by micro-electromechanical system (MEMS) technology to provide a rapid, sensitive and reliable method for the direct determination in NE dynamic secretion. To improve the electrical performance, the MEA was electrodeposited with the reduced graphene oxide and Pt nanoparticles (rGOPNps). rGOPNps-MEA was investigated using scanning electron microscopy, atomic force microscopy and electrochemical impedance spectroscopy, differential pulse voltammetry exhibited remarkably electrocatalytic properties towards NE. Calibration results showed a sensitivity of 1.03 nA µM-1 to NE with a detection limit of 0.08 µM. In Particular, the MEA was successfully used for measuring dynamic extracellular NE secretion from the locus coeruleus brain slice, as well as monitoring spike firing from the hippocampal brain slice. This fabricated device has potential in studies of spatially resolved delivery of trace neurochemicals and electrophysiological activities of a variety of biological tissues in vitro.

  15. Recurrent hypoglycemia increases anxiety and amygdala norepinephrine release during subsequent hypoglycemia

    Directory of Open Access Journals (Sweden)

    Ewan eMcNay

    2015-11-01

    Full Text Available Recurrent hypoglycemia (RH is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp, a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and pre-frontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e. less time spent in the open arms of the plus-maze. The results show that RH has widespread effects on subsequent brain function, which vary by neural system.

  16. Perinatal methadone exposure affects dopamine, norepinephrine, and serotonin in the weanling rat.

    Science.gov (United States)

    Robinson, S E; Maher, J R; Wallace, M J; Kunko, P M

    1997-01-01

    On gestational day 7 pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. On postnatal day 21, dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites were analyzed. Perinatal methadone exposure disrupted dopaminergic, noradrenergic, and serotonergic activity in a brain region- and gender-specific fashion. The ratio of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) to DA was reduced in the frontal cortex of males exposed to methadone postnatally. No effects of perinatal methadone exposure were observed on DA and DOPAC in the striatum. The ratio of 3-methoxy-4-hydroxyphenylglycol (MOPEG) to NE in the hippocampus was increased significantly in males exposed to methadone prenatally. Striatal and parietal cortical 5-hydroxyindoleacetic acid (5-HIAA), but not its ratio to 5-HT, was increased slightly in rats exposed to methadone postnatally. Although parietal cortical 5-HT, 5-HIAA, and 5-hydroxytryptophan were all affected by perinatal methadone exposure, the ratios of metabolite and precursor to 5-HT were not affected. Effects of methadone exposure appeared to depend upon the developmental stage at which exposure occurred and did not appear to result from the phenomenon of neonatal withdrawal. Changes in activity of these three neurotransmitter systems may contribute to the effect of perinatal methadone on the activity of other neurons, such as cholinergic neurons.

  17. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

    Science.gov (United States)

    Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

    2016-06-15

    Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. The emerging role of norepinephrine in cognitive dysfunctions of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Elena eVazey

    2012-07-01

    Full Text Available Parkinson’s disease (PD is the second most common neurodegenerative disorder, affecting 1% of the population over age 60. In those patients cognitive dysfunction is a persistent issue that impairs quality of life and productivity. Neuropathological studies demonstrate significant damage in brain regions outside the nigral dopamine (DA system, including early degeneration of locus coeruleus norepinephrine (LC-NE neurons, yet discussion of PD and treatment focus has remained dopaminergic-based. Motor symptoms benefit from DA replacement for many years, but other symptoms including several cognitive deficits continue unabated. Recent interest in non-DA substrates of PD highlights early involvement of LC-NE neurons and provides evidence for a prodromal phase, with cognitive disturbance, even in sporadic PD. We outline insights from basic research in LC-NE function to clinical and pathological evidence highlighting a role for NE in PD cognitive dysfunction. We propose that loss of LC-NE regulation, particularly in higher cortical regions, critically underlies certain cognitive dysfunctions in early PD. As a major unmet need for patients, research and use of NE drugs in PD may provide significant benefits for cognitive processing.

  19. Improved radioenzymatic assay for plasma norepinephrine using purified phenylethanolamine n-methyltransferase

    International Nuclear Information System (INIS)

    Bowsher, R.R.; Henry, D.P.

    1986-01-01

    Radioenzymatic assays have been developed for catecholamines using either catechol O-methyltransferase (COMT) or phenylethanolamine N-methyltransferase (PNMT). Assays using PNMT are specific for norepinephrine (NE) and require minimal manipulative effort but until now have been less sensitive than the more complex procedures using COMT. The authors report an improved purification scheme for bovine PNMT which has permitted development of an NE assay with dramatically improved sensitivity (0.5 pg), specificity and reproducibility (C.V. < 5%). PNMT was purified by sequential pH 5.0 treatment and dialysis and by column chromatographic procedures using DEAE-Sephacel, Sepharcryl S-200 and Phenyl-Boronate Agarose. Recovery of PNMT through the purification scheme was 50%, while blank recovery was <.001%. NE can be directly quantified in 25 ul of human plasma and an 80 tube assay can be completed within 4 h. The capillary to venous plasma NE gradient was examined in 8 normotensive male subjects. Capillary plasma (NE (211.2 +/- 61.3 pg/ml)) was lower than venous plasma NE (366.6 +/- 92.5 pg/ml) in all subjects (p < 0.005). This difference suggests that capillary (NE) may be a unique indicator of sympathetic nervous system activity in vivo. In conclusion, purification of PNMT has facilitated development of an improved radioenzymatic for NE with significantly improved sensitivity

  20. Norepinephrine signaling through β-adrenergic receptors is critical for expression of cocaine-induced anxiety

    Science.gov (United States)

    Schank, Jesse R.; Liles, L. Cameron; Weinshenker, David

    2008-01-01

    Background Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine’s rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. Methods In this study we evaluated the performance of dopamine β-hydroxylase knockout (Dbh −/−) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. Results We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/−) mice, as measured by a decrease in open arm exploration. Dbh −/− mice had normal baseline performance in the EPM, but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/− mice following administration of disulfiram, a DBH inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the β-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/− and wild-type C57BL6/J mice, while the α1 antagonist prazosin and the α2 antagonist yohimbine had no effect. Conclusions These results indicate that noradrenergic signaling via β-adrenergic receptors is required for cocaine-induced anxiety in mice. PMID:18083142

  1. Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

    Science.gov (United States)

    Schank, Jesse R; Liles, L Cameron; Weinshenker, David

    2008-06-01

    Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

  2. Meningeal norepinephrine produces headache behaviors in rats via actions both on dural afferents and fibroblasts.

    Science.gov (United States)

    Wei, Xiaomei; Yan, Jin; Tillu, Dipti; Asiedu, Marina; Weinstein, Nicole; Melemedjian, Ohannes; Price, Theodore; Dussor, Gregory

    2015-10-01

    Stress is commonly reported to contribute to migraine although mechanisms by which this may occur are not fully known. The purpose of these studies was to examine whether norepinephrine (NE), the primary sympathetic efferent transmitter, acts on processes in the meninges that may contribute to the pain of migraine. NE was applied to rat dura using a behavioral model of headache. Primary cultures of rat trigeminal ganglia retrogradely labeled from the dura mater and of rat dural fibroblasts were prepared. Patch-clamp electrophysiology, Western blot, and ELISA were performed to examine the effects of NE. Conditioned media from NE-treated fibroblast cultures was applied to the dura using the behavioral headache model. Dural injection both of NE and media from NE-stimulated fibroblasts caused cutaneous facial and hindpaw allodynia in awake rats. NE application to cultured dural afferents increased action potential firing in response to current injections. Application of NE to dural fibroblasts increased phosphorylation of ERK and caused the release of interleukin-6 (IL-6). These data demonstrate that NE can contribute to pro-nociceptive signaling from the meninges via actions on dural afferents and dural fibroblasts. Together, these actions of NE may contribute to the headache phase of migraine. © International Headache Society 2015.

  3. Expression of the capacity to release [3H]norepinephrine by neural crest cultures

    International Nuclear Information System (INIS)

    Maxwell, G.D.; Sietz, P.D.

    1983-01-01

    Cultures of trunk neural crest cells from quail embryos were tested for their ability to release [ 3 H]norepinephrine [( 3 H]NE) in response to depolarization. After 7 days in vitro, exposure of the cultures to either the alkaloid veratridine or 40 mM K+ results in the evoked release of [ 3 H]NE. The release evoked by veratridine is blocked in the presence of tetrodotoxin. The release evoked by increased K+ is blocked by the calcium antagonist cobalt. Release in response to the nicotinic cholinergic agonist 1,1-dimethyl-4-phenylpiperazine was also observed. The amount of evoked release is highly correlated with the number of histochemically demonstrable catecholamine-containing cells in a given culture. Autoradiography reveals that the radioactivity taken up by these cultures is located in a subpopulation of cells whose morphology resembles that of the histochemically detectable catecholamine-containing cell population. Whereas capacity for the release of [ 3 H] NE is readily detectable after 7 days in vitro, it is detectable only with difficulty after 4 days in vitro. There is a greater than 6-fold increase in uptake capacity over the period of 4 to 7 days in vitro. These results demonstrate that neural crest cultures grown without their normal synaptic inputs or targets can exhibit the capacity for stimulus secretion coupling characteristic of synaptic neurotransmitter release

  4. External and internal standards in the single-isotope derivative (radioenzymatic) measurement of plasma norepinephrine and epinephrine

    International Nuclear Information System (INIS)

    Shah, S.D.; Clutter, W.E.; Cryer, P.E.

    1985-01-01

    In plasma from normal humans (n = 9, 35 samples) and from patients with diabetes mellitus (n = 12, 24 samples) single-isotope derivative (radioenzymatic) plasma norepinephrine and epinephrine concentrations calculated from external standard curves constructed in a normal plasma pool were identical to those calculated from internal standards added to an aliquot of each plasma sample. In plasma from patients with end-stage renal failure receiving long-term dialysis (n = 34, 109 samples), competitive catechol-O-methyltransferase (COMT) inhibitory activity resulted in a systematic error when external standards in a normal plasma pool were used, as reported previously; values so calculated averaged 21% (+/- 12%, SD) lower than those calculated from internal standards. However, when external standard curves were constructed in plasma from a given patient with renal failure and used to calculate that patient's values, or in a renal failure plasma pool and used to calculate all renal failure values, norepinephrine and epinephrine concentrations were not significantly different from those calculated from internal standards. We conclude: (1) External standard curves constructed in plasma from a given patient with renal failure can be used to measure norepinephrine and epinephrine in plasma from that patient; further, external standards in a renal failure plasma pool can be used for assays in patients with end-stage renal failure receiving long-term dialysis. (2) Major COMT inhibitory activity is not present commonly if samples from patients with renal failure are excluded. Thus, it would appear that external standard curves constructed in normal plasma can be used to measure norepinephrine and epinephrine precisely in samples from persons who do not have renal failure

  5. Influence of chronic captopril treatment on norepinephrine-induced vasoconstriction in SHR and WKY : In vivo study

    Czech Academy of Sciences Publication Activity Database

    Pintérová, Mária; Kuneš, Jaroslav; Dobešová, Zdenka; Zicha, Josef

    2008-01-01

    Roč. 26, Suppl.1 (2008), S174-S174 ISSN 0263-6352. [Scientific Meeting International Society of Hypertension /22./ , Scientific Meeting European Society of Hypertension /18./. 14.06.2008-19.06.2008, Berlin] Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * captopril teratment * norepinephrine-induced vasoconstriction * SHR and WKY Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  6. Influência do ciclo estral sobre a sensibilidade da resposta cronotrópica à norepinefrina em ratas submetidas a estresse agudo Influence of estrous cycle on the sensitivity of cronotropic answer to norepinephrine in rats submitted to acute stress

    Directory of Open Access Journals (Sweden)

    Ana Paula Tanno

    2002-03-01

    Full Text Available O estresse pode alterar a sensibilidade da resposta cronotrópica às catecolaminas em vários tecidos. O objetivo deste estudo foi avaliar a sensibilidade à norepinefrina (NE em átrios direitos de ratas submetidas ao estresse agudo por natação nas fases de estro e proestro. Ratas Wistar em estro ou proestro foram submetidas a uma sessão de 50 min de natação, após a qual foram anestesiadas e sacrifícadas. Os átrios direitos destes animais e de ratas controle foram isolados para obtenção de curvas concentração-efeito à NE antes e após o bloqueio dos sistemas de metabolização das catecolaminas (fenoxibenzamina + estradiol. Os dados foram analisados por ANOVA ou teste t de Student. Não houve diferenças de sensibilidade à NE entre as fases de estro e proestro nos tecidos isolados de animais controle (p>0,05. No proestro, a natação induziu supersensibilidade à NE (pStress may change the response to catecholamines in many tissues. The aim of this study was to investigate the influence of the estrous cycle on the sensitivity to norepinephrine in right atria from female rats submitted to a single swimming session. Wistar female rats were submitted to one swimming session at estrus or proestrus. Immediately after the stress session, the animal was sacrificed and its right atria set up for isometric recording of spontaneous beating. Concentration-effect curves to norepinephrine were obtained before and after inhibition of uptake1 (phenoxibenzamine and uptake2 (estradiol. Swimming stress did not change the sensitivity to noradrenaline in right atria from rats at estrus. However, at proestrus swimming induced supersensitivity to norepinephrine (pD2 control: 7.14 ± 0.03 vs. pD2 swimming: 7.55 ± 0.04; p< 0.05. Moreover at proestrus, the inhibition of the uptake systems induced a lower shift to the left in the concentration-effect curves to norepinephrine compared to the estrus. Changes on the uptake systems seem to be involved in the

  7. Voltammetric determination of norepinephrine in the presence of acetaminophen using a novel ionic liquid/multiwall carbon nanotubes paste electrode

    International Nuclear Information System (INIS)

    Salmanpour, Sadegh; Tavana, Toktam; Pahlavan, Ali; Khalilzadeh, Mohammad A.; Ensafi, Ali A.; Karimi-Maleh, Hassan; Beitollahi, Hadi; Kowsari, Elaheh; Zareyee, Daryoush

    2012-01-01

    A novel multiwall carbon nanotubes (MWCNTs) modified carbon ionic liquid electrode (CILE) was fabricated and used to investigate the electrochemical behavior of norepinephrine (NP). MWCNTs/CILE was prepared by mixing hydrophilic ionic liquid, 1-methyl-3-butylimidazolium bromide (MBIDZBr), with graphite powder, MWCNTs, and liquid paraffin. The fabricated MWCNTs/CILE showed great electrocatalytic ability to the oxidation of NE. The electron transfer coefficient, diffusion coefficient, and charge transfer resistant (R ct ) of NE at the modified electrode were calculated. Differential pulse voltammetry of NE at the modified electrode exhibited two linear dynamic ranges with slopes of 0.0841 and 0.0231 μA/μM in the concentration ranges of 0.3 to 30.0 μM and 30.0 to 450.0 μM, respectively. The detection limit (3σ) of 0.09 μM NP was achieved. This modified electrode exhibited a good ability for well separated oxidation peaks of NE and acetaminophen (AC) in a buffer solution, pH 7.0. The proposed sensor was successfully applied for the determination of NE in human urine, pharmaceutical, and serum samples. Highlights: ► Electrochemical behavior of norepinephrine study using carbon ionic liquid electrode ► This sensor resolved the overlap response of norepinephrine and acetaminophen. ► This sensor is also used for the determination of above compounds in real samples.

  8. Influence of allelic variations in relation to norepinephrine and mineralocorticoid receptors on psychopathic traits: a pilot study

    Directory of Open Access Journals (Sweden)

    Guillaume Durand

    2018-03-01

    Full Text Available Background Past findings support a relationship between abnormalities in the amygdala and the presence of psychopathic traits. Among other genes and biomarkers relevant to the amygdala, norepinephrine and mineralocorticoid receptors might both play a role in psychopathy due to their association with traits peripheral to psychopathy. The purpose is to examine if allelic variations in single nucleotide polymorphisms related to norepinephrine and mineralocorticoid receptors play a role in the display of psychopathic traits and executive functions. Methods Fifty-seven healthy participants from the community provided a saliva sample for SNP sampling of rs5522 and rs5569. Participants then completed the Psychopathic Personality Inventory–Short Form (PPI-SF and the Tower of Hanoi. Results Allelic variations of both rs5522 and rs5569 were significant when compared to PPI-SF total score and the fearless dominance component of the PPI-SF. A significant result was also obtained between rs5522 and the number of moves needed to complete the 5-disk Tower of Hanoi. Conclusion This pilot study offers preliminary results regarding the effect of allelic variations in SNPs related to norepinephrine and mineralocorticoid receptors on the presence of psychopathic traits. Suggestions are provided to enhance the reliability and validity of a larger-scale study.

  9. Non-parametric smoothing of experimental data

    International Nuclear Information System (INIS)

    Kuketayev, A.T.; Pen'kov, F.M.

    2007-01-01

    Full text: Rapid processing of experimental data samples in nuclear physics often requires differentiation in order to find extrema. Therefore, even at the preliminary stage of data analysis, a range of noise reduction methods are used to smooth experimental data. There are many non-parametric smoothing techniques: interval averages, moving averages, exponential smoothing, etc. Nevertheless, it is more common to use a priori information about the behavior of the experimental curve in order to construct smoothing schemes based on the least squares techniques. The latter methodology's advantage is that the area under the curve can be preserved, which is equivalent to conservation of total speed of counting. The disadvantages of this approach include the lack of a priori information. For example, very often the sums of undifferentiated (by a detector) peaks are replaced with one peak during the processing of data, introducing uncontrolled errors in the determination of the physical quantities. The problem is solvable only by having experienced personnel, whose skills are much greater than the challenge. We propose a set of non-parametric techniques, which allows the use of any additional information on the nature of experimental dependence. The method is based on a construction of a functional, which includes both experimental data and a priori information. Minimum of this functional is reached on a non-parametric smoothed curve. Euler (Lagrange) differential equations are constructed for these curves; then their solutions are obtained analytically or numerically. The proposed approach allows for automated processing of nuclear physics data, eliminating the need for highly skilled laboratory personnel. Pursuant to the proposed approach is the possibility to obtain smoothing curves in a given confidence interval, e.g. according to the χ 2 distribution. This approach is applicable when constructing smooth solutions of ill-posed problems, in particular when solving

  10. Potassium-induced contraction in the lamb proximal urethra: Involvement of norepinephrine and different calcium entry pathways

    International Nuclear Information System (INIS)

    Garcia-Pascual, A.; Costa, G.; Isla, M.; Jimenez, E.; Garcia-Sacristan, A.

    1991-01-01

    The purpose of this work was to investigate the mechanisms involved in the peculiar biphasic response of the lamb urethral smooth muscle to high K+ solutions. The relative amplitude of the phasic and tonic components of the contraction and its reproducibility were dependent on the concentration of K+ used. Only concentrations higher than 80 mM (i.e., 120 mM) showed a tonic component greater in amplitude than the phasic one and manifested a tachyphylactic effect. Phentolamine (10(-6) M), prazosin (10(-6) M) and chemical denervation with 6-hydroxydopamine significantly inhibited the tonic component of the K+ (120 mM)-induced contraction, modifying its morphology. Reproducible contractions to K+ (120 mM) could be obtained in the presence of prazosin (10(-6) M) or cocaine (10(-6) M). The preparations were also shown to accumulate [3H]noradrenaline and release it upon depolarization with K+ (60 and 120 mM). Calcium removal inhibited the K+ (120 mM)-induced contraction. After addition of calcium (0.5-5 mM) the contractile activity was restored. Nifedipine (10(-6) M) and verapamil (10(-6) M) but not sodium nitroprusside (10(-6) M) significantly blocked the contractile response for calcium as well as the phasic component of the K+ contraction in calcium-containing medium. In preparations treated with prazosin (10(-6) M) the tonic component of the K+ (120 mM) contraction was more sensitive to nifedipine and removal of extracellular calcium than the phasic one

  11. Effect of smoothing on robust chaos.

    Science.gov (United States)

    Deshpande, Amogh; Chen, Qingfei; Wang, Yan; Lai, Ying-Cheng; Do, Younghae

    2010-08-01

    In piecewise-smooth dynamical systems, situations can arise where the asymptotic attractors of the system in an open parameter interval are all chaotic (e.g., no periodic windows). This is the phenomenon of robust chaos. Previous works have established that robust chaos can occur through the mechanism of border-collision bifurcation, where border is the phase-space region where discontinuities in the derivatives of the dynamical equations occur. We investigate the effect of smoothing on robust chaos and find that periodic windows can arise when a small amount of smoothness is present. We introduce a parameter of smoothing and find that the measure of the periodic windows in the parameter space scales linearly with the parameter, regardless of the details of the smoothing function. Numerical support and a heuristic theory are provided to establish the scaling relation. Experimental evidence of periodic windows in a supposedly piecewise linear dynamical system, which has been implemented as an electronic circuit, is also provided.

  12. TAX SMOOTHING: TESTS ON INDONESIAN DATA

    Directory of Open Access Journals (Sweden)

    Rudi Kurniawan

    2011-01-01

    Full Text Available This paper contributes to the literature of public debt management by testing for tax smoothing behaviour in Indonesia. Tax smoothing means that the government smooths the tax rate across all future time periods to minimize the distortionary costs of taxation over time for a given path of government spending. In a stochastic economy with an incomplete bond market, tax smoothing implies that the tax rate approximates a random walk and changes in the tax rate are nearly unpredictable. For that purpose, two tests were performed. First, random walk behaviour of the tax rate was examined by undertaking unit root tests. The null hypothesis of unit root cannot be rejected, indicating that the tax rate is nonstationary and, hence, it follows a random walk. Second, the predictability of the tax rate was examined by regressing changes in the tax rate on its own lagged values and also on lagged values of changes in the goverment expenditure ratio, and growth of real output. They are found to be not significant in predicting changes in the tax rate. Taken together, the present evidence seems to be consistent with the tax smoothing, therefore provides support to this theory.

  13. Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

    Directory of Open Access Journals (Sweden)

    Cornelia Tolg

    Full Text Available Smooth muscle cell containing organs (bladder, heart, blood vessels are damaged by a variety of pathological conditions necessitating surgery or organ replacement. Currently, regeneration of contractile tissues is hampered by lack of functional smooth muscle cells. Multipotent skin derived progenitor cells (SKPs can easily be isolated from adult skin and can be differentiated in vitro into contractile smooth muscle cells by exposure to FBS. Here we demonstrate an inhibitory effect of a pathologic contractile organ microenvironment on smooth muscle cell differentiation of SKPs. In vivo, urinary bladder strain induces microenvironmental changes leading to de-differentiation of fully differentiated bladder smooth muscle cells. Co-culture of SKPs with organoids isolated from ex vivo stretched bladders or exposure of SKPs to diffusible factors released by stretched bladders (e.g. bFGF suppresses expression of smooth muscle markers (alpha SMactin, calponin, myocardin, myosin heavy chain as demonstrated by qPCR and immunofluorescent staining. Rapamycin, an inhibitor of mTOR signalling, previously observed to prevent bladder strain induced de-differentiation of fully differentiated smooth muscle cells in vitro, inhibits FBS-induced smooth muscle cell differentiation of undifferentiated SKPs. These results suggest that intended precursor cell differentiation may be paradoxically suppressed by the disease context for which regeneration may be required. Organ-specific microenvironment contexts, particularly prevailing disease, may play a significant role in modulating or attenuating an intended stem cell phenotypic fate, possibly explaining the variable and inefficient differentiation of stem cell constructs in in vivo settings. These observations must be considered in drafting any regeneration strategies.

  14. Modeling and analysis of PET studies with norepinephrine transporter ligands: the search for a reference region

    Energy Technology Data Exchange (ETDEWEB)

    Logan, Jean [Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)]. E-mail: logan@bnl.gov; Ding, Y.-S. [Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Lin, K.-S. [Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Pareto, Deborah [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Functional Imaging, Berkeley National Laboratory, Berkeley, CA 94720 (United States); Fowler, Joanna [Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Biegon, Anat [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)

    2005-07-01

    The development of positron emission tomography (PET) ligands for the norepinephrine transporter (NET) has been slow compared to the development of radiotracers for others systems, such as the dopamine (DAT) or the serotonin transporters (SERT). The main reason for this appears to be the high nonspecific (non-NET) binding exhibited by many of these tracers, which makes the identification of a reference region difficult. With other PET ligands the use of a reference region increases the reproducibility of the outcome measure in test/retest studies. The focus of this work is to identify a suitable reference region or means of normalizing data for the NET ligands investigated. Methods: We have analyzed the results of PET studies in the baboon brain with labeled reboxetine derivatives (S,S)-[{sup 11}C]O-methyl reboxetine (SS-MRB), (S,S)-[{sup 18}F]fluororeboxetine (SS-FRB) as well as O-[{sup 11}C]nisoxetine and N-[{sup 11}C]nisoxetine (NIS), and, for comparison, the less active (R,R) enantiomers (RR-MRB, RR-FRB) in terms of the distribution volume (DV) using measured arterial input functions. Results: (1) For a given subject, a large variation in DV for successive baseline studies was observed in regions with both high and low NET density. (2) The occipital cortex and the basal ganglia were found to be the regions with the smallest change between baseline (SS-MRB) and pretreatment with cocaine, and were therefore used as a composite reference region for calculation of a distribution volume ratio (DVR). (3) The variability [as measured by the coefficient of variation (CV)=standard deviation/mean] in the distribution volume ratio (DVR) of thalamus (to reference region) was considerably reduced over that of the DV using this composite reference region. (4) Pretreatment with nisoxetine (1.0 mg/kg 10 min prior to tracer) in one study produced (in decreasing order) reductions in thalamus, cerebellum, cingulate and frontal cortex consistent with known NET densities. (5) [{sup

  15. Modeling and analysis of PET studies with norepinephrine transporter ligands: the search for a reference region.

    Science.gov (United States)

    Logan, Jean; Ding, Yu-Shin; Lin, Kuo-Shyan; Pareto, Deborah; Fowler, Joanna; Biegon, Anat

    2005-07-01

    The development of positron emission tomography (PET) ligands for the norepinephrine transporter (NET) has been slow compared to the development of radiotracers for others systems, such as the dopamine (DAT) or the serotonin transporters (SERT). The main reason for this appears to be the high nonspecific (non-NET) binding exhibited by many of these tracers, which makes the identification of a reference region difficult. With other PET ligands the use of a reference region increases the reproducibility of the outcome measure in test/retest studies. The focus of this work is to identify a suitable reference region or means of normalizing data for the NET ligands investigated. We have analyzed the results of PET studies in the baboon brain with labeled reboxetine derivatives (S,S)-[(11)C]O-methyl reboxetine (SS-MRB), (S,S)-[(18)F]fluororeboxetine (SS-FRB) as well as O-[(11)C]nisoxetine and N-[(11)C]nisoxetine (NIS), and, for comparison, the less active (R,R) enantiomers (RR-MRB, RR-FRB) in terms of the distribution volume (DV) using measured arterial input functions. (1) For a given subject, a large variation in DV for successive baseline studies was observed in regions with both high and low NET density. (2) The occipital cortex and the basal ganglia were found to be the regions with the smallest change between baseline (SS-MRB) and pretreatment with cocaine, and were therefore used as a composite reference region for calculation of a distribution volume ratio (DVR). (3) The variability [as measured by the coefficient of variation (CV) = standard deviation/mean] in the distribution volume ratio (DVR) of thalamus (to reference region) was considerably reduced over that of the DV using this composite reference region. (4) Pretreatment with nisoxetine (1.0 mg/kg 10 min prior to tracer) in one study produced (in decreasing order) reductions in thalamus, cerebellum, cingulate and frontal cortex consistent with known NET densities. (5) [(11)C]Nisoxetine had a higher

  16. Modeling and analysis of PET studies with norepinephrine transporter ligands: the search for a reference region

    International Nuclear Information System (INIS)

    Logan, Jean; Ding, Y.-S.; Lin, K.-S.; Pareto, Deborah; Fowler, Joanna; Biegon, Anat

    2005-01-01

    The development of positron emission tomography (PET) ligands for the norepinephrine transporter (NET) has been slow compared to the development of radiotracers for others systems, such as the dopamine (DAT) or the serotonin transporters (SERT). The main reason for this appears to be the high nonspecific (non-NET) binding exhibited by many of these tracers, which makes the identification of a reference region difficult. With other PET ligands the use of a reference region increases the reproducibility of the outcome measure in test/retest studies. The focus of this work is to identify a suitable reference region or means of normalizing data for the NET ligands investigated. Methods: We have analyzed the results of PET studies in the baboon brain with labeled reboxetine derivatives (S,S)-[ 11 C]O-methyl reboxetine (SS-MRB), (S,S)-[ 18 F]fluororeboxetine (SS-FRB) as well as O-[ 11 C]nisoxetine and N-[ 11 C]nisoxetine (NIS), and, for comparison, the less active (R,R) enantiomers (RR-MRB, RR-FRB) in terms of the distribution volume (DV) using measured arterial input functions. Results: (1) For a given subject, a large variation in DV for successive baseline studies was observed in regions with both high and low NET density. (2) The occipital cortex and the basal ganglia were found to be the regions with the smallest change between baseline (SS-MRB) and pretreatment with cocaine, and were therefore used as a composite reference region for calculation of a distribution volume ratio (DVR). (3) The variability [as measured by the coefficient of variation (CV)=standard deviation/mean] in the distribution volume ratio (DVR) of thalamus (to reference region) was considerably reduced over that of the DV using this composite reference region. (4) Pretreatment with nisoxetine (1.0 mg/kg 10 min prior to tracer) in one study produced (in decreasing order) reductions in thalamus, cerebellum, cingulate and frontal cortex consistent with known NET densities. (5) [ 11 C]Nisoxetine had

  17. Rho Kinase (ROCK) collaborates with Pak to Regulate Actin Polymerization and Contraction in Airway Smooth Muscle.

    Science.gov (United States)

    Zhang, Wenwu; Bhetwal, Bhupal P; Gunst, Susan J

    2018-05-10

    The mechanisms by which Rho kinase (ROCK) regulates airway smooth muscle contraction were determined in tracheal smooth muscle tissues. ROCK may mediate smooth muscle contraction by inhibiting myosin regulatory light chain (RLC) phosphatase. ROCK can also regulate F-actin dynamics during cell migration, and actin polymerization is critical for airway smooth muscle contraction. Our results show that ROCK does not regulate airway smooth muscle contraction by inhibiting myosin RLC phosphatase or by stimulating myosin RLC phosphorylation. We find that ROCK regulates airway smooth muscle contraction by activating the serine-threonine kinase Pak, which mediates the activation of Cdc42 and Neuronal-Wiskott-Aldrich Syndrome protein (N-WASp). N-WASP transmits signals from cdc42 to the Arp2/3 complex for the nucleation of actin filaments. These results demonstrate a novel molecular function for ROCK in the regulation of Pak and cdc42 activation that is critical for the processes of actin polymerization and contractility in airway smooth muscle. Rho kinase (ROCK), a RhoA GTPase effector, can regulate the contraction of airway and other smooth muscle tissues. In some tissues, ROCK can inhibit myosin regulatory light chain (RLC) phosphatase, which increases the phosphorylation of myosin RLC and promotes smooth muscle contraction. ROCK can also regulate cell motility and migration by affecting F-actin dynamics. Actin polymerization is stimulated by contractile agonists in airway smooth muscle tissues and is required for contractile tension development in addition to myosin RLC phosphorylation. We investigated the mechanisms by which ROCK regulates the contractility of tracheal smooth muscle tissues by expressing a kinase inactive mutant of ROCK, ROCK-K121G, in the tissues or by treating them with the ROCK inhibitor, H-1152P. Our results show no role for ROCK in the regulation of non-muscle or smooth muscle myosin RLC phosphorylation during contractile stimulation in this tissue

  18. Effect of lovastatin on rabbit vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Luan Zhaoxia; Pei Zhuguo

    2003-01-01

    Objective: To investigate the effect of lovastatin on binding activity of nuclear factor activator protein-1 (AP-1) to NF-κB and the expression of matrix metalloproteinase-9 (MMP-9) in rabbit vascular smooth muscle cells (VSMCs). Methods: The oligonucleotide corresponding to the consensus NF-κB element or the consensus AP-1 element was labeled by [γ- 32 P]-ATP. AP-1 and NF-κB binding activity was detected by electrophoretic mobility shift assay (EMSA), expression of MMP-9 was detected by zymography. Results: Lovastatin inhibited the expression of MMP-9 in a dose-dependent manner, this effect was reversed by mevalonate and GGPP but not by squalene; lovastatin significantly decreased AP-1 and NF-κB binding activity. Conclusion: Lovastatin decreased AP-1 and NF-κB binding activity and inhibited MMP-9 expression in rabbit VSMCs by the way of inhibiting prenylation of protein but not by cholestrol-lowering, and this might be the mechanism of its arteriosclerostic plaque stabilizing effects

  19. Angiogenesis is induced by airway smooth muscle strain.

    Science.gov (United States)

    Hasaneen, Nadia A; Zucker, Stanley; Lin, Richard Z; Vaday, Gayle G; Panettieri, Reynold A; Foda, Hussein D

    2007-10-01

    Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.

  20. Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Availability in the Locus Coeruleus

    Science.gov (United States)

    Pietrzak, Robert H.; Gallezot, Jean-Dominique; Ding, Yu-Shin; Henry, Shannan; Potenza, Marc N.; Southwick, Steven M.; Krystal, John H.; Carson, Richard E.; Neumeister, Alexander

    2014-01-01

    IMPORTANCE Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. RESULTS The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity

  1. Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function.

    Science.gov (United States)

    Wengrowski, Anastasia M; Wang, Xin; Tapa, Srinivas; Posnack, Nikki Gillum; Mendelowitz, David; Kay, Matthew W

    2015-02-01

    Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of β-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of β-adrenergic modulation of cardiac function typically involve the administration of exogenous β-adrenergic receptor agonists to directly elicit global β-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work, we use a novel method to activate sympathetic fibres within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function. The light-activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibres were then photoactivated to examine changes in contractile force, HR, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibres, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and HR after photostimulated release of NE, with increases in contractile force and HR of 34.5 ± 5.5 and 25.0 ± 9.3%, respectively. Photostimulation of sympathetic fibres also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5 ± 1.0 ms) after photostimulation. This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte β-adrenergic receptors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  2. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    International Nuclear Information System (INIS)

    Mosaddeghi, M.

    1989-01-01

    The function of α 1 -adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with [ 3 H]inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 μM potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC 50 was decreased from 3.93 ± 0.42 to 1.91 ± 0.31 μM NE. Concentrations of 0.1-100 μM and 0.1-10 μM cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 μM NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 μM prazosin. Cocaine (10 μM) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 μM prazosin. [ 3 H]Prazosin saturation and NE [ 3 H]prazosin competition binding studies using crude membrane preparations showed that 10 μM cocaine did not alter binding parameters B max , K d , Hill slope, and IC 50 . Together, these results implied that cocaine in vitro potentiated NE-stimulated PI hydrolysis by blocking NE reuptake. For in vivo studies, the locomotor activity was determined after an acute or chronic injections of either cocaine or saline. Cocaine or saline-treated rats were killed after measurement of the locomotor activity, and NE-stimulated PI hydrolysis was measured. Acute administration of cocaine 3.2-42 mg/kg (i.p.) produced an inverted U shaped dose-response curve on locomotor activity. The peak increase in locomotor activity was at 32 mg/kg cocaine. A dose of 42 mg/kg cocaine produced a significant depression of maximal NE-stimulated PI hydrolysis

  3. Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance

    Science.gov (United States)

    Martino, Matteo; Rocchi, Giulio; Escelsior, Andrea; Fornaro, Michele

    2012-01-01

    Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies. PMID:23204981

  4. Napping reverses the salivary interleukin-6 and urinary norepinephrine changes induced by sleep restriction.

    Science.gov (United States)

    Faraut, Brice; Nakib, Samir; Drogou, Catherine; Elbaz, Maxime; Sauvet, Fabien; De Bandt, Jean-Pascal; Léger, Damien

    2015-03-01

    Neuroendocrine and immune stresses imposed by chronic sleep restriction are known to be involved in the harmful cardiovascular effects associated with poor sleep. Despite a well-known beneficial effect of napping on alertness, its effects on neuroendocrine stress and immune responses after sleep restriction are largely unknown. This study was a strictly controlled (sleep-wake status, light environment, caloric intake), crossover, randomized design in continuously polysomnography-monitored subjects. The study was conducted in a laboratory-based study. The subjects were 11 healthy young men. We investigated the effects on neuroendocrine and immune biomarkers of a night of sleep restricted to 2 h followed by a day without naps or with 30 minute morning and afternoon naps, both conditions followed by an ad libitum recovery night starting at 20:00. Salivary interleukin-6 and urinary catecholamines were assessed throughout the daytime study periods. The increase in norepinephrine values seen at the end of the afternoon after the sleep-restricted night was not present when the subjects had the opportunity to take naps. Interleukin-6 changes observed after sleep deprivation were also normalized after napping. During the recovery day in the no-nap condition, there were increased levels of afternoon epinephrine and dopamine, which was not the case in the nap condition. A recovery night after napping was associated with a reduced amount of slow-wave sleep compared to after the no-nap condition. Our data suggest that napping has stress-releasing and immune effects. Napping could be easily applied in real settings as a countermeasure to the detrimental health consequences of sleep debt.

  5. Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability.

    Science.gov (United States)

    Bresch, A; Rullmann, M; Luthardt, J; Becker, G A; Patt, M; Ding, Y-S; Hilbert, A; Sabri, O; Hesse, S

    2017-10-01

    The relationship between food-intake related behaviours measured by the Three-Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m 2 ) and ten normal-weight healthy controls (HC, BMI 23.9 ± 2.5 kg/m 2 ) with (S,S)-[ 11 C]-O-methylreboxetine ([ 11 C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region. Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BP ND of the locus coeruleus was detected. In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Norepinephrine-modified glassy carbon electrode for the simultaneous determination of ascorbic acid and uric acid

    International Nuclear Information System (INIS)

    Zare, H.R.; Memarzadeh, F.; Ardakani, M. Mazloum; Namazian, M.; Golabi, S.M.

    2005-01-01

    The oxidation of norepinephrine (NE) on a preactivated glassy carbon electrode leads to the formation of a deposited layer of about 4.2 x 10 -10 mol cm -2 at the surface of the electrode. The electron transfer rate constant, k s , and charge transfer coefficient, α, for electron transfer between the electrode and immobilized NE film were calculated as 44 s -1 and 0.46, respectively. The NE-modified glassy carbon electrode exhibited good electrocatalytic properties towards ascorbic acid (AA) oxidation in phosphate buffer (pH 7.0) with an overpotential of about 475 mV lower than that of the bare electrode. The electrocatalytic response was evaluated by cyclic voltammetry, chronoamperometry, amperometry and rotating disk voltammetry. The overall number of electrons involved in the catalytic oxidation of AA and the number of electrons involved in the rate-determining step are 2 and 1, respectively. The rate constant for the catalytic oxidation of AA was evaluated by RDE voltammetry and an average value of k h was found to be 8.42 x 10 3 M -1 s -1 . Amperometric determination of AA in stirred solution exhibits a linear range of 2.0-1300.0 μM (correlation coefficient 0.9999) and a detection limit of 0.076 μM. The precision of amperometry was found to be 1.9% for replicate determination of a 49.0 μM solution of AA (n = 6). In differential pulse voltammetric measurements, the NE-modified glassy carbon electrode can separate the AA and uric acid (UA) signals. Ascorbic acid oxidizes at more negative potential than UA. Also, the simultaneous determination of UA and AA is achieved at the NE-modified electrode

  7. Norepinephrine and dopamine increase motility, biofilm formation, and virulence of Vibrio harveyi.

    Science.gov (United States)

    Yang, Qian; Anh, Nguyen D Q; Bossier, Peter; Defoirdt, Tom

    2014-01-01

    Vibrio harveyi is one of the major pathogens of aquatic organisms, affecting both vertebrates and invertebrates, and causes important losses in the aquaculture industry. In order to develop novel methods to control disease caused by this pathogen, we need to obtain a better understanding of pathogenicity mechanisms. Sensing of catecholamines increases both growth and production of virulence-related factors in pathogens of terrestrial animals and humans. However, at this moment, knowledge on the impact of catecholamines on the virulence of pathogens of aquatic organisms is lacking. In the present study, we report that in V. harveyi, norepinephrine (NE) and dopamine (Dopa) increased growth in serum-supplemented medium, siderophore production, swimming motility, and expression of genes involved in flagellar motility, biofilm formation, and exopolysaccharide production. Consistent with this, pretreatment of V. harveyi with catecholamines prior to inoculation into the rearing water resulted in significantly decreased survival of gnotobiotic brine shrimp larvae, when compared to larvae challenged with untreated V. harveyi. Further, NE-induced effects could be neutralized by α-adrenergic antagonists or by the bacterial catecholamine receptor antagonist LED209, but not by β-adrenergic or dopaminergic antagonists. Dopa-induced effects could be neutralized by dopaminergic antagonists or LED209, but not by adrenergic antagonists. Together, our results indicate that catecholamine sensing increases the success of transmission of V. harveyi and that interfering with catecholamine sensing might be an interesting strategy to control vibriosis in aquaculture. We hypothesize that upon tissue and/or hemocyte damage during infection, pathogens come into contact with elevated catecholamine levels, and that this stimulates the expression of virulence factors that are required to colonize a new host.

  8. Selective oxidation of serotonin and norepinephrine over eriochrome cyanine R film modified glassy carbon electrode

    Energy Technology Data Exchange (ETDEWEB)

    Yao Hong; Li Shaoguang [Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350004 (China); Tang Yuhai [Institute of Analytical Sciences, Xi' an Jiaotong University, Xi' an 710061 (China); Chen Yan [Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350004 (China); Chen Yuanzhong [Fujian Institute of Hematology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou 350001 (China)], E-Mail: chenyz@pub3.fz.fj.cn; Lin Xinhua [Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350004 (China)], E-mail: xhlin1963@sin.com

    2009-08-01

    A novel ECR-modified electrode is fabricated by electrodeposition of Eriochrome Cyanine R (ECR) at a glassy carbon (GC) electrode by cyclic voltammetry (CV) in double-distilled water. The characterization of the ECR film modified electrode is carried out by atomic force microscopy (AFM), infrared spectra (IR), spectroelectrochemistry and cyclic voltammetry. The results show that a slightly heterogeneous film formed on the surface of the modified electrode, and the calculated surface concentration of ECR is 2 x 10{sup -10} mol/cm{sup -2}. The ECR film modified GC electrode shows excellent electrocatalytic activities toward the oxidation of serotonin (5-HT) and norepinephrine (NE). Furthermore, the modified electrode can separately detect 5-HT and NE, even in the presence of 200-fold concentration of ascorbic acid (AA) and 25-fold concentration of uric acid (UA). Using differential pulse voltammetry (DPV), the peak currents of 5-HT and NE recorded in pH 7 solution are linearly dependent on their concentrations in the range of 0.05-5 {mu}M and 2-50 {mu}M, respectively. The limits of detection are 0.05 and 1.5 {mu}M for 5-HT and NE, respectively. The ECR film modified electrode can be stored stable for at least 1 week in 0.05 M PBS (pH 7) at 4 {sup o}C in a refrigerator. Owing to its excellent selectivity and sensitivity, the modified electrode could provide a promising tool for the simultaneous determination of 5-HT and NE in complex biosamples.

  9. Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia.

    Science.gov (United States)

    Davidson, M; Kahn, R S; Stern, R G; Hirschowitz, J; Apter, S; Knott, P; Davis, K L

    1993-02-01

    Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA), is an indirect tool to assess changes in dopamine turnover. Levels of pHVA have been reported to decrease during treatment with conventional antidopaminergic, neuroleptics, with the decrement correlating with symptomatic improvement in schizophrenic symptoms. Clozapine, an atypical neuroleptic, is the only drug proved to be effective in treatment-refractory patients. However, the mechanism mediating this unique efficacy has not been fully elucidated. This study examined the effect of clozapine on pHVA concentrations in schizophrenic patients. Since clozapine potently binds to alpha 2-adrenergic receptors, plasma norepinephrine (pNE) concentrations were also measured. Twenty-eight treatment-refractory schizophrenic patients (24 men, 4 women) were treated with clozapine (up to 600 mg/day) for 5 weeks, after a minimum 1-week drug-free period. Symptomatology and pHVA and pNE concentrations were measured at the last drug-free day and weekly for 5 weeks. Fourteen patients responded to clozapine treatment, while an equal number did not. Mean pHVA concentrations did not significantly change during treatment with clozapine. Although clozapine tended to lower pHVA concentrations in treatment responders, the effect was small and not significant. Clozapine treatment significantly raised pNE concentrations, but this did not differentiate responders from nonresponders to clozapine. These findings suggest that clozapine's effect on DA turnover is small and that clozapine may be effective in treatment-refractory schizophrenia by mechanisms other than, or in addition to, dopamine receptor blockade. However, since about one-third of NE is metabolized into HVA, the clozapine-induced increase in pNE may have overshadowed a possible lowering effect of clozapine on pHVA.

  10. Lyapunov exponents and smooth ergodic theory

    CERN Document Server

    Barreira, Luis

    2001-01-01

    This book is a systematic introduction to smooth ergodic theory. The topics discussed include the general (abstract) theory of Lyapunov exponents and its applications to the stability theory of differential equations, stable manifold theory, absolute continuity, and the ergodic theory of dynamical systems with nonzero Lyapunov exponents (including geodesic flows). The authors consider several non-trivial examples of dynamical systems with nonzero Lyapunov exponents to illustrate some basic methods and ideas of the theory. This book is self-contained. The reader needs a basic knowledge of real analysis, measure theory, differential equations, and topology. The authors present basic concepts of smooth ergodic theory and provide complete proofs of the main results. They also state some more advanced results to give readers a broader view of smooth ergodic theory. This volume may be used by those nonexperts who wish to become familiar with the field.

  11. Multiple predictor smoothing methods for sensitivity analysis

    International Nuclear Information System (INIS)

    Helton, Jon Craig; Storlie, Curtis B.

    2006-01-01

    The use of multiple predictor smoothing methods in sampling-based sensitivity analyses of complex models is investigated. Specifically, sensitivity analysis procedures based on smoothing methods employing the stepwise application of the following nonparametric regression techniques are described: (1) locally weighted regression (LOESS), (2) additive models, (3) projection pursuit regression, and (4) recursive partitioning regression. The indicated procedures are illustrated with both simple test problems and results from a performance assessment for a radioactive waste disposal facility (i.e., the Waste Isolation Pilot Plant). As shown by the example illustrations, the use of smoothing procedures based on nonparametric regression techniques can yield more informative sensitivity analysis results than can be obtained with more traditional sensitivity analysis procedures based on linear regression, rank regression or quadratic regression when nonlinear relationships between model inputs and model predictions are present

  12. Adsorption on smooth electrodes: A radiotracer study

    International Nuclear Information System (INIS)

    Rice-Jackson, L.M.

    1990-01-01

    Adsorption on solids is a complicated process and in most cases, occurs as the early stage of other more complicated processes, i.e. chemical reactions, electrooxidation, electroreduction. The research reported here combines the electroanalytical method, cyclic voltammetry, and the use of radio-labeled isotopes, soft beta emitters, to study adsorption processes at smooth electrodes. The in-situ radiotracer method is highly anion (molecule) specific and provides information on the structure and composition of the electric double layer. The emphasis of this research was on studying adsorption processes at smooth electrodes of copper, gold, and platinum. The application of the radiotracer method to these smooth surfaces have led to direct in-situ measurements from which surface coverage was determined; anions and molecules were identified; and weak interactions of adsorbates with the surface of the electrodes were readily monitored. 179 refs

  13. Multiple predictor smoothing methods for sensitivity analysis.

    Energy Technology Data Exchange (ETDEWEB)

    Helton, Jon Craig; Storlie, Curtis B.

    2006-08-01

    The use of multiple predictor smoothing methods in sampling-based sensitivity analyses of complex models is investigated. Specifically, sensitivity analysis procedures based on smoothing methods employing the stepwise application of the following nonparametric regression techniques are described: (1) locally weighted regression (LOESS), (2) additive models, (3) projection pursuit regression, and (4) recursive partitioning regression. The indicated procedures are illustrated with both simple test problems and results from a performance assessment for a radioactive waste disposal facility (i.e., the Waste Isolation Pilot Plant). As shown by the example illustrations, the use of smoothing procedures based on nonparametric regression techniques can yield more informative sensitivity analysis results than can be obtained with more traditional sensitivity analysis procedures based on linear regression, rank regression or quadratic regression when nonlinear relationships between model inputs and model predictions are present.

  14. MURC deficiency in smooth muscle attenuates pulmonary hypertension.

    Science.gov (United States)

    Nakanishi, Naohiko; Ogata, Takehiro; Naito, Daisuke; Miyagawa, Kotaro; Taniguchi, Takuya; Hamaoka, Tetsuro; Maruyama, Naoki; Kasahara, Takeru; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-08-22

    Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling.

  15. Biophysical induction of vascular smooth muscle cell podosomes.

    Directory of Open Access Journals (Sweden)

    Na Young Kim

    Full Text Available Vascular smooth muscle cell (VSMC migration and matrix degradation occurs with intimal hyperplasia associated with atherosclerosis, vascular injury, and restenosis. One proposed mechanism by which VSMCs degrade matrix is through the use of podosomes, transient actin-based structures that are thought to play a role in extracellular matrix degradation by creating localized sites of matrix metalloproteinase (MMP secretion. To date, podosomes in VSMCs have largely been studied by stimulating cells with phorbol esters, such as phorbol 12,13-dibutyrate (PDBu, however little is known about the physiological cues that drive podosome formation. We present the first evidence that physiological, physical stimuli mimicking cues present within the microenvironment of diseased arteries can induce podosome formation in VSMCs. Both microtopographical cues and imposed pressure mimicking stage II hypertension induce podosome formation in A7R5 rat aortic smooth muscle cells. Moreover, wounding using a scratch assay induces podosomes at the leading edge of VSMCs. Notably the effect of each of these biophysical stimuli on podosome stimulation can be inhibited using a Src inhibitor. Together, these data indicate that physical cues can induce podosome formation in VSMCs.

  16. Polarization beam smoothing for inertial confinement fusion

    International Nuclear Information System (INIS)

    Rothenberg, Joshua E.

    2000-01-01

    For both direct and indirect drive approaches to inertial confinement fusion (ICF) it is imperative to obtain the best possible drive beam uniformity. The approach chosen for the National Ignition Facility uses a random-phase plate to generate a speckle pattern with a precisely controlled envelope on target. A number of temporal smoothing techniques can then be employed to utilize bandwidth to rapidly change the speckle pattern, and thus average out the small-scale speckle structure. One technique which generally can supplement other smoothing methods is polarization smoothing (PS): the illumination of the target with two distinct and orthogonally polarized speckle patterns. Since these two polarizations do not interfere, the intensity patterns add incoherently, and the rms nonuniformity can be reduced by a factor of (√2). A number of PS schemes are described and compared on the basis of the aggregate rms and the spatial spectrum of the focused illumination distribution. The (√2) rms nonuniformity reduction of PS is present on an instantaneous basis and is, therefore, of particular interest for the suppression of laser plasma instabilities, which have a very rapid response time. When combining PS and temporal methods, such as smoothing by spectral dispersion (SSD), PS can reduce the rms of the temporally smoothed illumination by an additional factor of (√2). However, it has generally been thought that in order to achieve this reduction of (√2), the increased divergence of the beam from PS must exceed the divergence of SSD. It is also shown here that, over the time scales of interest to direct or indirect drive ICF, under some conditions PS can reduce the smoothed illumination rms by nearly (√2) even when the PS divergence is much smaller than that of SSD. (c) 2000 American Institute of Physics

  17. Some properties of the smoothed Wigner function

    International Nuclear Information System (INIS)

    Soto, F.; Claverie, P.

    1981-01-01

    Recently it has been proposed a modification of the Wigner function which consists in smoothing it by convolution with a phase-space gaussian function; this smoothed Wigner function is non-negative if the gaussian parameters Δ and delta satisfy the condition Δdelta > h/2π. We analyze in this paper the predictions of this modified Wigner function for the harmonic oscillator, for anharmonic oscillator and finally for the hydrogen atom. We find agreement with experiment in the linear case, but for strongly nonlinear systems, such as the hydrogen atom, the results obtained are completely wrong. (orig.)

  18. Cardiac, Skeletal, and smooth muscle mitochondrial respiration

    DEFF Research Database (Denmark)

    Park, Song-Young; Gifford, Jayson R; Andtbacka, Robert H I

    2014-01-01

    , skeletal, and smooth muscle was harvested from a total of 22 subjects (53±6 yrs) and mitochondrial respiration assessed in permeabilized fibers. Complex I+II, state 3 respiration, an index of oxidative phosphorylation capacity, fell progressively from cardiac, skeletal, to smooth muscle (54±1; 39±4; 15......±1 pmol•s(-1)•mg (-1), prespiration rates were normalized by CS (respiration...... per mitochondrial content), oxidative phosphorylation capacity was no longer different between the three muscle types. Interestingly, Complex I state 2 normalized for CS activity, an index of non-phosphorylating respiration per mitochondrial content, increased progressively from cardiac, skeletal...

  19. Smooth massless limit of field theories

    International Nuclear Information System (INIS)

    Fronsdal, C.

    1980-01-01

    The massless limit of Fierz-Pauli field theories, describing fields with fixed mass and spin interacting with external sources, is examined. Results are obtained for spins, 1, 3/2, 2 and 3 using conventional models, and then for all half-integral spins in a relatively model-independent manner. It is found that the massless limit is smooth provided that the sources satisfy certain conditions. In the massless limit these conditions reduce to the conservation laws required by internal consistency of massless field theory. Smoothness simply requires that quantities that vanish in the massless case approach zero in a certain well-defined manner. (orig.)

  20. Smooth muscle relaxant activity of Crocus sativus (saffron and its constituents: possible mechanisms

    Directory of Open Access Journals (Sweden)

    Amin Mokhtari-Zaer

    2015-08-01

    Full Text Available Saffron, Crocus sativus L. (C. sativus is rich in carotenoids and used in traditional medicine for treatment of various conditions such as coughs, stomach disorders, amenorrhea, asthma and cardiovascular disorders. These therapeutic effects of the plant are suggested to be due to its relaxant effect on smooth muscles. The effect of C. sativus and its constituents on different smooth muscles and the underlying mechanisms have been studied. Several studies have shown the relaxant effects of C. sativus and its constituents including safranal, crocin, crocetin and kaempferol on blood vessels. In addition, it was reported that saffron stigma lowers systolic blood pressure. The present review highlights the relaxant effects of C. sativus and its constituents on various smooth muscles. The possible mechanisms of this relaxing effect including activation of ß2-adrenoceptors, inhibition of histamine H1 and muscarinic receptors and calcium channels and modulation of nitric oxide (NO are also reviewed.

  1. 16-dimensional smooth projective planes with large collineation groups

    OpenAIRE

    Bödi, Richard

    1998-01-01

    Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch) Smooth projective planes are projective planes defined on smooth manifolds (i.e. the set of points and the set of lines are smooth manifolds) such that the geometric operations of join and intersection are smooth. A systematic study of such planes and of their collineation groups can be found in previous works of the author. We prove in this paper that a 16-dimensional smooth projective plane which admits a ...

  2. Involvement of norepinephrine activity in the regulation of α1 adrenergic receptors in the medial preoptic nucleus of estradiol-treated rats

    International Nuclear Information System (INIS)

    Sortino, M.A.; Weiland, N.G.; Wise, P.M.

    1989-01-01

    To establish whether the diurnal decrease in the density of α1 receptors observed in the medial preoptic nucleus (MPN) of estrogen (E 2 )-treated rats is related to the concomitant diurnal increase in norepinephrine (NE) turnover rates, we quantitiated the density of [ 3 H]-Prazosin binding to α1 receptors after blockade of NE turnover with alpha-methyl-paratyrosine (αMPT). A series of preliminary studies was performed to rule out an interference of this drug with [ 3 H]-Prazosin binding to α1 adrenergic receptors in vitro and in vivo. Incubation of brain slices with αMPT produced a dose-dependent inhibition of [ 3 H]-Prazosin binding to α1 adrenergic receptors with an IC 50 of approximately 6 mM. Scatchard analysis demonstrated that αMPT exhibited a simple competitive interaction with [ 3 H]-Prazosin binding sites as shown by an increase in the apparent dissociation constant (Kd) of the ligand and no change in the number of α1 receptors (B/sub max/). In contrast, preincubation of brain slices with αMPT and prior in vivo administration of αMPT did not affect [ 3 H]-Prazosin binding to α1 adrenergic receptors. The density of α1 adrenergic receptors in MPN was quantitated autoradiographically. Blockade of NE turnover with αMPT only partially prevented the reduction in α1 receptor density observed in the E 2 -treated rats, suggesting that the decrease in the level of [ 3 H]-Prazosin binding sites cannot be completely ascribed to increased NE turnover rates

  3. Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Annegret Ulke-Lemée

    2010-05-01

    Full Text Available Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine; therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but its dysfunction is associated with morbidity and mortality. Rho-associated protein kinase (ROCK is central to calcium-independent, actomyosin-mediated contractile force generation in the vasculature, thereby playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence supports an important role for ROCK in the increased vasoconstriction and remodeling observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications might also benefit from ROCK inhibition. Apart from the importance of ROCK in smooth muscle contraction, a variety of other protein kinases are known to play similar roles in regulating contractile force. The zipper-interacting protein kinase (ZIPK and integrin-linked kinase (ILK are two well-described regulators of contraction. The relative contribution of each kinase to contraction depends on the muscle bed as well as hormonal and neuronal stimulation. Unfortunately, specific inhibitors for ZIPK and ILK are still in the development phase, but the success of fasudil suggests that inhibitors for these other kinases may also have valuable clinical applications. Notably, the directed inhibition of ZIPK with a pseudosubstrate molecule shows unexpected effects on the contractility of gastrointestinal smooth muscle.

  4. An adaptive method for γ spectra smoothing

    International Nuclear Information System (INIS)

    Xiao Gang; Zhou Chunlin; Li Tiantuo; Han Feng; Di Yuming

    2001-01-01

    Adaptive wavelet method and multinomial fitting gliding method are used for smoothing γ spectra, respectively, and then FWHM of 1332 keV peak of 60 Co and activities of 238 U standard specimen are calculated. Calculated results show that adaptive wavelet method is better than the other

  5. Smoothness in Banach spaces. Selected problems

    Czech Academy of Sciences Publication Activity Database

    Fabian, Marián; Montesinos, V.; Zizler, Václav

    2006-01-01

    Roč. 100, č. 2 (2006), s. 101-125 ISSN 1578-7303 R&D Projects: GA ČR(CZ) GA201/04/0090; GA AV ČR(CZ) IAA100190610 Institutional research plan: CEZ:AV0Z10190503 Keywords : smooth norm * renorming * weakly compactly generated space Subject RIV: BA - General Mathematics

  6. The Koch curve as a smooth manifold

    International Nuclear Information System (INIS)

    Epstein, Marcelo; Sniatycki, Jedrzej

    2008-01-01

    We show that there exists a homeomorphism between the closed interval [0,1] is contained in R and the Koch curve endowed with the subset topology of R 2 . We use this homeomorphism to endow the Koch curve with the structure of a smooth manifold with boundary

  7. on Isolated Smooth Muscle Preparation in Rats

    African Journals Online (AJOL)

    Samuel Olaleye

    ABSTRACT. This study investigated the receptor effects of methanolic root extract of ... Phytochemical Analysis: Photochemistry of the methanolic extract was ... mounted with resting tension 0.5g in an organ bath containing .... Effects of extra cellular free Ca2+ and 0.5mM ... isolated smooth muscle by high K+ on the other.

  8. PHANTOM: Smoothed particle hydrodynamics and magnetohydrodynamics code

    Science.gov (United States)

    Price, Daniel J.; Wurster, James; Nixon, Chris; Tricco, Terrence S.; Toupin, Stéven; Pettitt, Alex; Chan, Conrad; Laibe, Guillaume; Glover, Simon; Dobbs, Clare; Nealon, Rebecca; Liptai, David; Worpel, Hauke; Bonnerot, Clément; Dipierro, Giovanni; Ragusa, Enrico; Federrath, Christoph; Iaconi, Roberto; Reichardt, Thomas; Forgan, Duncan; Hutchison, Mark; Constantino, Thomas; Ayliffe, Ben; Mentiplay, Daniel; Hirsh, Kieran; Lodato, Giuseppe

    2017-09-01

    Phantom is a smoothed particle hydrodynamics and magnetohydrodynamics code focused on stellar, galactic, planetary, and high energy astrophysics. It is modular, and handles sink particles, self-gravity, two fluid and one fluid dust, ISM chemistry and cooling, physical viscosity, non-ideal MHD, and more. Its modular structure makes it easy to add new physics to the code.

  9. Data driven smooth tests for composite hypotheses

    NARCIS (Netherlands)

    Inglot, Tadeusz; Kallenberg, Wilbert C.M.; Ledwina, Teresa

    1997-01-01

    The classical problem of testing goodness-of-fit of a parametric family is reconsidered. A new test for this problem is proposed and investigated. The new test statistic is a combination of the smooth test statistic and Schwarz's selection rule. More precisely, as the sample size increases, an

  10. Full Waveform Inversion Using Nonlinearly Smoothed Wavefields

    KAUST Repository

    Li, Y.; Choi, Yun Seok; Alkhalifah, Tariq Ali; Li, Z.

    2017-01-01

    The lack of low frequency information in the acquired data makes full waveform inversion (FWI) conditionally converge to the accurate solution. An initial velocity model that results in data with events within a half cycle of their location in the observed data was required to converge. The multiplication of wavefields with slightly different frequencies generates artificial low frequency components. This can be effectively utilized by multiplying the wavefield with itself, which is nonlinear operation, followed by a smoothing operator to extract the artificially produced low frequency information. We construct the objective function using the nonlinearly smoothed wavefields with a global-correlation norm to properly handle the energy imbalance in the nonlinearly smoothed wavefield. Similar to the multi-scale strategy, we progressively reduce the smoothing width applied to the multiplied wavefield to welcome higher resolution. We calculate the gradient of the objective function using the adjoint-state technique, which is similar to the conventional FWI except for the adjoint source. Examples on the Marmousi 2 model demonstrate the feasibility of the proposed FWI method to mitigate the cycle-skipping problem in the case of a lack of low frequency information.

  11. On the theory of smooth structures. 2

    International Nuclear Information System (INIS)

    Shafei Deh Abad, A.

    1992-09-01

    In this paper we continue by introducing the concepts of substructures, quotient structures and tensor product, and examine some of their properties. By using the concept of tensor product, in the next paper, we will give another product for smooth structures which is a characterization of integral domains which are not fields. (author). 2 refs

  12. Full Waveform Inversion Using Nonlinearly Smoothed Wavefields

    KAUST Repository

    Li, Y.

    2017-05-26

    The lack of low frequency information in the acquired data makes full waveform inversion (FWI) conditionally converge to the accurate solution. An initial velocity model that results in data with events within a half cycle of their location in the observed data was required to converge. The multiplication of wavefields with slightly different frequencies generates artificial low frequency components. This can be effectively utilized by multiplying the wavefield with itself, which is nonlinear operation, followed by a smoothing operator to extract the artificially produced low frequency information. We construct the objective function using the nonlinearly smoothed wavefields with a global-correlation norm to properly handle the energy imbalance in the nonlinearly smoothed wavefield. Similar to the multi-scale strategy, we progressively reduce the smoothing width applied to the multiplied wavefield to welcome higher resolution. We calculate the gradient of the objective function using the adjoint-state technique, which is similar to the conventional FWI except for the adjoint source. Examples on the Marmousi 2 model demonstrate the feasibility of the proposed FWI method to mitigate the cycle-skipping problem in the case of a lack of low frequency information.

  13. Local smoothness for global optical flow

    DEFF Research Database (Denmark)

    Rakêt, Lars Lau

    2012-01-01

    by this technique and work on local-global optical flow we propose a simple method for fusing optical flow estimates of different smoothness by evaluating interpolation quality locally by means of L1 block match on the corresponding set of gradient images. We illustrate the method in a setting where optical flows...

  14. Interval Forecast for Smooth Transition Autoregressive Model ...

    African Journals Online (AJOL)

    In this paper, we propose a simple method for constructing interval forecast for smooth transition autoregressive (STAR) model. This interval forecast is based on bootstrapping the residual error of the estimated STAR model for each forecast horizon and computing various Akaike information criterion (AIC) function. This new ...

  15. Supplementary speed control for wind power smoothing

    NARCIS (Netherlands)

    Haan, de J.E.S.; Frunt, J.; Kechroud, A.; Kling, W.L.

    2010-01-01

    Wind fluctuations result in even larger wind power fluctuations because the power of wind is proportional to the cube of the wind speed. This report analyzes wind power fluctuations to investigate inertial power smoothing, in particular for the frequency range of 0.08 - 0.5 Hz. Due to the growing

  16. Role of Smooth Muscle in Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Stephen M Collins

    1996-01-01

    Full Text Available The notion that smooth muscle function is altered in inflammation is prompted by clinical observations of altered motility in patients with inflammatory bowel disease (IBD. While altered motility may reflect inflammation-induced changes in intrinsic or extrinsic nerves to the gut, changes in gut hormone release and changes in muscle function, recent studies have provided in vitro evidence of altered muscle contractility in muscle resected from patients with ulcerative colitis or Crohn’s disease. In addition, the observation that smooth muscle cells are more numerous and prominent in the strictured bowel of IBD patients compared with controls suggests that inflammation may alter the growth of intestinal smooth muscle. Thus, inflammation is associated with changes in smooth muscle growth and contractility that, in turn, contribute to important symptoms of IBD including diarrhea (from altered motility and pain (via either altered motility or stricture formation. The involvement of smooth muscle in this context may be as an innocent bystander, where cells and products of the inflammatory process induce alterations in muscle contractility and growth. However, it is likely that intestinal muscle cells play a more active role in the inflammatory process via the elaboration of mediators and trophic factors, including cytokines, and via the production of collagen. The concept of muscle cells as active participants in the intestinal inflammatory process is a new concept that is under intense study. This report summarizes current knowledge as it relates to these two aspects of altered muscle function (growth and contractility in the inflamed intestine, and will focus on mechanisms underlying these changes, based on data obtained from animal models of intestinal inflammation.

  17. Age-related differences in norepinephrine kinetics: Effect of posture and sodium-restricted diet

    International Nuclear Information System (INIS)

    Supiano, M.A.; Linares, O.A.; Smith, M.J.; Halter, J.B.

    1990-01-01

    We used compartmental analysis to study the influence of age on the kinetics of norepinephrine (NE) distribution and metabolism. Plasma NE and [3H]NE levels were measured in 10 young (age 19-33 yr) and 13 elderly (age 62-73 yr) subjects in the basal supine position, during upright posture, and after 1 wk of a sodium-restricted diet. We found that the basal supine release rate of NE into the extravascular compartment, which is the site of endogenous NE release (NE2), was significantly increased in the elderly group (young, 9.6 +/- 0.5; elderly, 12.3 +/- 0.8 nmol.min-1.m-2; means +/- SE; P = 0.016), providing direct evidence for an age-related increase in sympathetic nervous system (SNS) tone. Although upright posture led to a greater increase in plasma NE in the young (0.90 +/- 0.07 to 2.36 +/- 0.16 nM) than in the elderly (1.31 +/- 0.11 to 2.56 +/- 0.31 nM; age group-posture interaction, P = 0.02), the increase in NE2 was similar between the young (9.6 +/- 0.6 to 16.2 +/- 1.5 nmol.min-1.m-2) and the elderly (11.6 +/- 1.4 to 16.1 +/- 2.4 nmol.min-1.m-2; posture effect, P = 0.001; age group-posture interaction, P = 0.15). Thus the increase in SNS tone resulting from upright posture was similar in young and elderly subjects. Plasma NE levels increased similarly in both groups after a sodium-restricted diet (diet effect, P = 0.001; age group-diet interaction, P = 0.23). However, NE2 did not increase significantly in either group (diet effect, P = 0.26), suggesting that SNS tone did not increase after a sodium-restricted diet. Compartmental analysis provides a description of age-related differences in NE kinetics, including an age-related increase in the extravascular NE release rate

  18. Smoothing a Piecewise-Smooth: An Example from Plankton Population Dynamics

    DEFF Research Database (Denmark)

    Piltz, Sofia Helena

    2016-01-01

    In this work we discuss a piecewise-smooth dynamical system inspired by plankton observations and constructed for one predator switching its diet between two different types of prey. We then discuss two smooth formulations of the piecewise-smooth model obtained by using a hyperbolic tangent funct...... function and adding a dimension to the system. We compare model behaviour of the three systems and show an example case where the steepness of the switch is determined from a comparison with data on freshwater plankton....

  19. Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction, and renal release

    DEFF Research Database (Denmark)

    Ring-Larsen, H; Hesse, B; Henriksen, Jens Henrik Sahl

    1982-01-01

    as previously reported in healthy controls. The right kidney released NE into the systemic circulation. Renal venous plasma NE exceeded arterial concentration by 34% (p less than 0.01). It is concluded that sympathetic nervous activity is enhanced in patients with cirrhosis, and that this hyperactivity may...... in patients than controls (82 vs. 95 mm Hg, p less than 0.05) but did not change during the tilt. Plasma norepinephrine (NE) concentration was significantly higher in another eight patients with cirrhosis than in eight healthy controls (mean: 0.45 vs. 0.21 ng per ml in recumbency, p less than 0.02). Following...

  20. KCl cotransport regulation and protein kinase G in cultured vascular smooth muscle cells.

    Science.gov (United States)

    Adragna, N C; Zhang, J; Di Fulvio, M; Lincoln, T M; Lauf, P K

    2002-05-15

    K-Cl cotransport is activated by vasodilators in erythrocytes and vascular smooth muscle cells and its regulation involves putative kinase/phosphatase cascades. N-ethylmaleimide (NEM) activates the system presumably by inhibiting a protein kinase. Nitrovasodilators relax smooth muscle via cGMP-dependent activation of protein kinase G (PKG), a regulator of membrane channels and transporters. We investigated whether PKG regulates K-Cl cotransport activity or mRNA expression in normal, PKG-deficient-vector-only-transfected (PKG-) and PKG-catalytic-domain-transfected (PKG+) rat aortic smooth muscle cells. K-Cl cotransport was calculated as the Cl-dependent Rb influx, and mRNA was determined by semiquantitative RT-PCR. Baseline K-Cl cotransport was higher in PKG+ than in PKG- cells (p <0.01). At 0.5 mM, NEM stimulated K-Cl cotransport by 5-fold in PKG- but not in PKG+ cells. However, NEM was more potent although less effective to activate K-Cl cotransport in normal (passage 1-3) and PKG+ than in PKG- cells. In PKG- cells, [(dihydroindenyl) oxy] alkanoic acid (300 mM) but not furosemide (1 mM) inhibited K-Cl cotransport. Furthermore, no difference in K-Cl cotransport mRNA expression was observed between these cells. In conclusion, this study shows that manipulation of PKG expression in vascular smooth muscle cells affects K-Cl cotransport activity and its activation by NEM.

  1. Phosphodiesterases regulate airway smooth muscle function in health and disease.

    Science.gov (United States)

    Krymskaya, Vera P; Panettieri, Reynold A

    2007-01-01

    On the basis of structure, regulation, and kinetic properties, phosphodiesterases (PDEs) represent a superfamily of enzymes divided into 11 subfamilies that catalyze cytosolic levels of 3',5'-cyclic adenosine monophosphate (cAMP) or 3',5'-cyclic guanosine monophosphate (cGMP) to 5'-AMP or 5'-GMP, respectively. PDE4 represents the major PDE expressed in inflammatory cells as well as airway smooth muscle (ASM), and selective PDE4 inhibitors provide a broad spectrum of anti-inflammatory effects such as abrogating cytokine and chemokine release from inflammatory cells and inhibiting inflammatory cell trafficking. Due to cell- and tissue-specific gene expression and regulation, PDEs modulate unique organ-based functions. New tools or compounds that selectively inhibit PDE subfamilies and genetically engineered mice deficient in selective isoforms have greatly enhanced our understanding of PDE function in airway inflammation and resident cell function. This chapter will focus on recent advances in our understanding of the role of PDE in regulating ASM function.

  2. In vivo assessment of [11C]MRB as a prospective PET ligand for imaging the norepinephrine transporter

    International Nuclear Information System (INIS)

    Severance, Alin J.; Milak, Matthew S.; Dileep Kumar, J.S.; Arango, Victoria; Parsey, Ramin V.; Prabhakaran, Jaya; Majo, Vattoly J.; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J.J.

    2007-01-01

    Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter's role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates. Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test-retest and blocking conditions using 1 mg/kg nisoxetine. MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine. Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [ 11 C]MRB lacks sensitivity and reliability as a PET radiotracer in humans. (orig.)

  3. Hypersensitivity to norepinephrine in vasa deferentia from diabetic rats. Possible participation of metabolic products of arachidonic acid

    Energy Technology Data Exchange (ETDEWEB)

    Peredo, H; Agostini, M D; Gimeno, M F; Borda, E S

    1984-08-01

    Contractile responses to norepinephrine of the vas deferens isolated from normal and diabetic rats as well as tissue radio-conversion of exogenous arachidonic acid, were studied. Vasa deferentia from rats with acute streptozotocin-induced diabetes showed hypersensitivity to exogenous norepinephrine (NE). This increased contractile response was associated with the interaction of the agonist with alpha adrenoceptors. Inhibitors of cyclooxygenase increased and inhibitors of lipoxygenase(s) abolished the enhanced response to NE of diabetic vas deferens. Vasa deferentia from both normal and diabetic rats, converted (1-/sup 14/C)-arachidonic acid (AA) into PGF, PGE, PGD and thromboxane (TX) B2, but the % of AA metabolites formed was significantly higher in the diabetic than in the normal condition. Moreover, the predominant prostanoid generated by tissue preparations from diabetic animals was PGD2. Taken together the present experimental findings indicate that preparations from rats with acute streptozotocin-induced diabetes have an augmented reactivity towards NE, which appeared associated with changes in metabolites of AA generated via cyclooxygenase and lipoxygenase catalized pathways.

  4. Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder.

    Science.gov (United States)

    Kim, Yong-Ku; Hwang, Jung-A; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Ko, Young-Hoon; Lee, Bun-Hee; Jung, Han-Yong; Hahn, Sang-Woo; Na, Kyoung-Sae

    2014-04-01

    Although several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. Three single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. In the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446-rs28386840-rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. Modest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. Our results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. On smoothness-asymmetric null infinities

    International Nuclear Information System (INIS)

    Valiente Kroon, Juan Antonio

    2006-01-01

    We discuss the existence of asymptotically Euclidean initial data sets for the vacuum Einstein field equations which would give rise (modulo an existence result for the evolution equations near spatial infinity) to developments with a past and a future null infinity of different smoothness. For simplicity, the analysis is restricted to the class of conformally flat, axially symmetric initial data sets. It is shown how the free parameters in the second fundamental form of the data can be used to satisfy certain obstructions to the smoothness of null infinity. The resulting initial data sets could be interpreted as those of some sort of (nonlinearly) distorted Schwarzschild black hole. Their developments would be that they admit a peeling future null infinity, but at the same time have a polyhomogeneous (non-peeling) past null infinity

  6. Smooth homogeneous structures in operator theory

    CERN Document Server

    Beltita, Daniel

    2005-01-01

    Geometric ideas and techniques play an important role in operator theory and the theory of operator algebras. Smooth Homogeneous Structures in Operator Theory builds the background needed to understand this circle of ideas and reports on recent developments in this fruitful field of research. Requiring only a moderate familiarity with functional analysis and general topology, the author begins with an introduction to infinite dimensional Lie theory with emphasis on the relationship between Lie groups and Lie algebras. A detailed examination of smooth homogeneous spaces follows. This study is illustrated by familiar examples from operator theory and develops methods that allow endowing such spaces with structures of complex manifolds. The final section of the book explores equivariant monotone operators and Kähler structures. It examines certain symmetry properties of abstract reproducing kernels and arrives at a very general version of the construction of restricted Grassmann manifolds from the theory of loo...

  7. Does responsive pricing smooth demand shocks?

    OpenAIRE

    Pascal, Courty; Mario, Pagliero

    2011-01-01

    Using data from a unique pricing experiment, we investigate Vickrey’s conjecture that responsive pricing can be used to smooth both predictable and unpredictable demand shocks. Our evidence shows that increasing the responsiveness of price to demand conditions reduces the magnitude of deviations in capacity utilization rates from a pre-determined target level. A 10 percent increase in price variability leads to a decrease in the variability of capacity utilization rates between...

  8. The Smooth Muscle of the Artery

    Science.gov (United States)

    1975-01-01

    of vascular smooth muscle are contrac- tion, thereby mediating vaso constriction, and the synthesis of the extracellular proteins and polysaccharides ...of the monosaccharides turned out to be different for instance from cornea to aorta (229, 283). In the conditions yed (4 hours incubation at 37 degrees... polysaccharides only. This glyco- protein is not very rich in sugar components (- 5Z) (228, 284), but is a very acidic protein (286). Fig.66 shows

  9. Log canonical thresholds of smooth Fano threefolds

    International Nuclear Information System (INIS)

    Cheltsov, Ivan A; Shramov, Konstantin A

    2008-01-01

    The complex singularity exponent is a local invariant of a holomorphic function determined by the integrability of fractional powers of the function. The log canonical thresholds of effective Q-divisors on normal algebraic varieties are algebraic counterparts of complex singularity exponents. For a Fano variety, these invariants have global analogues. In the former case, it is the so-called α-invariant of Tian; in the latter case, it is the global log canonical threshold of the Fano variety, which is the infimum of log canonical thresholds of all effective Q-divisors numerically equivalent to the anticanonical divisor. An appendix to this paper contains a proof that the global log canonical threshold of a smooth Fano variety coincides with its α-invariant of Tian. The purpose of the paper is to compute the global log canonical thresholds of smooth Fano threefolds (altogether, there are 105 deformation families of such threefolds). The global log canonical thresholds are computed for every smooth threefold in 64 deformation families, and the global log canonical thresholds are computed for a general threefold in 20 deformation families. Some bounds for the global log canonical thresholds are computed for 14 deformation families. Appendix A is due to J.-P. Demailly.

  10. Smooth Nb surfaces fabricated by buffered electropolishing

    International Nuclear Information System (INIS)

    Wu, Andy T.; Mammosser, John; Phillips, Larry; Delayen, Jean; Reece, Charles; Wilkerson, Amy; Smith, David; Ike, Robert

    2007-01-01

    It was demonstrated that smooth Nb surfaces could be obtained through buffered electropolishing (BEP) employing an electrolyte consisting of lactic, sulfuric, and hydrofluoric acids. Parameters that control the polishing process were optimized to achieve a smooth surface finish. The polishing rate of BEP was determined to be 0.646 μm/min which was much higher than 0.381 μm/min achieved by the conventional electropolishing (EP) process widely used in the superconducting radio frequency (SRF) community. Root mean square measurements using a 3D profilometer revealed that Nb surfaces treated by BEP were an order of magnitude smoother than those treated by the optimized EP process. The chemical composition of the Nb surfaces after BEP was analyzed by static and dynamic secondary ion mass spectrometry (SIMS) systems. SIMS results implied that the surface oxide structure of Nb might be more complicated than what usually believed and could be inhomogeneous. Preliminary results of BEP on Nb SRF single cell cavities and half-cells were reported. It was shown that smooth and bright surfaces could be obtained in 1800 s when the electric field inside a SRF cavity was uniform during a BEP process. This study showed that BEP is a promising technique for surface treatment on Nb SRF cavities to be used in particle accelerators

  11. A comparison of N-methyl-D-aspartate-evoked release of adenosine and [3H]norepinephrine from rat cortical slices

    International Nuclear Information System (INIS)

    Hoehn, K.; Craig, C.G.; White, T.D.

    1990-01-01

    Tetrodotoxin reduced N-methyl-D-aspartate (NMDA)-evoked release of adenosine by 35% but virtually abolished [3H]norepinephrine release. Although [3H]norepinephrine release from rat cortical slices evoked by 500 microM NMDA was abolished by 1.2 mM Mg++, which produces a voltage-sensitive, uncompetitive block of NMDA-channels, adenosine release was increased in the presence of Mg++. Partial depolarization with 12 mM K+ relieved the Mg++ block of 500 microM NMDA-evoked [3H]norepinephrine release but did not affect adenosine release, indicating that a Mg++ requirement for the adenosine release process per se cannot account for this discrepancy. NMDA was 33 times more potent in releasing adenosine than [3H]norepinephrine. At submaximal concentrations of NMDA (10 and 20 microM), adenosine release was augmented in Mg+(+)-free medium. Although a high concentration of the uncompetitive NMDA antagonist MK-801 [(+)-5-methyl-10,11,dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate] (3 microM) blocked NMDA-evoked release of [3H]norepinephrine and adenosine, a lower concentration (300 nM) decreased NMDA-evoked [3H]norepinephrine release by 66% without affecting adenosine release. These findings suggest that maximal adenosine release occurs when relatively few NMDA receptors are activated, raising the possibility that spare receptors exist for NMDA-evoked adenosine release. Rather than acting as a protectant against excessive NMDA excitation, released adenosine might provide an inhibitory threshold which must be overcome for NMDA-mediated neurotransmission to proceed

  12. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men

    Directory of Open Access Journals (Sweden)

    Schilling Brian K

    2009-01-01

    Full Text Available Abstract Background Dietary supplements targeting fat loss and increased thermogenesis are prevalent within the sport nutrition/weight loss market. While some isolated ingredients have been reported to be efficacious when used at high dosages, in particular in animal models and/or via intravenous delivery, little objective evidence is available pertaining to the efficacy of a finished product taken by human subjects in oral form. Moreover, many ingredients function as stimulants, leading to increased hemodynamic responses. The purpose of this investigation was to determine the effects of a finished dietary supplement on plasma catecholamine concentration, markers of lipolysis, metabolic rate, and hemodynamics. Methods Ten resistance trained men (age = 27 ± 4 yrs; BMI = 25 ± 3 kg· m-2; body fat = 9 ± 3%; mean ± SD ingested a dietary supplement (Meltdown®, Vital Pharmaceuticals or a placebo, in a random order, double blind cross-over design, with one week separating conditions. Fasting blood samples were collected before, and at 30, 60, and 90 minutes post ingestion and were assayed for epinephrine (EPI, norepinephrine (NE, glycerol, and free fatty acids (FFA. Area under the curve (AUC was calculated for all variables. Gas samples were collected from 30–60 minutes post ingestion for measurement of metabolic rate. Heart rate and blood pressure were recorded at all blood collection times. Results AUC was greater for the dietary supplement compared to the placebo for NE (1332 ± 128 pg·mL-1·90 min-1 vs. 1003 ± 133 pg·mL-1·90 min-1; p = 0.03, glycerol (44 ± 3 μg·mL-1·90 min-1 vs. 26 ± 2 μg·mL-1·90 min-1; p -1·90 min-1 vs. 0.88 ± 0.12 mmol·L-1·90 min-1; p = 0.0003. No difference between conditions was noted for EPI AUC (p > 0.05. For all variables, values were highest at 90 minutes post ingestion. Total kilocalorie expenditure during the 30 minute collection period was 29.6% greater (p = 0.02 for the dietary supplement (35 ± 3

  13. Evidence for altered brain reactivity to norepinephrine in Veterans with a history of traumatic stress

    Directory of Open Access Journals (Sweden)

    Rebecca C. Hendrickson

    2018-02-01

    Full Text Available Background: Increases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD. This increased signaling may result from increased norepinephrine (NE release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. Methods: Using a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF. CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS, which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]. Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. Results: Fifty

  14. Rapid effects of phytoestrogens on human colonic smooth muscle are mediated by oestrogen receptor beta.

    LENUS (Irish Health Repository)

    Hogan, A M

    2012-02-01

    Epidemiological studies have correlated consumption of dietary phytoestrogens with beneficial effects on colon, breast and prostate cancers. Genomic and non-genomic mechanisms are responsible for anti-carcinogenic effects but, until now, the effect on human colon was assumed to be passive and remote. No direct effect on human colonic smooth muscle has previously been described. Institutional research board approval was granted. Histologically normal colon was obtained from the proximal resection margin of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended under 1g of tension in organ baths containing oxygenated Krebs solution at 37 degrees C. After an equilibration period, tissues were exposed to diarylpropionitrile (DPN) (ER beta agonist) and 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (ER alpha agonist) or to the synthetic phytoestrogen compounds genistein (n=8), daidzein (n=8), fisetin (n=8) and quercetin (n=8) in the presence or absence of fulvestrant (oestrogen receptor antagonist). Mechanism of action was investigated by inhibition of downstream pathways. The cholinergic agonist carbachol was used to induce contractile activity. Tension was recorded isometrically. Phytoestrogens inhibit carbachol-induced colonic contractility. In keeping with a non-genomic, rapid onset direct action, the effect was within minutes, reversible and similar to previously described actions of 17 beta oestradiol. No effect was seen in the presence of fulvestrant indicating receptor modulation. While the DPN exerted inhibitory effects, PPT did not. The effect appears to be reliant on a p38\\/mitogen activated protein kinase mediated induction of nitric oxide production in colonic smooth muscle. The present data set provides the first description of a direct effect of genistein, daidzein, fisetin and quercetin on human colonic smooth muscle. The presence of ER in colonic smooth muscle has been functionally proven and the beta

  15. Experimental study on effect of arsenic trioxide on vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Lu Qin; An Yanli; Niu Huanzhang; Teng Gaojun; Wang Zihao; Zhang Dongsheng; Fang Juanjuan

    2007-01-01

    Objective: To investigate the effect of arsenic trioxide (As 2 O 3 ) nanoparticles on rabbit vascular smooth muscle cells in vitro in comparison with normal form As 2 O 3 . Methods: The rabbit vascular smooth muscle cells were cultured in vitro. Nano and normal forms of As 2 O 3 with drug concentrations of 3 μmol/L were added into the cells. Cell proliferation curve was drawn according to the light absorption values of MTT test. Flow cytometry was applied to observe the apoptosis. DNA was extracted and underwent electrophoresis. Results: Cell proliferation treated with the 3 μmol/L concentration of As 2 O 3 was inhibited. Cell growth was inhibited markedly with increased treatment time, and the inhibition effect of nano drug form seemed stronger than that of normal form. MTT light absorption values of cells treated at 24, 48 and 72 h showed statistically significant difference (H=10.934, 15.039, 15.539, P 2 O 3 , normal drug form of As 2 O 3 and control group of cells without As 2 O 3 were 44.97%, 58.54%, 74.02% respectively. The early apoptosis rates were 16.89%, 11.27%, 11.20%, late apoptosis rates were 26.56%, 23.60%, 12.46%, and necrosis rates were 11.58%, 6.59%, 2.32% respectively. Agarose gel electrophoresis showed 'ladder' strand of DNA, with more strands and obscurity for nano drug form treated cells. Conclusion: Arsenic trioxide may inhibit the growth of rabbit vascular smooth muscle cells. The nano drug form showed stronger inhibition effect than that of the normal drug form. (authors)

  16. Nodular smooth muscle metaplasia in multiple peritoneal endometriosis

    OpenAIRE

    Kim, Hyun-Soo; Yoon, Gun; Ha, Sang Yun; Song, Sang Yong

    2015-01-01

    We report here an unusual presentation of peritoneal endometriosis with smooth muscle metaplasia as multiple protruding masses on the lateral pelvic wall. Smooth muscle metaplasia is a common finding in rectovaginal endometriosis, whereas in peritoneal endometriosis, smooth muscle metaplasia is uncommon and its nodular presentation on the pelvic wall is even rarer. To the best of our knowledge, this is the first case of nodular smooth muscle metaplasia occurring in peritoneal endometriosis. A...

  17. Radial Basis Function Based Quadrature over Smooth Surfaces

    Science.gov (United States)

    2016-03-24

    Radial Basis Functions φ(r) Piecewise Smooth (Conditionally Positive Definite) MN Monomial |r|2m+1 TPS thin plate spline |r|2mln|r| Infinitely Smooth...smooth surfaces using polynomial interpolants, while [27] couples Thin - Plate Spline interpolation (see table 1) with Green’s integral formula [29

  18. Smoothing-Norm Preconditioning for Regularizing Minimum-Residual Methods

    DEFF Research Database (Denmark)

    Hansen, Per Christian; Jensen, Toke Koldborg

    2006-01-01

    take into account a smoothing norm for the solution. This technique is well established for CGLS, but it does not immediately carry over to minimum-residual methods when the smoothing norm is a seminorm or a Sobolev norm. We develop a new technique which works for any smoothing norm of the form $\\|L...

  19. Neurophysiology and Neuroanatomy of Smooth Pursuit in Humans

    Science.gov (United States)

    Lencer, Rebekka; Trillenberg, Peter

    2008-01-01

    Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved…

  20. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.

    Science.gov (United States)

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M; Kirkby, Nicholas S; van de Putte, Elisabeth E Fransen; Christen, Sibylle; Kimmitt, Robert A; Moorhouse, Rebecca; Castellan, Raphael F P; Kotelevtsev, Yuri V; Kuc, Rhoda E; Davenport, Anthony P; Dhaun, Neeraj; Webb, David J; Hadoke, Patrick W F

    2017-02-01

    The role of smooth muscle endothelin B (ET B ) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET B receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET B receptors were selectively deleted from smooth muscle by crossing floxed ET B mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET B deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET B was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET B -mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET B -mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET B knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ET B blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET B -mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET B knockout mice. In the absence of other pathology, ET B receptors in vascular smooth muscle make a small but significant contribution to ET B -dependent regulation of BP. These ET B receptors have no effect on vascular contraction or neointimal remodeling. © 2016 The Authors.

  1. Smooth and non-smooth travelling waves in a nonlinearly dispersive Boussinesq equation

    International Nuclear Information System (INIS)

    Shen Jianwei; Xu Wei; Lei Youming

    2005-01-01

    The dynamical behavior and special exact solutions of nonlinear dispersive Boussinesq equation (B(m,n) equation), u tt -u xx -a(u n ) xx +b(u m ) xxxx =0, is studied by using bifurcation theory of dynamical system. As a result, all possible phase portraits in the parametric space for the travelling wave system, solitary wave, kink and anti-kink wave solutions and uncountably infinite many smooth and non-smooth periodic wave solutions are obtained. It can be shown that the existence of singular straight line in the travelling wave system is the reason why smooth waves converge to cusp waves, finally. When parameter are varied, under different parametric conditions, various sufficient conditions guarantee the existence of the above solutions are given

  2. ASIC PROTEINS REGULATE SMOOTH MUSCLE CELL MIGRATION

    OpenAIRE

    Grifoni, Samira C.; Jernigan, Nikki L.; Hamilton, Gina; Drummond, Heather A.

    2007-01-01

    The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated Epithelial Na+ Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration, however the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence indi...

  3. A smooth exit from eternal inflation?

    Science.gov (United States)

    Hawking, S. W.; Hertog, Thomas

    2018-04-01

    The usual theory of inflation breaks down in eternal inflation. We derive a dual description of eternal inflation in terms of a deformed Euclidean CFT located at the threshold of eternal inflation. The partition function gives the amplitude of different geometries of the threshold surface in the no-boundary state. Its local and global behavior in dual toy models shows that the amplitude is low for surfaces which are not nearly conformal to the round three-sphere and essentially zero for surfaces with negative curvature. Based on this we conjecture that the exit from eternal inflation does not produce an infinite fractal-like multiverse, but is finite and reasonably smooth.

  4. On spaces of functions of smoothness zero

    International Nuclear Information System (INIS)

    Besov, Oleg V

    2012-01-01

    The paper is concerned with the new spaces B-bar p,q 0 of functions of smoothness zero defined on the n-dimensional Euclidean space R n or on a subdomain G of R n . These spaces are compared with the spaces B p,q 0 (R n ) and bmo(R n ). The embedding theorems for Sobolev spaces are refined in terms of the space B-bar p,q 0 with the limiting exponent. Bibliography: 8 titles.

  5. Smooth Nanowire/Polymer Composite Transparent Electrodes

    KAUST Repository

    Gaynor, Whitney; Burkhard, George F.; McGehee, Michael D.; Peumans, Peter

    2011-01-01

    Smooth composite transparent electrodes are fabricated via lamination of silver nanowires into the polymer poly-(4,3-ethylene dioxythiophene): poly(styrene-sulfonate) (PEDOT:PSS). The surface roughness is dramatically reduced compared to bare nanowires. High-efficiency P3HT:PCBM organic photovoltaic cells can be fabricated using these composites, reproducing the performance of cells on indium tin oxide (ITO) on glass and improving the performance of cells on ITO on plastic. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Workshop on advances in smooth particle hydrodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Wingate, C.A.; Miller, W.A.

    1993-12-31

    This proceedings contains viewgraphs presented at the 1993 workshop held at Los Alamos National Laboratory. Discussed topics include: negative stress, reactive flow calculations, interface problems, boundaries and interfaces, energy conservation in viscous flows, linked penetration calculations, stability and consistency of the SPH method, instabilities, wall heating and conservative smoothing, tensors, tidal disruption of stars, breaking the 10,000,000 particle limit, modelling relativistic collapse, SPH without H, relativistic KSPH avoidance of velocity based kernels, tidal compression and disruption of stars near a supermassive rotation black hole, and finally relativistic SPH viscosity and energy.

  7. Smooth Nanowire/Polymer Composite Transparent Electrodes

    KAUST Repository

    Gaynor, Whitney

    2011-04-29

    Smooth composite transparent electrodes are fabricated via lamination of silver nanowires into the polymer poly-(4,3-ethylene dioxythiophene): poly(styrene-sulfonate) (PEDOT:PSS). The surface roughness is dramatically reduced compared to bare nanowires. High-efficiency P3HT:PCBM organic photovoltaic cells can be fabricated using these composites, reproducing the performance of cells on indium tin oxide (ITO) on glass and improving the performance of cells on ITO on plastic. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Quantum key distribution with finite resources: Smooth Min entropy vs. Smooth Renyi entropy

    Energy Technology Data Exchange (ETDEWEB)

    Mertz, Markus; Abruzzo, Silvestre; Bratzik, Sylvia; Kampermann, Hermann; Bruss, Dagmar [Institut fuer Theoretische Physik III, Duesseldorf (Germany)

    2010-07-01

    We consider different entropy measures that play an important role in the analysis of the security of QKD with finite resources. The smooth min entropy leads to an optimal bound for the length of a secure key. Another bound on the secure key length was derived by using Renyi entropies. Unfortunately, it is very hard or even impossible to calculate these entropies for realistic QKD scenarios. To estimate the security rate it becomes important to find computable bounds on these entropies. Here, we compare a lower bound for the smooth min entropy with a bound using Renyi entropies. We compare these entropies for the six-state protocol with symmetric attacks.

  9. The effect of pertussis toxin (PTX) treatment on blood pressure (BP), norepinephrine pressor responsiveness and BP response to acute nifedipine administration in genetic hypertension

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Pintérová, Mária; Dobešová, Zdenka; Líšková, Silvia; Kuneš, Jaroslav

    2006-01-01

    Roč. 48, č. 4 (2006), s. 773-774 ISSN 0194-911X. [Annual Meeting of the European Council for Cardiovascular Research (ECCR) /11./. 29.09.2006-01.10.2006, La Colle sur Loup] R&D Projects: GA MZd(CZ) NR7786 Keywords : pertussis toxin * blood pressure * norepinephrine * nifedipine Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  10. Effect of an Ethanol Extract of Scutellaria baicalensis on Relaxation in Corpus Cavernosum Smooth Muscle

    Directory of Open Access Journals (Sweden)

    Xiang Li

    2012-01-01

    Full Text Available Aims of study. The aim of the present study was to investigate whether an ethanol extract of Scutellaria baicalensis (ESB relaxes penile corpus cavernosum muscle in organ bath experiments. Materials and methods. Changes in tension of cavernous smooth muscle strips were determined by penile strip chamber model and in penile perfusion model. Isolated endothelium-intact rabbit corpus cavernosum was precontracted with phenylephrine (PE and then treated with ESB. Results. ESB relaxed penile smooth muscle in a dose-dependent manner, and this was inhibited by pre-treatment with NG-nitro-l-arginine methyl ester (l-NAME, a nitric oxide (NO synthase inhibitor, and 1H-[1, 2, 4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ, a soluble guanylyl cyclase (sGC inhibitor. ESB-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA, a nonselective K+ channel blocker, and charybdotoxin, a selective Ca2+-dependent K+ channel inhibitor. ESB increased the cGMP levels of rabbit corpus cavernosum in a concentration-dependent manner without changes in cAMP levels. In a perfusion model of penile tissue, ESB also relaxed penile corpus cavernosum smooth muscle in a dose-dependent manner. Conclusion. Taken together, these results suggest that ESB relaxed rabbit cavernous smooth muscle via the NO/cGMP system and Ca2+-sensitive K+ channels in the corpus cavernosum.

  11. Laboratory practical to study the differential innervation pathways of urinary tract smooth muscle.

    Science.gov (United States)

    Rembetski, Benjamin E; Cobine, Caroline A; Drumm, Bernard T

    2018-06-01

    In the mammalian lower urinary tract, there is a reciprocal relationship between the contractile state of the bladder and urethra. As the bladder fills with urine, it remains relaxed to accommodate increases in volume, while the urethra remains contracted to prevent leakage of urine from the bladder to the exterior. Disruptions to the normal contractile state of the bladder and urethra can lead to abnormal micturition patterns and urinary incontinence. While both the bladder and urethra are smooth-muscle organs, they are differentially contracted by input from cholinergic and sympathetic nerves, respectively. The laboratory practical described here provides an experiential approach to understanding the anatomy of the lower urinary tract. Several key factors in urinary tract physiology are outlined, e.g., the bladder is contracted by activation of the parasympathetic pathway via cholinergic stimulation on muscarinic receptors, whereas the urethra is contracted by activation of the sympathetic pathway via adrenergic stimulation on α 1 -adrenoceptors. This is achieved by measuring the force generated by bladder and urethra smooth muscle to demonstrate that acetylcholine contracts the smooth muscle of the bladder, whereas adrenergic agonists contract the urethral smooth muscle. An inhibition of these effects is also demonstrated by application of the muscarinic receptor antagonist atropine and the α 1 -adrenergic receptor blocker phentolamine. A list of suggested techniques and exam questions to evaluate student understanding on this topic is also provided.

  12. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

    Science.gov (United States)

    Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1–4 Hz) to θ (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  13. Possible association of norepinephrine transporter -3081(A/T polymorphism with methylphenidate response in attention deficit hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Shin Min-Sup

    2010-10-01

    Full Text Available Abstract Background Attention-deficit/hyperactivity disorder (ADHD is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH has been shown to block the norepinephrine transporter (NET, and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2 is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T and G1287A polymorphisms with MPH response in ADHD. Methods This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I score, and the ADHD Rating Scale-IV (ARS score was also assessed at baseline and 8 weeks after MPH treatment. Results We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes at the -3081(A/T polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment. Conclusion Our findings provide evidence for the involvement of the -3081(A/T polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.

  14. Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

    International Nuclear Information System (INIS)

    Wilson, Alan A.; Patrick Johnson, David; Mozley, David; Hussey, Doug; Ginovart, Nathalie; Nobrega, Jose; Garcia, Armando; Meyer, Jeffery; Houle, Sylvain

    2003-01-01

    The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific activity. These radiotracers are close analogues of reboxetine, a potent and selective ligand for the norepinephrine transporter (NET). They were examined as potential ligands for imaging NET in vivo by positron emission tomography (PET). The in vivo brain distribution of both [ 11 C]-labeled enantiomers were evaluated in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain uptake and washout of radioactivity was homogeneous at all time points examined (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a heterogeneous distribution of radioactivity in brain with highest uptake in the hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved at 60 min post injection of (S,S)-[ 11 C]-MeNER. Pre-injection of the norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced hypothalamus to striatum ratios to near unity while reuptake inhibitors of dopamine and serotonin had no significant effect on binding. In vitro autoradiography studies (rat brain slices) with (S,S)-[ 11 C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[ 11 C]-MeNER has the potential to be the first successful PET ligand to image NET

  15. Dextroamphetamine (but Not Atomoxetine Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    Directory of Open Access Journals (Sweden)

    Jonathan D Kenny

    Full Text Available Methylphenidate induces reanimation (active emergence from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each. When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6. After a single dose of propofol (8 mg/kg i.v., the mean emergence times for rats that received normal saline (vehicle and dextroamphetamine (1 mg/kg i.v. were 641 sec and 404 sec, respectively (n = 8 each. The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8, this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz to θ (4-8 Hz during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation

  16. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    Science.gov (United States)

    Kenny, Jonathan D; Taylor, Norman E; Brown, Emery N; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  17. Mechanism of norepinephrine release elicited by renal nerve stimulation, veratridine and potassium chloride in the isolated rat kidney

    International Nuclear Information System (INIS)

    el-Din, M.M.; Malik, K.U.

    1987-01-01

    We have investigated the mechanism by which renal nerve stimulation (RNS), veratridine (Vt) and KCl promote release of norepinephrine in the isolated rat kidney perfused with Tyrode's solution and prelabeled with [ 3 H]norepinephrine by examining the overflow of tritium elicited by these stimuli during 1) extracellular Ca++ depletion, 2) alterations in extracellular Na+ concentration and 3) administration of tetrodotoxin, amiloride, LiCl and calcium channel blockers. RNS (1-4 Hz), Vt (15-90 nmol) and KCl (150-500 mumol) produced renal vasoconstriction and enhanced the tritium overflow in a frequency- and concentration-dependent manner, respectively. Omission of Ca++ (1.8 mM) from the perfusion fluid abolished the renal vasoconstriction and the increase in tritium overflow elicited by RNA and KCl and substantially reduced that caused by Vt. Lowering the Na+ concentration in the perfusion medium (from 150 to 25 mM) reduced the overflow of tritium and the renal vasoconstriction caused by RNS (2 Hz) or Vt (45 nmol); the increase in tritium overflow in response to these stimuli was positively correlated with extracellular Na+ (25-150 mM). In contrast, KCl-induced tritium overflow was negatively correlated with extracellular Na+ concentration. Tetrodotoxin (0.3 microM) abolished the effect of RNS and Vt, but not that of KCl, to increase overflow of tritium and to produce renal vasoconstriction. Administration of amiloride (180 microM) enhanced the overflow of tritium but attenuated the associated renal vasoconstriction produced by RNS, Vt and KCl. Replacement of NaCl (75 mM) with equimolar concentration of LiCl enhanced the overflow of tritium elicited by RNS, Vt and KCl; the associated renal vasoconstriction remained unaltered

  18. Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Alan A. E-mail: aaw@camhpet.on.ca; Patrick Johnson, David; Mozley, David; Hussey, Doug; Ginovart, Nathalie; Nobrega, Jose; Garcia, Armando; Meyer, Jeffery; Houle, Sylvain

    2003-02-01

    The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific activity. These radiotracers are close analogues of reboxetine, a potent and selective ligand for the norepinephrine transporter (NET). They were examined as potential ligands for imaging NET in vivo by positron emission tomography (PET). The in vivo brain distribution of both [{sup 11}C]-labeled enantiomers were evaluated in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain uptake and washout of radioactivity was homogeneous at all time points examined (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a heterogeneous distribution of radioactivity in brain with highest uptake in the hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved at 60 min post injection of (S,S)-[{sup 11}C]-MeNER. Pre-injection of the norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced hypothalamus to striatum ratios to near unity while reuptake inhibitors of dopamine and serotonin had no significant effect on binding. In vitro autoradiography studies (rat brain slices) with (S,S)-[{sup 11}C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[{sup 11}C]-MeNER has the potential to be the first successful PET ligand to image NET.

  19. Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

    Science.gov (United States)

    Rosa, Jessica; Myskiw, Jociane C; Furini, Cristiane R G; Sapiras, Gerson G; Izquierdo, Ivan

    2014-09-01

    We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Isotropic Growth of Graphene toward Smoothing Stitching.

    Science.gov (United States)

    Zeng, Mengqi; Tan, Lifang; Wang, Lingxiang; Mendes, Rafael G; Qin, Zhihui; Huang, Yaxin; Zhang, Tao; Fang, Liwen; Zhang, Yanfeng; Yue, Shuanglin; Rümmeli, Mark H; Peng, Lianmao; Liu, Zhongfan; Chen, Shengli; Fu, Lei

    2016-07-26

    The quality of graphene grown via chemical vapor deposition still has very great disparity with its theoretical property due to the inevitable formation of grain boundaries. The design of single-crystal substrate with an anisotropic twofold symmetry for the unidirectional alignment of graphene seeds would be a promising way for eliminating the grain boundaries at the wafer scale. However, such a delicate process will be easily terminated by the obstruction of defects or impurities. Here we investigated the isotropic growth behavior of graphene single crystals via melting the growth substrate to obtain an amorphous isotropic surface, which will not offer any specific grain orientation induction or preponderant growth rate toward a certain direction in the graphene growth process. The as-obtained graphene grains are isotropically round with mixed edges that exhibit high activity. The orientation of adjacent grains can be easily self-adjusted to smoothly match each other over a liquid catalyst with facile atom delocalization due to the low rotation steric hindrance of the isotropic grains, thus achieving the smoothing stitching of the adjacent graphene. Therefore, the adverse effects of grain boundaries will be eliminated and the excellent transport performance of graphene will be more guaranteed. What is more, such an isotropic growth mode can be extended to other types of layered nanomaterials such as hexagonal boron nitride and transition metal chalcogenides for obtaining large-size intrinsic film with low defect.

  1. Smooth Tubercle Bacilli: Neglected Opportunistic Tropical Pathogens

    Directory of Open Access Journals (Sweden)

    Djaltou eAboubaker

    2016-01-01

    Full Text Available Smooth tubercle bacilli (STB including ‘‘Mycobacterium canettii’’ are members of the Mycobacterium tuberculosis complex (MTBC which cause non-contagious tuberculosis in human. This group comprises less than one hundred isolates characterized by smooth colonies and cordless organisms. Most STB isolates have been obtained from patients exposed to the Republic of Djibouti but seven isolates, including the three seminal ones obtained by Georges Canetti between 1968 and 1970, were recovered from patients in France, Madagascar, Sub-Sahara East Africa and French Polynesia. STB form a genetically heterogeneous group of MTBC organisms with large 4.48 ± 0.05 Mb genomes which may link Mycobacterium kansasii to MTBC organisms. Lack of inter-human transmission suggested a yet unknown environmental reservoir. Clinical data indicate a respiratory tract route of contamination and the digestive tract as an alternative route of contamination. Further epidemiological and clinical studies are warranted to elucidate areas of uncertainty regarding these unusual mycobacteria and the tuberculosis they cause.

  2. Snap evaporation of droplets on smooth topographies.

    Science.gov (United States)

    Wells, Gary G; Ruiz-Gutiérrez, Élfego; Le Lirzin, Youen; Nourry, Anthony; Orme, Bethany V; Pradas, Marc; Ledesma-Aguilar, Rodrigo

    2018-04-11

    Droplet evaporation on solid surfaces is important in many applications including printing, micro-patterning and cooling. While seemingly simple, the configuration of evaporating droplets on solids is difficult to predict and control. This is because evaporation typically proceeds as a "stick-slip" sequence-a combination of pinning and de-pinning events dominated by static friction or "pinning", caused by microscopic surface roughness. Here we show how smooth, pinning-free, solid surfaces of non-planar topography promote a different process called snap evaporation. During snap evaporation a droplet follows a reproducible sequence of configurations, consisting of a quasi-static phase-change controlled by mass diffusion interrupted by out-of-equilibrium snaps. Snaps are triggered by bifurcations of the equilibrium droplet shape mediated by the underlying non-planar solid. Because the evolution of droplets during snap evaporation is controlled by a smooth topography, and not by surface roughness, our ideas can inspire programmable surfaces that manage liquids in heat- and mass-transfer applications.

  3. Overexpression of functional TrkA receptors after internalisation in human airway smooth muscle cells.

    Science.gov (United States)

    Freund-Michel, Véronique; Frossard, Nelly

    2008-10-01

    Trafficking of the TrkA receptor after stimulation by NGF is of emerging importance in structural cells in the context of airway inflammatory diseases. We have recently reported the expression of functional TrkA receptors in human airway smooth muscle cells (HASMC). We have here studied the TrkA trafficking mechanisms in these cells. TrkA disappearance from the cell membrane was induced within 5 min of NGF (3pM) stimulation. Co-immunoprecipitation of clathrin-TrkA was revealed, and TrkA internalisation inhibited either by clathrin inhibitors or by siRNA inducing downregulation of endogenous clathrin. TrkA internalised receptors were totally degraded in lysosomes, with no recycling phenomenon. Newly synthesized TrkA receptors were thereafter re-expressed at the cell membrane within 10 h. TrkA re-synthesis was inhibited by blockade of clathrin-dependent internalisation, but not of TrkA receptors lysosomal degradation. Finally, we observed that NGF multiple stimulations progressively increased TrkA expression in HASMC, which was associated with an increase in NGF/TrkA-dependent proliferation. In conclusion, we show here the occurrence of clathrin-dependent TrkA internalisation and lysosomal degradation in the airway smooth muscle, followed by upregulated re-synthesis of functional TrkA receptors and increased proliferative effect in the human airway smooth muscle. This may have pathophysiological consequences in airway inflammatory diseases.

  4. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Directory of Open Access Journals (Sweden)

    Udvardi PT

    2013-12-01

    Full Text Available Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip] or saline (0.9%, ip for 21 consecutive days on postnatal days (PND 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR, mesencephalon (MES, and hippocampus (HC was analyzed either directly after treatment (PND 42 or 2 months after termination of treatment (PND 101 to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects

  5. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Science.gov (United States)

    Udvardi, Patrick T; Föhr, Karl J; Henes, Carolin; Liebau, Stefan; Dreyhaupt, Jens; Boeckers, Tobias M; Ludolph, Andrea G

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of

  6. Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2 in ADHD: relation to maternal smoking during pregnancy.

    Directory of Open Access Journals (Sweden)

    Geeta A Thakur

    Full Text Available Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.Children (6-12 years old diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT, including categorical and quantitative trait analyses, were conducted in 377 nuclear families.A highly significant association was observed with rs36021 (and linked SNPs in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002, behavioral assessments by parents (CBCL, P=0.00008, as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006 and parents (P=0.006. In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001, parents (Z=2.62, P=0.009, as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003.By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical

  7. Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.

    Directory of Open Access Journals (Sweden)

    Kenji Suita

    Full Text Available Atrial fibrillation (AF is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR subtypes, which may be involved in the onset and duration of AF.Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0 ± 8.1 sec. We found that adrenergic activation by intraperitoneal norepinephrine (NE injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2 ± 104.8 sec; P<0.001. In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors' effects on AF, we assessed the SR Ca(2+ leak, a major trigger of AF, and consequent spontaneous SR Ca(2+ release (SCR in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca(2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

  8. The Locus Coeruleus–Norepinephrine System Mediates Empathy for Pain through Selective Up-Regulation of P2X3 Receptor in Dorsal Root Ganglia in Rats

    Directory of Open Access Journals (Sweden)

    Yun-Fei Lü

    2017-09-01

    Full Text Available Empathy for pain (vicariously felt pain, an ability to feel, recognize, understand and share the painful emotions of others, has been gradually accepted to be a common identity in both humans and rodents, however, the underlying neural and molecular mechanisms are largely unknown. Recently, we have developed a rat model of empathy for pain in which pain can be transferred from a cagemate demonstrator (CD in pain to a naïve cagemate observer (CO after 30 min dyadic priming social interaction. The naïve CO rats display both mechanical pain hypersensitivity (hyperalgesia and enhanced spinal nociception. Chemical lesions of bilateral medial prefrontal cortex (mPFC abolish the empathic pain response completely, suggesting existence of a top-down facilitation system in production of empathy for pain. However, the social transfer of pain was not observed in non-cagemate observer (NCO after dyadic social interaction with a non-cagemate demonstrator (NCD in pain. Here we showed that dyadic social interaction with a painful CD resulted in elevation of circulating norepinephrine (NE and increased neuronal activity in the locus coeruleus (LC in the CO rats. Meanwhile, CO rats also had over-expression of P2X3, but not TRPV1, in the dorsal root ganglia (DRG. Chemical lesion of the LC-NE neurons by systemic DSP-4 and pharmacological inhibition of central synaptic release of NE by clonidine completely abolished increase in circulating NE and P2X3 receptor expression, as well as the sympathetically-maintained development of empathic mechanical hyperalgesia. However, in the NCO rats, neither the LC-NE neuronal activity nor the P2X3 receptor expression was altered after dyadic social interaction with a painful NCD although the circulating corticosterone and NE were elevated. Finally, in the periphery, both P2X3 receptor and α1 adrenergic receptor were found to be involved in the development of empathic mechanical hyperalgesia. Taken together with our previous

  9. Smoothness without smoothing: why Gaussian naive Bayes is not naive for multi-subject searchlight studies.

    Directory of Open Access Journals (Sweden)

    Rajeev D S Raizada

    Full Text Available Spatial smoothness is helpful when averaging fMRI signals across multiple subjects, as it allows different subjects' corresponding brain areas to be pooled together even if they are slightly misaligned. However, smoothing is usually not applied when performing multivoxel pattern-based analyses (MVPA, as it runs the risk of blurring away the information that fine-grained spatial patterns contain. It would therefore be desirable, if possible, to carry out pattern-based analyses which take unsmoothed data as their input but which produce smooth images as output. We show here that the Gaussian Naive Bayes (GNB classifier does precisely this, when it is used in "searchlight" pattern-based analyses. We explain why this occurs, and illustrate the effect in real fMRI data. Moreover, we show that analyses using GNBs produce results at the multi-subject level which are statistically robust, neurally plausible, and which replicate across two independent data sets. By contrast, SVM classifiers applied to the same data do not generate a replication, even if the SVM-derived searchlight maps have smoothing applied to them. An additional advantage of GNB classifiers for searchlight analyses is that they are orders of magnitude faster to compute than more complex alternatives such as SVMs. Collectively, these results suggest that Gaussian Naive Bayes classifiers may be a highly non-naive choice for multi-subject pattern-based fMRI studies.

  10. Adrenergic manipulation inhibits pavlovian conditioned approach behaviors.

    Science.gov (United States)

    Pasquariello, Kyle Z; Han, Marina; Unal, Cagla; Meyer, Paul J

    2018-02-26

    Environmental rewards and Pavlovian reward cues can acquire incentive salience, thereby eliciting incentive motivational states and instigate reward-seeking. In rats, the incentive salience of food cues can be measured during a Pavlovian conditioned approach paradigm, in which rats engage in cue-directed approach ("sign-tracking") or approach the food delivery location ("goal-tracking"). While it has been shown that dopamine signaling is necessary for sign-tracking, some studies have suggested that norepinephrine is involved in learning to sign-track as well. Thus, in order to investigate the influence of norepinephrine in Pavlovian conditioned approach, we administered three adrenergic drugs while rats learned that a food cue (an illuminated, retractable lever) preceded the delivery of banana-flavored food pellets into a food-cup. We found that pre-session injections of disulfiram (a dopamine-β-hydroxylase inhibitor) inhibited the development of sign-tracking, but goal-tracking was only affected at the high dose. In one experiment, post-session injections of disulfiram blocked the development of sign-tracking, although this effect was not replicated in a separate set of rats. Post-session injections of prazosin (an α1-adrenergic receptor antagonist) and propranolol (a β-adrenergic receptor antagonist) also blocked the development of sign-tracking but not goal-tracking. Taken together, these results suggest that adrenergic transmission mediates the acquisition of sign-tracking but not goal-tracking, and thus plays a selective role in the attribution of incentive salience food cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Smooth function approximation using neural networks.

    Science.gov (United States)

    Ferrari, Silvia; Stengel, Robert F

    2005-01-01

    An algebraic approach for representing multidimensional nonlinear functions by feedforward neural networks is presented. In this paper, the approach is implemented for the approximation of smooth batch data containing the function's input, output, and possibly, gradient information. The training set is associated to the network adjustable parameters by nonlinear weight equations. The cascade structure of these equations reveals that they can be treated as sets of linear systems. Hence, the training process and the network approximation properties can be investigated via linear algebra. Four algorithms are developed to achieve exact or approximate matching of input-output and/or gradient-based training sets. Their application to the design of forward and feedback neurocontrollers shows that algebraic training is characterized by faster execution speeds and better generalization properties than contemporary optimization techniques.

  12. Smooth driving of Moessbauer electromechanical transducers

    Energy Technology Data Exchange (ETDEWEB)

    Veiga, A., E-mail: veiga@fisica.unlp.edu.ar; Mayosky, M. A. [Universidad Nacional de La Plata, Facultad de Ingenieria (Argentina); Martinez, N.; Mendoza Zelis, P.; Pasquevich, G. A.; Sanchez, F. H. [Instituto de Fisica La Plata, CONICET (Argentina)

    2011-11-15

    Quality of Moessbauer spectra is strongly related to the performance of source velocity modulator. Traditional electromechanical driving techniques demand hard-edged square or triangular velocity waveforms that introduce long settling times and demand careful driver tuning. For this work, the behavior of commercial velocity transducers and drive units was studied under different working conditions. Different velocity reference waveforms in constant-acceleration, constant-velocity and programmable-velocity techniques were tested. Significant improvement in spectrometer efficiency and accuracy was achieved by replacing triangular and square hard edges with continuous smooth-shaped transitions. A criterion for best waveform selection and synchronization is presented and attainable enhancements are evaluated. In order to fully exploit this driving technique, a compact microprocessor-based architecture is proposed and a suitable data acquisition system implementation is presented. System linearity and efficiency characterization are also shown.

  13. Smooth muscle cell phenotypic switching in stroke.

    Science.gov (United States)

    Poittevin, Marine; Lozeron, Pierre; Hilal, Rose; Levy, Bernard I; Merkulova-Rainon, Tatiana; Kubis, Nathalie

    2014-06-01

    Disruption of cerebral blood flow after stroke induces cerebral tissue injury through multiple mechanisms that are not yet fully understood. Smooth muscle cells (SMCs) in blood vessel walls play a key role in cerebral blood flow control. Cerebral ischemia triggers these cells to switch to a phenotype that will be either detrimental or beneficial to brain repair. Moreover, SMC can be primarily affected genetically or by toxic metabolic molecules. After stroke, this pathological phenotype has an impact on the incidence, pattern, severity, and outcome of the cerebral ischemic disease. Although little research has been conducted on the pathological role and molecular mechanisms of SMC in cerebrovascular ischemic diseases, some therapeutic targets have already been identified and could be considered for further pharmacological development. We examine these different aspects in this review.

  14. Smoothed Particle Hydrodynamics Coupled with Radiation Transfer

    Science.gov (United States)

    Susa, Hajime

    2006-04-01

    We have constructed a brand-new radiation hydrodynamics solver based upon Smoothed Particle Hydrodynamics, which works on a parallel computer system. The code is designed to investigate the formation and evolution of first-generation objects at z ≳ 10, where the radiative feedback from various sources plays important roles. The code can compute the fraction of chemical species e, H+, H, H-, H2, and H+2 by by fully implicit time integration. It also can deal with multiple sources of ionizing radiation, as well as radiation at Lyman-Werner band. We compare the results for a few test calculations with the results of one-dimensional simulations, in which we find good agreements with each other. We also evaluate the speedup by parallelization, which is found to be almost ideal, as long as the number of sources is comparable to the number of processors.

  15. Viscoplastic augmentation of the smooth cap model

    International Nuclear Information System (INIS)

    Schwer, Leonard E.

    1994-01-01

    The most common numerical viscoplastic implementations are formulations attributed to Perzyna. Although Perzyna-type algorithms are popular, they have several disadvantages relating to the lack of enforcement of the consistency condition in plasticity. The present work adapts a relatively unknown viscoplastic formulation attributed to Duvaut and Lions and generalized to multi-surface plasticity by Simo et al. The attraction of the Duvaut-Lions formulation is its ease of numerical implementation in existing elastoplastic algorithms. The present work provides a motivation for the Duvaut-Lions viscoplastic formulation, derivation of the algorithm and comparison with the Perzyna algorithm. A simple uniaxial strain numerical simulation is used to compare the results of the Duvaut-Lions algorithm, as adapted to the ppercase[dyna3d] smooth cap model with results from a Perzyna algorithm adapted by Katona and Muleret to an implicit code. ((orig.))

  16. Contruction of a smoothed DEA frontier

    Directory of Open Access Journals (Sweden)

    Mello João Carlos Correia Baptista Soares de

    2002-01-01

    Full Text Available It is known that the DEA multipliers model does not allow a unique solution for the weights. This is due to the absence of unique derivatives in the extreme-efficient points, which is a consequence of the piecewise linear nature of the frontier. In this paper we propose a method to solve this problem, consisting of changing the original DEA frontier for a new one, smooth (with continuous derivatives at every point and closest to the original frontier. We present the theoretical development for the general case, exemplified with the particular case of the BCC model with one input and one output. The 3-dimensional problem is briefly discussed. Some uses of the model are summarised, and one of them, a new Cross-Evaluation model, is presented.

  17. The modulatory effect of substance P on rat pineal norepinephrine release and melatonin secretion

    DEFF Research Database (Denmark)

    Mukda, Sujira; Møller, Morten; Ebadi, Manuchair

    2009-01-01

    innervate the pineal gland. Some of these peptidergic nerve fibers contain substance P. Previously, we have characterized neurokinin 1 type substance P receptors in the pineal gland. However, the function of this receptor in the pineal gland remains unclear. Here, we examined the modulatory effect...... of substance P on rat pineal NE transmission. We show that at the presynaptic level, substance P stimulates the KCl-induced [(3)H]NE release from the pineal nerve ending. However, we found that substance P did not affect the basal levels of either arylalkylamine-N-acetyltransferase (AANAT) activity...... or melatonin secretion in rat pineal organ cultures. However, in the presence of NE, substance P inhibited the NE-induced increase in AANAT activity and melatonin secretion. This is the first time that a function for substance P in the mammalian pineal gland has been demonstrated....

  18. Diffusion tensor smoothing through weighted Karcher means

    Science.gov (United States)

    Carmichael, Owen; Chen, Jun; Paul, Debashis; Peng, Jie

    2014-01-01

    Diffusion tensor magnetic resonance imaging (MRI) quantifies the spatial distribution of water Diffusion at each voxel on a regular grid of locations in a biological specimen by Diffusion tensors– 3 × 3 positive definite matrices. Removal of noise from DTI is an important problem due to the high scientific relevance of DTI and relatively low signal to noise ratio it provides. Leading approaches to this problem amount to estimation of weighted Karcher means of Diffusion tensors within spatial neighborhoods, under various metrics imposed on the space of tensors. However, it is unclear how the behavior of these estimators varies with the magnitude of DTI sensor noise (the noise resulting from the thermal e!ects of MRI scanning) as well as the geometric structure of the underlying Diffusion tensor neighborhoods. In this paper, we combine theoretical analysis, empirical analysis of simulated DTI data, and empirical analysis of real DTI scans to compare the noise removal performance of three kernel-based DTI smoothers that are based on Euclidean, log-Euclidean, and affine-invariant metrics. The results suggest, contrary to conventional wisdom, that imposing a simplistic Euclidean metric may in fact provide comparable or superior noise removal, especially in relatively unstructured regions and/or in the presence of moderate to high levels of sensor noise. On the contrary, log-Euclidean and affine-invariant metrics may lead to better noise removal in highly structured anatomical regions, especially when the sensor noise is of low magnitude. These findings emphasize the importance of considering the interplay of sensor noise magnitude and tensor field geometric structure when assessing Diffusion tensor smoothing options. They also point to the necessity for continued development of smoothing methods that perform well across a large range of scenarios. PMID:25419264

  19. Nuclear import mechanism for myocardin family members and their correlation with vascular smooth muscle cell phenotype.

    Science.gov (United States)

    Nakamura, Seiji; Hayashi, Ken'ichiro; Iwasaki, Kazuhiro; Fujioka, Tomoaki; Egusa, Hiroshi; Yatani, Hirofumi; Sobue, Kenji

    2010-11-26

    Myocardin (Mycd), which is essential for the differentiation of the smooth muscle cell lineage, is constitutively located in the nucleus, although its family members, myocardin-related transcription factors A and B (MRTF-A/B), mostly reside in the cytoplasm and translocate to the nucleus in response to Rho signaling. The mechanism for their nuclear import is unclear. Here we investigated the mechanism for the nuclear import of Mycd family members and demonstrated any correlation between such mechanism and the phenotype of vascular smooth muscle cells (VSMCs). In cultured VSMCs, the knockdown of importin β1 inhibited the nuclear import of Mycd and MRTF-A/B. Their NH(2)-terminal basic domain was identified as a binding site for importin α/β1 by in vitro analyses. However, Mycd had a higher affinity for importin α/β1 than did MRTF-A/B, even in the absence of G-actin, and Mycd affinity for importin α1/β1 was stronger than for any other importin α/β1 heterodimers. The binding of Mycd to importin α/β1 was insensitive to G-actin, whereas that of MRTF-A/B was differently inhibited by G-actin. In dedifferentiated VSMCs, the levels of importins α1 and β1 were reduced concomitant with down-regulation of Mycd, serum response factor, and smooth muscle cell markers. By contrast, in differentiated VSMCs, their expressions were up-regulated. Thus, the nuclear import of Mycd family members in VSMCs depends on importin α/β1, and their relative affinities for importin α/β1 heterodimers determine Mycd nuclear import. The expression of Mycd nuclear import machineries is related to the expression levels of VSMC phenotype-dependent smooth muscle cell markers.

  20. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  1. Human lung mast cells modulate the functions of airway smooth muscle cells in asthma.

    Science.gov (United States)

    Alkhouri, H; Hollins, F; Moir, L M; Brightling, C E; Armour, C L; Hughes, J M

    2011-09-01

    Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma. © 2011 John Wiley & Sons A/S.

  2. β-adrenergic receptor binding characteristics and responsiveness in cultured Wistar-Kyoto rat arterial smooth muscle cells

    International Nuclear Information System (INIS)

    Jazayeri, A.; Meyer, W.J. III

    1988-01-01

    The tone of arterial blood vessels is regulated by the catecholamines through their receptors on arterial smooth muscle cells (ASMC). β- 2 -adrenergic receptors of ASMC mediate vasodilation through agonist mediated c-AMP production. Previous reports have described these receptors on freshly isolated blood vessels. This study demonstrates the presence of β 2 -adrenergic receptors on cultured rat ASMC and that these receptors are functional. β-adrenergic receptor binding was measured using [ 3 H]-dihydroalprenolol (DHA) binding to the membrane of cultured ASMC from normotensive Wistar-Kyoto rats. The ASMC β-adrenergic receptors have a Kd of 0.56 +/- 0.16 nM and a Bmax of 57.2 +/- 21.7 fmol/mg protein. Competition binding studies revealed a much greater affinity of these receptors for epinephrine than norepinephrine, indicating the preponderance of a β 2 -adrenergic receptor subtype. Isoproterenol stimulation of cultured ASMC resulted in a 14 +/- 7 fold increase in intracellular c-AMP content of these cells indicating these receptors are functional. β-adrenergic receptors of cultured ASMC provide an excellent system in which the association between hypertension and observed β-adrenergic receptor differences can be further explored

  3. Bifurcation theory for finitely smooth planar autonomous differential systems

    Science.gov (United States)

    Han, Maoan; Sheng, Lijuan; Zhang, Xiang

    2018-03-01

    In this paper we establish bifurcation theory of limit cycles for planar Ck smooth autonomous differential systems, with k ∈ N. The key point is to study the smoothness of bifurcation functions which are basic and important tool on the study of Hopf bifurcation at a fine focus or a center, and of Poincaré bifurcation in a period annulus. We especially study the smoothness of the first order Melnikov function in degenerate Hopf bifurcation at an elementary center. As we know, the smoothness problem was solved for analytic and C∞ differential systems, but it was not tackled for finitely smooth differential systems. Here, we present their optimal regularity of these bifurcation functions and their asymptotic expressions in the finite smooth case.

  4. Impact of spectral smoothing on gamma radiation portal alarm probabilities

    International Nuclear Information System (INIS)

    Burr, T.; Hamada, M.; Hengartner, N.

    2011-01-01

    Gamma detector counts are included in radiation portal monitors (RPM) to screen for illicit nuclear material. Gamma counts are sometimes smoothed to reduce variance in the estimated underlying true mean count rate, which is the 'signal' in our context. Smoothing reduces total error variance in the estimated signal if the bias that smoothing introduces is more than offset by the variance reduction. An empirical RPM study for vehicle screening applications is presented for unsmoothed and smoothed gamma counts in low-resolution plastic scintillator detectors and in medium-resolution NaI detectors. - Highlights: → We evaluate options for smoothing counts from gamma detectors deployed for portal monitoring. → A new multiplicative bias correction (MBC) is shown to reduce bias in peak and valley regions. → Performance is measured using mean squared error and detection probabilities for sources. → Smoothing with the MBC improves detection probabilities and the mean squared error.

  5. Six-term exact sequences for smooth generalized crossed products

    DEFF Research Database (Denmark)

    Gabriel, Olivier; Grensing, Martin

    2013-01-01

    We define smooth generalized crossed products and prove six-term exact sequences of Pimsner–Voiculescu type. This sequence may, in particular, be applied to smooth subalgebras of the quantum Heisenberg manifolds in order to compute the generators of their cyclic cohomology. Further, our results...... include the known results for smooth crossed products. Our proof is based on a combination of arguments from the setting of (Cuntz–)Pimsner algebras and the Toeplitz proof of Bott periodicity....

  6. Star Products with Separation of Variables Admitting a Smooth Extension

    Science.gov (United States)

    Karabegov, Alexander

    2012-08-01

    Given a complex manifold M with an open dense subset Ω endowed with a pseudo-Kähler form ω which cannot be smoothly extended to a larger open subset, we consider various examples where the corresponding Kähler-Poisson structure and a star product with separation of variables on (Ω, ω) admit smooth extensions to M. We give a simple criterion of the existence of a smooth extension of a star product and apply it to these examples.

  7. Star products with separation of variables admitting a smooth extension

    OpenAIRE

    Karabegov, Alexander

    2010-01-01

    Given a complex manifold $M$ with an open dense subset $\\Omega$ endowed with a pseudo-Kaehler form $\\omega$ which cannot be smoothly extended to a larger open subset, we consider various examples where the corresponding Kaehler-Poisson structure and a star product with separation of variables on $(\\Omega, \\omega)$ admit smooth extensions to $M$. We suggest a simple criterion of the existence of a smooth extension of a star product and apply it to these examples.

  8. Fast compact algorithms and software for spline smoothing

    CERN Document Server

    Weinert, Howard L

    2012-01-01

    Fast Compact Algorithms and Software for Spline Smoothing investigates algorithmic alternatives for computing cubic smoothing splines when the amount of smoothing is determined automatically by minimizing the generalized cross-validation score. These algorithms are based on Cholesky factorization, QR factorization, or the fast Fourier transform. All algorithms are implemented in MATLAB and are compared based on speed, memory use, and accuracy. An overall best algorithm is identified, which allows very large data sets to be processed quickly on a personal computer.

  9. Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder.

    Science.gov (United States)

    Kim, Bung-Nyun; Kim, Jae-Won; Cummins, Tarrant D R; Bellgrove, Mark A; Hawi, Ziarih; Hong, Soon-Beom; Yang, Young-Hui; Kim, Hyo-Jin; Shin, Min-Sup; Cho, Soo-Churl; Kim, Ji-Hoon; Son, Jung-Woo; Shin, Yun-Mi; Chung, Un-Sun; Han, Doug-Hyun

    2013-06-01

    Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time

  10. Influence of neonatal and adult hyperthyroidism on behavior and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain.

    Science.gov (United States)

    Rastogi, R B; Singhal, R L

    1976-09-01

    In neonatal rats, administration of l-triiodothyronine (10 mug/100 g/day) for 30 days presented signs of hyperthyroidism which included accelerated development of a variety of physical and behavioral characteristics accompanying maturation. The spontaneous motor activity was increased by 69%. Exposure of developing rats to thyroid hormone significantly increased the endogenous concentration of striatal tyrosine and the activity of tyrosine hydroxylase as well as the levels of dopamine in several brain regions. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid, the chief metabolites of dopamine, was also increased and the magnitude of change was greater than the rise in dopamine. Despite increases in the activity of tyrosine hydroxylase and the availability of the substrate tyrosine, the steady-state levels of norepinephrine remained unaltered in various regions of brain except in cerebellum. Futhermore, neonatal hyperthyroidism significantly increased the levels of midbrain tryptophan and tryptophan hydroxylase activity but produced no change in 5-hydroxytryptamine levels of several discrete brain regions, except hypothalamus and cerebellum where its concentration was slightly decreased. However, the 5-hydroxyindoleacetic acid levels were enhanced in hypothalamus, ponsmedulla, midbrain, striatum and hippocampus. The elevated levels of 5-hydroxyindoleacetic acid did not seem to be due to increased intraneuronal deamination of 5-hydroxytryptamine since monoamine oxidase activity was not affected in cerebral cortex and midbrain of hyperthyroid rats. The data demonstrate that hyperthyroidism significantly increased the synthesis as well as the utilization of catecholamines and 5-hydroxytryptamine in maturing brain. Since the mature brain is known to respond differently to thyroid hormone action than does the developing brain, the effect of L-triiodothyronine treatment on various putative neurohumors also was examined in adult rats

  11. [The predictive value of dynamic arterial elastance in arterial pressure response after norepinephrine dosage reduction in patients with septic shock].

    Science.gov (United States)

    Liang, F M; Yang, T; Dong, L; Hui, J J; Yan, J

    2017-05-01

    Objective: To assess whether dynamic arterial elastance(Ea(dyn))can be used to predict the reduction of arterial pressure after decreasing norepinephrine (NE) dosage in patients with septic shock. Methods: A prospective observational cohort study was conducted. Thirty-two patients with septic shock and mechanical ventilationwere enrolledfrom January 2014 to December 2015 in ICU of Wuxi People's Hospital of Nanjing Medical University. Hemodynamic parameters were recorded by pulse contour cardiac output(PiCCO)monitoring technology before and after decreasing norepinephrine dosage. Ea(dyn) was defined as the ratio of pulse pressure variation (PPV) to stroke volume variation (SVV). Mean arterial pressure(MAP) variation was calculated after decreasing the dose of NE. Response was defined as a ≥15% decrease of MAP. AUC was plotted to assess the value of Ea(dyn) in predicting MAP response. Results: A total of 32 patients were enrolled in our study, with 13 responding to NE dose decrease where as the other 19 did not. Ea(dyn) was lower in responders than in nonresponders (0.77±0.13 vs 1.09±0.31, P blood pressure variation, diastolic blood pressure variation, systemic vascular resistance variation and MAP variation( r =0.621, P =0.000; r =0.735, P =0.000; r =0.756, P =0.000; r =0.568, P =0.000 respectively). However, stoke volume variation, baseline level of systemic vascular resistance and NE baseline dose were not correlated with Ea(dyn) baseline value( r =0.264, P =0.076; r =0.078, P =0.545; r =0.002, P =0.987 respectively). Ea(dyn)≤0.97 predicted a decrease of MAP when decreasing NE dose, with an area under the receiver-operating characteristic curve of 0.85.The sensitivity was 100.0% and specificity was 73.7%. Conclusions: In septic shock patients treated with NE, Ea(dyn) is an index to predict the decrease of arterial pressure in response to NE dose reduction.

  12. The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

    Science.gov (United States)

    Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

    2016-02-01

    Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

  13. Sizing of Energy Storage Systems for Output Smoothing of Renewable Energy Systems

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    Renewable energy sources (RESs), such as photovoltaic (PV) and wind power generation, have the characteristics of random fluctuation and intermittence. The output of RESs should be smoothed to inhibit the adverse effects of RESs fluctuations on the power grid. The energy storage system (ESS) is playing a more and more important role in the application of RESs due to its discharge/charge characteristic. Therefore, the optimal planning and design of ESS is of vital importance because of the expensive cost of ESS.

  14. Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment.

    Science.gov (United States)

    Zhang, Rong; Jack, Gregory S; Rao, Nagesh; Zuk, Patricia; Ignarro, Louis J; Wu, Benjamin; Rodríguez, Larissa V

    2012-03-01

    Human adipose-derived stem cells hASC have been isolated and were shown to have multilineage differentiation capacity. Although both plasticity and cell fusion have been suggested as mechanisms for cell differentiation in vivo, the effect of the local in vivo environment on the differentiation of adipose-derived stem cells has not been evaluated. We previously reported the in vitro capacity of smooth muscle differentiation of these cells. In this study, we evaluate the effect of an in vivo smooth muscle environment in the differentiation of hASC. We studied this by two experimental designs: (a) in vivo evaluation of smooth muscle differentiation of hASC injected into a smooth muscle environment and (b) in vitro evaluation of smooth muscle differentiation capacity of hASC exposed to bladder smooth muscle cells. Our results indicate a time-dependent differentiation of hASC into mature smooth muscle cells when these cells are injected into the smooth musculature of the urinary bladder. Similar findings were seen when the cells were cocultured in vitro with primary bladder smooth muscle cells. Chromosomal analysis demonstrated that microenvironment cues rather than nuclear fusion are responsible for this differentiation. We conclude that cell plasticity is present in hASCs, and their differentiation is accomplished in the absence of nuclear fusion. Copyright © 2011 AlphaMed Press.

  15. An implicit Smooth Particle Hydrodynamic code

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, Charles E. [Univ. of New Mexico, Albuquerque, NM (United States)

    2000-05-01

    An implicit version of the Smooth Particle Hydrodynamic (SPH) code SPHINX has been written and is working. In conjunction with the SPHINX code the new implicit code models fluids and solids under a wide range of conditions. SPH codes are Lagrangian, meshless and use particles to model the fluids and solids. The implicit code makes use of the Krylov iterative techniques for solving large linear-systems and a Newton-Raphson method for non-linear corrections. It uses numerical derivatives to construct the Jacobian matrix. It uses sparse techniques to save on memory storage and to reduce the amount of computation. It is believed that this is the first implicit SPH code to use Newton-Krylov techniques, and is also the first implicit SPH code to model solids. A description of SPH and the techniques used in the implicit code are presented. Then, the results of a number of tests cases are discussed, which include a shock tube problem, a Rayleigh-Taylor problem, a breaking dam problem, and a single jet of gas problem. The results are shown to be in very good agreement with analytic solutions, experimental results, and the explicit SPHINX code. In the case of the single jet of gas case it has been demonstrated that the implicit code can do a problem in much shorter time than the explicit code. The problem was, however, very unphysical, but it does demonstrate the potential of the implicit code. It is a first step toward a useful implicit SPH code.

  16. The influence of norepinephrine and phenylephrine on cerebral perfusion and oxygenation during propofol-remifentanil and propofol-remifentanil-dexmedetomidine anaesthesia in piglets

    DEFF Research Database (Denmark)

    Mikkelsen, Mai Louise Grandsgaard; Ambrus, Rikard; Rasmussen, Rune

    2018-01-01

    of dexmedetomidine. Cerebral perfusion measured by laser speckle contrast imaging was related to cerebral oxygenation as measured by an intracerebral Licox probe (partial pressure of oxygen) and transcranial near infrared spectroscopy technology (NIRS) (cerebral oxygen saturation). Results During propofol......–remifentanil anaesthesia, increases in blood pressure by norepinephrine and phenylephrine did not change cerebral perfusion significantly, but cerebral partial pressure of oxygen (Licox) increased following vasopressors in both groups and increases following norepinephrine were significant (NBP: P = 0.04, LBP: P = 0......–remifentanil–dexmedetomidine anaesthesia was not followed by significant changes in cerebral perfusion. Licox measures increased significantly following both vasopressors in both groups, whereas the decreases in NIRS measures were only significant in the NBP group. Conclusions Cerebral partial pressure of oxygen measured by Licox...

  17. Pavlovian autoshaping procedures increase plasma corticosterone and levels of norepinephrine and serotonin in prefrontal cortex in rats.

    Science.gov (United States)

    Tomie, Arthur; Tirado, Aidaluz D; Yu, Lung; Pohorecky, Larissa A

    2004-08-12

    Pavlovian autoshaping procedures provide for pairings of a small object conditioned stimulus (CS) with a rewarding substance unconditioned stimulus (US), resulting in the acquisition of complex sequences of CS-directed skeletal-motor responses or autoshaping conditioned responses (CRs). Autoshaping procedures induce higher post-session levels of corticosterone than in controls receiving CS and US randomly, and the enhanced post-session corticosterone levels have been attributed to the appetitive or arousal-inducing effects of autoshaping procedures. Enhanced corticosterone release can be induced by aversive stimulation or stressful situations, where it is often accompanied by higher levels of norepinephrine (NE) and serotonin (5-HT) in prefrontal cortex (PFC) but not in striatum (ST). Effects of autoshaping procedures on post-session corticosterone levels, NE contents in PFC, and 5-HT contents in PFC and ST were investigated in male Long-Evans rats. Post-session blood samples revealed higher corticosterone levels in the CS-US Paired group (n = 46) than in the CS-US Random control group (n = 21), and brain samples revealed higher levels of PFC NE and 5-HT in CS-US Paired group. Striatal 5-HT levels were unaltered by the autoshaping procedures. Autoshaping procedures provide for appetitive stimulation and induce an arousal-like state, as well as simultaneous stress-like changes in plasma corticosterone and monoamine levels in PFC. Autoshaping, therefore, may be useful for the study of endocrine and central processes associated with appetitive conditions.

  18. Effect of the alkaloid (-)cathinone on the release of radioactivity from rabbit atria prelabelled with 3H-norepinephrine

    International Nuclear Information System (INIS)

    Kalix, P.

    1983-01-01

    In certain countries of East Africa and the Arab Peninsula, fresh leaves of the khat shrub are used as a stimulant. The effect of the plant material can be explained by the presence of the phenylalklamine alkaloid (-)cathinone in the leaves, since this substance has been shown to have an amphetamine-like releasing effect on CNS tissue prelabelled with 3 H-dopamine. Characteristically, the chewing of khat is accompanied by sympathomimetic effects, especially at the cardiovascular level. To test whether these might be due to release of neurotransmitter from adrenergic nerve endings, the effect of (-)cathinone on the efflux of radioactivity from isolated rabbit atrium tissue prelabelled with 3 H-norepinephrine was investigated. It was found that, at concentrations below 1 μM, (-)cathinone caused an immediate increase of efflux. The effect was dose-dependent and was potentiated by pretreatment of the rabbits with reserpine. Preincubation of the tissue with desipramine and cocaine prevented the induction of release by (-)cathinone. The results indicate that the alkaloid (-)cathinone has an amphetamine-like releasing effect on noradrenergic nerve endings and they suggest that the cardiovascular symptoms observed during khat consumption are due to release of neurotransmitter from physiologicl storage sites

  19. Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence.

    Science.gov (United States)

    Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes, Beverly As; Van Bockstaele, Elisabeth J; Valentino, Rita J

    2013-09-01

    Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

  20. Norepinephrine, {beta}-adrenoceptor and {sup 123}I-MIBG myocardial scintigram in patients with congestive heart failure

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Kenichi; Miyajima, Seiichi; Kusano, Yoriko; Tanabe, Naohito [Tsubame Rosai Hospital, Niigata (Japan); Nagatomo, Takafumi

    1997-06-01

    Authors studied the relationships of norepinephrine (NE), {beta}-adrenoceptor and {sup 123}I-MIBG (meta-iodo-benzylguanidine) uptake in 26 patients with dilated cardiomyopathy or valvulitis. Blood NE concentrations were determined by high performance liquid chromatography in those patients and 10 healthy volunteers, and myocardial NE, in 7 patients and 5 cases without the congestive heart failure. The amounts of beta-receptors in lymphocytes of 21 patients and 7 volunteers and in myocardium obtained at autopsy of 3 patients and 3 other cases were estimated by the radioligand binding assay. Planar and SPECT images were taken at 15 min and 3 hr post intravenous administration of 111 MBq of {sup 123}I-MIBG. In the planar and SPECT images, the ratio heart/mediastinum (H/M) and MIBG uptake were computed respectively. Blood flow was evaluated by {sup 201}Tl scintigraphy. In patients with congestive heart failure, blood NE concentration was elevated and the number of lymphocytic and myocardial receptors was decreased. The H/M ratio was low. Low MIBG uptake was seen at the posterior to lateral wall. (K.H.)

  1. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

    Full Text Available Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE and/or, butyrylcholinesterase (BChE, the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  2. Radioenzymatic paper-chromatographic assay for dopamine and norepinephrine in cerebroventricular cisternal perfusate of cat following administration of cocaine or d-amphetamine

    Energy Technology Data Exchange (ETDEWEB)

    Chiueh, C C; Kopin, I J [National Inst. of Mental Health, Bethesda, MD (USA)

    1978-08-01

    A sensitive radioenzymatic paper chromatographic method was used to measure the endogenous dopamine and norepinephrine content of cerebroventricular cisternal perfusate from cats to provide direct evidence for the catecholamine releasing action of cocaine from brain in vivo. Although relatively less potent than d-emphetamine, cocaine was shown to release endogenous catechloramines, mainly dopamine from the brain. This similarity may be the neurochemical basis for their similar behavioral effects.

  3. Radioenzymatic paper-chromatographic assay for dopamine and norepinephrine in cerebroventricular cisternal perfusate of cat following administration of cocaine or d-amphetamine

    International Nuclear Information System (INIS)

    Chiueh, C.C.; Kopin, I.J.

    1978-01-01

    A sensitive radioenzymatic paper chromatographic method was used to measure the endogenous dopamine and norepinephrine content of cerebroventricular cisternal perfusate from cats to provide direct evidence for the catecholamine releasing action of cocaine from brain in vivo. Although relatively less potent than d-emphetamine, cocaine was shown to release endogenous catechloramines, mainly dopamine from the brain. This similarity may be the neurochemical basis for their similar behavioral effects. (U.K.)

  4. Effects of aging and hypertension on the participation of endothelium-derived constricting factor (EDCF) in norepinephrine-induced contraction of rat femoral artery

    Czech Academy of Sciences Publication Activity Database

    Líšková, Silvia; Petrová, M.; Karen, Petr; Kuneš, Jaroslav; Zicha, Josef

    2011-01-01

    Roč. 667, 1-3 (2011), s. 265-270 ISSN 0014-2999 R&D Projects: GA ČR(CZ) GA305/09/0336; GA AV ČR(CZ) IAA500110902 Institutional research plan: CEZ:AV0Z50110509 Keywords : EDCF * SHR * norepinephrine * L-NNA * indomethacin Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.516, year: 2011

  5. Bandwidth selection in smoothing functions | Kibua | East African ...

    African Journals Online (AJOL)

    ... inexpensive and, hence, worth adopting. We argue that the bandwidth parameter is determined by two factors: the kernel function and the length of the smoothing region. We give an illustrative example of its application using real data. Keywords: Kernel, Smoothing functions, Bandwidth > East African Journal of Statistics ...

  6. Three-phase electric drive with modified electronic smoothing inductor

    DEFF Research Database (Denmark)

    Singh, Yash Veer; Rasmussen, Peter Omand; Andersen, Torben Ole

    2010-01-01

    This paper presents a three-phase electric drive with a modified electronic smoothing inductor (MESI) having reduced size of passive components. The classical electronic smoothing inductor (ESI) is able to control a diode bridge output current and also reduce not only mains current harmonics...

  7. Smooth Maps of a Foliated Manifold in a Symplectic Manifold

    Indian Academy of Sciences (India)

    Let be a smooth manifold with a regular foliation F and a 2-form which induces closed forms on the leaves of F in the leaf topology. A smooth map f : ( M , F ) ⟶ ( N , ) in a symplectic manifold ( N , ) is called a foliated symplectic immersion if restricts to an immersion on each leaf of the foliation and further, the ...

  8. Classification of smooth structures on a homotopy complex ...

    Indian Academy of Sciences (India)

    Abstract. We classify, up to diffeomorphism, all closed smooth manifolds homeo- morphic to the complex projective n-space CPn, where n = 3 and 4. Let M2n be a closed smooth 2n-manifold homotopy equivalent to CPn. We show that, up to diffeo- morphism, M6 has a unique differentiable structure and M8 has at most two ...

  9. Classification of smooth structures on a homotopy complex ...

    Indian Academy of Sciences (India)

    We classify, up to diffeomorphism, all closed smooth manifolds homeomorphic to the complex projective n -space C P n , where n = 3 and 4. Let M 2 n be a closed smooth 2 n -manifold homotopy equivalent to C P n . We show that, up to diffeomorphism, M 6 has a unique differentiable structure and M 8 has at most two ...

  10. Some asymptotic theory for variance function smoothing | Kibua ...

    African Journals Online (AJOL)

    Simple selection of the smoothing parameter is suggested. Both homoscedastic and heteroscedastic regression models are considered. Keywords: Asymptotic, Smoothing, Kernel, Bandwidth, Bias, Variance, Mean squared error, Homoscedastic, Heteroscedastic. > East African Journal of Statistics Vol. 1 (1) 2005: pp. 9-22 ...

  11. On smoothed analysis of quicksort and Hoare's find

    NARCIS (Netherlands)

    Fouz, Mahmoud; Kufleitner, Manfred; Manthey, Bodo; Zeini Jahromi, Nima; Ngo, H.Q.

    2009-01-01

    We provide a smoothed analysis of Hoare’s find algorithm and we revisit the smoothed analysis of quicksort. Hoare’s find algorithm – often called quickselect – is an easy-to-implement algorithm for finding the $k$-th smallest element of a sequence. While the worst-case number of comparisons that

  12. Investigation of angular and axial smoothing of PET data

    International Nuclear Information System (INIS)

    Daube-Witherspoon, M.E.; Carson, R.E.

    1996-01-01

    Radial filtering of emission and transmission data is routinely performed in PET during reconstruction in order to reduce image noise. Angular smoothing is not typically done, due to the introduction of a non-uniform resolution loss; axial filtering is also not usually performed on data acquired in 2D mode. The goal of this paper was to assess the effects of angular and axial smoothing on noise and resolution. Angular and axial smoothing was incorporated into the reconstruction process on the Scanditronix PC2048-15B brain PET scanner. In-plane spatial resolution and noise reduction were measured for different amounts of radial and angular smoothing. For radial positions away from the center of the scanner, noise reduction and degraded tangential resolution with no loss of radial resolution were seen. Near the center, no resolution loss was observed, but there was also no reduction in noise for angular filters up to a 7 degrees FWHM. These results can be understood by considering the combined effects of smoothing projections across rows (angles) and then summing (backprojecting). Thus, angular smoothing is not optimal due to its anisotropic noise reduction and resolution degradation properties. However, uniform noise reduction comparable to that seen with radial filtering can be achieved with axial smoothing of transmission data. The axial results suggest that combined radial and axial transmission smoothing could lead to improved noise characteristics with more isotropic resolution degradation