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Sample records for norepinephrine transporter reduction

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

    PubMed

    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. PMID:20176067

  2. Familial orthostatic tachycardia due to norepinephrine transporter deficiency

    NASA Technical Reports Server (NTRS)

    Robertson, D.; Flattem, N.; Tellioglu, T.; Carson, R.; Garland, E.; Shannon, J. R.; Jordan, J.; Jacob, G.; Blakely, R. D.; Biaggioni, I.

    2001-01-01

    Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

  3. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.

  4. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  5. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency

    NASA Technical Reports Server (NTRS)

    Shannon, J. R.; Flattem, N. L.; Jordan, J.; Jacob, G.; Black, B. K.; Biaggioni, I.; Blakely, R. D.; Robertson, D.

    2000-01-01

    BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic

  6. Association of Norepinephrine Transporter Gene with Methylphenidate Response.

    ERIC Educational Resources Information Center

    Yang, Li; Wang, Yu-Feng; Li, Jun; Faraone, Stephen V.

    2004-01-01

    Objective: This study aimed to explore the association between alleles of the norepinephrine transporter gene and the methylphenidate response. Method: Chinese Han youths with attention-deficit/hyperactivity disorder recruited in the Outpatient Department of the Institute of Mental Health from 2001 to 2004 were treated with methylphenidate in…

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

    PubMed

    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. PMID:26910400

  8. Norepinephrines effect on adenosine transport in the proximal straight tubule

    SciTech Connect

    Barfuss, D.W.; McCann, W.P.; Katholi, R.E.

    1986-03-01

    The effect of norepinephrine on C/sup 14/-adenosine transport in the rabbit proximal tubule (S/sub 2/) was studied. The transepithelial transport of adenosine (0.02 mM0 from lumin to bathing solution was measured by its rate of appearance (J/sub A/) in the bathing solution and by its disappearances (J/sub D/) from the luminal fluid. Norepinephrine (0.24 ..mu..M) was added to the bathing solution after a control flux period. After three samples from the experiment period the tubules were quickly harvested and the cellular concentration of C/sup 14/-adenosine was determined. The high cellular adenosine concentration and th marked difference in adenosine appearance rate in the bathing solution compared to the luminal disappearance rate indicates the absorbed adenosine is trapped in the cells. This trapping may be due to adenosine metabolism or difficulty of crossing the basolateral membrane. Whichever is the case, norepinephrine appears to stimulate movement of adenosine or its metabolites into the bathing solution across the basolateral membrane.

  9. Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse

    PubMed Central

    Hall, F. Scott; Uhl, George R.; Bearer, Elaine L.; Jacobs, Russell E.

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

  10. Altered reward circuitry in the norepinephrine transporter knockout mouse.

    PubMed

    Gallagher, Joseph J; Zhang, Xiaowei; Hall, F Scott; Uhl, George R; Bearer, Elaine L; Jacobs, Russell E

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn(2+) tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

  11. Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis

    PubMed Central

    Robertson, Sabrina D.; Matthies, Heinrich J.G.; Owens, Anthony W.; Sathananthan, Vidiya; Bibus Christianson, Nicole S.; Kennedy, J. Phillip; Lindsley, Craig W.; Daws, Lynette C.; Galli, Aurelio

    2010-01-01

    Noradrenergic signaling in the central nervous system plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicates that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high co-morbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron (SCGN) boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin (STZ), a drug that induces a Type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis. PMID:20739551

  12. Endothelin-1 and -3 modulate the neuronal norepinephrine transporter through multiple signalling pathways in the rat posterior hypothalamus.

    PubMed

    Hope, Sandra I; Nabhen, Sabrina L; Soria, Celeste; Bianciotti, Liliana G; Vatta, Marcelo S

    2010-10-01

    We have previously reported that endothelin-1 and -3 modulate different steps of noradrenergic transmission in the hypothalamus. We showed that endothelins modify neuronal norepinephrine transport activity through the regulation of the kinetic constant and internalization. In the present work we sought to define the endothelin receptors and intracellular mechanisms involved in the down-regulation of neuronal norepinephrine uptake induced by endothelin-1 and -3 in the rat posterior hypothalamic region. Results showed that endothelin-1 reduced norepinephrine uptake through ET(B) receptors, whereas endothelin-3 through a non-conventional or atypical endothelin receptor. In both cases, the effect on norepinephrine uptake was coupled to protein kinase A and C as well as nitric oxide pathways. However, neither protein kinase G nor intracellular or extracellular calcium and calcium/calmodulin-dependent protein kinase II were involved. In addition, the same intracellular mechanisms participated in the reduction of nisoxetine binding (norepinephrine transporter internalization index) induced by both endothelins. Present findings reveal the underlying mechanisms involved in the regulation of the neuronal norepinephrine transporter by endothelins and further support the role of these peptides in the modulation of noradrenergic transmission at the presynaptic nerve endings in the posterior hypothalamus.

  13. Norepinephrine transporter knock-out alters expression of the genes connected with antidepressant drugs action.

    PubMed

    Solich, Joanna; Kolasa, Magdalena; Kusmider, Maciej; Faron-Gorecka, Agata; Pabian, Paulina; Zurawek, Dariusz; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2015-01-12

    Norepinephrine transporter knock-out mice (NET-KO) exhibit depression-resistant phenotypes. They manifest significantly shorter immobility times in both the forced swim test and the tail suspension test. Moreover, biochemical studies have revealed the up-regulation of other monoamine transporters (dopamine and serotonin) in the brains of NET-KO mice, similar to the phenomenon observed after the chronic pharmacological blockade of norepinephrine transporter by desipramine in wild-type (WT) animals. NET-KO mice are also resistant to stress, as we demonstrated previously by measuring plasma corticosterone concentration. In the present study, we used a microdissection technique to separate target brain regions and the TaqMan Low Density Array approach to test the expression of a group of genes in the NET-KO mice compared with WT animals. A group of genes with altered expression were identified in four brain structures (frontal and cingulate cortices, dentate gyrus of hippocampus and basal-lateral amygdala) of NET-KO mice compared with WT mice. These genes are known to be altered by antidepressant drugs administration. The most interesting gene is Crh-bp, which modulates the activity of corticotrophin--releasing hormone (CRH) and several CRH-family members. Generally, genetic disturbances within noradrenergic neurons result in biological changes, such as in signal transduction and intercellular communication, and may be linked to changes in noradrenaline levels in the brains of NET-KO mice.

  14. Regulated Norepinephrine Transporter Interaction with the Neurokinin-1 Receptor Establishes Transporter Subcellular Localization*

    PubMed Central

    Arapulisamy, Obulakshmi; Mannangatti, Padmanabhan; Jayanthi, Lankupalle D.

    2013-01-01

    Neurokinin-1 receptor (NK1R) mediates down-regulation of human norepinephrine (NE) transporter (hNET) via protein kinase C (PKC). However, native NET regulation by NK1R and the mechanism by which NK1R targets NET among other potential effectors are unknown. Effect of NK1R activation on native NET regulation and NET/NK1R interaction were studied using rat brain synaptosomes expressing native NET and NK1R as well as human placental trophoblast (HTR) cells coexpressing WT-hNET or NK1R/PKC-resistant hNET-T258A,S259A double mutant (NET-DM) and hNK1R. The selective NK1R agonist, GR73632, and Substance-P (SP) inhibited NE transport and reduced plasma membrane expression of NET and NK1R. Pretreatment with the NK1R antagonist, EMEND (aprepitant) prevented these NK1R-mediated effects. Immunoprecipitation experiments showed that NET forms stable complexes with NK1R. In HTR cells, combined biotinylation and immunoprecipitation studies revealed plasma membrane localization of NET·NK1R complexes. Receptor activation resulted in the internalization of NET·NK1R complexes. Lipid raft and immunoprecipitation analyses revealed the presence of NET·NK1R complexes exclusively in non-raft membrane fractions under basal/unstimulated conditions. However, NK1R activation led to translocation of NET·NK1R complexes to raft-rich membrane fractions. Importantly, PKCα was found in association with raft-localized NET following SP treatment. Similar to WT-NET, PKC-resistant NET-DM was found in association with NK1R exclusively in non-raft fractions. However, SP treatment failed to translocate NET-DM·NK1R complexes from non-raft fractions to raft fractions. Collectively, these results suggest that NK1R forms physical complexes with NET and that the receptor-mediated Thr258 + Ser259 motif-dependent translocation of NET·NK1R complexes into raft-rich microdomains facilitates NET/NK1R interaction with PKCα to coordinate spatially restricted NET regulation. PMID:23979140

  15. Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

    PubMed

    Neudorfer, Catharina; Seddik, Amir; Shanab, Karem; Jurik, Andreas; Rami-Mark, Christina; Holzer, Wolfgang; Ecker, Gerhard; Mitterhauser, Markus; Wadsak, Wolfgang; Spreitzer, Helmut

    2015-01-01

    Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET. PMID:25608857

  16. Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

    NASA Astrophysics Data System (ADS)

    Schroeder, Christoph; Strempel, Sebastian; Boese, Andrea; Hemmersbach, Ruth; Tank, Jens; Luft, Friedrich C.; Jordan, Jens

    Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance.

  17. Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport.

    PubMed

    Morelli, Andrea; Lange, Matthias; Ertmer, Christian; Broeking, Katrin; Van Aken, Hugo; Orecchioni, Alessandra; Rocco, Monica; Bachetoni, Alessandra; Traber, Daniel L; Landoni, Giovanni; Pietropaoli, Paolo; Westphal, Martin

    2007-11-01

    Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. In addition to standard therapy, patients were randomized to receive either 10, 20, or 30 mg of enteral glibenclamide. Systemic hemodynamics, global oxygen transport including arterial lactate concentrations, gas exchange, plasma glucose concentrations, and electrolytes were determined at baseline and after 3, 6, and 12 h after administration of the study drug. Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.

  18. The N-terminus of the norepinephrine transporter regulates the magnitude and selectivity of the transporter-associated leak current.

    PubMed

    Binda, Francesca; Lute, Brandon J; Dipace, Concetta; Blakely, Randy D; Galli, Aurelio

    2006-03-01

    The norepinephrine (NE) transporter (NET) mediates the removal of NE from synaptic spaces and is a major target for antidepressants, amphetamine and cocaine. Previously, we have shown that syntaxin 1A (SYN 1A) supports human NET (hNET) cell surface expression, that hNET/SYN 1A interactions are direct and mediated by the hNET N-terminus, and that the hNET/SYN 1A association limits substrate-induced hNET-associated currents [Sung, U., Apparsundaram, S., Galli, A., Kahlig, K.M., Savchenko, V., Schroeter, S., Quick, M.W., Blakely, R.D., 2003. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity. J. Neurosci. 23, 1697-1709]. These data raise the possibility that the hNET N-terminus, and potentially its interaction with SYN 1A, might regulate other hNET conductance states, including the hNET-mediated leak current. Importantly for monoamine transporters, the leak conductance has been shown to play a critical role in regulating cell membrane potential and possibly neuronal excitability [Quick, M.W., 2003. Regulating the conducting states of a mammalian serotonin transporter. Neuron 40, 537-549]. Here we demonstrate that deletion of the binding domain for SYN 1A in the NET N-terminus robustly enhances the NET-mediated leak current as well as its selectivity for Cl- permeation under particular intracellular ionic compositions. In addition, we show that the NET N-terminus coordinates the ability of intracellular Na+ and Cl- to regulate the leak conductance. These data suggest that the NET N-terminus regulates and defines the ionic specificity of the NET-mediated leak current.

  19. Life-long norepinephrine transporter (NET) knock-out leads to the increase in the NET mRNA in brain regions rich in norepinephrine terminals.

    PubMed

    Solich, Joanna; Kolasa, Magdalena; Kusmider, Maciej; Pabian, Paulina; Faron-Gorecka, Agata; Zurawek, Dariusz; Szafran-Pilch, Kinga; Kedracka-Krok, Sylwia; Jankowska, Urszula; Swiderska, Bianka; Dziedzicka-Wasylewska, Marta

    2015-08-01

    These studies aimed to identify the genes differentially expressed in the frontal cortex of mice bearing a life-long norepinephrine transporter knock-out (NET-KO) and wild-type animals (WT). Differences in gene expression in the mouse frontal cortex were studied using a whole-genome microarray approach. Using an alternative approach, i.e. RT-PCR (reverse transcription polymerase chain reaction) with primers complementary to various exons of the NET gene, as well as TaqMan arrays, the level of mRNA encoding the NET in other brain regions of the NET-KO mice was also examined. The analyses revealed a group of 92 transcripts (27 genes) that differentiated the NET-KO mice from the WT mice. Surprisingly, the studies have shown that the mRNA encoding NET accumulated in the brain regions rich in norepinephrine nerve endings in the NET-KO mice. Because there is no other source of NET mRNA besides the noradrenergic terminals in the brain regions studied, these results might speak in favor of the presence of mRNA in axon terminals. RNA-Binding Protein Immunoprecipitation approach indicated that mRNA encoding NET was detected in the Ago2 protein/mRNA complex. In addition, the amount of Ago2 protein in the frontal cortex was significantly higher in NET-KO mice as compared with that of the WT animals. These results are important for further characterization of the NET-KO mice, which - besides other merits - might serve as a good model to study the fate of truncated mRNA in neurons.

  20. Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter.

    PubMed

    Mason, John N; Deecher, Darlene C; Richmond, Rhonda L; Stack, Gary; Mahaney, Paige E; Trybulski, Eugene; Winneker, Richard C; Blakely, Randy D

    2007-11-01

    Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.

  1. Nothing but NET: A review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy

    PubMed Central

    Streby, Keri A; Shah, Nilay; Ranalli, Mark A; Kunkler, Anne; Cripe, Timothy P

    2015-01-01

    Neuroblastoma is unique amongst common pediatric cancers for its expression of the norepinephrine transporter (NET), enabling tumor-selective imaging and therapy with radioactive analogues of norepinephrine. The majority of neuroblastoma tumors are avid for 123I-metaiodobenzaguanidine (mIBG) on imaging, yet the therapeutic response to 131I-mIBG is only 30% in clinical trials, and off-target effects cause short- and long-term morbidity. We review the contemporary understanding of the tumor-selective uptake, retention, and efflux of meta-iodobenzylguanidine (mIBG) and strategies currently in development for improving its efficacy. Combination treatment strategies aimed at enhancing NET are likely necessary to reach the full potential of 131I-mIBG therapy. PMID:25175627

  2. Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine.

    PubMed

    Del Bello, Fabio; Sakloth, Farhana; Partilla, John S; Baumann, Michael H; Glennon, Richard A

    2015-09-01

    N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; 'Ecstasy'; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(-) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET.

  3. Ethylenedioxy Homologs of N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its Corresponding Cathinone Analog Methylenedioxymethcathinone: Interactions with Transporters for Serotonin, Dopamine, and Norepinephrine

    PubMed Central

    Del Bello, Fabio; Sakloth, Farhana; Partilla, John S.; Baumann, Michael H.; Glennon, Richard A.

    2015-01-01

    N -Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; ‘Ecstasy’; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(−) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. PMID:26233799

  4. Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter

    PubMed Central

    Andersen, Jacob; Ringsted, Kristoffer B.; Bang-Andersen, Benny; Strømgaard, Kristian; Kristensen, Anders S.

    2015-01-01

    The transporters for norepinephrine and dopamine (NET and DAT, respectively) constitute the molecular targets for recreational drugs and therapeutics used in the treatment of psychiatric disorders. Despite a strikingly similar amino acid sequence and predicted topology between these transporters, some inhibitors display a high degree of selectivity between NET and DAT. Here, a systematic mutational analysis of non-conserved residues within the extracellular entry pathway and the high affinity binding site in NET and DAT was performed to examine their role for selective inhibitor recognition. Changing the six diverging residues in the central binding site of NET to the complementary residues in DAT transferred a DAT-like pharmacology to NET, showing that non-conserved binding site residues in NET are critical determinants for inhibitor selectivity. In contrast, changing the equivalent residues in the central site of DAT to the corresponding residues in NET had modest effects on the same inhibitors, suggesting that non-conserved binding site residues in DAT play a minor role for selective inhibitor recognition. Our data points towards distinct structural determinants governing inhibitor selectivity in NET and DAT, and provide important new insight into the molecular basis for NET/DAT selectivity of therapeutic and recreational drugs. PMID:26503701

  5. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.

    PubMed

    Perona, Maria T G; Waters, Shonna; Hall, Frank Scott; Sora, Ichiro; Lesch, Klaus-Peter; Murphy, Dennis L; Caron, Marc; Uhl, George R

    2008-09-01

    Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these

  6. Animal models of depression in dopamine, serotonin and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions

    PubMed Central

    Perona, Maria T.G.; Waters, Shonna; Hall, F. Scott; Sora, Ichiro; Lesch, Klaus-Peter; Murphy, Dennis L.; Caron, Marc; Uhl, George R.

    2008-01-01

    Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1) and dopamine (DAT/SLC6A3). Many antidepressants block several ofthese transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET and SERT KO mice and wildtype littermates were studied in the forced swim test (FST), the tail suspension test (TST) and for sucrose consumption. In order to dissociate general activity from the potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing and swimming. In confirmation of previous reports, both DAT KO and NET KO mice exhibited less immobility than wildtype littermates while SERT KO mice did not. Effects of DAT deletion were not simply due to hyperactivity as decreased immobility was observed in DAT +/- mice that were not hyperactive as well as in DAT -/- mice that displayed profound hyperactivity. Climbing was increased, while swimming was almost eliminated in DAT -/-mice, while a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of forced swim test results in antidepressant animal models, while selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the TST, where DAT, NET and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of

  7. Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini.

    PubMed

    Vuorenpää, Anne; Jørgensen, Trine N; Newman, Amy H; Madsen, Kenneth L; Scheinin, Mika; Gether, Ulrik

    2016-03-11

    The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the "long loop" recycling marker Rab11, whereas less overlap was seen with the "short loop" recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. PMID:26786096

  8. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.

    PubMed

    Shirey-Rice, Jana K; Klar, Rebecca; Fentress, Hugh M; Redmon, Sarah N; Sabb, Tiffany R; Krueger, Jessica J; Wallace, Nathan M; Appalsamy, Martin; Finney, Charlene; Lonce, Suzanna; Diedrich, André; Hahn, Maureen K

    2013-07-01

    Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.

  9. Norepinephrine transporter expression is inversely associated with glycaemic indices: a pilot study in metabolically diverse persons with overweight and obesity

    PubMed Central

    Guo, L.; Corcoran, S. J.; Esler, M. D.; Phillips, S. E.; Sari, C. I.; Grima, M. T.; Karapanagiotidis, S.; Wong, C. Y.; Eikelis, N.; Mariani, J. A.; Kobayashi, D.; Dixon, J. B.; Lambert, G. W.; Lambert, E. A.

    2016-01-01

    Summary Objective The objective of this study was to examine the cross‐sectional relationship between the expression of norepinephrine transporter (NET), the protein responsible for neuronal uptake‐1, and indices of glycaemia and hyperinsulinaemia, in overweight and obese individuals. Methods Thirteen non‐medicated, non‐smoking subjects, aged 58 ± 1 years (mean ± standard error of the mean), body mass index (BMI) 31.4 ± 1.0 kg m−2, with wide‐ranging plasma glucose and haemoglobin A1c (HbA1c, range 5.1% to 6.5%) participated. They underwent forearm vein biopsy to access sympathetic nerves for the quantification of NET by Western blot, oral glucose tolerance test (OGTT), euglycaemic hyperinsulinaemic clamp, echocardiography and assessments of whole‐body norepinephrine kinetics and muscle sympathetic nerve activity. Results Norepinephrine transporter expression was inversely associated with fasting plasma glucose (r = −0.62, P = 0.02), glucose area under the curve during OGTT (AUC0–120, r = −0.65, P = 0.02) and HbA1c (r = −0.67, P = 0.01), and positively associated with steady‐state glucose utilization during euglycaemic clamp (r = 0.58, P = 0.04). Moreover, NET expression was inversely related to left ventricular posterior wall dimensions (r = −0.64, P = 0.02) and heart rate (r = −0.55, P = 0.05). Indices of hyperinsulinaemia were not associated with NET expression. In stepwise linear regression analysis adjusted for age, body mass index and blood pressure, HbA1c was an independent inverse predictor of NET expression, explaining 45% of its variance. Conclusions Hyperglycaemia is associated with reduced peripheral NET expression. Further studies are required to identify the direction of causality. PMID:27812376

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

    PubMed

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

    2008-01-01

    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.

  11. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder.

    PubMed

    Somkuwar, Sucharita S; Kantak, Kathleen M; Dwoskin, Linda P

    2015-08-30

    Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)× first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.

  12. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of Attention Deficit Hyperactivity Disorder

    PubMed Central

    Somkuwar, Sucharita S.; Kantak, Kathleen M.; Dwoskin, Linda P.

    2015-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in Spontaneously Hypertensive Rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax) x first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD. PMID:25680322

  13. Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

    PubMed Central

    Narita, Shin; Nagahori, Kenta; Numajiri, Maki; Yoshihara, Eiji; Ohtani, Nobuyo; Ishigooka, Jun

    2015-01-01

    Objective Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model. Methods After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students. Results A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms. Conclusion We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires. PMID:26207133

  14. A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging

    PubMed Central

    Chen, Nanhai; Zhang, Qian; Yu, Yong A; Stritzker, Jochen; Brader, Peter; Schirbel, Andreas; Samnick, Samuel; Serganova, Inna; Blasberg, Ronald; Fong, Yuman; Szalay, Aladar A

    2009-01-01

    Noninvasive and repetitive monitoring of a virus in target tissues and/or specific organs of the body is highly desirable for the development of safe and efficient cancer virotherapeutics. We have previously shown that the oncolytic vaccinia virus GLV-1h68 can target and eradicate human tumors in mice and that its therapeutic effects can be monitored by using optical imaging. Here, we report on the development of a derivative of GLV-1h68, a novel recombinant vaccinia virus (VACV) GLV-1h99, which was constructed to carry the human norepinephrine transporter gene (hNET) under the VACV synthetic early promoter placed at the F14.5L locus for deep-tissue imaging. The hNET protein was expressed at high levels on the membranes of cells infected with this virus. Expression of the hNET protein did not negatively affect virus replication, cytolytic activity in cell culture, or in vivo virotherpeutic efficacy. GLV-1h99–mediated expression of the hNET protein in infected cells resulted in specific uptake of the radiotracer [131I]-meta-iodobenzylguanidine (MIBG). In mice, GLV-1h99–infected tumors were readily imaged by [124I]-MIBG positron emission tomography. To our knowledge, GLV-1h99 is the first oncolytic virus expressing the hNET protein that can efficiently eliminate tumors and simultaneously allow deep-tissue imaging of infected tumors. PMID:19287510

  15. Genetic Variation in the Presynaptic Norepinephrine Transporter is Associated with Blood Pressure Responses to Exercise in Healthy Humans

    PubMed Central

    Kohli, Utkarsh; Hahn, Maureen K.; English, Brett A.; Sofowora, Gbenga G.; Muszkat, Mordechai; Li, Chun; Blakely, Randy D.; Stein, C. Michael; Kurnik, Daniel

    2011-01-01

    Background The presynaptic norepinephrine (NE) transporter (NET) mediates synaptic clearance and recycling of NE. NET-deficient transgenic mice have elevated blood pressure, heart rate, and catecholamine concentrations. However, the in vivo effects of common NET variants on cardiovascular regulation at rest and during exercise are unknown. Methods We studied cardiovascular responses and plasma catecholamine concentrations at rest and during bicycle exercise at increasing workloads (25, 50 and 75 W) in 145 healthy subjects. We used multiple linear regressions to analyze the effect of common, purportedly functional polymorphisms in NET (rs2242446 and rs28386840) on cardiovascular measures. Results 44% and 58.9% of subjects carried at least one variant allele for NET T-182C and A-3081T, respectively. Systolic blood pressure (SBP) during exercise and SBP area-under-the-curve were higher in carriers of variant NET alleles (P=0.003 and 0.009 for T-182C and A-3081T, respectively) and NET haplotype -182C/-081T compared to -82T/-3081A (all P<0.01). Diastolic blood pressure (DBP) during exercise was also higher at lower, but not at higher exercise stages in carriers of NET -182C (P<0.01) and -081T (P< 0.05). NET genotypes were not associated with catecholamine concentrations or heart rate. Conclusion Common genetic NET variants (-182C and -081T) are associated with greater blood pressure response to exercise in humans. PMID:21412203

  16. Association between polymorphism of the norepinephrine transporter gene rs2242446 and rs5669 loci and depression disorders

    PubMed Central

    Pan, Yu; Cheng, Qi; Shan, Mo-Shui; Yan, Jin

    2015-01-01

    Objective: To explore the association between polymorphism of the norepinephrine transporter (NET) gene rs2242446 and rs5669 loci and depression in Chinese Han population. Methods: A case-control study was carried out, the gene types and allele distributions of NFT gene rs2242446 and rs5569 loci in 302 depression patients and 302 healthy controls were detected by Taqman SNP genotyping technology. Results: The gene types and allele frequency distributions of NFT gene rs2242446 and rs5569 loci had significant differences between case group and control group (rs2242446, x2=26.045, P<0.05, x2=8.827, P<0.05, rs5569, x2=42.47, P<0.05, x2=20.9, P<0.05). The CC genotype of NET gene rs2242446 locus and rs5569 loci was a protective factor of depression compared with the CT and TT genotypes. Conclusion: The NET genepoly morphism of rs2242446 and rs5569 loci was a ssociated with depression in Chinese Han population, in which the CC genotype of rs2242446 and rs5569 loci was a protective factor of depression. PMID:26770504

  17. Chronic serotonin-norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo

    PubMed Central

    Warren, Kelly A.; Solomon, Irene C.

    2012-01-01

    Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin-norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (TE), and the inspiratory duty cycle (TI/Ttot) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy. PMID:22871263

  18. Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

    PubMed Central

    Jin, Chunyang; Navarro, Hernán A.; Carroll, F. Ivy

    2010-01-01

    Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3β-(substituted phenyl)tropane-2β-carboxylic acid methyl esters 7a-g, 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid esters 8a-j, and 3β-(4-methoxyphenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and Ki values of 3.5 nM and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study. PMID:19053748

  19. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

    PubMed Central

    Sigurdardottir, Helen L.; Kranz, Georg S.; Rami‐Mark, Christina; James, Gregory M.; Vanicek, Thomas; Gryglewski, Gregor; Kautzky, Alexander; Hienert, Marius; Traub‐Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried

    2016-01-01

    Abstract Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:26678348

  20. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET.

    PubMed

    Sigurdardottir, Helen L; Kranz, Georg S; Rami-Mark, Christina; James, Gregory M; Vanicek, Thomas; Gryglewski, Gregor; Kautzky, Alexander; Hienert, Marius; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried; Lanzenberger, Rupert

    2016-03-01

    Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND ) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)-[18F]FMeNER-D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI-TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype-dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (-3081 A/T) and a 5'-untranslated region (5'UTR) SNP (-182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3'UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD.

  1. Evaluation of [11C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates

    PubMed Central

    Gallezot, Jean-Dominique; Weinzimmer, David; Nabulsi, Nabeel; Lin, Shu-Fei; Fowles, Krista; Sandiego, Christine; McCarthy, Timothy J.; Maguire, R. Paul; Carson, Richard E.; Ding, Yu-Shin

    2013-01-01

    [11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [11C]MRB volume of distribution was observed after correction for [11C]MRB plasma free fraction. ATX IC50 was estimated to be 31±10 ng/mL plasma. This corresponds to an effective dose (ED50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5 mg/kg). [11C]MRB binding potential BPND in the thalamus was estimated to be 1.8±0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC50 estimate obtained using MRTM2 BPND without arterial blood sampling was 21±3 ng/mL (using caudate as the reference region). This study demonstrated that [11C]MRB is suitable for drug occupancy studies of NET. PMID:20869448

  2. Imaging human brown adipose tissue under room temperature conditions with 11C-MRB, a selective norepinephrine transporter PET ligand

    PubMed Central

    Hwang, Janice J.; Yeckel, Catherine W.; Gallezot, Jean-Dominique; Aguiar, Renata Belfort-De; Ersahin, Devrim; Gao, Hong; Kapinos, Michael; Nabulsi, Nabeel; Huang, Yiyun; Cheng, David; Carson, Richard E.; Sherwin, Robert; Ding, Yu-Shin

    2015-01-01

    Introduction Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with 11C-MRB ((S,S)-11C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. Methods Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7 kg/m2; 5 F: age 25.4±2.1, BMI 22.1±1.0 kg/m2) underwent 11C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to 18F-FDG PET-CT imaging. Uptake of 11C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. Results As expected, 18F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT 11C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of 11C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with 18F-FDG (p=0.63). Furthermore, there were gender differences in 11C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in 11C-MRB as a function of both body composition and body temperature. Conclusions Unlike 18F-FDG, the uptake of 11C-MRB in BAT offers a unique opportunity to

  3. Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization and stille coupling - switch of activity toward the serotonin and/or norepinephrine transporter.

    PubMed

    Hoepping, A; Johnson, K M; George, C; Flippen-Anderson, J; Kozikowski, A P

    2000-05-18

    A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the tropane ring and the orientation of the additional bridge (and therefore of the nitrogen lone pair) together with the unusual placement of the aromatic moiety. All compounds were tested for their ability to inhibit monoamine reuptake under identical conditions. The ability to inhibit reuptake of dopamine in comparison to cocaine is generally decreased in this series but for one compound. (1S,3R, 6S)-(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0(3, 7)]decane-2beta-carboxylic acid methyl ester (5h) exhibits reasonable activity at the dopamine transporter (DAT) (K(i) = 268 nM) and good activity at the norepinephrine transporter (NET) (K(i) = 26 nM). The potency and selectivity shown by some of these ligands for the NET, serotonine transporter (SERT), or NET/SERT is striking, particularly in view of the displacement of the aromatic ring in this series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R,6S)-(Z)-9-(4-biphenylylmethylene)-7-azatricyclo[4.3.1 . 0(3,7)]decane-2beta-carboxylic acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K(i) = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K(i) = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,6S)-2-(acetoxymethyl)-(Z)-9-(3, 4-dichlorophenylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decane ]. This compound is a potent (K(i) = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbrain synaptosomes. Its selectivity is about

  4. Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.

    PubMed

    Dyck, Brian; Tamiya, Junko; Jovic, Florence; Pick, Rebecca R; Bradbury, Margaret J; O'Brien, Julie; Wen, Jenny; Johns, Michael; Madan, Ajay; Fleck, Beth A; Foster, Alan C; Li, Binfeng; Zhang, Mingzhu; Tran, Joe A; Vickers, Troy; Grey, Jonathan; Saunders, John; Chen, Chen

    2008-11-27

    Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

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

    PubMed

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

    2016-06-15

    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 sub-regions 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. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26774596

  6. NASA's Subsonic Jet Transport Noise Reduction Research

    NASA Technical Reports Server (NTRS)

    Powell, Clemans A.; Preisser, John S.

    2000-01-01

    Although new jet transport airplanes in today s fleet are considerably quieter than the first jet transports introduced about 40 years ago, airport community noise continues to be an important environmental issue. NASA s Advanced Subsonic Transport (AST) Noise Reduction program was begun in 1994 as a seven-year effort to develop technology to reduce jet transport noise 10 dB relative to 1992 technology. This program provides for reductions in engine source noise, improvements in nacelle acoustic treatments, reductions in the noise generated by the airframe, and improvements in the way airplanes are operated in the airport environs. These noise reduction efforts will terminate at the end of 2001 and it appears that the objective will be met. However, because of an anticipated 3-8% growth in passenger and cargo operations well into the 21st Century and the slow introduction of new the noise reduction technology into the fleet, world aircraft noise impact will remain essentially constant until about 2020 to 2030 and thereafter begin to rise. Therefore NASA has begun planning with the Federal Aviation Administration, industry, universities and environmental interest groups in the USA for a new noise reduction initiative to provide technology for significant further reductions.

  7. Proteomic analysis of human norepinephrine transporter complexes reveals associations with protein phosphatase 2A anchoring subunit and 14-3-3 proteins

    SciTech Connect

    Sung, Uhna; Jennings, Jennifer L.; Link, Andrew J.; Blakely, Randy D.; E-mail: andy.blakely@vanderbilt.edu

    2005-08-05

    The norepinephrine transporter (NET) terminates noradrenergic signals by clearing released NE at synapses. NET regulation by receptors and intracellular signaling pathways is supported by a growing list of associated proteins including syntaxin1A, protein phosphatase 2A (PP2A) catalytic subunit (PP2A-C), PICK1, and Hic-5. In the present study, we sought evidence for additional partnerships by mass spectrometry-based analysis of proteins co-immunoprecipitated with human NET (hNET) stably expressed in a mouse noradrenergic neuroblastoma cell line. Our initial proteomic analyses reveal multiple peptides derived from hNET, peptides arising from the mouse PP2A anchoring subunit (PP2A-Ar) and peptides derived from 14-3-3 proteins. We verified physical association of NET with PP2A-Ar via co-immunoprecipitation studies using mouse vas deferens extracts and with 14-3-3 via a fusion pull-down approach, implicating specifically the hNET NH{sub 2}-terminus for interactions. The transporter complexes described likely support mechanisms regulating transporter activity, localization, and trafficking.

  8. Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites.

    PubMed

    Zhou, Jia; Zhang, Ao; Kläss, Thomas; Johnson, Kenneth M; Wang, Cheng Z; Ye, Yan Ping; Kozikowski, Alan P

    2003-05-01

    A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes, were synthesized and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxycarbonyl substituent at C-10 exhibit moderate to high inhibitory activity at the NET but lower activity at the DAT and SERT. Among these new compounds, some potent, NET-selective ligands were identified. The p-methoxy derivative 11a has a K(i) value of 39 nM for uptake inhibition at the NET and moderate to high selectivity over the SERT (100-fold) and the DAT (20-fold). Compound 11f exhibits a remarkable potency (K(i) = 9.7 nM) at the NET and a 25-fold selectivity over both the SERT and the DAT. Analogue 23 containing a thiophene ring as a bioisosteric replacement of the phenyl ring Ar(1) displays a high activity (K(i) = 10.3 nM) for the NET and similar selectivity over the SERT (50-fold) and the DAT (37-fold). The selectivity profile of biaryl analogues differs from that of the monoaryl series, as most members of that series display excellent potency at and selectivity for the SERT (J. Med. Chem. 2002, 45, 1930). This finding suggests that the different shape and size of the lipophilic recognition pocket that encompasses the aryl ring(s) of these tropanes are major determinants of a ligand's transporter activity at either the NET or the SERT. Some of the compounds in this series may also be valuable in sorting out the contribution of the individual transporters to cocaine's reinforcing properties.

  9. NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model.

    PubMed

    Pacak, Karel; Sirova, Marta; Giubellino, Alessio; Lencesova, Lubomira; Csaderova, Lucia; Laukova, Marcela; Hudecova, Sona; Krizanova, Olga

    2012-11-15

    Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis. PMID:22407736

  10. Effects of Electroacupuncture on Pain Threshold of Laboring Rats and the Expression of Norepinephrine Transporter and α2 Adrenergic Receptor in the Central Nervous System

    PubMed Central

    Lin, Shike; Feng, Yuanyuan; Zhang, Qi; Wang, Meili; Wang, Yu

    2016-01-01

    To observe the effects of electroacupuncture on pain threshold of laboring rats and the expression of norepinephrine transporter and α2 adrenergic receptor in the central nervous system to determine the mechanism of the analgesic effect of labor. 120 pregnant rats were divided into 6 groups: a control group, 4 electroacupuncture groups, and a meperidine group. After interventions, the warm water tail-flick test was used to observe pain threshold. NE levels in serum, NET, and α2AR mRNA and protein expression levels in the central nervous system were measured. No difference in pain threshold was observed between the 6 groups before intervention. After intervention, increased pain thresholds were observed in all groups except the control group with a higher threshold seen in the electroacupuncture groups. Serum NE levels decreased in the electroacupuncture and MP groups. Increases in NET and α2AR expression in the cerebral cortex and decreases in enlarged segments of the spinal cord were seen. Acupuncture increases uptake of NE via cerebral NET and decreases its uptake by spinal NET. The levels of α2AR are also increased and decreased, respectively, in both tissues. This results in a decrease in systemic NE levels and may be the mechanism for its analgesic effects. PMID:27547232

  11. Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study

    PubMed Central

    Singh, Ajeet Bhagat; Bousman, Chad A.; Ng, Chee Hong; Byron, Keith; Berk, Michael

    2015-01-01

    Objective Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility. PMID:25912538

  12. Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

    PubMed Central

    Haenisch, Britta; Bilkei-Gorzo, Andras; Caron, Marc G.; Bönisch, Heinz

    2009-01-01

    Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout (KO) of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, NGF and NT-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NETKO mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants. PMID:19694905

  13. In vivo imaging and quantitation of adoptively transferred human antigen-specific T cells transduced to express a human norepinephrine transporter gene.

    PubMed

    Doubrovin, Mikhail M; Doubrovina, Ekaterina S; Zanzonico, Pat; Sadelain, Michel; Larson, Steven M; O'Reilly, Richard J

    2007-12-15

    Sequential imaging of genetically marked effector cells after adoptive transfer in vivo has greatly enhanced analyses of their biodistribution, growth, and activity both in animal models and in clinical trials of cellular immunotherapy. However, the immunogenicity of cells expressing xenogeneic reporter constructs limits their survival and clinical utility. To address this limitation, we have evaluated a human norepinephrine transporter (hNET) permitting imaging of transduced cells in vivo with a previously approved clinical grade radiolabeled probe, metaiodobenzylguanidine (MIBG). The hNET gene cDNA was cloned from the SK-N-SH cell line and inserted into a bicistronic retroviral vector also encoding green fluorescent protein. Following transfection, human EBV-specific T lymphocytes seemed fully functional in vitro and also selectively accumulated [(123)I]MIBG. In nonobese diabetic/severe combined immunodeficient mice bearing human EBV lymphoma xenografts, as few as 10(4) transduced T cells injected into the tumors could be imaged by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after i.v. infusion of [(123)I]MIBG or [(124)I]MIBG, respectively. When hNET(+) EBV-specific T cells were infused i.v., their migration and specific accumulation in EBV(+) tumors expressing their restricting HLA allele could be imaged by SPECT or PET over 28 days. Image intensity was closely correlated with the number of T cells accumulated in targeted tumors. The use of two reporter probes (MIBG and 2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl-5-iodouracil) permitted independent contemporaneous tracking of two distinct EBV-specific T-cell subpopulations expressing different reporter genes (hNET-CD4(+) T cells and HSV-TK-CD8(+) T cells) in the same animal using three-dimensional nuclear modalities (SPECT and PET). The hNET-based system described may thus have significant potential as a nonimmunogenic reporter for extended repeated quantitative in

  14. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: a post-mortem autoradiographic study.

    PubMed

    Gulyás, Balázs; Brockschnieder, Damian; Nag, Sangram; Pavlova, Elena; Kása, Péter; Beliczai, Zsuzsa; Légrádi, Adám; Gulya, Károly; Thiele, Andrea; Dyrks, Thomas; Halldin, Christer

    2010-01-01

    Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD. PMID:20211213

  15. A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference*

    PubMed Central

    Mannangatti, Padmanabhan; NarasimhaNaidu, Kamalakkannan; Damaj, Mohamad Imad; Ramamoorthy, Sammanda; Jayanthi, Lankupalle Damodara

    2015-01-01

    The noradrenergic and p38 mitogen-activated protein kinase (p38 MAPK) systems are implicated in cocaine-elicited behaviors. Previously, we demonstrated a role for p38 MAPK-mediated norepinephrine transporter (NET) Thr30 phosphorylation in cocaine-induced NET up-regulation (Mannangatti, P., Arapulisamy, O., Shippenberg, T. S., Ramamoorthy, S., and Jayanthi, L. D. (2011) J. Biol. Chem. 286, 20239–20250). The present study explored the functional interaction between p38 MAPK-mediated NET regulation and cocaine-induced behaviors. In vitro cocaine treatment of mouse prefrontal cortex synaptosomes resulted in enhanced NET function, surface expression, and phosphorylation. Pretreatment with PD169316, a p38 MAPK inhibitor, completely blocked cocaine-mediated NET up-regulation and phosphorylation. In mice, in vivo administration of p38 MAPK inhibitor SB203580 completely blocked cocaine-induced NET up-regulation and p38 MAPK activation in the prefrontal cortex and nucleus accumbens. When tested for cocaine-induced locomotor sensitization and conditioned place preference (CPP), mice receiving SB203580 on cocaine challenge day or on postconditioning test day exhibited significantly reduced cocaine sensitization and CPP. A transactivator of transcription (TAT) peptide strategy was utilized to test the involvement of the NET-Thr30 motif. In vitro treatment of synaptosomes with TAT-NET-Thr30 (wild-type peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In vivo administration of TAT-NET-Thr30 peptide but not TAT-NET-T30A (mutant peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In the cocaine CPP paradigm, mice receiving TAT-NET-Thr30 but not TAT-NET-T30A on postconditioning test day exhibited significantly reduced cocaine CPP. Following extinction, TAT-NET-Thr30 when given prior to cocaine challenge significantly reduced reinstatement of cocaine CPP. These results demonstrate that the direct inhibition of p38

  16. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    PubMed

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs.

  17. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    PubMed

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs. PMID:26277325

  18. Acute blockade of the Caenorhabditis elegans dopamine transporter DAT-1 by the mammalian norepinephrine transporter inhibitor nisoxetine reveals the influence of genetic modifications of dopamine signaling in vivo.

    PubMed

    Bermingham, Daniel P; Hardaway, J Andrew; Snarrenberg, Chelsea L; Robinson, Sarah B; Folkes, Oakleigh M; Salimando, Greg J; Jinnah, Hussain; Blakely, Randy D

    2016-09-01

    Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis (Swip), a phenotype first described in animals with loss of function mutations in the presynaptic DA transporter (dat-1). Swip has proven to be a phenotype suitable for the identification of novel dat-1 mutations as well as the identification of novel genes that impact DA signaling. Pharmacological manipulations can also induce Swip, though the reagents employed to date lack specificity and potency, limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent on DA release and signaling, and non-additive with Swip triggered by dat-1 deletion. Using nisoxetine in combination with genetic mutations that impact DA release, we further demonstrate the utility of the drug for demonstrating contributions of presynaptic DA receptors and ion channels to Swip. Together, these findings reveal nisoxetine as a powerful reagent for monitoring multiple dimensions of DA signaling in vivo, thus providing a new resource that can be used to evaluate contributions of dat-1 and other genes linked to DA signaling without the potential for compensations that attend constitutive genetic mutations.

  19. Secondary amine analogues of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters and N-norcocaine exhibit enhanced affinity for serotonin and norepinephrine transporters.

    PubMed

    Boja, J W; Kuhar, M J; Kopajtic, T; Yang, E; Abraham, P; Lewin, A H; Carroll, F I

    1994-04-15

    N-Norcocaine (2) and six N-nor-3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters (4a-f) were synthesized by N-demethylation of cocaine (1) and the appropriate 3 beta-(substituted phenyl)-tropane analogues (3a-f) with alpha-chloroethyl chloroformate. Radioligand binding affinities of 2 and 4a-f at the DA, 5-HT, and NE transporter were measured and compared to those of 1 and 3a-f. N-Demethylation produced relatively small effects at the DA transporter. In contrast, 4-19-fold and 2-44-fold enhanced affinity at the serotonin and norepinephrine transporter resulted from demethylation. N-Nor-3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (4d) with an IC50 = 0.36 nM showed the greatest affinity for the serotonin transporter. However, N-nor-3 beta-(4'-ethylphenyl)tropane-2 beta-carboxylic acid methyl ester (4e) showed the greatest selectivity for the serotonin transporter.

  20. Guam Transportation Petroleum-Use Reduction Plan

    SciTech Connect

    Johnson, C.

    2013-04-01

    The island of Guam has set a goal to reduce petroleum use 20% by 2020. Because transportation is responsible for one-third of on-island petroleum use, the Guam Energy Task Force (GETF), a collaboration between the U.S. Department of Energy and numerous Guam-based agencies and organizations, devised a specific plan by which to meet the 20% goal within the transportation sector. This report lays out GETF's plan.

  1. Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2).

    PubMed

    Nogami, Tsuyoshi; Takano, Harumasa; Arakawa, Ryosuke; Ichimiya, Tetsuya; Fujiwara, Hironobu; Kimura, Yasuyuki; Kodaka, Fumitoshi; Sasaki, Takeshi; Takahata, Keisuke; Suzuki, Masayuki; Nagashima, Tomohisa; Mori, Takaaki; Shimada, Hitoshi; Fukuda, Hajime; Sekine, Mizuho; Tateno, Amane; Takahashi, Hidehiko; Ito, Hiroshi; Okubo, Yoshiro; Suhara, Tetsuya

    2013-06-01

    Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients. PMID:23067569

  2. Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets.

    PubMed

    Zhang, Jingyi; McDonald, Alexander J

    2016-04-01

    Modulatory interactions of opioids and norepinephrine (NE) in the anterior subdivision of the basolateral nucleus of the amygdala (BLa) are critical for the consolidation of memories of emotionally arousing experiences. Although there have been several studies of the noradrenergic system in the amygdalar basolateral nuclear complex (BLC), little is known about the chemical neuroanatomy of opioid systems in this region. To address this knowledge gap the present study first examined the distribution of met-enkephalin-like immunoreactivity (ENK-ir) in the BLC at the light microscopic level, and then utilized dual-labeling immunocytochemistry combined with electron microscopy to investigate the extent of convergence of NE and ENK terminals onto common structures in the BLa. Antibodies to ENK and the norepinephrine transporter (NET) were used in these studies. Light microscopic examination revealed that a subpopulation of small nonpyramidal neurons expressed ENK-ir in all nuclei of the BLC. In addition, the somata of some pyramidal cells exhibited light to moderate ENK-ir. ENK+ axon terminals were also observed. Ultrastructural analysis confined to the BLa revealed that most ENK+ axon terminals formed asymmetrical synapses that mainly contacted spines and shafts of thin dendrites. ENK+ terminals forming symmetrical synapses mainly contacted dendritic shafts. Approximately 20% of NET+ terminals contacted a structure that was also contacted by an ENK+ terminal and 6% of NET+ terminals contacted an ENK+ terminal. These findings suggest that ENK and NE terminals in the BLa may interact by targeting common dendrites and by direct interactions between the two types of terminals. PMID:26835559

  3. Reverse electron transport effects on NADH formation and metmyoglobin reduction.

    PubMed

    Belskie, K M; Van Buiten, C B; Ramanathan, R; Mancini, R A

    2015-07-01

    The objective was to determine if NADH generated via reverse electron flow in beef mitochondria can be used for electron transport-mediated reduction and metmyoglobin reductase pathways. Beef mitochondria were isolated from bovine hearts (n=5) and reacted with combinations of succinate, NAD, and mitochondrial inhibitors to measure oxygen consumption and NADH formation. Mitochondria and metmyoglobin were reacted with succinate, NAD, and mitochondrial inhibitors to measure electron transport-mediated metmyoglobin reduction and metmyoglobin reductase activity. Addition of succinate and NAD increased oxygen consumption, NADH formation, electron transport-mediated metmyoglobin reduction, and reductase activity (p<0.05). Addition of antimycin A prevented electron flow beyond complex III, therefore, decreasing oxygen consumption and electron transport-mediated metmyoglobin reduction. Addition of rotenone prevented reverse electron flow, increased oxygen consumption, increased electron transport-mediated metmyoglobin reduction, and decreased NADH formation. Succinate and NAD can generate NADH in bovine tissue postmortem via reverse electron flow and this NADH can be used by both electron transport-mediated and metmyoglobin reductase pathways. PMID:25828162

  4. Reverse electron transport effects on NADH formation and metmyoglobin reduction.

    PubMed

    Belskie, K M; Van Buiten, C B; Ramanathan, R; Mancini, R A

    2015-07-01

    The objective was to determine if NADH generated via reverse electron flow in beef mitochondria can be used for electron transport-mediated reduction and metmyoglobin reductase pathways. Beef mitochondria were isolated from bovine hearts (n=5) and reacted with combinations of succinate, NAD, and mitochondrial inhibitors to measure oxygen consumption and NADH formation. Mitochondria and metmyoglobin were reacted with succinate, NAD, and mitochondrial inhibitors to measure electron transport-mediated metmyoglobin reduction and metmyoglobin reductase activity. Addition of succinate and NAD increased oxygen consumption, NADH formation, electron transport-mediated metmyoglobin reduction, and reductase activity (p<0.05). Addition of antimycin A prevented electron flow beyond complex III, therefore, decreasing oxygen consumption and electron transport-mediated metmyoglobin reduction. Addition of rotenone prevented reverse electron flow, increased oxygen consumption, increased electron transport-mediated metmyoglobin reduction, and decreased NADH formation. Succinate and NAD can generate NADH in bovine tissue postmortem via reverse electron flow and this NADH can be used by both electron transport-mediated and metmyoglobin reductase pathways.

  5. Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

    PubMed Central

    2013-01-01

    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. PMID:24900709

  6. U.S. Virgin Islands Transportation Petroleum Reduction Plan

    SciTech Connect

    Johnson, C.

    2011-09-01

    This NREL technical report determines a way for USVI to meet its petroleum reduction goal in the transportation sector. It does so first by estimating current petroleum use and key statistics and characteristics of USVI transportation. It then breaks the goal down into subordinate goals and estimates the petroleum impacts of these goals with a wedge analysis. These goals focus on reducing vehicle miles, improving fuel economy, improving traffic flow, using electric vehicles, using biodiesel and renewable diesel, and using 10% ethanol in gasoline. The final section of the report suggests specific projects to achieve the goals, and ranks the projects according to cost, petroleum reduction, time frame, and popularity.

  7. Future developments in transport aircraft noise reduction technology

    SciTech Connect

    Pendley, R.E.

    1982-01-01

    During the past 13 years, important advances in the technology of aircraft noise control have resulted from industry and government research programs. Quieter commercial transport airplanes have entered the fleet and additional new designs now committed to production will begin service in a few years. This paper indicates the noise reductions that will be achieved by the quieter transports that will replace the older designs and remarks on the outlook for still quieter designs.

  8. In vitro binding assays using (3)H nisoxetine and (3)H WIN 35,428 reveal selective effects of gonadectomy and hormone replacement in adult male rats on norepinephrine but not dopamine transporter sites in the cerebral cortex.

    PubMed

    Meyers, B; Kritzer, M F

    2009-03-01

    The prefrontal cortices mediate cognitive functions that critically depend on local dopamine levels. In male rats, many prefrontal tasks where performance is disrupted by changes in dopamine signaling are also impaired by gonadectomy, a manipulation that increases cortical dopamine concentration, prefrontal dopamine axon density and possibly extracellular prefrontal dopamine levels as well. Because these actions could be responsible for the impairing effects of gonadectomy on prefrontal function, the question of how they might arise comes to the fore. Accordingly, the present studies asked whether dopamine levels might be increased via a hormone sensitivity of transporter-mediated dopamine uptake. Specifically, (3)H WIN 35,428 and (3)H nisoxetine, ligands selective for the dopamine (DAT)- and norepinephrine transporter (NET) respectively, were used in in vitro binding assays to ask whether gonadectomy altered transporter affinity (Kd) and/or binding site number (Bmax) in prefrontal cortex, sensorimotor cortex and/or caudate. Assays performed on tissues dissected from sham-operated, gonadectomized and gonadectomized rats supplemented with testosterone propionate or estradiol for 4 or 28 days revealed no significant group differences or obvious trends in Kd or Bmax for DAT binding or in measures of Bmax for NET binding. However, affinity constants for (3)H nisoxetine were found to be significantly higher in sensorimotor and/or prefrontal cortex of rats gonadectomized and gonadectomized and supplemented with estradiol for 4 or 28 days but similar to control in gonadectomized rats given testosterone. Because the NET contributes substantially to extracellular prefrontal dopamine clearance, these androgen-mediated effects could influence prefrontal dopamine levels and might thus be relevant for observed effects of gonadectomy on dopamine-dependent prefrontal behaviors. A hormone sensitivity of the NET could also have bearing on the prefrontal dopamine dysfunction seen in

  9. Campus Sustainability: Climate Change, Transport and Paper Reduction

    ERIC Educational Resources Information Center

    Atherton, Alison; Giurco, Damien

    2011-01-01

    Purpose: This paper aims to detail the design of a campus climate change strategy, transport strategy and paper reduction strategy at the University of Technology, Sydney (Australia). Design/methodology/approach: The approach to strategy development used desktop research and staff/student consultation to inform the development of objectives,…

  10. Reductive dissolution and metal transport in lake coeur d alenesediments

    SciTech Connect

    Sengor, Sevinc.S.; Spycher, Nicolas.F.; Ginn, Timothy.R.; Moberly, James; Peyton, B.; Sani, Rajesh.K.

    2007-04-27

    The benthic sediments in Lake Coeur d Alene, northern Idaho,have been contaminated by metals (primarily Zn, Pb, and Cu) from decadesof upstream mining activities. As part of ongoing research on thebiogeo-chemical cycling of metals in this area, a diffusivereactive-transport model has been developed to simulate metal transportin the lake sediments. The model includes 1-D inorganic diffusivetransport coupled to a biotic reaction network with multiple terminalelectron acceptors under redox disequilibrium conditions. Here, the modelis applied to evaluate the competing effects of heavy-metal mobilizationthrough biotic reductive dissolution of Fe(III) (hydr)oxides, andimmobilization as biogenic sulfide minerals. Results indicate that therelative rates of Fe and sulfate reduction could play an important rolein metal transport through the envi-ronment, and that the formation of(bi)sulfide complexes could significantly enhance metal solubility, aswell as desorption from Fe hydroxides.

  11. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison.

    PubMed

    Sansone, Randy A; Sansone, Lori A

    2014-03-01

    The serotonin norepinephrine reuptake inhibitors are a family of antidepressants that inhibit the reuptake of both serotonin and norepinephrine. While these drugs are traditionally considered a group of inter-related antidepressants based upon reuptake inhibition, they generally display different chemical structures as well as different pharmacological properties. In this article, we discuss these and other differences among the serotonin norepinephrine reuptake inhibitors, including the year of approval by the United States Food and Drug Administration, generic availability, approved clinical indications, half-lives, metabolism and excretion, presence or not of active metabolites, dosing schedules, proportionate effects on serotonin and norepinephrine, and the timing of serotonin and norepinephrine reuptake (i.e., sequential or simultaneous). Again, while serotonin norepinephrine reuptake inhibitors are grouped as a family of antidepressants, they exhibit a surprising number of differences- differences that may ultimately relate to clinical nuances in patient care. PMID:24800132

  12. Control, Transport Reduction and Diagnostic use of Feedback

    NASA Astrophysics Data System (ADS)

    Sen, A. K.

    1999-11-01

    In the past we have reported on feedback suppression of a variety of micro-instabilities in the Columbia Linear Machine via an electron/ion beam suppressor. These include a curvature driven trapped particle mode, an E×B flute mode and an ITG mode; sometimes two of them simultaneously. We now report on reduction and scaling of transport under feedback. The anomalous particle transport due to an E×B centrifugally driven mode has been measured via cross-correlation of density and potential fluctuations. The transport is found to be reduced by up to a factor of three under feedback. By controlling the fluctuation amplitudes and consequently the transport via feedback, we find the scaling of diffusion coefficient to be linear with RMS fluctuation level. The scaling appears not to agree with any generic theory. Recently, we have performed a numerical experiment on feedback control of dissipative drift wave instability in collaboration with ETP, University of Marseille. The preliminary result is that even a highly chaotic state of the instability can be suppressed, if the feedback delay is less than the correlation time of fluctuations. We will explore the implication of these results for the remote prospect of reduction of micro-turbulence and associated transport. We are also persuing a variety of diagnostic uses of feedback. The primary goal is an experimental methodology for the determination of dynamic models of plasma turbulence, both for better transport understanding and more credible feedback controller designs. A specific motivation is to search for a low order dynamic model, suitable for the convenient study of both transport and feedback. First, we use time series analysis method for the determination of chaotic attractor dimension of plasma fluctuations. For E×B rotational flute modes it is found to be close to three, indicating that a model of three coupled modes may be adequate for transport prediction and feedback controller design. Secondly, we have

  13. Muscle and whole body metabolism after norepinephrine.

    PubMed

    Kurpad, A V; Khan, K; Calder, A G; Elia, M

    1994-06-01

    The effect of an infusion of norepinephrine (0.42 nmol.kg-1.min-1) on energy metabolism in the whole body (using indirect calorimetry and the arteriovenous forearm catheterization techniques in eight healthy young male adults. The activity of the triglyceride-fatty acid cycle, which mainly operates in nonmuscular tissues, was also assessed by measuring glycerol turnover using [2H5]glycerol (to indicate lipolysis) and indirect calorimetry (to indicate net fat oxidation). Norepinephrine increased whole body oxygen consumption by almost 10% (P < 0.01), but the estimated oxygen consumption of muscles tended to decrease. Muscle blood flow (measured by 133Xe) and forearm blood flow (measured by strain-gauge plethysmography) were not significantly affected by norepinephrine, but the rate of uptake of nonesterified fatty acids and beta-hydroxybutyrate increased severalfold (P < 0.05), whereas that of glucose did not. The activity of the triglyceride-fatty acid cycle increased fourfold after norepinephrine administration, having a marginal effect on resting energy expenditure (approximately 1.5%) but accounting for approximately 15% of the increase in whole body energy expenditure. This study provides no evidence that skeletal muscle is an important site for norepinephrine-induced thermogenesis and suggests that an increase in the activity of the triglyceride-fatty acid cycle contributes to the norepinephrine-induced increase in energy expenditure of nonmuscular tissues.

  14. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A

    2014-11-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report on the Children's Depression Inventory and adult counselor report on the Teacher Report Form. DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter, and corticotropin releasing hormone receptor 1. Analyses of covariance with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their Gene × Environment (G × E) interactions. Maltreatment consistently was associated with higher Children's Depression Inventory and Teacher Report Form symptoms. The results for child self-report symptoms indicated a G × E interaction for BDNF and maltreatment. In addition, BDNF and triallelic 5-HTTLPR interacted with child maltreatment in a G × G × E interaction. Analyses for counselor report of child anxiety/depression symptoms on the Teacher Report Form indicated moderation of child maltreatment effects by triallelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. Norepinephrine transporter was found to further moderate the G × E interaction of 5-HTTLPR and maltreatment status, revealing a G × G × E interaction. This G × G × E was extended by consideration of variation in maltreatment subtype experiences. Finally, G × G × E effects were observed for the co-action of BDNF and the corticotropin releasing hormone receptor 1

  15. Dietary nitrogen reduction enhances urea transport across goat rumen epithelium.

    PubMed

    Muscher, A S; Schröder, B; Breves, G; Huber, K

    2010-10-01

    Ruminants are very capable of adapting their N homeostasis to a reduced dietary N intake. However, the limits of this physiological adaptation are still unknown. The aim of the present study was to determine the quantity of dietary N intake at which the needs of the animal are still satisfied. A study was performed in young White Saanen goats under conditions of dietary N reduction. Different semisynthetic diets with 19 to 7% CP were fed. Urea transport rates across the rumen epithelium from the blood into the ruminal fluid were quantified by Ussing chamber experiments. Reduced N intake increased urea transport rates across the mucosa, which could be inhibited by phloretin. The role of parietal urease in driving urea transfer across the epithelium was negligible because its activity was inhibited by antibiotics during in vitro incubations of the epithelium. Concentrations of ammonia in the ruminal fluid were decreased by reducing dietary N intake, accompanied by diminished urease activity at the smallest dietary N intake. Over the range of plasma urea concentrations observed in the different feeding groups, salivary urea concentrations were 73% of plasma urea concentrations. By plotting plasma urea concentrations against serosal to mucosal urea flux rates, a threshold at 1.75 mmol of urea/L of plasma could be assessed, below which urea flux was strongly increased. This indicates that rumen urea transfer could be stimulated by decreased plasma urea concentrations via unknown mechanisms. The physiological relevance of this adaptation of the rumen epithelium is that it is considered a central mechanism in the N homeostasis of growing goats under reduced N intake.

  16. Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis.

    PubMed

    Stolk, Roeland F; van der Poll, Tom; Angus, Derek C; van der Hoeven, Johannes G; Pickkers, Peter; Kox, Matthijs

    2016-09-01

    Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth-promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted. PMID:27398737

  17. Perinatal reduction of functional serotonin transporters results in developmental delay.

    PubMed

    Kroeze, Yvet; Dirven, Bart; Janssen, Stefan; Kröhnke, Marijke; Barte, Ramona M; Middelman, Anthonieke; van Bokhoven, Hans; Zhou, Huiqing; Homberg, Judith R

    2016-10-01

    While there is strong evidence from rodent and human studies that a reduction in serotonin transporter (5-HTT) function in early-life can increase the risk for several neuropsychiatric disorders in adulthood, the effects of reduced 5-HTT function on behavior across developmental stages are underinvestigated. To elucidate how perinatal pharmacological and lifelong genetic inactivation of the 5-HTT affects behavior across development, we conducted a battery of behavioral tests in rats perinatally exposed to fluoxetine or vehicle and in 5-HTT(-/-) versus 5-HTT(+/+) rats. We measured motor-related behavior, olfactory function, grooming behavior, sensorimotor gating, object directed behavior and novel object recognition in the first three postnatal weeks and if possible the tests were repeated in adolescence and adulthood. We also measured developmental milestones such as eye opening, reflex development and body weight. We observed that both pharmacological and genetic inactivation of 5-HTT resulted in a developmental delay. Except for hypo-locomotion, most of the observed early-life effects were normalized later in life. In adolescence and adulthood we observed object directed behavior and decreased novel object recognition in the 5-HTT(-/-) rats, which might be related to the lifelong inactivation of 5-HTT. Together, these data provide an important contribution to the understanding of the effects of perinatal and lifelong 5-HTT inactivation on behavior across developmental stages. PMID:27208789

  18. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction.

    PubMed

    Zaniewska, Magdalena; Filip, Małgorzata; Przegalinski, Edmund

    2015-01-01

    Although it is generally accepted that the abuse-related effects of amphetamines and cocaine result from the activation of the brain dopaminergic (DA) system, the psychostimulants also alter other neurotransmitter systems. In particular, they increase extracellular levels of norepinephrine (NE) and serotonin by inhibiting respective plasma membrane transporters and/or inducing release. The present review will discuss the preclinical findings on the effects of the NE system modulation (lesions, pharmacological and genetic approaches) on behaviors (locomotor hyperactivity, behavioral sensitization, modification of intracranial self-stimulation, conditioned place preference, drug self-administration, extinction/reinstatement of drug seeking behavior) related to the psychostimulant addiction. PMID:26411968

  19. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction

    PubMed Central

    Zaniewska, Magdalena; Filip, Małgorzata; Przegaliński, Edmund

    2015-01-01

    Although it is generally accepted that the abuse-related effects of amphetamines and cocaine result from the activation of the brain dopaminergic (DA) system, the psychostimulants also alter other neurotransmitter systems. In particular, they increase extracellular levels of norepinephrine (NE) and serotonin by inhibiting respective plasma membrane transporters and/or inducing release. The present review will discuss the preclinical findings on the effects of the NE system modulation (lesions, pharmacological and genetic approaches) on behaviors (locomotor hyperactivity, behavioral sensitization, modification of intracranial self-stimulation, conditioned place preference, drug self-administration, extinction/reinstatement of drug seeking behavior) related to the psychostimulant addiction. PMID:26411968

  20. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction.

    PubMed

    Zaniewska, Magdalena; Filip, Małgorzata; Przegalinski, Edmund

    2015-01-01

    Although it is generally accepted that the abuse-related effects of amphetamines and cocaine result from the activation of the brain dopaminergic (DA) system, the psychostimulants also alter other neurotransmitter systems. In particular, they increase extracellular levels of norepinephrine (NE) and serotonin by inhibiting respective plasma membrane transporters and/or inducing release. The present review will discuss the preclinical findings on the effects of the NE system modulation (lesions, pharmacological and genetic approaches) on behaviors (locomotor hyperactivity, behavioral sensitization, modification of intracranial self-stimulation, conditioned place preference, drug self-administration, extinction/reinstatement of drug seeking behavior) related to the psychostimulant addiction.

  1. Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors.

    PubMed

    Mease, Philip J

    2009-12-01

    Fibromyalgia and associated conditions such as irritable bowel syndrome and temporomandibular disorder involve dysfunctions in central sensitization and pain modulation. Central nervous system dysfunction may also contribute to other symptoms characteristic of fibromyalgia, such as fatigue and sleep disturbance. Two key neurotransmitters in the pain modulation pathway are serotonin and norepinephrine. Preclinical studies using animal models of chronic pain have shown that pharmacologic agents that combine serotonergic and noradrenergic reuptake inhibition, thus augmenting the function of these neurotransmitters, have stronger analgesic effects than agents that inhibit reuptake of either neurotransmitter alone. Although tricyclic antidepressants (TCAs) inhibit reuptake of both serotonin and norepinephrine and have shown efficacy for the treatment of fibromyalgia, long-term use of these drugs is limited owing to poor tolerability. Unlike TCAs, the newer dual reuptake inhibitors of serotonin and norepinephrine, such as the drugs approved by the US Food and Drug Administration (FDA) for fibromyalgia, milnacipran and duloxetine, do not possess significant affinity for other neurotransmitter systems, resulting in diminished side effects and enhanced tolerability. Both duloxetine and milnacipran have shown efficacy in clinical trials by improving pain and other symptoms associated with fibromyalgia. Both compounds inhibit the serotonin and norepinephrine transporters; however, there is a difference in their affinities and selectivity for these transporters. Although duloxetine has affinity for both receptors, it is somewhat more selective for the serotonin transporter. In contrast, milnacipran is somewhat more selective for norepinephrine than serotonin reuptake inhibition. Pharmacologic agents that specifically target serotonin and norepinephrine reuptake may prove to be valuable tools in the treatment of fibromyalgia.

  2. Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity.

    PubMed

    Brown, Dean G; Bernstein, Peter R; Wu, Ye; Urbanek, Rebecca A; Becker, Christopher W; Throner, Scott R; Dembofsky, Bruce T; Steelman, Gary B; Lazor, Lois A; Scott, Clay W; Wood, Michael W; Wesolowski, Steven S; Nugiel, David A; Koch, Stephanie; Yu, Jian; Pivonka, Donald E; Li, Shuang; Thompson, Carol; Zacco, Anna; Elmore, Charles S; Schroeder, Patricia; Liu, JianWei; Hurley, Christopher A; Ward, Stuart; Hunt, Hazel J; Williams, Karen; McLaughlin, Joseph; Hoesch, Valerie; Sydserff, Simon; Maier, Donna; Aharony, David

    2013-01-10

    Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay. PMID:24900562

  3. Reduction of asymmetry transport in the annular Penning trap

    NASA Astrophysics Data System (ADS)

    Robertson, Scott; Sternovsky, Zoltan; Walch, Bob

    2004-05-01

    In the Penning trap, there is transport of electrons in the limit of zero gas pressure that arises from asymmetric stray electric fields. In an annular version of the Penning trap, this asymmetry transport is shown to be greatly reduced when the plasma-facing surfaces are coated with colloidal graphite. In a separate device, an emissive probe is used to examine the space potential a few millimeters above coated and uncoated surfaces. It is found that the rms potential variation is approximately 250 mV for uncoated surfaces and 15 mV for coated surfaces. The characteristic length scale of the inhomogeneities is ˜1 cm. Glow-discharge cleaning, which is easily renewed, is shown to reduce the potential variation to the same level that is obtained with the colloidal graphite coating.

  4. Transportation Energy Futures: Combining Strategies for Deep Reductions in Energy Consumption and GHG Emissions (Brochure)

    SciTech Connect

    Not Available

    2013-03-01

    This fact sheet summarizes actions in the areas of light-duty vehicle, non-light-duty vehicle, fuel, and transportation demand that show promise for deep reductions in energy use. Energy efficient transportation strategies have the potential to simultaneously reduce oil consumption and greenhouse gas (GHG) emissions. The Transportation Energy Futures (TEF) project examined how the combination of multiple strategies could achieve deep reductions in GHG emissions and petroleum use on the order of 80%. Led by NREL, in collaboration with Argonne National Laboratory, the project's primary goal was to help inform domestic decisions about transportation energy strategies, priorities, and investments, with an emphasis on underexplored opportunities. TEF findings reveal three strategies with the potential to displace most transportation-related petroleum use and GHG emissions: 1) Stabilizing energy use in the transportation sector through efficiency and demand-side approaches. 2) Using additional advanced biofuels. 3) Expanding electric drivetrain technologies.

  5. MASS TRANSPORT EFFECTS ON THE KINETICS OF NITROBENZENE REDUCTION BY IRON METAL. (R827117)

    EPA Science Inventory

    To evaluate the importance of external mass transport on the overall rates of
    contaminant reduction by iron metal (Fe0), we have compared measured
    rates of surface reaction for nitrobenzene (ArNO2) to estimated rates
    of external mass transport...

  6. Estrogen depletion increases blood pressure and hypothalamic norepinephrine in middle-aged spontaneously hypertensive rats.

    PubMed

    Peng, Ning; Clark, John T; Wei, Chi-Chang; Wyss, J Michael

    2003-05-01

    In male spontaneously hypertensive rats (SHR) a high NaCl diet increases arterial pressure via a reduction in anterior hypothalamic nucleus norepinephrine release. Young female SHR are relatively well protected from this NaCl-sensitive hypertension, but depletion of both endogenous and dietary estrogens greatly exacerbates NaCl-sensitive hypertension. This study tests the hypothesis that estrogen also protects late middle-aged female SHR from NaCl-sensitive hypertension and that this effect is mediated by an estrogen-related effect on hypothalamic norepinephrine release. Ten-month-old female SHR were ovariectomized and placed on a phytoestrogen-free diet containing either basal or high NaCl. Each rat was implanted with a silastic tube containing 17beta estradiol or vehicle. Three months later, arterial pressure and hypothalamic norepinephrine metabolite levels (MOPEG) were measured. On the basal NaCl diet, estrogen-depleted rats displayed increased arterial pressure (12 mm Hg) and decreased anterior hypothalamic nucleus MOPEG (20%). Both effects were reversed by estrogen treatment. In all groups, the high NaCl diet increased arterial pressure by over 35 mm Hg and reduced anterior hypothalamic nucleus MOPEG by >60%. Across all groups, there was a significant inverse correlation between arterial pressure and anterior hypothalamic nucleus MOPEG. These data suggest that both dietary NaCl excess and estrogen depletion raise arterial pressure in middle-aged female SHR by a decreasing hypothalamic norepinephrine.

  7. VEGF-induced antidepressant effects involve modulation of norepinephrine and serotonin systems.

    PubMed

    Udo, Hiroshi; Hamasu, Kousuke; Furuse, Mitsuhiro; Sugiyama, Hiroyuki

    2014-12-15

    Throughout life, we are exposed to a variety of stresses, which may be inevitable and noxious sometimes. During evolution, animals must have acquired some physiological means to counteract stress. Vascular endothelial growth factor (VEGF) is an angiogenic and neurogenic factor, which has been shown to elicit antidepressant-like effects in response to different external stimuli, potentially functioning as an anti-stress molecule. However, it remains largely unknown how VEGF modulates mood-related behaviors. To investigate molecular correlates, we analyzed monoaminergic systems of VEGF transgenic mice that display antidepressant-like behavior. Immunostaining showed that overall morphologies of monoaminergic nuclei and their processes were normal. However, we found imbalances in brain monoamine contents, in which the levels of norepinephrine and serotonin, but not dopamine, were decreased exclusively in the regions where VEGF was expressed. The turnover of norepinephrine showed a marked increase and serotonin turnover showed a modest reduction, whereas dopamine turnover was not affected. The protein levels of tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes of catecholamine and serotonin synthesis, remained constant. The mRNA levels of monoamine receptors were generally similar but adrenergic receptors of ADRα1A and ADRβ1 were down-regulated. Behavioral tests showed that serotonin- or norepinephrine-selective antidepressant drugs failed to additively enhance antidepressant-like behaviors, whereas monoamine depleting drugs attenuated VEGF-mediated antidepressant-like effect. These data suggest that VEGF-induced antidepressant-like effects involve modulation of norepinephrine and serotonin systems.

  8. Transportation Energy Futures Series. Effects of Travel Reduction and Efficient Driving on Transportation. Energy Use and Greenhouse Gas Emissions

    SciTech Connect

    Porter, C. D.; Brown, A.; DeFlorio, J.; McKenzie, E.; Tao, W.; Vimmerstedt, L.

    2013-03-01

    Since the 1970s, numerous transportation strategies have been formulated to change the behavior of drivers or travelers by reducing trips, shifting travel to more efficient modes, or improving the efficiency of existing modes. This report summarizes findings documented in existing literature to identify strategies with the greatest potential impact. The estimated effects of implementing the most significant and aggressive individual driver behavior modification strategies range from less than 1% to a few percent reduction in transportation energy use and GHG emissions. Combined strategies result in reductions of 7% to 15% by 2030. Pricing, ridesharing, eco-driving, and speed limit reduction/enforcement strategies are widely judged to have the greatest estimated potential effect, but lack the widespread public acceptance needed to accomplish maximum results. This is one of a series of reports produced as a result of the Transportation Energy Futures (TEF) project, a Department of Energy-sponsored multi-agency project initiated to pinpoint underexplored strategies for abating GHGs and reducing petroleum dependence related to transportation.

  9. Transportation Energy Futures Series: Effects of Travel Reduction and Efficient Driving on Transportation: Energy Use and Greenhouse Gas Emissions

    SciTech Connect

    Porter, C. D.; Brown, A.; DeFlorio, J.; McKenzie, E.; Tao, W.; Vimmerstedt, L.

    2013-03-01

    Since the 1970s, numerous transportation strategies have been formulated to change the behavior of drivers or travelers by reducing trips, shifting travel to more efficient modes, or improving the efficiency of existing modes. This report summarizes findings documented in existing literature to identify strategies with the greatest potential impact. The estimated effects of implementing the most significant and aggressive individual driver behavior modification strategies range from less than 1% to a few percent reduction in transportation energy use and GHG emissions. Combined strategies result in reductions of 7% to 15% by 2030. Pricing, ridesharing, eco-driving, and speed limit reduction/enforcement strategies are widely judged to have the greatest estimated potential effect, but lack the widespread public acceptance needed to accomplish maximum results. This is one of a series of reports produced as a result of the Transportation Energy Futures (TEF) project, a Department of Energy-sponsored multi-agency project initiated to pinpoint underexplored strategies for abating GHGs and reducing petroleum dependence related to transportation.

  10. Transformative Reduction of Transportation Greenhouse Gas Emissions. Opportunities for Change in Technologies and Systems

    SciTech Connect

    Vimmerstedt, Laura; Brown, Austin; Newes, Emily; Markel, Tony; Schroeder, Alex; Zhang, Yimin; Chipman, Peter; Johnson, Shawn

    2015-04-30

    The transportation sector is changing, influenced by concurrent, ongoing, dynamic trends that could dramatically affect the future energy landscape, including effects on the potential for greenhouse gas emissions reductions. Battery cost reductions and improved performance coupled with a growing number of electric vehicle model offerings are enabling greater battery electric vehicle market penetration, and advances in fuel cell technology and decreases in hydrogen production costs are leading to initial fuel cell vehicle offerings. Radically more efficient vehicles based on both conventional and new drivetrain technologies reduce greenhouse gas emissions per vehicle-mile. Net impacts also depend on the energy sources used for propulsion, and these are changing with increased use of renewable energy and unconventional fossil fuel resources. Connected and automated vehicles are emerging for personal and freight transportation systems and could increase use of low- or non-emitting technologies and systems; however, the net effects of automation on greenhouse gas emissions are uncertain. The longstanding trend of an annual increase in transportation demand has reversed for personal vehicle miles traveled in recent years, demonstrating the possibility of lower-travel future scenarios. Finally, advanced biofuel pathways have continued to develop, highlighting low-carbon and in some cases carbon-negative fuel pathways. We discuss the potential for transformative reductions in petroleum use and greenhouse gas emissions through these emerging transportation-sector technologies and trends and present a Clean Transportation Sector Initiative scenario for such reductions, which are summarized in Table ES-1.

  11. Effects of optimal initial errors on predicting the seasonal reduction of the upstream Kuroshio transport

    NASA Astrophysics Data System (ADS)

    Zhang, Kun; Wang, Qiang; Mu, Mu; Liang, Peng

    2016-10-01

    With the Regional Ocean Modeling System (ROMS), we realistically simulated the transport variations of the upstream Kuroshio (referring to the Kuroshio from its origin to the south of Taiwan), particularly for the seasonal transport reduction. Then, we investigated the effects of the optimal initial errors estimated by the conditional nonlinear optimal perturbation (CNOP) approach on predicting the seasonal transport reduction. Two transport reduction events (denoted as Event 1 and Event 2) were chosen, and CNOP1 and CNOP2 were obtained for each event. By examining the spatial structures of the two types of CNOPs, we found that the dominant amplitudes are located around (128°E, 17°N) horizontally and in the upper 1000 m vertically. For each event, the two CNOPs caused large prediction errors. Specifically, at the prediction time, CNOP1 (CNOP2) develops into an anticyclonic (cyclonic) eddy-like structure centered around 124°E, leading to the increase (decrease) of the upstream Kuroshio transport. By investigating the time evolution of the CNOPs in Event 1, we found that the eddy-like structures originating from east of Luzon gradually grow and simultaneously propagate westward. The eddy-energetic analysis indicated that the errors obtain energy from the background state through barotropic and baroclinic instabilities and that the latter plays a more important role. These results suggest that improving the initial conditions in east of Luzon could lead to better prediction of the upstream Kuroshio transport variation.

  12. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury.

    PubMed

    Lankadeva, Yugeesh R; Kosaka, Junko; Evans, Roger G; Bailey, Simon R; Bellomo, Rinaldo; May, Clive N

    2016-07-01

    Norepinephrine is the principal vasopressor used to restore blood pressure in sepsis, but its effects on intrarenal oxygenation are unknown. To clarify this, we examined renal cortical, medullary, and urinary oxygenation in ovine septic acute kidney injury and the response to resuscitation with norepinephrine. A renal artery flow probe and fiberoptic probes were placed in the cortex and medulla of sheep to measure tissue perfusion and oxygenation. A probe in the bladder catheter measured urinary oxygenation. Sepsis was induced in conscious sheep by infusion of Escherichia coli for 32 hours. At 24 to 30 hours of sepsis, either norepinephrine, to restore mean arterial pressure to preseptic levels or vehicle-saline was infused (8 sheep per group). Septic acute kidney injury was characterized by a reduction in blood pressure of ∼12 mm Hg, renal hyperperfusion, and oliguria. Sepsis reduced medullary perfusion (from an average of 1289 to 628 blood perfusion units), medullary oxygenation (from 32 to 16 mm Hg), and urinary oxygenation (from 36 to 24 mm Hg). Restoring blood pressure with norepinephrine further reduced medullary perfusion to an average of 331 blood perfusion units, medullary oxygenation to 8 mm Hg and urinary oxygenation to 18 mm Hg. Cortical perfusion and oxygenation were preserved. Thus, renal medullary hypoxia caused by intrarenal blood flow redistribution may contribute to the development of septic acute kidney injury, and resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. The parallel changes in medullary and urinary oxygenation suggest that urinary oxygenation may be a useful real-time biomarker for risk of acute kidney injury. PMID:27165831

  13. Anaerobic Fe(III) reduction by Shewanella putrefaciens: Analysis of the electron transport chain

    SciTech Connect

    Daad Saffarini

    2004-01-20

    The goals of the project were to isolate mutants that are deficient in metal reduction, identify components of the electron transport chain that are involved in this process, and purify some of these proteins for biochemical analyses. In the 3-year period since the start of the project, we have accomplished many of these goals. We have isolated several new S. oneidensis mutants that are deficient in metal reduction, and have initiated the development of vectors for the overexpression of cytochromes and other proteins in S. oneidensis. We have also overexpressed CymA, one of the c cytochromes that are involved in metal reduction.

  14. Conductivity reduction due to emulsification during surfactant enhanced-aquifer remediation. 1. Emulsion transport.

    PubMed

    Jain, Vivek; Demond, Avery H

    2002-12-15

    Surfactant-enhanced aquifer remediation (SEAR) is a promising technology for the remediation of subsurface zones contaminated with organic liquids. To ensure the success of SEAR, the potential reduction in hydraulic conductivity must be evaluated. The objective of this study was to examine the process of conductivity reduction due to the transport of an emulsion, generated by mixing tetrachloroethylene with 4% solutions of two nonionic surfactants, in packed beds of sand-sized silica particles. The injection of the emulsion resulted in a 75-85% reduction in conductivity, depending on the properties of the surfactant and the porous medium. The greater viscosity of the emulsion relative to that of water accounted for about 25% of the reduction. The remainder was attributed to the clogging of the porous medium by the emulsion. The relative sizes of the emulsion droplets and the packed bed's pores, coupled with measurements of zeta potential of the emulsion droplets and silica particles, suggested that multilayer deposition was the principal mechanism of clogging. This hypothesis was corroborated by direct observation of the emulsion transport process in a micromodel. To simulate the reduction in hydraulic conductivity in these systems accurately, it was necessary to modify the emulsion transport model by Soo and Radke to include the phenomena of viscosity variation and multilayering.

  15. Physiology and biochemistry of reduction of azo compounds by Shewanella strains relevant to electron transport chain

    PubMed Central

    Gu, Ji-Dong

    2010-01-01

    Azo dyes are toxic, highly persistent, and ubiquitously distributed in the environments. The large-scale production and application of azo dyes result in serious environmental pollution of water and sediments. Bacterial azo reduction is an important process for removing this group of contaminants. Recent advances in this area of research reveal that azo reduction by Shewanella strains is coupled to the oxidation of electron donors and linked to the electron transport and energy conservation in the cell membrane. Up to date, several key molecular components involved in this reaction have been identified and the primary electron transportation system has been proposed. These new discoveries on the respiration pathways and electron transfer for bacterial azo reduction has potential biotechnological implications in cleaning up contaminated sites. PMID:20706834

  16. Physiology and biochemistry of reduction of azo compounds by Shewanella strains relevant to electron transport chain.

    PubMed

    Hong, Yi-Guo; Gu, Ji-Dong

    2010-10-01

    Azo dyes are toxic, highly persistent, and ubiquitously distributed in the environments. The large-scale production and application of azo dyes result in serious environmental pollution of water and sediments. Bacterial azo reduction is an important process for removing this group of contaminants. Recent advances in this area of research reveal that azo reduction by Shewanella strains is coupled to the oxidation of electron donors and linked to the electron transport and energy conservation in the cell membrane. Up to date, several key molecular components involved in this reaction have been identified and the primary electron transportation system has been proposed. These new discoveries on the respiration pathways and electron transfer for bacterial azo reduction has potential biotechnological implications in cleaning up contaminated sites.

  17. Human class II (pi) alcohol dehydrogenase has a redox-specific function in norepinephrine metabolism.

    PubMed Central

    Mårdh, G; Dingley, A L; Auld, D S; Vallee, B L

    1986-01-01

    Studies of the function of human alcohol dehydrogenase (ADH) have revealed substrates that are virtually unique for class II ADH (pi ADH). It catalyzes the formation of the intermediary glycols of norepinephrine metabolism, 3,4-dihydroxyphenylglycol and 4-hydroxy-3-methoxyphenylglycol, from the corresponding aldehydes 3,4-dihydroxymandelaldehyde and 4-hydroxy-3-methoxymandelaldehyde with Km values of 55 and 120 microM and kcat/Km ratios of 14,000 and 17,000 mM-1 X min-1; these are from 60- to 210-fold higher than those obtained with class I ADH isozymes. The catalytic preference of class II ADH also extends to benzaldehydes. The kcat/Km values for the reduction of benzaldehyde, 3,4-dihydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde by pi ADH are from 9- to 29-fold higher than those for a class I isozyme, beta 1 gamma 2 ADH. Furthermore, the norepinephrine aldehydes are potent inhibitors of alcohol (ethanol) oxidation by pi ADH. The high catalytic activity of pi ADH-catalyzed reduction of the aldehydes in combination with a possible regulatory function of the aldehydes in the oxidative direction leads to essentially "unidirectional" catalysis by pi ADH. These features and the presence of pi ADH in human liver imply a physiological role for pi ADH in the degradation of circulating epinephrine and norepinephrine. PMID:3466164

  18. Reductive dissolution and reactive solute transport in a sewage-contaminated glacial outwash aquifer

    USGS Publications Warehouse

    Lee, R.W.; Bennett, P.C.

    1998-01-01

    Contamination of shallow ground water by sewage effluent typically contains reduced chemical species that consume dissolved oxygen, developing either a low oxygen geochemical environment or an anaerobic geochemical environment. Based on the load of reduced chemical species discharged to shallow ground water and the amounts of reactants in the aquifer matrix, it should be possible to determine chemical processes in the aquifer and compare observed results to predicted ones. At the Otis Air Base research site (Cape Cod, Massachusetts) where sewage effluent has infiltrated the shallow aquifer since 1936, bacterially mediated processes such as nitrification, denitrification, manganese reduction, and iron reduction have been observed in the contaminant plume. In specific areas of the plume, dissolved manganese and iron have increased significantly where local geochemical conditions are favorable for reduction and transport of these constituents from the aquifer matrix. Dissolved manganese and iron concentrations ranged from 0.02 to 7.3 mg/L, and 0.001 to 13.0 mg/L, respectively, for 21 samples collected from 1988 to 1989. Reduction of manganese and iron is linked to microbial oxidation of sewage carbon, producing bicarbonate and the dissolved metal ions as by-products. Calculated production and flux of CO2 through the unsaturated zone from manganese reduction in the aquifer was 0.035 g/m2/d (12% of measured CO2 flux during winter). Manganese is limited in the aquifer, however. A one-dimensional, reaction-coupled transport model developed for the mildly reducing conditions in the sewage plume nearest the source beds showed that reduction, transport, and removal of manganese from the aquifer sediments should result in iron reduction where manganese has been depleted.

  19. Evaluation of simultaneous reduction and transport of selenium in saturated soil columns

    NASA Astrophysics Data System (ADS)

    Guo, Lei; Frankenberger, William T.; Jury, William A.

    1999-03-01

    Speciation plays an important role in determining the overall leachability of selenium in soil. In this study we present a mathematical model and results of miscible displacement experiments that were conducted to evaluate simultaneous reduction and transport of selenate in saturated soil columns. The experiments were carried out in organic amended (compost manure or gluten) or unamended soil, with O2-sparged or nonsparged influent solution. In all columns, reduction of selenate was fast enough to produce selenite flux in the effluent and elemental Se in the soil profile during a mean residence time of ˜30 hours. Reduction was accelerated in the presence of organic amendments and under low O2 concentrations, resulting in an increased retardation of selenium transport as a whole. The results of our experiments show that although selenate does not sorb to solid surfaces during transport, it reduces rapidly to forms that are strongly retarded. On the basis of simulation with the consecutive reaction and transport model using parameters derived from this study, selenium is expected to be retained near the soil surface, even under extreme leaching conditions.

  20. Reactive transport modeling of chromium isotope fractionation during Cr(VI) reduction.

    PubMed

    Jamieson-Hanes, Julia H; Amos, Richard T; Blowes, David W

    2012-12-18

    Chromium isotope fractionation is indicative of mass-transfer processes, such as reduction of Cr(VI) to Cr(III) during groundwater remediation. Laboratory experiments comparing batch and column treatment of Cr(VI) using organic carbon suggest that the associated isotope fractionation may be influenced by solute-transport mechanisms. These batch and column experiments were simulated using the reactive transport model MIN3P to further evaluate the effects of Cr reduction and transport on isotope fractionation under saturated flow conditions. Simulation of the batch experiment provided a good fit to the experimental data, where a fractionation factor (α₅₃) of 0.9965 was attributed to a single, dominant Cr(VI) removal mechanism. Calibration of the column simulations to the experimental results suggested the presence of a second, more rapid Cr(VI) removal mechanism with α₅₃ = 0.9992. Results from this study demonstrate that the interpretation of Cr isotope fractionation during reduction can be complex, particularly where multiple removal mechanisms are evident. Reactive transport modeling of Cr isotope fractionation can provide a quantitative assessment of the contaminant removal mechanisms, thus improving the application of Cr isotope measurements as a tool to track Cr(VI) migration and attenuation in groundwater.

  1. Histamine, norepinephrine and serotonin content of nasal polyps.

    PubMed

    Bumsted, R M; El-Ackad, T; Smith, J M; Brody, M J

    1979-05-01

    Histamine, norepinephrine and serotonin were assayed and localized by fluorescence histochemistry in normal mucosa and nasal polyps because of their possible role in the development of inflammation and edema. Histamine was present in greater concentration in nasal polyps than in normal mucosa. Norepinephrine was present primarily in the base of nasal polyps and in greater concentration than in normal mucosa. Patients with aspirin sensitivity and asthma had much lower histamine concentrations in their nasal polyps than all other patients with nasal polyps. A proposal for a possible mechanism of formation of nasal polyps based on vascular and inflammatory mechanisms and incorporative roles for histamine and norepinephrine is presented.

  2. Ascorbate Efflux as a New Strategy for Iron Reduction and Transport in Plants*

    PubMed Central

    Grillet, Louis; Ouerdane, Laurent; Flis, Paulina; Hoang, Minh Thi Thanh; Isaure, Marie-Pierre; Lobinski, Ryszard; Curie, Catherine; Mari, Stéphane

    2014-01-01

    Iron (Fe) is essential for virtually all living organisms. The identification of the chemical forms of iron (the speciation) circulating in and between cells is crucial to further understand the mechanisms of iron delivery to its final targets. Here we analyzed how iron is transported to the seeds by the chemical identification of iron complexes that are delivered to embryos, followed by the biochemical characterization of the transport of these complexes by the embryo, using the pea (Pisum sativum) as a model species. We have found that iron circulates as ferric complexes with citrate and malate (Fe(III)3Cit2Mal2, Fe(III)3Cit3Mal1, Fe(III)Cit2). Because dicotyledonous plants only transport ferrous iron, we checked whether embryos were capable of reducing iron of these complexes. Indeed, embryos did express a constitutively high ferric reduction activity. Surprisingly, iron(III) reduction is not catalyzed by the expected membrane-bound ferric reductase. Instead, embryos efflux high amounts of ascorbate that chemically reduce iron(III) from citrate-malate complexes. In vitro transport experiments on isolated embryos using radiolabeled 55Fe demonstrated that this ascorbate-mediated reduction is an obligatory step for the uptake of iron(II). Moreover, the ascorbate efflux activity was also measured in Arabidopsis embryos, suggesting that this new iron transport system may be generic to dicotyledonous plants. Finally, in embryos of the ascorbate-deficient mutants vtc2-4, vtc5-1, and vtc5-2, the reducing activity and the iron concentration were reduced significantly. Taken together, our results identified a new iron transport mechanism in plants that could play a major role to control iron loading in seeds. PMID:24347170

  3. Reduction of Fuel Consumption and Exhaust Pollutant Using Intelligent Transport Systems

    PubMed Central

    Nasir, Mostofa Kamal; Md Noor, Rafidah; Kalam, M. A.; Masum, B. M.

    2014-01-01

    Greenhouse gas emitted by the transport sector around the world is a serious issue of concern. To minimize such emission the automobile engineers have been working relentlessly. Researchers have been trying hard to switch fossil fuel to alternative fuels and attempting to various driving strategies to make traffic flow smooth and to reduce traffic congestion and emission of greenhouse gas. Automobile emits a massive amount of pollutants such as Carbon Monoxide (CO), hydrocarbons (HC), carbon dioxide (CO2), particulate matter (PM), and oxides of nitrogen (NOx). Intelligent transport system (ITS) technologies can be implemented to lower pollutant emissions and reduction of fuel consumption. This paper investigates the ITS techniques and technologies for the reduction of fuel consumption and minimization of the exhaust pollutant. It highlights the environmental impact of the ITS application to provide the state-of-art green solution. A case study also advocates that ITS technology reduces fuel consumption and exhaust pollutant in the urban environment. PMID:25032239

  4. Reduction of fuel consumption and exhaust pollutant using intelligent transport systems.

    PubMed

    Nasir, Mostofa Kamal; Md Noor, Rafidah; Kalam, M A; Masum, B M

    2014-01-01

    Greenhouse gas emitted by the transport sector around the world is a serious issue of concern. To minimize such emission the automobile engineers have been working relentlessly. Researchers have been trying hard to switch fossil fuel to alternative fuels and attempting to various driving strategies to make traffic flow smooth and to reduce traffic congestion and emission of greenhouse gas. Automobile emits a massive amount of pollutants such as Carbon Monoxide (CO), hydrocarbons (HC), carbon dioxide (CO2), particulate matter (PM), and oxides of nitrogen (NO x ). Intelligent transport system (ITS) technologies can be implemented to lower pollutant emissions and reduction of fuel consumption. This paper investigates the ITS techniques and technologies for the reduction of fuel consumption and minimization of the exhaust pollutant. It highlights the environmental impact of the ITS application to provide the state-of-art green solution. A case study also advocates that ITS technology reduces fuel consumption and exhaust pollutant in the urban environment.

  5. Reduction of fuel consumption and exhaust pollutant using intelligent transport systems.

    PubMed

    Nasir, Mostofa Kamal; Md Noor, Rafidah; Kalam, M A; Masum, B M

    2014-01-01

    Greenhouse gas emitted by the transport sector around the world is a serious issue of concern. To minimize such emission the automobile engineers have been working relentlessly. Researchers have been trying hard to switch fossil fuel to alternative fuels and attempting to various driving strategies to make traffic flow smooth and to reduce traffic congestion and emission of greenhouse gas. Automobile emits a massive amount of pollutants such as Carbon Monoxide (CO), hydrocarbons (HC), carbon dioxide (CO2), particulate matter (PM), and oxides of nitrogen (NO x ). Intelligent transport system (ITS) technologies can be implemented to lower pollutant emissions and reduction of fuel consumption. This paper investigates the ITS techniques and technologies for the reduction of fuel consumption and minimization of the exhaust pollutant. It highlights the environmental impact of the ITS application to provide the state-of-art green solution. A case study also advocates that ITS technology reduces fuel consumption and exhaust pollutant in the urban environment. PMID:25032239

  6. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.

    PubMed

    Deecher, Darlene C; Beyer, Chad E; Johnston, Grace; Bray, Jenifer; Shah, S; Abou-Gharbia, M; Andree, Terrance H

    2006-08-01

    The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.

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

    SciTech Connect

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

    1987-06-01

    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 ..mu..M) stimulates increased neuronal (/sup 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 (/sup 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.

  8. Solutions and reductions for radiative energy transport in laser-heated plasma

    SciTech Connect

    Broadbridge, P.; Ivanova, N. M.

    2015-01-15

    A full symmetry classification is given for models of energy transport in radiant plasma when the mass density is spatially variable and the diffusivity is nonlinear. A systematic search for conservation laws also leads to some potential symmetries and to an integrable nonlinear model. Classical point symmetries, potential symmetries, and nonclassical symmetries are used to effect variable reductions and exact solutions. The simplest time-dependent solution is shown to be stable and relevant to a closed system.

  9. A bacterial glutathione transporter (Escherichia coli CydDC) exports reductant to the periplasm.

    PubMed

    Pittman, Marc S; Robinson, Hilary C; Poole, Robert K

    2005-09-16

    Glutathione (GSH), a major biological antioxidant, maintains redox balance in prokaryotes and eukaryotic cells and forms exportable conjugates with compounds of pharmacological and agronomic importance. However, no GSH transporter has been characterized in a prokaryote. We show here that a heterodimeric ATP-binding cassette-type transporter, CydDC, mediates GSH transport across the Escherichia coli cytoplasmic membrane. In everted membrane vesicles, GSH is imported via an ATP-driven, protonophore-insensitive, orthovanadate-sensitive mechanism, equating with export to the periplasm in intact cells. GSH transport and cytochrome bd quinol oxidase assembly are abolished in the cydD1 mutant. Glutathione disulfide (GSSG) was not transported in either Cyd(+) or Cyd(-) strains. Exogenous GSH restores defective swarming motility and benzylpenicillin sensitivity in a cydD mutant and also benzylpenicillin sensitivity in a gshA mutant defective in GSH synthesis. Overexpression of the cydDC operon in dsbD mutants defective in disulfide bond formation restores dithiothreitol tolerance and periplasmic cytochrome b assembly, revealing redundant pathways for reductant export to the periplasm. These results identify the first prokaryotic GSH transporter and indicate a key role for GSH in periplasmic redox homeostasis. PMID:16040611

  10. Prostanoids inhibit release of endogenous norepinephrine from rat isolated trachea.

    PubMed

    Racké, K; Bähring, J; Langer, C; Bräutigam, M; Wessler, I

    1992-11-01

    Prostanoids, of epithelial origin, are known as modulators of several processes in the airways. The present study examined whether prostanoids are involved in the local control of sympathetic neurotransmission. The release of endogenous norepinephrine from rat isolated tracheae was evoked by electrical field stimulation (3 Hz, 540 pulses) in the presence of yohimbine, desipramine, and tyrosine. In different series of experiments, indomethacin (3 mumol/L) increased the evoked release of endogenous norepinephrine by 70 to 80%. In the presence of indomethacin, prostaglandin E2 (PGE2) and several prostanoid receptor agonists inhibited the evoked release of norepinephrine in a concentration-dependent manner, maximally by 60 to 70%. According to the concentration producing 35% inhibition of norepinephrine release (half-maximal effect), the following rank order of potencies was observed (EC35): nocloprost (8 nmol/L), sulprostone (30 nmol/L), PGE2 (308 nmol/L), iloprost (2 mumol/L), and U46619 (> 10 mumol/L). The EP1 receptor antagonist AH 6809 (3 mumol/L) had no effect on the evoked norepinephrine release and did not affect the inhibitory effect of 1 mumol/L of sulprostone. In the absence of indomethacin, the inhibitory effect of PGE2 was similar to that observed in the presence of indomethacin. After removal of the epithelium, the evoked norepinephrine release was markedly reduced. However, no significant effect of indomethacin was observed in epithelium-denuded tracheae. In conclusion, norepinephrine release in the rat trachea is inhibited via prostaglandin receptors that have the pharmacologic characteristics of the EP3 subtype. Endogenous eicosanoids, most likely of epithelial origin, are involved in the local control of the release of norepinephrine. PMID:1443867

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

    NASA Astrophysics Data System (ADS)

    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.

  12. Reduction of L-type amino acid transporter 1 mRNA expression in brain capillaries in a mouse model of Parkinson's disease.

    PubMed

    Ohtsuki, Sumio; Yamaguchi, Hirofumi; Kang, Young-Sook; Hori, Satoko; Terasaki, Tetsuya

    2010-01-01

    The blood-brain barrier (BBB) expresses transporters that influence both dopaminergic neuronal function and drug therapy for Parkinson's disease (PD). The purpose of the present study was to clarify changes of transporter mRNA expression at the BBB in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model of PD, in order to understand the pathophysiological role of BBB transport function in PD. At 7 d after MPTP treatment, mice showed a motor deficit and a loss of dopaminergic neurons. At the same time, L-type amino acid transporter 1 (LAT1) mRNA expression in the brain capillary fraction of the MPTP-treated mice was significantly reduced by 62.6% compared with saline-treated mice, while no significant change was observed in the expression of glucose transporter 1, creatine transporter 1, taurine transporter, organic cation transporter 2, serotonin transporter, norepinephrine transporter and dopamine transporter. LAT1 mRNA expression in whole brain was not affected at 1, 3 and 5 d after the treatment, but was reduced by 46.3% at 7 d. LAT1 mediates the transport of large neutral amino acids, including tyrosine, as well as the PD-therapeutic drug levodopa, across the BBB. Our findings indicate that decreased LAT1 expression at the BBB in PD patients may adversely affect amino acid supply from the circulating blood and levodopa distribution into the brain.

  13. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β

    PubMed Central

    Xu, Jordan C.; Fomenko, Vira; Miyamoto, Takashi; Suberbielle, Elsa; Knox, Joseph A.; Ho, Kaitlyn; Kim, Daniel H.; Yu, Gui-Qiu

    2015-01-01

    Axonal transport deficits in Alzheimer’s disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aβ oligomers. Relevance of these findings to naturally secreted Aβ and mechanisms underlying tau’s enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aβ1–42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3β (GSK3β) activity or expression also abolished Aβ-induced transport deficits. Tau ablation prevented Aβ-induced GSK3β activation. Thus, tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β, possibly by facilitating aberrant neuronal activity. PMID:25963821

  14. Neuroimmunomodulatory interactions of norepinephrine and serotonin.

    PubMed

    Walker, R F; Codd, E E

    1985-11-01

    Monoamine neuroleptics alter rodents responses to immunization, suggesting that norepinephrine (NE) and serotonin (5HT) are neuroimmunomodulatory in these animals. Although endocrine factors participate in their mechanism(s) of action, recent studies suggest that NE and 5HT also interact more directly with immunocompetent cells. This review provides an overview of evidence for a direct regulatory link between the nervous and immune systems and further speculates on the process by which NE and 5HT realize in part, their neuroimmunomodulatory potential. Anatomical data show that noradrenergic fibers of the sympathetic nervous system innervate lymphoid organs providing a channel of communication between neurons and lymphocytes. Presumably neural signals transmitted by NE are received by platelets that in turn, transduce them via 5HT into immunomodulatory messages. It is proposed that NE alters the capacity of platelets to sequester and/or catabolize 5HT, thus regulating its physiologically active pool in the plasma. Macrophages possess a 5HT uptake system, the kinetic properties of which make them sensitive to changes in plasma levels of the amine. Thus, through its ability to regulate plasma levels of 5HT, an immunosuppressive amine with access to macrophages, the nervous system can influence cells involved in antigen recognition. Support for this hypothetical immunomodulatory mechanism is gleaned from clinical and experimental studies. For example, individuals suffering emotional trauma are more susceptible than others to developing physical illness. It is of interest that platelet 5HT pharmacodynamics are often abnormal in patients with psychological disorders characterized by catecholamine deficits. Similar platelet changes have been achieved experimentally by treating rats with catecholamine antimetabolites. Additional support for the hypothesis derives from aging research since 'monoamine imbalance' and immune dysfunction are co-characteristics of senescence. In

  15. Symmetry reductions of a nonlinear convection-dispersion model arising in contaminant transport theory

    NASA Astrophysics Data System (ADS)

    Ntsime, Basetsana P.; Moitsheki, Raseelo J.

    2016-06-01

    In this paper we consider a nonlinear convection-dispersion equation arising in contaminant transport. The water flow velocity is considered to be spatially-dependent and dispersion coefficient depends on concentration. A direct group classification resulted in a number of cases for which the governing equation admits Lie point symmetries. In each case the one dimensional optimal system of subalgebras is constructed. Reductions are performed. The reduced ordinary differential equations (ODEs) are nonlinear and difficult to solve exactly. On the other hand we consider the steady state problem and applied the method of canonical coordinates to determine exact solutions.

  16. An approximate framework for quantum transport calculation with model order reduction

    SciTech Connect

    Chen, Quan; Li, Jun; Yam, Chiyung; Zhang, Yu; Wong, Ngai; Chen, Guanhua

    2015-04-01

    A new approximate computational framework is proposed for computing the non-equilibrium charge density in the context of the non-equilibrium Green's function (NEGF) method for quantum mechanical transport problems. The framework consists of a new formulation, called the X-formulation, for single-energy density calculation based on the solution of sparse linear systems, and a projection-based nonlinear model order reduction (MOR) approach to address the large number of energy points required for large applied biases. The advantages of the new methods are confirmed by numerical experiments.

  17. Reactive Transport Modeling of Microbially-Mediated Chromate Reduction in 1-D Soil Columns

    NASA Astrophysics Data System (ADS)

    Qiu, H.; Viamajala, S.; Alam, M. M.; Peyton, B. M.; Petersen, J. N.; Yonge, D. R.

    2002-12-01

    Cr(VI) reduction tests were performed with the well known metal reducing bacterium Shewanella oneidensis MR-1 in liquid phase batch reactors and continuous flow soil columns under anaerobic conditions. In the batch tests, the cultures were grown with fumarate as the terminal electron acceptor and lactate as the electron donor in a simulated groundwater medium to determine yield coefficients and specific growth rates. The bench-scale soil column experiments were carried out with MR-1 to test the hypothesis that the kinetic parameters obtained in batch studies, combined with microbial attachment /detachment processes, will accurately predict reactive transport of Cr(VI) during bacterial Cr(VI) reduction in a soil matrix. Cr(VI)-free simulated groundwater media containing fumarate as the limiting substrate and lactate was supplied to a 2.1cm (ID) x 15 cm soil column inoculated with MR-1 for a duration of 9 residence times to allow for biomass to build-up in the column. Thereafter the column was supplied with both Cr(VI) and substrate. The concentrations of effluent substrate, biomass and Cr(VI) were monitored on a periodic basis and attached biomass in the column was measured in the termination of each column test. A reactive transport model was developed in which 6 governing equations deal with Cr(VI) bioreaction, fumarate (as electron donor) consumption, aqueous biomass growth and transport, solid biomass detachment and attachment kinetics, aqueous and solid phase enzyme reaction and transport, respectively. The model incorporating the enzyme reaction kinetics for Cr(VI) reduction, Monod kinetic expressions for substrate depletion, nonlinear attachment and detachment kinetics for aqueous and solid phase microorganism concentration, was solved by a fully implicit, finite-difference procedure using RT3D (A Modular Computer Code for Reactive Multi-species Transport in 3-Dimensional Groundwater Systems) platform in one dimension. Cr(VI)-free column data was used to

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

    SciTech Connect

    Henriksen, J.H.; Christensen, N.J.; Ring-Larsen, H. )

    1989-08-01

    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 and not in controls (41 vs. -5 ng/min, p less than 0.02). In the lower limb, net release of NE was similar in patients and controls, and extraction ratios of (3H)NE decreased almost equally with infusion time (from 0.35 to 0.30, p less than 0.01 and from 0.40 to 0.24, p less than 0.1, respectively). Whole-body clearance of (3H)NE decreased over time in patients (-6%, p less than 0.01) and controls (-20%, p less than 0.01), but significant difference was not observed between the groups. We conclude that failure to attain a steady state with respect to (3H)NE removal was demonstrated in areas of large tissue volume relative to blood flow.

  19. Aeronautical fuel conservation possibilities for advanced subsonic transports. [application of aeronautical technology for drag and weight reduction

    NASA Technical Reports Server (NTRS)

    Braslow, A. L.; Whitehead, A. H., Jr.

    1973-01-01

    The anticipated growth of air transportation is in danger of being constrained by increased prices and insecure sources of petroleum-based fuel. Fuel-conservation possibilities attainable through the application of advances in aeronautical technology to aircraft design are identified with the intent of stimulating NASA R and T and systems-study activities in the various disciplinary areas. The material includes drag reduction; weight reduction; increased efficiency of main and auxiliary power systems; unconventional air transport of cargo; and operational changes.

  20. A local'' exponential transform method for global variance reduction in Monte Carlo transport problems

    SciTech Connect

    Baker, R.S. ); Larsen, E.W. . Dept. of Nuclear Engineering)

    1992-01-01

    Numerous variance reduction techniques, such as splitting/Russian roulette, weight windows, and the exponential transform exist for improving the efficiency of Monte Carlo transport calculations. Typically, however, these methods, while reducing the variance in the problem area of interest tend to increase the variance in other, presumably less important, regions. As such, these methods tend to be not as effective in Monte Carlo calculations which require the minimization of the variance everywhere. Recently, Local'' Exponential Transform (LET) methods have been developed as a means of approximating the zero-variance solution. A numerical solution to the adjoint diffusion equation is used, along with an exponential representation of the adjoint flux in each cell, to determine local'' biasing parameters. These parameters are then used to bias the forward Monte Carlo transport calculation in a manner similar to the conventional exponential transform, but such that the transform parameters are now local in space and energy, not global. Results have shown that the Local Exponential Transform often offers a significant improvement over conventional geometry splitting/Russian roulette with weight windows. Since the biasing parameters for the Local Exponential Transform were determined from a low-order solution to the adjoint transport problem, the LET has been applied in problems where it was desirable to minimize the variance in a detector region. The purpose of this paper is to show that by basing the LET method upon a low-order solution to the forward transport problem, one can instead obtain biasing parameters which will minimize the maximum variance in a Monte Carlo transport calculation.

  1. A ``local`` exponential transform method for global variance reduction in Monte Carlo transport problems

    SciTech Connect

    Baker, R.S.; Larsen, E.W.

    1992-08-01

    Numerous variance reduction techniques, such as splitting/Russian roulette, weight windows, and the exponential transform exist for improving the efficiency of Monte Carlo transport calculations. Typically, however, these methods, while reducing the variance in the problem area of interest tend to increase the variance in other, presumably less important, regions. As such, these methods tend to be not as effective in Monte Carlo calculations which require the minimization of the variance everywhere. Recently, ``Local`` Exponential Transform (LET) methods have been developed as a means of approximating the zero-variance solution. A numerical solution to the adjoint diffusion equation is used, along with an exponential representation of the adjoint flux in each cell, to determine ``local`` biasing parameters. These parameters are then used to bias the forward Monte Carlo transport calculation in a manner similar to the conventional exponential transform, but such that the transform parameters are now local in space and energy, not global. Results have shown that the Local Exponential Transform often offers a significant improvement over conventional geometry splitting/Russian roulette with weight windows. Since the biasing parameters for the Local Exponential Transform were determined from a low-order solution to the adjoint transport problem, the LET has been applied in problems where it was desirable to minimize the variance in a detector region. The purpose of this paper is to show that by basing the LET method upon a low-order solution to the forward transport problem, one can instead obtain biasing parameters which will minimize the maximum variance in a Monte Carlo transport calculation.

  2. Changes in quantitative norepinephrine levels in delayed pig flank flaps.

    PubMed

    Cutting, C; Bumsted, R; Bardach, J; Mooney, M; Johnson, S

    1982-04-01

    A quantitative norepinephrine assay was used to follow tissue norepinephrine concentrations serially in bipedicle delayed pig flank flaps. In contrast to a previous study by Palmer, norepinephrine concentration decreased significantly after 24 hr, but then gradually returned to normal at 10 days. This suggests that the pig flank flap maintains much of its adrenergic innervation following bipedicle delay. It appears unlikely that adrenergic denervation explains the delay phenomenon in this model. The combined results of this study and others suggest that the degree of adrenergic denervation of a flap is determined by the anatomic layout of the flap with respect to the underlying cutaneous adrenergic neural anatomy. This experiment suggests that the effectiveness of adrenergic blocking agents in improving flap survival is dependent on the degree of adrenergic denervation of the flap.

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

    PubMed Central

    Cox, Elizabeth Thomas; Jarrett, Thomas Merryfield; McMurray, Matthew Stephen; Greenhill, Kevin; Hofler, Vivian E.; Williams, Sarah Kaye; Joyner, Paul Wayland; Middleton, Christopher L.; Walker, Cheryl H.; Johns, Josephine M.

    2011-01-01

    Background: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB 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 MB, 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. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. Results: Amitriptyline and desipramine differentially reduced MB, 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 maternal care. PMID:21713063

  4. Micromodel Investigation of Transport Effect on the Kinetics of Reductive Dissolution of Hematite

    SciTech Connect

    Zhang, Changyong; Liu, Chongxuan; Shi, Zhi

    2013-03-13

    Reductive dissolution of hematite in porous media was investigated using a micromodel with realistic pore network structures that include distinctive advection domain, macro-pores and micro-pores created in silicon substrate. The micromodel pore surface was sputter deposited with a thin layer (230 nm) of hematite. The hematite in the micromodel was reduced by injecting pH-varying solutions containing a reduced form of flavin mononucleotide (FMNH2), a biogenic soluble electron transfer mediator produced by Shewanella species. The reduction kinetics was determined by measuring effluent Fe(II) concentration and by spectroscopically monitoring the hematite dissolution front in the micromodel. Batch experiment was also performed to estimate the hematite reduction rate under the well-mixed condition. The results showed a significant spatial variation in local redox reaction rate that was controlled by the coupled diffusion and reaction. The overall rate of the redox reaction in the micromodel required a three-domain numerical model to effectively describe with distinctive rate parameters in different pore domains. Results from this study demonstrated the important scaling effect when extrapolating geochemical or biogeochemical reaction rate from batch reactor to porous media and indicated a significant control of physical transport mechanisms on the reaction rate scaling.

  5. From facial mimicry to emotional empathy: a role for norepinephrine?

    PubMed

    Harrison, Neil A; Morgan, Robert; Critchley, Hugo D

    2010-01-01

    Tendency to mimic others' emotional facial expressions predicts empathy and may represent a physiological marker of psychopathy. Anatomical connectivity between amygdala, cingulate motor cortex (M3, M4), and facial nucleus demonstrates a potential neuroanatomical substrate for mimicry, though pharmacological influences are largely unknown. Norepinephrine modulation selectively impairs negative emotion recognition, reflecting a potential role in processing empathy-eliciting facial expressions. We examined effects of single doses of propranolol (beta-adrenoceptor blocker) and reboxetine (selective norepinephrine reuptake inhibitor) on automatic facial mimicry of sadness, anger, and happiness, and the relationship between mimicry and empathy. Forty-five healthy volunteers were randomized to 40 mg propranolol or 4 mg reboxetine. Two hours after drug subjects viewed and rated facial expressions of sadness, anger, and happiness, while corrugator, zygomatic, and mentalis EMG were recorded. Trait emotional empathy was measured using the Balanced Emotional Empathy Scale. EMG confirmed emotion-specific mimicry and the relationship between corrugator mimicry and empathy. Norepinephrine modulation did not alter mimicry to any expression or influence the relationship between mimicry and empathy. Corrugator but not zygomaticus mimicry predicts trait empathy, consistent with greater anatomical connectivity between amygdala and M3 coding upper facial muscle representations. Although influencing emotion perception, norepinephrine does not influence emotional facial mimicry or its relationship with trait empathy. PMID:20486012

  6. Presence of norepinephrine and related enzymes in isolated brain microvessels.

    PubMed Central

    Lai, F M; Udenfriend, S; Spector, S

    1975-01-01

    Norepinephrine and the enzymes involved in its synthesis and degradation were found to be associated with isolated brain microvessels. The significance of these results are discussed with respect to adrenergic innervation of the cerebral microvessels and thereby neural regulation of the cerebral microcirculation. Images PMID:678

  7. Experimental investigation of the ground transportation systems (GTS) project for heavy vehicle drag reduction

    SciTech Connect

    Croll, R.H.; Gutierrez, W.T.; Hassan, B.; Suazo, J.E.; Riggins, A.J.

    1995-12-31

    A wind tunnel experimental research program was conducted on a heavily instrumented Ground Transportation System (GTS) vehicle. The GTS baseline model represented a generic 1:8 scale Class-8 van-type tractor trailer geometry. Five base drag reduction add-on devices, instrumented with surface pressure ports, were also tested. These add-on devices included two ogive boattail shapes and three slant geometry devices. Six component force and moment data, surface pressure contours, and wake velocity surveys are presented for each configuration along with qualitative insights gained from flow visualization. This wind tunnel program was designed to complement a parallel research effort in computational fluid dynamics (CFD) which modeled many of these same vehicle geometries. The wind tunnel data are documented and archived in ASCII format on floppy discs and available to researchers interested in further analysis or comparison to other CFD solutions.

  8. Experimental study on noise reduction effect of a muffler inserted in liquid transporting pipeline

    NASA Astrophysics Data System (ADS)

    Du, T.; Xu, W. W.; Wu, D. Z.; Wang, L. Q.

    2013-12-01

    In order to reduce the noise of liquid transporting pipelines caused by the motion of the power unit, a kind of compact hydrodynamic muffler used in pipes with small diameters is proposed which achieves good vibration damping as well as hydrodynamic noise reduction. Based on the rubber damper tube, according to the structure characteristics, the muffler is composed of two main parts, the rubber damper tube and the inner noise reducing structure. Experiment on insertion loss of the muffler in stationary state is conducted. It is found that the rubber damper tube itself has a good performance at noise reducing at the frequency band considered here, total insertion loss values can reach 10 dB and the inner structures improve the performance of the muffler at low frequency band.

  9. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance

    NASA Technical Reports Server (NTRS)

    Schroeder, Christoph; Tank, Jens; Boschmann, Michael; Diedrich, Andre; Sharma, Arya M.; Biaggioni, Italo; Luft, Friedrich C.; Jordan, Jens; Robertson, D. (Principal Investigator)

    2002-01-01

    BACKGROUND: Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. METHODS AND RESULTS: We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65+/-2 bpm with placebo and 71+/-3 bpm with reboxetine. At 75 degrees HUT, heart rate was 84+/-3 and 119+/-4 bpm with placebo and with reboxetine (P<0.0001). Mean arterial pressure was 85+/-2 with placebo and 91+/-2 mm Hg with reboxetine while supine (P<0.01) and 88+/-2 mm Hg and 90+/-3 mm Hg at 75 degrees HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine. CONCLUSIONS: Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

  10. Genetic influence on brain catecholamines: high brain norepinephrine in salt-sensitive rats

    SciTech Connect

    Iwai, J; Friedman, R; Tassinari, L

    1980-01-01

    Rats genetically sensitive to salt-induced hypertension evinced higher levels of plasma norepinephrine and epinephrine than rats genetically resistant to hypertension. The hypertension-sensitive rats showed higher hypothalamic norepinephrine and lower epinephrine than resistant rats. In response to a high salt diet, brain stem norepinephrine increased in sensitive rats while resistant rats exhibited a decrease on the same diet.

  11. Electrification of the transportation sector offers limited country-wide greenhouse gas reductions

    NASA Astrophysics Data System (ADS)

    Meinrenken, Christoph J.; Lackner, Klaus S.

    2014-03-01

    Compared with conventional propulsion, plugin and hybrid vehicles may offer reductions in greenhouse gas (GHG) emissions, regional air/noise pollution, petroleum dependence, and ownership cost. Comparing only plugins and hybrids amongst themselves, and focusing on GHG, relative merits of different options have been shown to be more nuanced, depending on grid-carbon-intensity, range and thus battery manufacturing and weight, and trip patterns. We present a life-cycle framework to compare GHG emissions for three drivetrains (plugin-electricity-only, gasoline-only-hybrid, and plugin-hybrid) across driving ranges and grid-carbon-intensities, for passenger cars, vans, buses, or trucks (well-to-wheel plus storage manufacturing). Parameter and model uncertainties are quantified via sensitivity analyses. We find that owing to the interplay of range, GHG/km, and portions of country-wide kms accessible to electrification, GHG reductions achievable from plugins (whether electricity-only or hybrids) are limited even when assuming low-carbon future grids. Furthermore, for policy makers considering GHG from electricity and transportation sectors combined, plugin technology may in fact increase GHG compared to gasoline-only-hybrids, regardless of grid-carbon-intensity.

  12. 34S/32S fractionation during sulfate reduction in groundwater treatment systems: reactive transport modeling.

    PubMed

    Gibson, Blair D; Amos, Richard T; Blowes, David W

    2011-04-01

    Isotope ratio measurements provide a tool for indicating the relative significance of biogeochemical reactions and for constraining estimates of the extent and rate of reactions in passive treatment systems. In this paper, the reactive transport model MIN3P is used to evaluate sulfur isotope fractionation in column experiments designed to simulate treatment of contaminated water by microbially mediated sulfate reduction occurring within organic carbon-based and iron and carbon-based permeable reactive barriers. A mass dependent fractionation model was used to determine reaction rates for 32S and 34S compounds during reduction, precipitation, and dissolution reactions and to track isotope-dependent mass transfer during SO4 removal. The δ34S values obtained from the MIN3P model were similar to those obtained from the Rayleigh equation, indicating that there was not a significant difference between the conceptual models. Differences between the MIN3P derived α value and the Rayleigh equation derived value were attributed to minor changes in the dissolution and precipitation rate of gypsum and mathematical differences in the fitting models. The results indicated that the prediction of δ34S was fairly insensitive to differences in the fractionation factor at the concentration ranges measured in the current study. However, more significant differences would be expected at low sulfate conditions.

  13. Systematic Dimensionality Reduction for Quantum Walks: Optimal Spatial Search and Transport on Non-Regular Graphs

    PubMed Central

    Novo, Leonardo; Chakraborty, Shantanav; Mohseni, Masoud; Neven, Hartmut; Omar, Yasser

    2015-01-01

    Continuous time quantum walks provide an important framework for designing new algorithms and modelling quantum transport and state transfer problems. Often, the graph representing the structure of a problem contains certain symmetries that confine the dynamics to a smaller subspace of the full Hilbert space. In this work, we use invariant subspace methods, that can be computed systematically using the Lanczos algorithm, to obtain the reduced set of states that encompass the dynamics of the problem at hand without the specific knowledge of underlying symmetries. First, we apply this method to obtain new instances of graphs where the spatial quantum search algorithm is optimal: complete graphs with broken links and complete bipartite graphs, in particular, the star graph. These examples show that regularity and high-connectivity are not needed to achieve optimal spatial search. We also show that this method considerably simplifies the calculation of quantum transport efficiencies. Furthermore, we observe improved efficiencies by removing a few links from highly symmetric graphs. Finally, we show that this reduction method also allows us to obtain an upper bound for the fidelity of a single qubit transfer on an XY spin network. PMID:26330082

  14. Incongruent reduction of dopamine transporter availability in different subgroups of alcohol dependence.

    PubMed

    Yen, Che-Hung; Shih, Mei-Chen; Cheng, Cheng-Yi; Ma, Kuo-Hsing; Lu, Ru-Band; Huang, San-Yuan

    2016-08-01

    The dopamine transporter (DAT) plays a crucial role in the pathogenesis of alcohol dependence (AD) and major depression (MD), and males have more risk factors for the development of AD. However, imaging studies on brain DAT availability in males with AD comorbid with MD (AD/MD) are limited, and the association of DAT availability with cognitive function and depressive scores in patients with AD/MD has not been analyzed. Hence, this study examined the relationship between brain DAT availability, cognitive function, and depressive symptoms in different subgroups of males with AD.Single-photon emission computed tomography imaging with Tc-TRODAT-1 as a ligand was used to measure striatal DAT availability in 49 patients with AD (28 pure AD and 21 AD/MD) and 24 age- and sex-matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and 17-item Hamilton Depression Rating Scale were used to assess neurocognitive function and depressive scores, respectively. Patients with AD showed a significant reduction of DAT availability in 3 brain regions (P < 0.001), and this reduction was more pronounced in the patients with pure AD compared to healthy controls. The patients with AD showed significantly poorer performance on the WCST, but only in the control group was DAT availability significantly negatively correlated with total errors and perseverative errors (P < 0.001).These preliminary findings suggest that DAT availability is associated with neurocognitive function, and incongruent reduction of DAT may play a pathophysiological role in different subgroups of AD. In addition, decreased DAT availability may be associated with the severity of depressive symptoms in patients with AD/MD. PMID:27537550

  15. Reduction in Energy Consumption for Pretreatment Process and Transportation of Pulverized Wood Fuel

    NASA Astrophysics Data System (ADS)

    Nishi, Kenji; Sawai, Toru; Ohmasa, Mitsushi; Hirokawa, Noriyasu; Shibue, Tadashi; Kajimoto, Takeshi

    In recent years, much attention has been focused on the energy utilization of biomass to reduce the emission of greenhouse gas. Especially, woody biomass such as the forestry biomass derived from logging and thinning operations in forests is one of the most promising domestic resources in Japan. Woody biomass contributes not only to the improvement of energy self-sufficiency in Japan, but also to the environmental protection of Japanese forests. When the woody biomass is utilized, it is necessary to examine the energy consumption for collection of resources, pretreatment, transportation and after-treatment. In the present study, woody biomass is assumed to be utilized as pulverized wood fuel in local area. The pretreatment of pulverized wood fuel is consisted of three procedures; drying, semi-carbonizaion and fine comminution. The main purpose of the study is to investigate the comminution characteristic of the Japanese cedar thinning and the reduction in energy consumption for pretreatment process and transportation of pulverized wood fuel. The results obtained in the present study are as follows. (1) Comminution energy increases as the water content increases and the sieve of screen becomes small. The comminution energy of hammer mill is largely affected by the water content. Difference in comminution energy between the hammer and cutter mills is large. The ratio of comminution energy of the hammer mill to that of the cutter mill exceeds 10 for the water content of 40% and sieve of screen of 3mm. (2) To estimate the comminution energy of woody biomass, empirical equations of work index in Bond's Law are presented. In woody biomass region, the empirical equations of work index depend on the comminution method. In semi-carbonization and carbonization regions, the empirical equation of work index is presented regardless of comminution method and sieve of screen. The comminution energy can be estimated by using the present empirical equations within accuracy ±50

  16. Reduction of cerebral edema after traumatic brain injury using an osmotic transport device.

    PubMed

    McBride, Devin W; Szu, Jenny I; Hale, Chris; Hsu, Mike S; Rodgers, Victor G J; Binder, Devin K

    2014-12-01

    Traumatic brain injury (TBI) is significant, from a public health standpoint, because it is a major cause of the morbidity and mortality of young people. Cerebral edema after a TBI, if untreated, can lead to devastating damage of the remaining tissue. The current therapies of severe TBI (sTBI), as outlined by the Brain Trauma Foundation, are often ineffective, thus a new method for the treatment of sTBI is necessary. Herein, the reduction of cerebral edema, after TBI, using an osmotic transport device (OTD) was evaluated. Controlled cortical impact (CCI) was performed on adult female CD-1 mice, and cerebral edema was allowed to form for 3 h, followed by 2 h of treatment. The treatment groups were craniectomy only, craniectomy with a hydrogel, OTD without bovine serum albumin (BSA), and OTD. After CCI, brain water content was significantly higher for animals treated with a craniectomy only, craniectomy with a hydrogel, and OTD without BSA, compared to that of control animals. However, when TBI animals were treated with an OTD, brain water content was not significantly higher than that of controls. Further, brain water content of TBI animals treated with an OTD was significantly reduced, compared to that of untreated TBI animals, TBI animals treated with a craniectomy and a hydrogel, and TBI animals treated with an OTD without BSA. Here, we demonstrate the successful reduction of cerebral edema, as determined by brain water content, after TBI using an OTD. These results demonstrate proof of principle for direct water extraction from edematous brain tissue by direct osmotherapy using an OTD.

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

    PubMed

    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. PMID:27305769

  18. Can a reduction in mass transport occur at invariant segmental time?

    NASA Astrophysics Data System (ADS)

    Napolitano, Simone; Sferrazza, Michele

    2015-03-01

    The glassy dynamics of polymer melts adsorbed onto solid substrates shows a peculiar confinement effect: a severe reduction in mass transport occurs without a corresponding increase in segmental relaxation time. This phenomenon provides a ``negative violation'' of the Stokes-Einstein (SE) relation, not observed in bulk melts or confined water. Explaining those findings in analogy to the large drop of thermal expansion reported in polymers under 1D confinement, we considered the presence of an interfacial dead layer where tracer diffusivity assumes negligible values. To verify this hypothesis, we performed an extensive investigation of the diffusion of styrene oligomers, acting as tracers, into matrices of high molecular weight polystyrene, irreversibly adsorbed onto aluminum oxide. We demonstrate that the reduced interfacial diffusion is due to larger residence times of the tracers inside the dead layer, tDL. In particular, we show that tDL is directly proportional to the amount of irreversibly adsorbed monomers, a quantity limiting the available space for diffusion. We thus discuss of a dynamic dead layer evolving within the adsorbed layer, and of its role on the dynamics of glassy polymers under confinement and the ``negative violation'' the SE relation.

  19. Mechanisms of immune regulation by norepinephrine and cholera toxin

    SciTech Connect

    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.

  20. Teratogenic effects of mescaline, epinephrine, and norepinephrine in the hamster.

    PubMed

    Hirsch, K S; Fritz, H I

    1981-06-01

    Mescaline was administered orally at doses of 16 and 32 mg/kg on the seventh through tenth days of gestation to pregnant cream-strain hamsters. This treatment resulted in a dose-dependent effect on reproductive success and skeletal ossification. The effect of mescaline on reproductive success included an increased number of resorptions resulting in a decreased litter size. The 32 mg/kg dose of mescaline caused 48.8% resorptions, while 16 mg/kg and control animals had 12.0% and 6.4% resorptions, respectively. Litter size was decreased from 12.0 pups in controls to 10.3 (16 mg/kg) and 6.5 (32 mg/kg) pups per litter in treated groups. No gross abnormalities were observed at necropsy; there was, however, a dose-dependent increased delay in the ossification of the skull, sternum, and metatarsals. Both epinephrine and norepinephrine caused a decrease in reproductive success when administered at 500 micrograms/kg. Epinephrine appeared to cause a trend toward preimplantation wastage as indicated by an increased corpora lutea to implantation site ratio (from 1.3-1.9). Norepinephrine, however, caused an increased number of resorptions (29.1% in controls). Both norepinephrine and epinephrine produced similar delays in ossification.

  1. [Anaerobic reduction of humus/Fe (III) and electron transport mechanism of Fontibacter sp. SgZ-2].

    PubMed

    Ma, Chen; Yang, Gui-qin; Lu, Qin; Zhou, Shun-gui

    2014-09-01

    Humus and Fe(III) respiration are important extracellular respiration metabolism. Electron transport pathway is the key issue of extracellular respiration. To understand the electron transport properties and the environmental behavior of a novel Fe(III)- reducing bacterium, Fontibacter sp. SgZ-2, capacities of anaerobic humus/Fe(III) reduction and electron transport mechanisms with four electron acceptors were investigated in this study. The results of anaerobic batch experiments indicated that strain SgZ-2 had the ability to reduce humus analog [ 9,10-anthraquinone-2,6-disulfonic acid (AQDS) and 9,10-anthraquinone-2-sulfonic acid (AQS)], humic acids (HA), soluble Fe(III) (Fe-EDTA and Fe-citrate) and Fe(III) oxides [hydrous ferric oxide (HFO)]. Fermentative sugars (glucose and sucrose) were the most effective electron donors in the humus/Fe(III) reduction by strain SgZ-2. Additionally, differences of electron carrier participating in the process of electron transport with different electron acceptors (i. e. , oxygen, AQS, Fe-EDTA and HFO) were investigated using respiratory inhibitors. The results suggested that similar respiratory chain components were involved in the reducing process of oxygen and Fe-EDTA, including dehydrogenase, quinones and cytochromes b-c. In comparison, only dehydrogenase was found to participate in the reduction of AQS and HFO. In conclusion, different electron transport pathways may be employed by strain SgZ-2 between insoluble and soluble electron acceptors or among soluble electron acceptors. Preliminary models of electron transport pathway with four electron acceptors were proposed for strain SgZ-2, and the study of electron transport mechanism was explored to the genus Fontibacter. All the results from this study are expected to help understand the electron transport properties and the environmental behavior of the genus Fontibacter.

  2. The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight

    PubMed Central

    Melasch, J; Rullmann, M; Hilbert, A; Luthardt, J; Becker, GA; Patt, M; Villringer, A; Arelin, K; Meyer, PM; Lobsien, D; Ding, Y-S; Müller, K; Sabri, O; Hesse, S; Pleger, B

    2016-01-01

    OBJECTIVES The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [11C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL–Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL–Lite). RESULTS In a small group of lean-to-morbidly obese individuals (n = 20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain’s homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n = 19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL–Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual’s emotional well-being was. CONCLUSIONS This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network. PMID:26620766

  3. Analysis of ballistic transport in nanoscale devices by using an accelerated finite element contact block reduction approach

    SciTech Connect

    Li, H.; Li, G.

    2014-08-28

    An accelerated Finite Element Contact Block Reduction (FECBR) approach is presented for computational analysis of ballistic transport in nanoscale electronic devices with arbitrary geometry and unstructured mesh. Finite element formulation is developed for the theoretical CBR/Poisson model. The FECBR approach is accelerated through eigen-pair reduction, lead mode space projection, and component mode synthesis techniques. The accelerated FECBR is applied to perform quantum mechanical ballistic transport analysis of a DG-MOSFET with taper-shaped extensions and a DG-MOSFET with Si/SiO{sub 2} interface roughness. The computed electrical transport properties of the devices obtained from the accelerated FECBR approach and associated computational cost as a function of system degrees of freedom are compared with those obtained from the original CBR and direct inversion methods. The performance of the accelerated FECBR in both its accuracy and efficiency is demonstrated.

  4. [Research on carbon reduction potential of electric vehicles for low-carbon transportation and its influencing factors].

    PubMed

    Shi, Xiao-Qing; Li, Xiao-Nuo; Yang, Jian-Xin

    2013-01-01

    Transportation is the key industry of urban energy consumption and carbon emissions. The transformation of conventional gasoline vehicles to new energy vehicles is an important initiative to realize the goal of developing low-carbon city through energy saving and emissions reduction, while electric vehicles (EV) will play an important role in this transition due to their advantage in energy saving and lower carbon emissions. After reviewing the existing researches on energy saving and emissions reduction of electric vehicles, this paper analyzed the factors affecting carbon emissions reduction. Combining with electric vehicles promotion program in Beijing, the paper analyzed carbon emissions and reduction potential of electric vehicles in six scenarios using the optimized energy consumption related carbon emissions model from the perspective of fuel life cycle. The scenarios included power energy structure, fuel type (energy consumption per 100 km), car type (CO2 emission factor of fuel), urban traffic conditions (speed), coal-power technologies and battery type (weight, energy efficiency). The results showed that the optimized model was able to estimate carbon emissions caused by fuel consumption more reasonably; electric vehicles had an obvious restrictive carbon reduction potential with the fluctuation of 57%-81.2% in the analysis of six influencing factors, while power energy structure and coal-power technologies play decisive roles in life-cycle carbon emissions of electric vehicles with the reduction potential of 78.1% and 81.2%, respectively. Finally, some optimized measures were proposed to reduce transport energy consumption and carbon emissions during electric vehicles promotion including improving energy structure and coal technology, popularizing energy saving technologies and electric vehicles, accelerating the battery R&D and so on. The research provides scientific basis and methods for the policy development for the transition of new energy vehicles

  5. [Research on carbon reduction potential of electric vehicles for low-carbon transportation and its influencing factors].

    PubMed

    Shi, Xiao-Qing; Li, Xiao-Nuo; Yang, Jian-Xin

    2013-01-01

    Transportation is the key industry of urban energy consumption and carbon emissions. The transformation of conventional gasoline vehicles to new energy vehicles is an important initiative to realize the goal of developing low-carbon city through energy saving and emissions reduction, while electric vehicles (EV) will play an important role in this transition due to their advantage in energy saving and lower carbon emissions. After reviewing the existing researches on energy saving and emissions reduction of electric vehicles, this paper analyzed the factors affecting carbon emissions reduction. Combining with electric vehicles promotion program in Beijing, the paper analyzed carbon emissions and reduction potential of electric vehicles in six scenarios using the optimized energy consumption related carbon emissions model from the perspective of fuel life cycle. The scenarios included power energy structure, fuel type (energy consumption per 100 km), car type (CO2 emission factor of fuel), urban traffic conditions (speed), coal-power technologies and battery type (weight, energy efficiency). The results showed that the optimized model was able to estimate carbon emissions caused by fuel consumption more reasonably; electric vehicles had an obvious restrictive carbon reduction potential with the fluctuation of 57%-81.2% in the analysis of six influencing factors, while power energy structure and coal-power technologies play decisive roles in life-cycle carbon emissions of electric vehicles with the reduction potential of 78.1% and 81.2%, respectively. Finally, some optimized measures were proposed to reduce transport energy consumption and carbon emissions during electric vehicles promotion including improving energy structure and coal technology, popularizing energy saving technologies and electric vehicles, accelerating the battery R&D and so on. The research provides scientific basis and methods for the policy development for the transition of new energy vehicles

  6. Norepinephrine release and reuptake by hypothalamic synaptosomes of spontaneously hypertensive rats

    SciTech Connect

    Hano, T.; Jeng, Y.; Rho, J.

    1989-03-01

    We compared the overflow of endogenous norepinephrine during electrical field stimulation, the norepinephrine content, and the rate of initial neuronal uptake of (3H)norepinephrine in synaptosomes isolated from hypothalamus and brainstem of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 7 and 13 weeks of age. The synaptosomes of two rats, a SHR and a WKY rat control, were simultaneously processed and subjected to the same electrical field stimulation. The overflow of endogenous norepinephrine during electrical stimulation (2 Hz, 2 minutes) in the hypothalamic synaptosomes of 7-week-old SHR was significantly greater, whereas the overflow of 13-week-old SHR was equivalent to the age-matched WKY rat. The norepinephrine content of synaptosomes was about the same in SHR and age-matched controls. There was also significantly enhanced (3H)norepinephrine uptake in the hypothalamic synaptosomes of young SHR, but neither the hypothalamic nor the brainstem samples of 13-week-old SHR showed any significant difference in their rate of (3H)norepinephrine uptake. These data are similar to those we observed (unpublished observations) in perfused mesenteric artery system in which norepinephrine release was significantly elevated during periarterial nerve stimulation only in young SHR. Thus, these results suggest that a parallel enhancement of norepinephrine release in hypothalamus with that of peripheral nervous system may play an important role during development of hypertension in young SHR.

  7. Pressure dependence of the oxygen reduction reaction at the platinum microelectrode/nafion interface - Electrode kinetics and mass transport

    NASA Technical Reports Server (NTRS)

    Parthasarathy, Arvind; Srinivasan, Supramaniam; Appleby, A. J.; Martin, Charles R.

    1992-01-01

    The investigation of oxygen reduction kinetics at the platinum/Nafion interface is of great importance in the advancement of proton-exchange-membrane (PEM) fuel-cell technology. This study focuses on the dependence of the oxygen reduction kinetics on oxygen pressure. Conventional Tafel analysis of the data shows that the reaction order with respect to oxygen is unity at both high and low current densities. Chronoamperometric measurements of the transport parameters for oxygen in Nafion show that oxygen dissolution follows Henry's isotherm. The diffusion coefficient of oxygen is invariant with pressure; however, the diffusion coefficient for oxygen is lower when air is used as the equilibrating gas as compared to when oxygen is used for equilibration. These results are of value in understanding the influence of O2 partial pressure on the performance of PEM fuel cells and also in elucidating the mechanism of oxygen reduction at the platinum/Nafion interface.

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

    SciTech Connect

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

    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

  9. Cardiac arrest: should we consider norepinephrine instead of epinephrine?

    PubMed

    Mion, Georges; Rousseau, Jean Marie; Selcer, Dominique; Samama, Charles-Marc

    2014-12-01

    A patient scheduled for a laparoscopic cholecystectomy had an anaphylactic shock during induction of anesthesia. After the injection of vecuronium, an unusual fall of arterial pressure occurred, with bradycardia, enlargement of the QRS complex, then a circulatory arrest. Chest compressions were initiated, while intravenous epinephrine 1 mg was administered. The cardiac rhythm turned into a ventricular fibrillation (VF). Despite continuous chest compressions with repeated boluses of epinephrine and several external electric shocks, the patient remained in VF. Because of obviously β-adrenergic adverse effects, epinephrine was replaced with norepinephrine. Return of spontaneous circulation was observed, with the recovering of sinusal activity. After staying for several weeks in intensive care unit because of multiorgan failure, the patient recovered without sequelae. Blood samples and cutaneous testing confirmed an allergy to vecuronium. This case report of a cardiac anaphylaxis with prolonged cardiac arrest illustrates the dual activity and adverse effects of epinephrine. Although vasoconstriction is mandated during cardiopulmonary resuscitation to provide an acceptable perfusion pressure to organs, β-adrenergic stimulation seems deleterious to the heart. Experimental studies have shown that blocking the β-adrenergic effects of epinephrine attenuates postresuscitation myocardial dysfunction or helps the return of spontaneous circulation after VF. Norepinephrine, a potent α-adrenergic drug nearly devoid of β-adrenergic properties, could be an interesting alternative to epinephrine. It can improve organ perfusion during cardiopulmonary resuscitation and could be more efficient than epinephrine in case of VF.

  10. Myocardial imaging with a radioiodinated norepinephrine storage analog

    SciTech Connect

    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.

  11. Norepinephrine release in the amygdala in response to footshock stimulation.

    PubMed

    Galvez, R; Mesches, M H; McGaugh, J L

    1996-11-01

    Extensive evidence suggests that many drugs and hormones influence memory storage by modulating training-induced release of norepinephrine (NE) within the amygdala. This experiment used in vivo microdialysis and high-performance liquid chromatography to examine norepinephrine NE release in the amygdala induced by footshock stimulation typically used in inhibitory avoidance training. Sprague-Dawley rats were implanted bilaterally with cannulae aimed at the amygdala. One to two weeks later, microdialysis probes were inserted (unilaterally) and the animals were placed in a box with a stainless-steel grid floor through which a single footshock (0.55 mA, 1.0 s) was administered either 45.5 (N = 5) or 180.5 (N = 4) min later. Samples were collected and analyzed at 15-min intervals. In both groups, the footshock stimulation increased NE levels to approximately 75% above basal levels in the first sample collected after the footshock and the levels returned to baseline within 30 min. The findings are consistent with pharmacological evidence suggesting that NE released by arousing stimulation is involved in regulating memory storage. PMID:8946419

  12. Norepinephrine Modulates Coding of Complex Vocalizations in the Songbird Auditory Cortex Independent of Local Neuroestrogen Synthesis

    PubMed Central

    Ikeda, Maaya Z.; Jeon, Sung David; Cowell, Rosemary A.

    2015-01-01

    The catecholamine norepinephrine plays a significant role in auditory processing. Most studies to date have examined the effects of norepinephrine on the neuronal response to relatively simple stimuli, such as tones and calls. It is less clear how norepinephrine shapes the detection of complex syntactical sounds, as well as the coding properties of sensory neurons. Songbirds provide an opportunity to understand how auditory neurons encode complex, learned vocalizations, and the potential role of norepinephrine in modulating the neuronal computations for acoustic communication. Here, we infused norepinephrine into the zebra finch auditory cortex and performed extracellular recordings to study the modulation of song representations in single neurons. Consistent with its proposed role in enhancing signal detection, norepinephrine decreased spontaneous activity and firing during stimuli, yet it significantly enhanced the auditory signal-to-noise ratio. These effects were all mimicked by clonidine, an α-2 receptor agonist. Moreover, a pattern classifier analysis indicated that norepinephrine enhanced the ability of single neurons to accurately encode complex auditory stimuli. Because neuroestrogens are also known to enhance auditory processing in the songbird brain, we tested the hypothesis that norepinephrine actions depend on local estrogen synthesis. Neither norepinephrine nor adrenergic receptor antagonist infusion into the auditory cortex had detectable effects on local estradiol levels. Moreover, pretreatment with fadrozole, a specific aromatase inhibitor, did not block norepinephrine's neuromodulatory effects. Together, these findings indicate that norepinephrine enhances signal detection and information encoding for complex auditory stimuli by suppressing spontaneous “noise” activity and that these actions are independent of local neuroestrogen synthesis. PMID:26109659

  13. A technical review of urban land use - transportation models as tools for evaluating vehicle travel reduction strategies

    SciTech Connect

    Southworth, F.

    1995-07-01

    The continued growth of highway traffic in the United States has led to unwanted urban traffic congestion as well as to noticeable urban air quality problems. These problems include emissions covered by the 1990 Clean Air Act Amendments (CAAA) and 1991 Intermodal Surface Transportation Efficiency Act (ISTEA), as well as carbon dioxide and related {open_quotes}greenhouse gas{close_quotes} emissions. Urban travel also creates a major demand for imported oil. Therefore, for economic as well as environmental reasons, transportation planning agencies at both the state and metropolitan area level are focussing a good deal of attention on urban travel reduction policies. Much discussed policy instruments include those that encourage fewer trip starts, shorter trip distances, shifts to higher-occupancy vehicles or to nonvehicular modes, and shifts in the timing of trips from the more to the less congested periods of the day or week. Some analysts have concluded that in order to bring about sustainable reductions in urban traffic volumes, significant changes will be necessary in the way our households and businesses engage in daily travel. Such changes are likely to involve changes in the ways we organize and use traffic-generating and-attracting land within our urban areas. The purpose of this review is to evaluate the ability of current analytic methods and models to support both the evaluation and possibly the design of such vehicle travel reduction strategies, including those strategies involving the reorganization and use of urban land. The review is organized into three sections. Section 1 describes the nature of the problem we are trying to model, Section 2 reviews the state of the art in operational urban land use-transportation simulation models, and Section 3 provides a critical assessment of such models as useful urban transportation planning tools. A number of areas are identified where further model development or testing is required.

  14. Noise and Fuel Burn Reduction Potential of an Innovative Subsonic Transport Configuration

    NASA Technical Reports Server (NTRS)

    Guo, Yueping; Nickol, Craig L.; Thomas, Russell H.

    2014-01-01

    A study is presented for the noise and fuel burn reduction potential of an innovative double deck concept aircraft with two three-shaft direct-drive turbofan engines. The engines are mounted from the fuselage so that the engine inlet is over the main wing. It is shown that such an aircraft can achieve a cumulative Effective Perceived Noise Level (EPNL) about 28 dB below the current aircraft noise regulations of Stage 4. The combination of high bypass ratio engines and advanced wing design with laminar flow control technologies provide fuel burn reduction and low noise levels simultaneously. For example, the fuselage mounted engine position provides more than 4 EPNLdB of noise reduction by shielding the inlet radiated noise. To identify the potential effect of noise reduction technologies on this concept, parametric studies are presented to reveal the system level benefits of various emerging noise reduction concepts, for both engine and airframe noise reduction. These concepts are discussed both individually to show their respective incremental noise reduction potential and collectively to assess their aggregate effects on the total noise. Through these concepts approximately about 8 dB of additional noise reduction is possible, bringing the cumulative noise level of this aircraft to 36 EPNLdB below Stage 4, if the entire suite of noise reduction technologies would mature to practical application. In a final step, an estimate is made for this same aircraft concept but with higher bypass ratio, geared, turbofan engines. With this geared turbofan propulsion system, the noise is estimated to reach as low as 40-42 dB below Stage 4 with a fuel burn reduction of 43-47% below the 2005 best-in-class aircraft baseline. While just short of the NASA N+2 goals of 42 dB and 50% fuel burn reduction, for a 2025 in service timeframe, this assessment shows that this innovative concept warrants refined study. Furthermore, this design appears to be a viable potential future passenger

  15. [Anesthetic management for pheochromocytoma resection: a comparison of epinephrine predominant and norepinephrine predominant pheochromocytoma].

    PubMed

    Doi, M; Ikeda, K

    1994-04-01

    Eleven patients with pheochromocytoma were divided into two groups; epinephrine predominant group (n = 4) and norepinephrine predominant group (n = 7). In each case, anesthesia was given using only inhalational anesthetics and adenosine triphosphate (ATP); and the same strategy was used to control cardiovascular variables. If arterial blood pressure, pulmonary artery pressure, central venous pressure or heart rate failed to be controlled with the strategy before the tumor resection, phentolamine, trinitroglycerine or propranolol was used. After the tumor resection, if decreasing the anesthetic concentration, cessation of ATP infusion and rapid intravenous infusion could not maintain the systolic arterial blood pressure above 80 mmHg, norepinephrine was infused. Maximum heart rate and arterial blood pressure during the tumor exploration were similar in both groups. No ventricular arrhythmias were recognized in any case. The frequency of usage of the cardiovascular depressants was not different between the two groups. In the norepinephrine predominant group, five cases required norepinephrine infusion after the tumor resection, but in the epinephrine predominant group, none required the norepinephrine infusion. Desensitization of alpha 1 adrenergic receptor induced by continuous high plasma norepinephrine concentration, was considered to decrease vascular resistance. In conclusion, except for the hypotension after the tumor resection in the norepinephrine predominant pheochromocytoma, both epinephrine predominant and norepinephrine predominant pheochromocytoma could be managed with similar anesthetic risks. PMID:8189622

  16. Global threat reduction initiative efforts to address transportation challenges associated with the recovery of disused radioactive sealed sources - 10460

    SciTech Connect

    Whitworth, Julie; Abeyta, Cristy L; Griffin, Justin M; Matzke, James L; Pearson, Michael W; Cuthbertson, Abigail; Rawl, Richard; Singley, Paul

    2010-01-01

    Proper disposition of disused radioactive sources is essential for their safe and secure management and necessary to preclude their use in malicious activities. Without affordable, timely transportation options, disused sealed sources remain in storage at hundreds of sites throughout the country and around the world. While secure storage is a temporary measure, the longer sources remain disused or unwanted the chances increase that they will become unsecured or abandoned. The Global Threat Reduction Initiative's Off-Site Source Recovery Project (GTRIlOSRP), recovers thousands of disused and unwanted sealed sources annually as part of GTRl's larger mission to reduce and protect high risk nuclear and radiological materials located at civilian sites worldwide. Faced with decreasing availability of certified transportation containers to support movement of disused and unwanted neutron- and beta/gamma-emitting radioactive sealed sources, GTRIlOSRP has initiated actions to ensure the continued success of the project in timely recovery and management of sealed radioactive sources. Efforts described in this paper to enhance transportation capabilities include: {sm_bullet} Addition of authorized content to existing and planned Type B containers to support the movement of non-special form and other Type B-quantity sealed sources; {sm_bullet} Procurement of vendor services for the design, development, testing and certification of a new Type B container to support transportation of irradiators, teletherapy heads or sources removed from these devices using remote handling capabilities such as the IAEA portable hot cell facility; {sm_bullet} Expansion of shielded Type A container inventory for transportation of gamma-emitting sources in activity ranges requiring use of shielding for conformity with transportation requirements; {sm_bullet} Approval of the S300 Type A fissile container for transport of Pu-239 sealed sources internationally; {sm_bullet} Technology transfer of field

  17. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Deng, Baolin; Thornton, Edward C.; Cantrell, Kirk J.; Olsen, Khris B.; Amonette, James E.

    2003-06-01

    Immobilization of toxic and radioactive metals (e.g., Cr, Tc, and U) in the vadose zone by the In Situ Gaseous Reduction (ISGR) using hydrogen sulfide (H2S) is a promising technology for soil remediation. Earlier laboratory studies have shown that Cr(VI) in soil samples can be effectively immobilized by treatment with dilute gaseous H2S. A field test completed in 1999 at White Sand Missile Range, New Mexico, has shown a 70% immobilization of Cr(VI). The objective of this EMSP project is to characterize the interactions among H2S, the metal contaminants, and soil components. Understanding these interactions is needed to optimize the remediation system and to assess the long-term effectiveness of the technology. Proposed research tasks included: (A) Evaluation of the potential catalytic effect of mineral surfaces on the rate of Cr(VI) reduction by H2S and the rate of H2S oxidation by air; (B) Identification of the reactions of soil minerals with H2S and determination of associated reaction rates; (C) Evaluation of the role of soil water chemistry on the reduction of Cr(VI) by H2S; (D) Assessment of the reductive buffering capacity of H2S-reduced soil and the potential for emplacement of long-term vadose zone reactive barriers; and (E) Evaluation of the potential for immobilization of Tc and U in the vadose zone by reduction and an assessment of the potential for remobilization by subsequent reoxidation.

  18. Flight-test measurement of the noise reduction of a jet transport delayed flap approach procedure

    NASA Technical Reports Server (NTRS)

    Foster, J. D.; Lasagna, P. L.

    1976-01-01

    A delayed flap approach procedure was flight tested using the NASA CV-990 airplane to measure and analyze the noise produced beneath the flight path. Three other types of landing approaches were also flight tested to provide a comparison of the noise reduction benefits to the delayed flap approach. The conventional type of approach was used as a baseline to compare the effectiveness of the other approaches. The decelerating approach is a variation of the delayed flap approach. A detailed comparison of the ground perceived noise generated during the approaches is presented. For this comparison, the measured noise data were normalized to compensate for variations in aircraft weight and winds that occurred during the flight tests. The data show that the reduced flap approach offers some noise reduction, while the delayed flap and decelerating approaches offer significant noise reductions over the conventional approach.

  19. Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

    PubMed Central

    Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P.; Newman, Amy Hauck

    2016-01-01

    The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR >> D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays. PMID:26843180

  20. Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine

    NASA Technical Reports Server (NTRS)

    Brown, P. A.; Vernikos, J.

    1980-01-01

    A study on the effects of five H1 and H2 antihistamines on the synaptosomal uptake of serotonin (5HT), norepinephrine (NE), and dopamine (DA) is presented. Brain homogenates from female rats were incubated in Krebs-Ringer phosphate buffer solution in the presence of one of three radioactive neurotransmitters, and one of the five antihistamines. Low concentrations of pyrilamine competitively inhibited 5HT uptake, had little effect on NE uptake, and no effect on DA uptake. Promethazine, diphenhydramine, metiamide, and cimetidine had no effect on 5HT or DA uptake at the same concentration. Diphenhydramine had a small inhibitory effect on NE uptake. It is concluded that pyrilamine is a selective and potent competitive inhibitor of 5HT uptake at concentrations between .05 and .5 micromolars.

  1. Selective Serotonin–norepinephrine Reuptake Inhibitors-induced Takotsubo Cardiomyopathy

    PubMed Central

    Vasudev, Rahul; Rampal, Upamanyu; Patel, Hiten; Patel, Kunal; Bikkina, Mahesh; Shamoon, Fayez

    2016-01-01

    Context: Takotsubo translates to “octopus pot” in Japanese. Takotsubo cardiomyopathy (TTC) is characterized by a transient regional systolic dysfunction of the left ventricle. Catecholamine excess is the one most studied and favored theories explaining the pathophysiology of TTC. Case Report: We present the case of a 52-year-old Hispanic female admitted for venlafaxine-induced TTC with a review literature on all the cases of Serotonin–norepinephrine reuptake inhibitors (SNRI)-associated TTC published so far. Conclusion: SNRI inhibit the reuptake of catecholamines into the presynaptic neuron, resulting in a net gain in the concentration of epinephrine and serotonin in the neuronal synapses and causing iatrogenic catecholamine excess, ultimately leading to TTC. PMID:27583240

  2. The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

    PubMed Central

    Ferrucci, Michela; Giorgi, Filippo S; Bartalucci, Alessia; Busceti, Carla L; Fornai, Francesco

    2013-01-01

    The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters. PMID:23814540

  3. The Mammalian Neuroendocrine Hormone Norepinephrine Supplies Iron for Bacterial Growth in the Presence of Transferrin or Lactoferrin

    PubMed Central

    Freestone, Primrose P. E.; Lyte, Mark; Neal, Christopher P.; Maggs, Anthony F.; Haigh, Richard D.; Williams, Peter H.

    2000-01-01

    Norepinephrine stimulates the growth of a range of bacterial species in nutritionally poor SAPI minimal salts medium containing 30% serum. Addition of size-fractionated serum components to SAPI medium indicated that transferrin was required for norepinephrine stimulation of growth of Escherichia coli. Since bacteriostasis by serum is primarily due to the iron-withholding capacity of transferrin, we considered the possibility that norepinephrine can overcome this effect by supplying transferrin-bound iron for growth. Incubation with concentrations of norepinephrine that stimulated bacterial growth in serum-SAPI medium resulted in loss of bound iron from iron-saturated transferrin, as indicated by the appearance of monoferric and apo- isoforms upon electrophoresis in denaturing gels. Norepinephrine also caused the loss of iron from lactoferrin. The pharmacologically inactive metabolite norepinephrine 3-O-sulfate, by contrast, did not result in iron loss from transferrin or lactoferrin and did not stimulate bacterial growth in serum-SAPI medium. Norepinephrine formed stable complexes with transferrin, lactoferrin, and serum albumin. Norepinephrine-transferrin and norepinephrine-lactoferrin complexes, but not norepinephrine-apotransferrin or norepinephrine-albumin complexes, stimulated bacterial growth in serum-SAPI medium in the absence of additional norepinephrine. Norepinephrine-stimulated growth in medium containing 55Fe complexed with transferrin or lactoferrin resulted in uptake of radioactivity by bacterial cells. Moreover, norepinephrine-stimulated growth in medium containing [3H]norepinephrine indicated concomitant uptake of norepinephrine. In each case, addition of excess iron did not affect growth but significantly reduced levels of radioactivity (55Fe or 3H) associated with bacterial cells. A role for catecholamine-mediated iron supply in the pathophysiology of infectious diseases is proposed. PMID:11029429

  4. Effects of graded LBNP on MSNA and interstitial norepinephrine

    NASA Technical Reports Server (NTRS)

    Khan, Mazhar H.; Sinoway, Lawrence I.; MacLean, David A.

    2002-01-01

    Exposure to lower body negative pressure (LBNP) leads to an increased activation of the sympathetic nervous system (SNS) and an increase in muscle sympathetic nerve activity (MSNA). In this study, we examined the relationship between MSNA and interstitial norepinephrine (NE(i)) concentrations during LBNP. Twelve healthy volunteers were studied (26 +/- 6 yr). Simultaneous MSNA and microdialysis data were collected in six of these subjects. Measurements of MSNA (microneurography) and NE(i) (microdialysis, vastus lateralis) were performed at rest and then during an incremental LBNP paradigm (-10, -30, and -50 mmHg). MSNA rose as a function of LBNP (P < 0.001, n = 12). The plasma norepinephrine (NE(p)) concentration was 0.9 +/- 0.1 nmol/l at rest (n = 12). NE(i) measured in six subjects rose from 5.2 +/- 0.8 nmol/l at rest to 17.0 +/- 1.7 nmol/l at -50 mmHg (P < 0.001). Of note, the rise in NE(p) with LBNP was considerably less compared with the changes in NE(i) (Delta21 +/- 6% vs. Delta197 +/- 52%, n = 6, P < 0.015). MSNA and NE(i) showed a significant linear relationship (r = 0.721, P < 0.004). Activation of the SNS increased MSNA and NE(i) levels. The magnitude of the NE(i) increase was far greater than that seen for NE(p) suggesting that NE movement into the circulation decreases with baroreceptor unloading.

  5. Norepinephrine uptake by rat jejunum: Modulation by angiotensin II

    SciTech Connect

    Suvannapura, A.; Levens, N.R. )

    1988-02-01

    Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibition norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (K{sub m}) of 1.72 {mu}M and a maximum velocity (V{sub max}) of 1.19 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. The low-affinity component (uptake 2) exhibited a K{sub m} of 111.1 {mu}M and a V{sub max} of 37.1 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of ({sup 3}H)NE uptake into rat jejunum. ANG II inhibited intracellular ({sup 3}H)NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular ({sup 3}H)NE accumulation by 60%. Cocaine failed to potentiate the inhibition of ({sup 3}H)NE uptake produced by ANG II. Thus ANG II appears to prevent ({sup 3}H)NE accumulation within rat jejunum by inhibiting neuronal uptake.

  6. Arthroscopic Reduction and Transportal Screw Fixation of Acetabular Posterior Wall Fracture: Technical Note.

    PubMed

    Park, Jin Young; Chung, Woo Chull; Kim, Che Keun; Huh, Soon Ho; Kim, Se Jin; Jung, Bo Hyun

    2016-06-01

    Acetabular fractures can be treated with variable method. In this study, acetabular posterior wall fracture was treated with arthroscopic reduction and fixation using cannulated screw. The patient recovered immediately and had a satisfactory outcome. In some case of acetabular fracture could be good indication with additional advantages of joint debridement and loose body removal. So, we report our case with technical note. PMID:27536654

  7. Arthroscopic Reduction and Transportal Screw Fixation of Acetabular Posterior Wall Fracture: Technical Note

    PubMed Central

    Park, Jin young; Kim, Che Keun; Huh, Soon Ho; Kim, Se Jin; Jung, Bo Hyun

    2016-01-01

    Acetabular fractures can be treated with variable method. In this study, acetabular posterior wall fracture was treated with arthroscopic reduction and fixation using cannulated screw. The patient recovered immediately and had a satisfactory outcome. In some case of acetabular fracture could be good indication with additional advantages of joint debridement and loose body removal. So, we report our case with technical note. PMID:27536654

  8. Aircraft surface coatings study: Energy efficient transport program. [sprayed and adhesive bonded coatings for drag reduction

    NASA Technical Reports Server (NTRS)

    1979-01-01

    Surface coating materials for application on transport type aircraft to reduce drag, were investigated. The investigation included two basic types of materials: spray on coatings and adhesively bonded films. A cost/benefits analysis was performed, and recommendations were made for future work toward the application of this technology.

  9. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Principal Investigator: Baolin Deng, University of Missouri, Columbia, MO; Co-Principal Investigator: Silvia Sabine Jurisson, University of Missouri, Columbia, MO; Co-Principal Investigator: Edward C. Thornton, Pacific Northwest National Laboratory Richland, WA; Co-Principal Investigator: Jeff Terry, Illinois Institute of Technology, Chicago, IL

    2008-05-12

    There are many soil contamination sites at the Department of Energy (DOE) installations that contain radionuclides and toxic metals such as uranium (U), technetium (Tc), and chromium (Cr). Since these contaminants are the main 'risk drivers' at the Hanford site (WA) and some of them also pose significant risk at other DOE facilities (e.g., Oak Ridge Reservation - TN; Rocky Flats - CO), development of technologies for cost effective site remediation is needed. Current assessment indicates that complete removal of these contaminants for ex-situ disposal is infeasible, thus in-situ stabilization through reduction to insoluble species is considered one of the most important approaches for site remediation. In Situ Gaseous Reduction (ISGR) is a technology developed by Pacific Northwest National Laboratory (PNNL) for vadose zone soil remediation. The ISGR approach uses hydrogen sulfide (H{sub 2}S) for reductive immobilization of contaminants that show substantially lower mobility in their reduced forms (e.g., Tc, U, and Cr). The technology can be applied in two ways: (i) to immobilize or stabilize pre-existing contaminants in the vadose zone soils by direct H{sub 2}S treatment, or (ii) to create a permeable reactive barrier (PRB) that prevents the migration of contaminants. Direct treatment involves reduction of the contaminants by H{sub 2}S to less mobile species. Formation of a PRB is accomplished through reduction of ferric iron species in the vadose zone soils by H{sub 2}S to iron sulfides (e.g., FeS), which provides a means for capturing the contaminants entering the treated zone. Potential future releases may occur during tank closure activities. Thus, the placement of a permeable reactive barrier by ISGR treatment can be part of the leak mitigation program. Deployment of these ISGR approaches, however, requires a better understanding of the immobilization kinetics and mechanisms, and a better assessment of the long-term effectiveness of treatment. The primary

  10. Reduction of intra-hospital transport time using the easy tube arrange device

    PubMed Central

    Joo, Ki Hyuk; Yoo, In Sool; Lee, Jinwoong; Kim, Seung Whan; Ryu, Seung; You, Yeon Ho; Cho, Yong Chul; Jeong, Woon Jun; Ahn, Byung Jun; Cho, Sung Uk

    2016-01-01

    Objective Critically ill patients sometimes require transport to another location. Longer intra-hospital transport time increases the risk of hemodynamic instability and associated complications. Therefore, reducing intra-hospital transport time is critical. Our objective was to evaluate whether or not a new device the easy tube arrange device (ETAD) has the potential to reduce intra-hospital transport time of critically ill patients. Methods We enrolled volunteers for this prospective randomized controlled study. Each participant arranged four, five, and six fluid tubings, monitoring lines, and therapeutic equipment on a cardiopulmonary resuscitation training mannequin (Resusci Anne). The time required to arrange the fluid tubings for intra-hospital transport using two different methods was evaluated. Results The median time to arrange four, five, and six fluid tubings was 86.00 (76.50 to 98.50), 96.00 (86.00 to 113.00), and 115.50 (93.00 to 130.75) seconds, respectively, using the conventional method and 60.50 (52.50 to 72.75), 69.00 (57.75 to 80.80), and 72.50 (64.75 to 90.50) seconds using the ETAD (all P<0.001). The total duration (for preparing the basic setting and organizing before and after the transport) was 280.00 (268.75 to 293.00), 315.50 (304.75 to 330.75), and 338.00 (319.50 to 360.25) seconds for four, five, and six fluid tubings, respectively, using the conventional method and 274.50 (261.75 to 289.25), 288.00 (271.75 to 298.25), and 301.00 (284.50 to 310.75) seconds, respectively, using the new method (P=0.024, P<0.001, and P<0.001, respectively). Conclusion The ETAD was convenient to use, reduced the time to arrange medical tubings, and is expected to assist medical staff during intra-hospital transport. PMID:27752622

  11. Reduction of degradation in vapor phase transported InP/InGaAsP mushroom stripe lasers

    SciTech Connect

    Jung, H.; Burkhardt, E.G.; Pfister, W.

    1988-10-03

    The rapid degradation rate generally observed in InP/InGaAsP mushroom stripe lasers can be considerably decreased by regrowing the open sidewalls of the active stripe with low-doped InP in a second epitaxial step using the hydride vapor phase transport technique. This technique does not change the fundamental laser parameters like light-current and current-voltage characteristics. Because of this drastic reduction in degradation, the vapor phase epitaxy regrown InP/InGaAsP mushroom laser seems to be an interesting candidate for application in optical communication.

  12. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    SciTech Connect

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  13. Potential emissions reduction in road transport sector using biofuel in developing countries

    NASA Astrophysics Data System (ADS)

    Liaquat, A. M.; Kalam, M. A.; Masjuki, H. H.; Jayed, M. H.

    2010-10-01

    Use of biofuels as transport fuel has high prospect in developing countries as most of them are facing severe energy insecurity and have strong agricultural sector to support production of biofuels from energy crops. Rapid urbanization and economic growth of developing countries have spurred air pollution especially in road transport sector. The increasing demand of petroleum based fuels and their combustion in internal combustion (IC) engines have adverse effect on air quality, human health and global warming. Air pollution causes respiratory problems, adverse effects on pulmonary function, leading to increased sickness absenteeism and induces high health care service costs, premature birth and even mortality. Production of biofuels promises substantial improvement in air quality through reducing emission from biofuel operated automotives. Some of the developing countries have started biofuel production and utilization as transport fuel in local market. This paper critically reviews the facts and prospects of biofuel production and utilization in developing countries to reduce environmental pollution and petro dependency. Expansion of biofuel industries in developing countries can create more jobs and increase productivity by non-crop marginal lands and wastelands for energy crops plantation. Contribution of India and China in biofuel industry in production and utilization can dramatically change worldwide biofuel market and leap forward in carbon cut as their automotive market is rapidly increasing with a souring proportional rise of GHG emissions.

  14. The role of norepinephrine in the regulation of fluid absorption in the rat proximal tubule.

    PubMed

    Chan, Y L

    1980-10-01

    In order to investigate the possibility of a direct effect of adrenergic transmitter on tubular fluid absorption, we have studied the effects of norepinephrine and phenoxybenzamine on fluid absorption in the proximal convoluted tubule of the rat kidney. Net fluid absorption (Jv) was determined in the same proximal convoluted tubule before and after addition of norepinephrine or phenoxybenzamine while the tubular lumen and peritubular capillaries were simultaneously microperfused in situ. When the tubular lumen was perfused with Ringer's solution and the peritubular capillaries were perfused with albumin Ringer's solution, Jv was 2.85 +/- 0.25 nl/min X nm. Addition of 2 X 10(-6) M norepinephrine to the capillary perfusate caused at 30% increase in Jv which could be reversed by removing the adrenergic transmitter. The effect of norepinephrine was dose dependent with the maximal increase of Jv observed at a concentration of 10(-5) M. Addition of 2 X 10(-6) M phenoxybenzamine to the capillary perfusate caused a 16% decrease in Jv while the simultaneous administration of norepinephrine and phenoxybenzamine to the capillary perfusate caused a 25% decrease in Jv. On the other hand, there was no effect observed on Jv when either norepinephrine or phenoxybenzamine was added to the luminal perfusate. These results suggest that adrenergic nerves may participate in the regulation of tubular fluid absorption through the direct action of norepinephrine on alpha adrenergic receptors located on the basolateral membrane of proximal tubular cells.

  15. Escherichia coli O157:H7 gene expression in the presence of catecholamine norepinephrine.

    PubMed

    Dowd, Scot E

    2007-08-01

    Various forms of host stresses (e.g. physiological, psychological) are thought to influence susceptibility to pathogenic microorganisms. Catecholamines such as norepinephrine are released into the GI environment during acute stress and may influence the infective process of bacterial pathogens associated with the GI tract. To examine the effects of norepinephrine on expression of virulence factors in Escherichia coli O157:H7, the clinical-type isolate EDL933 (ATCC 43895) was grown in serum-Standard American Petroleum Institute media in the presence or absence of norepinephrine. After 5 h of exposure to norepinephrine, treatment and control cultures (not exposed to norepinephrine) were harvested, their RNA isolated, and gene expression evaluated. There was a dramatic increase in the expression of virulence factor transcripts including stx1, stx2, and eae. Also induced were transcripts involved in iron metabolism. Conversely, there was comparative repression of iron acquisition and phage shock protein-related transcripts in the presence of norepinephrine. Novel observations from these data suggested that exposure to norepinephrine induced glutamate decarboxylase acid resistance as well as an SOS response in E. coli O157:H7. The results corroborate many of the previous findings detailed in the literature and provide new observations that could expand the scope of microbial endocrinology. PMID:17573936

  16. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Baolin Deng; Edward Thornton; Kirk Cantrell; Khris Olsen; James Amonette

    2004-01-11

    Immobilization of toxic and radioactive metals in the vadose zone by In Situ Gaseous Reduction (ISGR) using hydrogen sulfide (H2S) is a promising technology for soil remediation. Earlier laboratory and field studies have shown that Cr(VI) can be effectively immobilized by treatment with dilute gaseous H2S. The objective of this project is to characterize the interactions among H2S, the metal contaminants, and soil components. Understanding these interactions is needed to assess the long-term effectiveness of the technology and to optimize the remediation system.

  17. A Combined Approach to Model Reduction for Nonlinear Groundwater Flow and Solute Transport Simulations Using POD and DEIM.

    NASA Astrophysics Data System (ADS)

    Stanko, Z.; Boyce, S. E.; Yeh, W. W. G.

    2015-12-01

    Model reduction techniques using proper orthogonal decomposition (POD) have been very effective in applications to confined groundwater flow models. These techniques consist of performing a projection of the solution of the full model onto a reduced basis. POD combined with the snapshot approach has been successfully applied to highly discretized linear models. In many cases, the reduced model is orders of magnitude smaller than the full model and runs 1,000 times faster. For nonlinear models, such as the unconfined groundwater flow, direct application of POD requires additional calls to the full model to generate additional snapshots. This is time consuming and increases the dimension of the reduced model. The discrete empirical interpolation method (DEIM) is a technique that avoids the additional full model calls and captures the dynamics of the nonlinear term while reducing the dimensions. Here, POD and DEIM are combined to reduce both the nonlinear unconfined groundwater flow and solute transport equations. To prove the concept, simple one-dimensional models are created for MODFLOW and MT3DMS separately. The dual approach is then tested on a density-dependent flow and transport simulation using the LMT package developed for MODFLOW. For each iteration of the nonlinear flow solver and the transport solver, the respective reduced models are solved instead. Numerical experiments show that significant reduction is obtainable before errors become too large. This method is well suited for a coastal aquifer seawater intrusion scenario, where nonlinearities only exist in small subregions of the model domain. A fine discretization can be utilized and POD will effectively eliminate unnecessary parameterization by projecting the full model system matrix onto a subspace with fewer column dimensions. DEIM can then reduce the row dimension of the original system by using only those state variable nodes with the most influence. This combined approach allows for full

  18. Performance evaluation of an on-site volume reduction system with synthetic urine using a water transport model.

    PubMed

    Pahore, Muhammad Masoom; Ito, Ryusei; Funamizu, Naoyuki

    2011-07-01

    The parameters of a model of the transport of water from a wet cloth sheet to the air, developed for deionized water, to establish design procedures of an on-site volume reduction system, were identified for high salt concentrations present in synthetic urine. The results showed that the water penetration was affected neither by the salts, urea or creatinine present in the synthetic urine nor by the salts accumulated on the surface of the vertical gauze sheet. However, the saturated vapour pressure decreased, leading to reduction in the evaporation rate, which occurred as a result of the salts accumulating on the surface of the vertical gauze sheet. Furthermore, a steady-state evaporation condition was established, illustrating salts falling back to the tank from the vertical gauze sheet. Accordingly, the existing design procedure was amended by incorporating the calculation procedure for the saturated vapour pressure using Raoult's law. Subsequently, the effective evaporation area of the vertical gauze sheet was estimated using the amended deign procedures to assess feasibility. This estimation showed that the arid, tropical, temperate and cold climates are suitable for the operation of this system, which require requires a small place at household level for 80% volume reduction of 10 L of urine per day for 12 hours' operation in the daytime. PMID:21882549

  19. Health Cobenefits and Transportation-Related Reductions in Greenhouse Gas Emissions in the San Francisco Bay Area

    PubMed Central

    Woodcock, James; Co, Sean; Ostro, Bart; Fanai, Amir; Fairley, David

    2013-01-01

    Objectives. We quantified health benefits of transportation strategies to reduce greenhouse gas emissions (GHGE). Methods. Statistics on travel patterns and injuries, physical activity, fine particulate matter, and GHGE in the San Francisco Bay Area, California, were input to a model that calculated the health impacts of walking and bicycling short distances usually traveled by car or driving low-emission automobiles. We measured the change in disease burden in disability-adjusted life years (DALYs) based on dose–response relationships and the distributions of physical activity, particulate matter, and traffic injuries. Results: Increasing median daily walking and bicycling from 4 to 22 minutes reduced the burden of cardiovascular disease and diabetes by 14% (32 466 DALYs), increased the traffic injury burden by 39% (5907 DALYS), and decreased GHGE by 14%. Low-carbon driving reduced GHGE by 33.5% and cardiorespiratory disease burden by less than 1%. Conclusions: Increased physical activity associated with active transport could generate a large net improvement in population health. Measures would be needed to minimize pedestrian and bicyclist injuries. Together, active transport and low-carbon driving could achieve GHGE reductions sufficient for California to meet legislative mandates. PMID:23409903

  20. Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

    NASA Astrophysics Data System (ADS)

    Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

    2016-05-01

    Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

  1. An automated variance reduction method for global Monte Carlo neutral particle transport problems

    NASA Astrophysics Data System (ADS)

    Cooper, Marc Andrew

    A method to automatically reduce the variance in global neutral particle Monte Carlo problems by using a weight window derived from a deterministic forward solution is presented. This method reduces a global measure of the variance of desired tallies and increases its associated figure of merit. Global deep penetration neutron transport problems present difficulties for analog Monte Carlo. When the scalar flux decreases by many orders of magnitude, so does the number of Monte Carlo particles. This can result in large statistical errors. In conjunction with survival biasing, a weight window is employed which uses splitting and Russian roulette to restrict the symbolic weights of Monte Carlo particles. By establishing a connection between the scalar flux and the weight window, two important concepts are demonstrated. First, such a weight window can be constructed from a deterministic solution of a forward transport problem. Also, the weight window will distribute Monte Carlo particles in such a way to minimize a measure of the global variance. For Implicit Monte Carlo solutions of radiative transfer problems, an inefficient distribution of Monte Carlo particles can result in large statistical errors in front of the Marshak wave and at its leading edge. Again, the global Monte Carlo method is used, which employs a time-dependent weight window derived from a forward deterministic solution. Here, the algorithm is modified to enhance the number of Monte Carlo particles in the wavefront. Simulations show that use of this time-dependent weight window significantly improves the Monte Carlo calculation.

  2. Reduction of spatial distribution of risk factors for transportation of contaminants released by coal mining activities.

    PubMed

    Karan, Shivesh Kishore; Samadder, Sukha Ranjan

    2016-09-15

    It is reported that water-energy nexus composes two of the biggest development and human health challenges. In the present study we presented a Risk Potential Index (RPI) model which encapsulates Source, Vector (Transport), and Target risks for forecasting surface water contamination. The main aim of the model is to identify critical surface water risk zones for an open cast mining environment, taking Jharia Coalfield, India as the study area. The model also helps in feasible sampling design. Based on spatial analysis various risk zones were successfully delineated. Monthly RPI distribution revealed that the risk of surface water contamination was highest during the monsoon months. Surface water samples were analysed to validate the model. A GIS based alternative management option was proposed to reduce surface water contamination risk and observed 96% and 86% decrease in the spatial distribution of very high risk areas for the months June and July respectively.

  3. Mass transport, corrosion, plugging, and their reduction in solar dish/Stirling heat pipe receivers

    SciTech Connect

    Adkins, D.R.; Andraka, C.E.; Bradshaw, R.W.; Goods, S.H.; Moreno, J.B.; Moss, T.A.

    1996-07-01

    Solar dish/Stirling systems using sodium heat pipe receivers are being developed by industry and government laboratories here and abroad. The unique demands of this application lead to heat pipe wicks with very large surface areas and complex three-dimensional flow patterns. These characteristics can enhance the mass transport and concentration of constituents of the wick material, resulting in wick corrosion and plugging. As the test times for heat pipe receivers lengthen, we are beginning to see these effects both indirectly, as they affect performance, and directly in post-test examinations. We are also beginning to develop corrective measures. In this paper, we report on our test experiences, our post-test examinations, and on our initial effort to ameliorate various problems.

  4. Reduction in tribological energy losses in the transportation and electric utilities sectors

    SciTech Connect

    Pinkus, O.; Wilcock, D.F.; Levinson, T.M.

    1985-09-01

    This report is part of a study of ways and means of advancing the national energy conservation effort, particularly with regard to oil, via progress in the technology of tribology. The report is confined to two economic sectors: transportation, where the scope embraces primarily the highway fleets, and electric utilities. Together these two sectors account for half of the US energy consumption. Goal of the study is to ascertain the energy sinks attributable to tribological components and processes and to recommend long-range research and development (R and D) programs aimed at reducing these losses. In addition to the obvious tribological machine components such as bearings, piston rings, transmissions and so on, the study also extends to processes which are linked to tribology indirectly such as wear of machine parts, coatings of blades, high temperature materials leading to higher cycle efficiencies, attenuation of vibration, and other cycle improvements.

  5. Effects of water transportation on subduction dynamics: Roles of viscosity and density reduction

    NASA Astrophysics Data System (ADS)

    Nakao, Atsushi; Iwamori, Hikaru; Nakakuki, Tomoeki

    2016-11-01

    The effects of water on subduction dynamics, e.g., plate migration rate, slab geometry, stress field, and back-arc spreading, are investigated by using a 2-D self-consistent model for lithosphere subduction and whole mantle convection. We solve water transportation coupled with hydrous mineral phase changes. Mantle flows and water transportation are interactive through constitutive and state equations for hydrous rocks. Our model has successfully reproduced the water distribution in a mantle wedge and along the slab with sufficient resolution comparable to that of previous models that focus on the mantle wedge structure. As a result, low density owing to hydration reduces subduction rates, back-arc spreading, and slab stagnation on the phase boundary at 660-km depth, whereas low viscosity owing to hydration enhances rapid subduction, trench migration, and slab stagnation. We attribute these results to mechanisms that cause the hydrous buoyancy of subducting plates to reduce the slab pull force and the accompanying tensile stress on overlying lithosphere. In addition, hydrous weakening diminishes the mechanical coupling of the subducted slab with the wedge mantle and overriding lithosphere. Thus, water is capable of generating two opposite situations in the stress field of the overlying lithosphere and the subduction rate. Water is therefore expected to be an important mechanism for generating broad styles of the subduction structure and kinematics, as observed in actual subduction zones such as Tonga and Mariana. Such observed variation in the subduction mode can be caused by variation in buoyancy corresponding to the water content from relatively dry to several thousands of parts per million for the wedge mantle and slab surface, whereas the extremely buoyant case does not appear to occur in nature. Water in the mantle is thus key to better understand the whole-mantle-scale slab dynamics as well as island arc volcanic processes.

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

    PubMed

    Mortensen, Jens; Holst, Uffe; Jakobsen, Jørn Skibsted; Andreasen, Frederik

    2008-11-01

    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 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 (0, 1, 5, 50 and 100 microg/ml). In group B, pelvis was perfused with 6 ml/min. norepinephrine solutions (0, 0.001, 0.01, 0.1 and 1 microg/ml). In group C, pelvis was perfused with 6 ml/min. norepinephrine, norepinephrine + sotalol 10(-) (6) mol/l and norepinephrine + phentolamine 10(-) (6) mol/l. Norepinephrine solutions of 0, 10(-) (8), 10(-) (7), 10(-) (6), 10(-) (5) and 10(-) (4) mol/l were used. In group A, all norepinephrine solutions lowered the pelvic pressure increase significantly. Large increases in plasma and urine norepinephrine occurred with 50 and 100 microg/ml, but cardiovascular and renal functions remained unchanged. In group B, a significant diminishing pelvic pressure increase with all solutions was seen with a significant difference between all solutions. In group C, norepinephrine demonstrated a concentration-response curve with EC(50) between 10(-) (8) and 10(-) (7) mol/l (10(-) (7.27+/-0.40)). Sotalol had a smooth muscle inhibitory effect on the pyeloureter and inhibited the effect of norepinephrine increasing EC(50) by about a factor 10 (10(-) (6.40+/-1.17)). No convincing effect of phentolamine was observed. Endoluminal norepinephrine probably stimulates beta-adrenoceptors and inhibits 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

  7. Leptin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    PubMed

    Peliciari-Garcia, Rodrigo Antonio; Andrade-Silva, Jéssica; Cipolla-Neto, José; Carvalho, Carla Roberta de Oliveira

    2013-01-01

    Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE ( 1 µM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception.

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

    PubMed

    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.

  9. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I; Tang, Jianrong; Dani, John A

    2015-03-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID:25445492

  10. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I; Tang, Jianrong; Dani, John A

    2015-03-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.

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

    SciTech Connect

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

    1987-06-01

    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 (/sup 3/H)NE was greater in diabetic hearts in isolated perfused preparations. In comparison with the control values, diabetic hearts showed a decrease in (/sup 3/H)NE in the granular fraction and an increase in the supernatant fraction. Diabetic hearts also showed an accelerated spontaneous release of (/sup 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. Genetic comparison of seizure control by norepinephrine and neuropeptide Y.

    PubMed

    Weinshenker, D; Szot, P; Miller, N S; Rust, N C; Hohmann, J G; Pyati, U; White, S S; Palmiter, R D

    2001-10-01

    Epilepsy is a disease of neuronal hyperexcitability, and pharmacological and genetic studies have identified norepinephrine (NE) and neuropeptide Y (NPY) as important endogenous regulators of neuronal excitability. Both transmitters signal through G-protein-coupled receptors, are expressed either together or separately, and are abundant in brain regions implicated in seizure generation. NPY knock-out (NPY KO) and dopamine beta-hydroxylase knock-out (DBH KO) mice that lack NE are susceptible to seizures, and agonists of NE and NPY receptors protect against seizures. To examine the relative contributions of NE and NPY to neuronal excitability, we tested Dbh;Npy double knock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were much more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizure phenotype. DKO mice were only slightly more sensitive than DBH KO mice to seizures induced by kainic acid, pentylenetetrazole, or flurothyl, although DKO mice were uniquely prone to handling-induced seizures. NPY contributed to the seizure phenotype of DKO mice at high doses of convulsant agents and advanced stages of seizures. These data suggest that NE is a more potent endogenous anticonvulsant than NPY, and that NPY has the greatest contribution under conditions of extreme neuronal excitability.

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

    PubMed

    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.

  14. The antidepressant-like pharmacological profile of Yuanzhi-1, a novel serotonin, norepinephrine and dopamine reuptake inhibitor.

    PubMed

    Jin, Zeng-liang; Gao, Nana; Li, Xiao-rong; Tang, Yu; Xiong, Jie; Chen, Hong-xia; Xue, Rui; Li, Yun-Feng

    2015-04-01

    Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (Ki=3.95, 4.52 and 0.87nM, respectively) and recombinant cells (Ki=2.87, 6.86 and 1.03nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (Ki=2.12, 4.85 and 1.08nM, respectively) and recombinant cells (Ki=1.65, 5.32 and 0.68nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity. PMID:25638027

  15. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

    PubMed

    Auclair, A L; Martel, J C; Assié, M B; Bardin, L; Heusler, P; Cussac, D; Marien, M; Newman-Tancredi, A; O'Connor, J A; Depoortère, R

    2013-07-01

    Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects. PMID:23499664

  16. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels.

    PubMed

    Singh, Meenesh R; Clark, Ezra L; Bell, Alexis T

    2015-11-10

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32-42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices.

  17. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels

    PubMed Central

    Singh, Meenesh R.; Clark, Ezra L.; Bell, Alexis T.

    2015-01-01

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32–42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0–0.9 V, 0.9–1.95 V, and 1.95–3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices. PMID:26504215

  18. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels

    NASA Astrophysics Data System (ADS)

    Singh, Meenesh R.; Clark, Ezra L.; Bell, Alexis T.

    2015-11-01

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32-42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices.

  19. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels.

    PubMed

    Singh, Meenesh R; Clark, Ezra L; Bell, Alexis T

    2015-11-10

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32-42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices. PMID:26504215

  20. Norepinephrine represses the expression of toxA and the siderophore genes in Pseudomonas aeruginosa.

    PubMed

    Li, Wang; Lyte, Mark; Freestone, Primrose P; Ajmal, Aziba; Colmer-Hamood, Jane A; Hamood, Abdul N

    2009-10-01

    Among the different extracellular virulence factors produced by Pseudomonas aeruginosa are exotoxin A (ETA) and the pyoverdine and pyochelin siderophores. Production of ETA and the siderophores requires the function of the iron-starvation sigma factor PvdS, the transcriptional activator RegA, and the AraC-activator PchR. Iron represses the production of ETA and the siderophores by repressing the expression of pvdS, regA, and pchR. PvdS regulates the expression of the ETA gene, toxA, regA, and the pyoverdine synthesis genes. The catecholamine norepinephrine enhances the growth of pathogenic bacteria by transferring iron from host-binding proteins. In this study, we elucidated the mechanism by which norepinephrine and other catecholamines induce P. aeruginosa growth. We also investigated whether norepinephrine regulates the expression of toxA and the siderophore genes, and the mechanism of this regulation. Norepinephrine enhanced the growth of P. aeruginosa by supplying iron from transferrin. This provision of iron repressed the expression of toxA, the pyoverdine genes pvdD and pvdE, and their regulators, pvdS, regA, and pchR, suggesting that norepinephrine accomplishes this repression through PvdS and PchR. Additionally, norepinephrine bypassed PvdS and supported the growth of a pvdS deletion mutant, indicating that norepinephrine transfers iron to P. aeruginosa independent of pyoverdine. Thus, norepinephrine apparently influences the pathogenesis of P. aeruginosa by affecting its pattern of growth and the production of virulence factors. PMID:19686346

  1. Reaction-based Transport Modeling of Iron Reduction and Uranium Immobilization at Area 2 of the NABIR Field Research Center

    SciTech Connect

    Tsyh Yeh, Gour

    2007-12-21

    This research sought to examine biogeochemical processes likely to take place in the less conductive materials above and below the gravel during the in situ ethanol biostimulation experiment conducted at Area 2 during 2005-2006. The in situ experiment in turn examined the hypothesis that injection of electron donor into this layer would induce formation of a redox barrier in the less conductive materials, resulting in decreased mass transfer of uranium out these materials and attendant declines in groundwater U(VI) concentration. Our project focuses on the development of a mechanistic understanding and quantitative models of coupled Fe(III)/U(VI) reduction in FRC Area 2 sediments. This report summarizes research activities conducted at The University of Central Florida (2004-2007), the development of biogeochemical and reactive transport models and the conduction of numerical simulations at laboratory, column, and field scales.

  2. Resonant Pedestal Pressure Reduction Induced by a Thermal Transport Enhancement due to Stochastic Magnetic Boundary Layers in High Temperature Plasmas

    SciTech Connect

    Schmitz, O.; Evans, T.E.; Fenstermacher, M. E.; Unterberg, E. A.; Austin, M. E.; Bray, B. D.; Brooks, N. H.; Frerichs, H.; Groth, M.; Jakubowski, M. W.; Lasnier, C. J.; Lehnen, M.; Leonard, A. W.; Mordijck, S.; Moyer, R.A.; Osborne, T. H.; Reiter, D.; Samm, U.; Schaffer, M. J.; Unterberg, B.; West, W. P.

    2009-01-01

    Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p(e) in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q(95) resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p(e) reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q(95) resonant character of type-I edge localized mode suppression by RMPs.

  3. Resonant Pedestal Pressure Reduction Induced by a Thermal Transport Enhancement due to Stochastic Magnetic Boundary Layers in High Temperature Plasmas

    SciTech Connect

    Schmitz, O.; Frerichs, H.; Lehnen, M.; Reiter, D.; Samm, U.; Unterberg, B.; Evans, T. E.; Austin, M. E.; Bray, B. D.; Brooks, N. H.; Leonard, A. W.; Osborne, T. H.; Schaffer, M. J.; West, W. P.; Fenstermacher, M. E.; Groth, M.; Lasnier, C. J.; Unterberg, E. A.; Jakubowski, M. W.; Mordijck, S.

    2009-10-16

    Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p{sub e} in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q{sub 95} resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p{sub e} reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q{sub 95} resonant character of type-I edge localized mode suppression by RMPs.

  4. Nicotine self-administration diminishes stress-induced norepinephrine secretion but augments adrenergic-responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

    PubMed Central

    Yu, Guoliang; Sharp, Burt M.

    2010-01-01

    Chronic nicotine self-administration augments the thalamo-pituitary-adrenal (HPA) responses to stress. Altered neuropeptide expression within corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) contributes to this enhanced HPA response to stress. Herein, we determined the role of norepinephrine, a primary regulator of CRF neurons, in the responses to footshock during nicotine self-administration. On day 12-15 of self-administration, microdialysis showed nicotine reduced PVN norepinephrine release by footshock (<50% of saline). Yet, the reduction in footshock-induced adrenocorticotropic hormone (ACTH) and corticosterone secretion due to intra-PVN prazosin (α1 adrenergic antagonist) was significantly greater in rats self-administering nicotine (2-fold) than saline. Additionally, PVN phenylephrine (α1 agonist) stimulated ACTH and corticosterone release to a similar extent in unstressed rats self-administering nicotine or saline. Nicotine self-administration also decreased footshock-induced c-Fos expression in the nucleus of the solitary tract (NTS)-A2/C2 catecholaminergic neurons that project to the PVN. Therefore, footshock-induced NTS activation and PVN norepinephrine input are both attenuated by nicotine self-administration, yet PVN CRF neurons are more responsive to α1 stimulation, but only during stress. This plasticity in noradrenergic regulation of PVN CRF neurons provides a new mechanism contributing to the HPA sensitization to stress by nicotine self-administration and smoking. PMID:20028457

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

    SciTech Connect

    Glick, Z.; Raum, W.J.

    1986-07-01

    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 ..cap alpha..-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.

  6. Reduction of angular divergence of laser-driven ion beams during their acceleration and transport

    NASA Astrophysics Data System (ADS)

    Zakova, M.; Pšikal, Jan; Margarone, Daniele; Maggiore, Mario; Korn, G.

    2015-05-01

    Laser plasma physics is a field of big interest because of its implications in basic science, fast ignition, medicine (i.e. hadrontherapy), astrophysics, material science, particle acceleration etc. 100-MeV class protons accelerated from the interaction of a short laser pulse with a thin target have been demonstrated. With continuing development of laser technology, greater and greater energies are expected, therefore projects focusing on various applications are being formed, e.g. ELIMAIA (ELI Multidisciplinary Applications of laser-Ion Acceleration). One of the main characteristic and crucial disadvantage of ion beams accelerated by ultra-short intense laser pulses is their large divergence, not suitable for the most of applications. In this paper two ways how to decrease beam divergence are proposed. Firstly, impact of different design of targets on beam divergence is studied by using 2D Particlein-cell simulations (PIC). Namely, various types of targets include at foils, curved foil and foils with diverse microstructures. Obtained results show that well-designed microstructures, i.e. a hole in the center of the target, can produce proton beam with the lowest divergence. Moreover, the particle beam accelerated from a curved foil has lower divergence compared to the beam from a flat foil. Secondly, another proposed method for the divergence reduction is using of a magnetic solenoid. The trajectories of the laser accelerated particles passing through the solenoid are modeled in a simple Matlab program. Results from PIC simulations are used as input in the program. The divergence is controlled by optimizing the magnetic field inside the solenoid and installing an aperture in front of the device.

  7. The effectiveness of policy on consumer choices for private road passenger transport emissions reductions in six major economies

    NASA Astrophysics Data System (ADS)

    Mercure, J.-F.; Lam, A.

    2015-06-01

    The effectiveness of fiscal policy to influence vehicle purchases for emissions reductions in private passenger road transport depends on its ability to incentivise consumers to make choices oriented towards lower emissions vehicles. However, car purchase choices are known to be strongly socially determined, and this sector is highly diverse due to significant socio-economic differences between consumer groups. Here, we present a comprehensive dataset and analysis of the structure of the 2012 private passenger vehicle fleet-years in six major economies across the World (UK, USA, China, India, Japan and Brazil) in terms of price, engine size and emissions distributions. We argue that choices and aggregate elasticities of substitution can be predicted using this data, enabling us to evaluate the effectiveness of potential fiscal and technological change policies on fleet-year emissions reductions. We provide tools to do so based on the distributive structure of prices and emissions in segments of a diverse market, both for conventional as well as unconventional engine technologies. We find that markets differ significantly between nations, and that correlations between engine sizes, emissions and prices exist strongly in some markets and not strongly in others. We furthermore find that markets for unconventional engine technologies have patchy coverages of varying levels. These findings are interpreted in terms of policy strategy.

  8. Reduction in vitro of red cell glutathione reproduces defects of cellular sodium transport seen in oedematous malnutrition.

    PubMed

    Forrester, T; Golden, M; Brand, S; Swales, J

    1990-05-01

    Red cells in oedematous malnutrition (kwashiorkor) have an increased sodium content, 'leakiness' to sodium and enhanced sodium pumping. In non-oedematous malnutrition (marasmus) there is a reduction in the sodium pump activity. The explanation has hitherto been unknown but the glutathione content of red cells is low in kwashiorkor and normal in marasmus. We artificially lowered the glutathione content of normal red cells to values characteristic of mild oedematous malnutrition, using the enzyme inhibitors bischloronitrosourea (BCNU) and buthionine sulfoximine (BSOX). After preincubation, the cells were washed to remove the inhibitors and oxidized glutathione. Cellular content of sodium and potassium, and 86Rb influx were then measured. The reduction in glutathione reproduced the abnormalities of sodium content and flux observed in kwashiorkor. We suggest that oxidant stress in kwashiorkor, by reducing cellular glutathione, may affect cell membrane electrolyte transport. This may act through alterations in membrane sulfhydryl groups. Glutathione depletion may therefore play an important role in the clinical picture and natural history of oedematous malnutrition and may have relevance to other conditions where oxidant stress occurs.

  9. Effects of desipramine on norepinephrine clearance in congestive heart failure

    SciTech Connect

    Clemson, B.; Baily, R.G.; Davis, D.; Zelis, R. )

    1990-08-01

    Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of (3H)NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

  10. Copper-deficient mice have higher cardiac norepinephrine turnover

    SciTech Connect

    Gross, A.M.; Prohaska, J.R. )

    1989-02-01

    Male Swiss albino mice were studied at 6 weeks of age. Their dams were fed a copper-deficient diet (modified AIN-76A) starting 4 days after birth and given deionized water (-Cu) or water with CuSO{sub 4} added (+Cu) (20 {mu}g Cu/ml). When 3 weeks of age mice were weaned and housed in stainless steel cages on the respective treatment of their dams. Turnover of norepinephrine (NE) was studied in 8 experiments using 2 separate techniques. The first procedure used {alpha}-methyl-p-tyrosine methyl ester (300 mg/kg i.p.) to inhibit tyrosine hydroxlase activity. The loss of residual NE was determined by HPLC with electrochemical detection. Regression lines were constructed and fractional turnover (%/h) and calculated turnover (ng/g/h) were determined for heart, cerebellum and adrenal gland. In 4 experiments loss of NE in cerebellum of -Cu ad +Cu mice was equivalent. Loss of NE from adrenal gland could not be detected in the 8 h time course. Loss of NE, both fractional turnover and calculated turnover, from heart of -Cu mice was 4-5 fold higher compared to +Cu controls. A second method using m- hydroxybenzylhydrazine (NSD-1015) (100 mg/kg i.p.), which inhibits aromatic amino acid decarboxylase, confirmed the results. For all 4 experiments the cardiac accumulation of L-DOPA (measured by HPLC) was faster in -Cu mice compared to controls. The higher turnover rate of NE in heart and perhaps other sympathetic nerves may contribute to the higher urinary NE output observed previously.

  11. Altered sleep latency and arousal regulation in mice lacking norepinephrine.

    PubMed

    Hunsley, Melissa S; Palmiter, Richard D

    2004-08-01

    Latency to sleep and the amount of sensory stimulation required to awaken an animal are measures of arousal threshold, which are ultimately modulated by an arousal regulation system involving many brain areas. Among these brain areas and network connections are wake-promoting nuclei of the brainstem and their corresponding neurotransmitters, including norepinephrine (NE). In this study, we used mice that are unable to produce NE to study its role in regulating sleep latency after a variety of interventions, and to study arousal from sleep after sleep deprivation (SD). Sleep latency was measured after gentle awakening or after injections of saline, caffeine or modafinil. Sleep latency was also measured before and after partial restoration of NE pharmacologically. Arousal threshold was measured by recording the number of decibels of white noise required to wake each mouse from NREM sleep after 0, 3 and 3 + 3 h SD (3 h SD followed by < 2 min sleep, followed by an additional 3 h SD). Results showed that when mice were awakened without being touched, there were no differences in sleep latency between the genotypes. However, after an injection of saline, the control mice increased their sleep latency, whereas the NE-deficient mice did not. There were no group differences in sleep latency after treatment with either stimulant. The sleep latency difference between the genotypes was ameliorated by partial restoration of NE. The arousal threshold experiments revealed that significantly more noise was required to wake the NE-deficient mice after 3 and 3 + 3 h of SD. These findings show that mice lacking NE fall asleep more rapidly only after a mild stressor, such as an intraperitoneal injection. NE-deficient mice are also more difficult to wake up using audio stimulation after SD. The results presented here suggest that NE promotes wakefulness during transitions between sleep and wake under conditions involving mild stress and SD, but not under baseline circumstances.

  12. Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

    PubMed

    Negus, S S; Mello, N K; Blough, B E; Baumann, M H; Rothman, R B

    2007-02-01

    Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse

  13. Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

    PubMed Central

    Ellenbroek, Bart A.; August, Caren; Youn, Jiun

    2016-01-01

    There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome. PMID:27708559

  14. Norepinephrine Inhibits Macrophage Migration by Decreasing CCR2 Expression

    PubMed Central

    Xiu, Fangming; Stanojcic, Mile; Jeschke, Marc G.

    2013-01-01

    Increased incidences of infectious and septic complications during post-burn courses represent the main contributor to burn injury mortality. Sustained increases in catecholamine levels, especially norepinephrine (NE), contribute to immune disturbances in severely burned patients. The precise mechanisms underlying NE-mediated immunoregulation are not fully understood. Here we hypothesize that persistently elevated NE levels are associated with immunodysfunctions. We examined the effects of NE on the phenotype and functions of bone marrow-derived macrophages (BMMs). Whole mouse bone marrow cells were treated in vitro with 40 ng/mL of M-CSF and with 1 x 10-6 M or 1 x 10-8 M of NE or without NE for 7 days; cells were collected and stained with antibodies for CD11b, F4/80, MHC II and the inflammatory CC chemokine receptor 2 (CCR2). We found 1 x 10-6 M of NE inhibited MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells. It also inhibited BMM proliferation by inhibiting CSF-1R expression. On the contrary, 1 x 10-8 M of NE slightly increased both MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells but inhibited CD11b+/F4/80+ BMM proliferation. MCP-1 based migration assay showed that the migration of 1 x 10-6 M of NE-treated BMM toward MCP-1 was significantly decreased compared to BMM without NE treatment. Both 1 x 10-8 M and 1 x 10-6 M of NE enhanced TNF-α production and phagocytosis of FITC-Dextran. Intracellular staining of transcriptional factor MafB showed that 1 x 10-6 M of NE treatment enhanced its expression, whereas 1 x 10-8 M of NE decreased expression. Stimulation with LPS in the last 24-hours of BMM culture further decreased CCR2 and MHC II expression of these BMM, suggesting the synergistic effect of LPS and NE on macrophage. Our results demonstrate that NE regulates macrophage differentiation, proliferation and function, and may play a critical role in the dysfunctional immune response post-burn. PMID:23844252

  15. Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study.

    PubMed

    Flik, Gunnar; Folgering, Joost H A; Cremers, Thomas I H F; Westerink, Ben H C; Dremencov, Eliyahu

    2015-06-01

    Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialysis and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

  16. The impact of transportation control measures on emission reductions during the 2008 Olympic Games in Beijing, China

    NASA Astrophysics Data System (ADS)

    Zhou, Yu; Wu, Ye; Yang, Liu; Fu, Lixin; He, Kebin; Wang, Shuxiao; Hao, Jiming; Chen, Jinchuan; Li, Chunyan

    2010-01-01

    Traffic congestion and air pollution were two major challenges for the planners of the 2008 Olympic Games in Beijing. The Beijing municipal government implemented a package of temporary transportation control measures during the event. In this paper, we report the results of a recent research project that investigated the effects of these measures on urban motor vehicle emissions in Beijing. Bottom-up methodology has been used to develop grid-based emission inventories with micro-scale vehicle activities and speed-dependent emission factors. The urban traffic emissions of volatile organic compounds (VOC), carbon monoxide (CO), nitrogen oxides (NO x) and particulate matter with an aerodynamic diameter of 10 μm or less (PM 10) during the 2008 Olympics were reduced by 55.5%, 56.8%, 45.7% and 51.6%, respectively, as compared to the grid-based emission inventory before the Olympics. Emission intensity was derived from curbside air quality monitoring at the North 4th Ring Road site, located about 7 km from the National Stadium. Comparison between the emission intensity before and during the 2008 Olympics shows a reduction of 44.5% and 49.0% in daily CO and NO x emission from motor vehicles. The results suggest that reasonable traffic system improvement strategies along with vehicle technology improvements can contribute to controlling total motor vehicle emissions in Beijing after the Olympic Games.

  17. Correction: Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials.

    PubMed

    Muñoz Rojo, Miguel; Martín, Jaime; Grauby, Stéphane; Borca-Tasciuc, Theodorian; Dilhaire, Stefan; Martin-Gonzalez, Marisol

    2015-03-01

    Correction for 'Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials' by Miguel Muñoz Rojo et al., Nanoscale, 2014, 6, 7858-7865. PMID:25668105

  18. Correction: Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials.

    PubMed

    Muñoz Rojo, Miguel; Martín, Jaime; Grauby, Stéphane; Borca-Tasciuc, Theodorian; Dilhaire, Stefan; Martin-Gonzalez, Marisol

    2015-03-01

    Correction for 'Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials' by Miguel Muñoz Rojo et al., Nanoscale, 2014, 6, 7858-7865.

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

    PubMed

    Mortensen, Stefan P; González-Alonso, José; Nielsen, Jens-Jung; Saltin, Bengt; Hellsten, Ylva

    2009-12-01

    ATP has been proposed to play multiple roles in local skeletal muscle blood flow regulation by inducing vasodilation and modulating sympathetic vasoconstrictor activity, but the mechanisms remain unclear. Here we evaluated the effects of arterial ATP infusion and exercise on leg muscle interstitial ATP and norepinephrine (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 NE concentrations were measured during 1) femoral arterial ATP infusion (0.42 +/- 0.04 and 2.26 +/- 0.52 micromol/min; mean +/- SE) and 2) one-leg knee-extensor exercise (18 +/- 0 and 37 +/- 2 W) in 10 healthy men. Arterial ATP infusion and exercise increased leg blood flow (LBF) in the experimental leg from approximately 0.3 l/min at baseline to 4.2 +/- 0.3 and 4.6 +/- 0.5 l/min, respectively, whereas it was reduced or unchanged in the control leg. During arterial ATP infusion, muscle interstitial ATP, ADP, AMP, and adenosine concentrations remained unchanged in both legs, but muscle interstitial NE increased from approximately 5.9 nmol/l at baseline to 8.3 +/- 1.2 and 8.7 +/- 0.7 nmol/l in the experimental and control leg, respectively (P < 0.05), in parallel to a reduction in arterial pressure (P < 0.05). During exercise, however, interstitial ATP, ADP, AMP, and adenosine concentrations increased in the contracting muscle (P < 0.05), but not in inactive muscle, 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 purinergic receptors. Intraluminal ATP and muscle contractions appear to modulate sympathetic nerve activity by inhibiting the effect of NE rather than blunting its local concentration. PMID:19797688

  20. Transportation.

    ERIC Educational Resources Information Center

    Crank, Ron

    This instructional unit is one of 10 developed by students on various energy-related areas that deals specifically with transportation and energy use. Its objective is for the student to be able to discuss the implication of energy usage as it applies to the area of transportation. Some topics covered are efficiencies of various transportation…

  1. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine.

    PubMed

    Janowsky, Aaron; Tosh, Dilip K; Eshleman, Amy J; Jacobson, Kenneth A

    2016-04-01

    Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter

  2. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

    PubMed Central

    Tosh, Dilip K.; Eshleman, Amy J.; Jacobson, Kenneth A.

    2016-01-01

    Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [125I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [3H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N6-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [125I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4′-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake

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

    SciTech Connect

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

    1981-08-01

    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.

  4. Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator?

    PubMed Central

    O’Donnell, John; Ding, Fengfei; Nedergaard, Maiken

    2015-01-01

    Astrocytes are the chief supportive cells in the central nervous system, but work over the past 20 years have documented that astrocytes also contribute to complex neural processes, such as working memory. Recent discoveries of norepinephrine-mediated astrocytic Ca2+ responses have raised the possibility that astrocytic activity in the adult brain is driven by global responses to changes in behavioral state. Moreover, analysis of the interstitial space volume suggests that astrocytes may undergo changes in cell volume in response to activation of norepinephrine receptors. This review will focus on what is known about astrocytic functions within the nervous system, and how these functions interrelate with rapid changes in behavioral state mediated by norepinephrine signaling. PMID:26618103

  5. Selective Serotonin-norepinephrine Re-uptake Inhibition Limits Renovas-cular-hypertension Induced Cognitive Impairment, Endothelial Dysfunction, and Oxidative Stress Injury.

    PubMed

    Singh, Prabhat; Sharma, Bhupesh

    2016-01-01

    Hypertension has been reported to induce cognitive decline and dementia of vascular origin. Serotonin- norepinephrine reuptake transporters take part in the control of inflammation, cognitive functions, motivational acts and deterioration of neurons. This study was carried out to examine the effect of venlafaxine; a specific serotonin-norepinephrine reuptake inhibitor (SNRI), in two-kidney-one-clip-2K1C (renovascular hypertension) provoked vascular dementia (VaD) in albino rats. 2K1C technique was performed to provoke renovascular-hypertension in adult male albino Wistar rats. Learning and memory were assessed by using the elevated plus maze and Morris water maze. Mean arterial blood pressure- MABP, as well as endothelial function, were assessed by means of BIOPAC system. Serum nitrosative stress (nitrite/ nitrate), aortic superoxide anion, brain oxidative stress, inflammation, cholinergic dysfunction and brain damage (2,3,5-triphenylterazolium chloride staining) were also assessed. 2K1C has increased MABP, endothelial dysfunction as well as learning and memory impairments. 2K1C method has increased serum nitrosative stress (reduced nitrite/nitrate level), oxidative stress (increased brain thiobarbituric acid reactive species and aortic superoxide anion content along with decreased levels of brain superoxide dismutase, glutathione, and catalase), brain inflammation (increased myeloperoxidase), cholinergic dysfunction (increased acetylcholinesterase activity) and brain damage. Treatment with venlafaxine considerably attenuated renovascular-hypertension induced cognition impairment, endothelial dysfunction, serum nitrosative stress, brain and aortic oxidative stress, cholinergic function, inflammation as well as cerebral damage. The finding of this study indicates that specific modulation of the serotonin-norepinephrine transporter perhaps regarded as potential interventions for the management of renovascular hypertension provoked VaD. PMID:26915517

  6. Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model of septic shock.

    PubMed

    Minneci, Peter C; Deans, Katherine J; Banks, Steven M; Costello, Renee; Csako, Gyorgy; Eichacker, Peter Q; Danner, Robert L; Natanson, Charles; Solomon, Steven B

    2004-12-01

    During sepsis, limited data on the survival effects of vasopressors are available to guide therapy. Therefore, we compared the effects of three vasopressors on survival in a canine septic shock model. Seventy-eight awake dogs infected with differing doses of intraperitoneal Escherichia coli to produce increasing mortality were randomized to receive epinephrine (0.2, 0.8, or 2.0 microg.kg(-1).min(-1)), norepinephrine (0.2, 1.0, or 2.0 microg.kg(-1).min(-1)), vasopressin (0.01 or 0.04 U/min), or placebo in addition to antibiotics and fluids. Serial hemodynamic and biochemical variables were measured. Increasing doses of bacteria caused progressively greater decreases in survival (P <0.06), mean arterial pressure (MAP) (P <0.05), cardiac index (CI) (P <0.02), and ejection fraction (EF) (P=0.02). The effects of epinephrine on survival were significantly different from those of norepinephrine and vasopressin (P=0.03). Epinephrine had a harmful effect on survival that was significantly related to drug dose (P=0.02) but not bacterial dose. Norepinephrine and vasopressin had beneficial effects on survival that were similar at all drug and bacteria doses. Compared with concurrent infected controls, epinephrine caused greater decreases in CI, EF, and pH, and greater increases in systemic vascular resistance and serum creatinine than norepinephrine and vasopressin. These epinephrine-induced changes were significantly related to the dose of epinephrine administered. In this study, the effects of vasopressors were independent of severity of infection but dependent on the type and dose of vasopressor used. Epinephrine adversely affected organ function, systemic perfusion, and survival compared with norepinephrine and vasopressin. In the ranges studied, norepinephrine and vasopressin have more favorable risk-benefit profiles than epinephrine during sepsis.

  7. Reduced naphthylphthalamic acid binding in the tir3 mutant of Arabidopsis is associated with a reduction in polar auxin transport and diverse morphological defects

    NASA Technical Reports Server (NTRS)

    Ruegger, M.; Dewey, E.; Hobbie, L.; Brown, D.; Bernasconi, P.; Turner, J.; Muday, G.; Estelle, M.

    1997-01-01

    Polar auxin transport plays a key role in the regulation of plant growth and development. To identify genes involved in this process, we have developed a genetic procedure to screen for mutants of Arabidopsis that are altered in their response to auxin transport inhibitors. We recovered a total of 16 independent mutants that defined seven genes, called TRANSPORT INHIBITOR RESPONSE (TIR) genes. Recessive mutations in one of these genes, TIR3, result in altered responses to transport inhibitors, a reduction in polar auxin transport, and a variety of morphological defects that can be ascribed to changes in indole-3-acetic acid distribution. Most dramatically, tir3 seedlings are strongly deficient in lateral root production, a process that is known to depend on polar auxin transport from the shoot into the root. In addition, tir3 plants display a reduction in apical dominance as well as decreased elongation of siliques, pedicels, roots, and the inflorescence. Biochemical studies indicate that tir3 plants have a reduced number of N-1-naphthylphthalamic (NPA) binding sites, suggesting that the TIR3 gene is required for expression, localization, or stabilization of the NPA binding protein (NBP). Alternatively, the TIR3 gene may encode the NBP. Because the tir3 mutants have a substantial defect in NPA binding, their phenotype provides genetic evidence for a role for the NBP in plant growth and development.

  8. Characteristics of the norepinephrine-stimulated phosphatidylinositol turnover in rat pineal cell dispersions

    SciTech Connect

    Hauser, G.; Smith, T.L.

    1981-10-01

    Dispersed rat pineal cells can be used for the study of the phosphatidylinositol effect. The response to ( - )-norepinephrine of the incorporation of 32Pi into phospholipids is linear with time and cell concentration, stereospecific, and mediated through alpha-1-adrenergic receptors. Na+ in the incubation medium is obligatory for labeling of phosphatidylinositol and phosphatidylcholine by 32P. In the absence of K+, incorporation of 32P is drastically lowered and no stimulation by norepinephrine occurs. Rb+ can replace K+. Omission of Ca2+ or substitution with Sr2+ preferentially lowers incorporation of radioactivity into phosphatidylcholine. Mg2+ is not required for basal or stimulated labeling.

  9. Feedback on the use of the MX6 Mox Fuel transport cask: reduction of the dose uptake during operations

    SciTech Connect

    Blachet, L.; Lallemant, Th.

    2007-07-01

    In the framework of the quality, safety and environment policy of AREVA, TN International has implemented a global management system according to ISO 9001, OHSAS 18001 and ISO 14001 requirements with certification obtained from third part organization (1). The design of the MX6 cask is an example of the implementation of this system in order to guarantee safety and the health of everyone involved and the protection of the environment. The MX6 design has allowed ALARA dose rates for the workers during all the phases of use of the cask, to be significantly reduced compared to previous design. The MX6 cask was developed by TN International for the transport of either BWR or PWR fresh MOX fuel assemblies. Replacing the previous SIEMENS type III and SIEMENS BWR packaging, the MX6 has been firstly used in the German Nuclear Power Plants. Complying with the TS-R-1 (IAEA 1996) regulations, the MX6 cask is based on innovative solutions implemented at each step of the design and the manufacturing. Its design includes an efficient neutron shielding for high Plutonium content and an easy use content restraining system. The large payload of the MX6 cask, 6 PWR MOX fuel assemblies or 16 BWR MOX fuel assemblies, minimizes the doses uptake during its unloading at the NPP. Moreover, new sequences of loading and unloading operations were proposed for testing and implementation in each Nuclear Facility. Concurrently, total dose uptakes by the operators were assessed in order to prove the efficiency of the packaging and the proposed sequences. In this paper, the main contributors to the transports to Germany with the MX6 cask will present their involvement and feedback for the reduction of the dose uptakes by the operators during the loading and unloading operations. Presently in use at GUNDREMMINGEN and ISAR Nuclear Power Plants (NPPs), the MX6 cask use will be extended to other German and Swiss NPPs from 2006 onwards. (1) AFAQ-AFNOR Certification for ISO 9001, OHSAS 18001 and ISO

  10. Genetic and chemical reductions in protein phosphatase activity alter auxin transport, gravity response, and lateral root growth

    NASA Technical Reports Server (NTRS)

    Rashotte, A. M.; DeLong, A.; Muday, G. K.; Brown, C. S. (Principal Investigator)

    2001-01-01

    Auxin transport is required for important growth and developmental processes in plants, including gravity response and lateral root growth. Several lines of evidence suggest that reversible protein phosphorylation regulates auxin transport. Arabidopsis rcn1 mutant seedlings exhibit reduced protein phosphatase 2A activity and defects in differential cell elongation. Here we report that reduced phosphatase activity alters auxin transport and dependent physiological processes in the seedling root. Root basipetal transport was increased in rcn1 or phosphatase inhibitor-treated seedlings but showed normal sensitivity to the auxin transport inhibitor naphthylphthalamic acid (NPA). Phosphatase inhibition reduced root gravity response and delayed the establishment of differential auxin-induced gene expression across a gravity-stimulated root tip. An NPA treatment that reduced basipetal transport in rcn1 and cantharidin-treated wild-type plants also restored a normal gravity response and asymmetric auxin-induced gene expression, indicating that increased basipetal auxin transport impedes gravitropism. Increased auxin transport in rcn1 or phosphatase inhibitor-treated seedlings did not require the AGR1/EIR1/PIN2/WAV6 or AUX1 gene products. In contrast to basipetal transport, root acropetal transport was normal in phosphatase-inhibited seedlings in the absence of NPA, although it showed reduced NPA sensitivity. Lateral root growth also exhibited reduced NPA sensitivity in rcn1 seedlings, consistent with acropetal transport controlling lateral root growth. These results support the role of protein phosphorylation in regulating auxin transport and suggest that the acropetal and basipetal auxin transport streams are differentially regulated.

  11. A HTAP Multi-Model Assessment of the Influence of Regional Anthropogenic Emission Reductions on Aerosol Direct Radiative Forcing and the Role of Intercontinental Transport

    NASA Technical Reports Server (NTRS)

    Yu, Hongbin; Chin, Mian; West, J. Jason; Atherton, Cynthia S.; Bellouin, Nicolas; Bergmann, Dan; Bey, Isabelle; Bian, Huisheng; Diehl, Thomas; Forberth, Gerd; Hess, Peter; Schulz, Michael; Shindell, Drew; Takemura, Toshihiko; Tan, Qian

    2012-01-01

    In this study, we assess changes of aerosol optical depth (AOD) and direct radiative forcing (DRF) in response to the reduction of anthropogenic emissions in four major pollution regions in the northern hemisphere by using results from 10 global chemical transport models in the framework of the Hemispheric Transport of Air Pollution (HTAP). The multi-model results show that on average, a 20% reduction of anthropogenic emissions in North America, Europe, East Asia and South Asia lowers the global mean AOD and DRF by about 9%, 4%, and 10% for sulfate, organic matter, and black carbon aerosol, respectively. The impacts of the regional emission reductions on AOD and DRF extend well beyond the source regions because of intercontinental transport. On an annual basis, intercontinental transport accounts for 10-30% of the overall AOD and DRF in a receptor region, with domestic emissions accounting for the remainder, depending on regions and species. While South Asia is most influenced by import of sulfate aerosol from Europe, North America is most influenced by import of black carbon from East Asia. Results show a large spread among models, highlighting the need to improve aerosol processes in models and evaluate and constrain models with observations.

  12. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  13. Norepinephrine Triggers Metaplasticity of LTP by Increasing Translation of Specific mRNAs

    ERIC Educational Resources Information Center

    Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G.; Nguyen, Peter V.

    2015-01-01

    Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist,…

  14. Modulation of norepinephrine-stimulated cyclic AMP accumulation in rat pinealocytes by n-3 fatty acids.

    PubMed

    Delton-Vandenbroucke, I; Sarda, N; Molière, P; Lagarde, M; Gharib, A

    1996-10-01

    This work showed that docosahexaenoic (22:6n-3) and eicosapentaenoic (20:5n-3) acid supplementation for 48 h have opposite effects on the norepinephrine-stimulated cyclic AMP accumulation in rat pinealocytes. We found that 22:6n-3 supplementation of pineal cells, done by increasing specifically 22:6n-3 in phospholipid and triacylglycerol pools, led to inhibition of norepinephrine-stimulated cyclic AMP production whereas 20:5n-3 supplementation, by increasing 20:5n-3, and 22:5n-3 and 22:6n-3 in the same pools, stimulated it. In contrast, direct treatment of pinealocytes with each fatty acid (50 microM) did not affect cyclic AMP production in the presence of (0.1-10 microM) norepinephrine. The results indicate that, using pharmacological agents such as forskolin or prazosin: (a) neither basal nor forskolin-stimulated cyclic AMP levels were modified in fatty acid-supplemented cells compared to control cells; (b) in the presence of 1 microM prazosin, the activation by 20:5n-3 was still effective whereas no additional inhibition of norepinephrine stimulation was observed in 22:6n-3-supplemented cells. Taken together our results suggest that 22:6n-3 or 20:5n-3 supplementation modulates specifically the alpha 1- or beta-adrenoceptors in the rat pineal gland.

  15. Vascular and extravascular volume expansion of dobutamine and norepinephrine in normovolemic sheep.

    PubMed

    Stephens, Christopher T; Uwaydah, Nabeel; Kramer, George C; Prough, Donald S; Salter, Michael; Kinsky, Michael P

    2011-09-01

    In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. Series 1 (n = 6 per group): no drug (control), dobutamine (10 μg x kg(-1) x min), or norepinephrine (1.0 μg x kg(-1) x min(-1)) was begun 30 min before a 24-mL x kg(-1), 20-min, 0.9% NaCl bolus. The effect of drug and fluid on plasma volume (ΔPV), urinary output (UOP), and extravascular volume (ΔEVV) was determined. Series 2: Identical protocol but no fluid bolus. Series 1: the fluid bolus resulted in a peak and sustained ΔPV expansion. Norepinephrine (7.5 ± 0.9 mL x kg(-1)) and dobutamine (9.5 ± 1.1 mL x kg(-1)) significantly increased ΔPV compared with control (3.8 ± 1.1 mL x kg(-1)). Cumulative UOP was reduced by dobutamine (3.8 ± 1.4 mL x kg) compared with norepinephrine (25.1 ± 3.9 mL x kg(-1)) and control (16.9 ± 4.0 mL x kg(-1)). Norepinephrine increased ΔPV, while reducing ΔEVV after bolus. Series 2: ΔPV was unchanged in the control group. Dobutamine and norepinephrine increased ΔPV over time, 5.1 ± 0.5 and 4.0 ± 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of ΔEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. β-Adrenergic agonists enhance vascular volume expansion, whereas α-adrenergic agonists eliminate extravascular fluid.

  16. Variation in key genes of serotonin and norepinephrine function predicts gamma-band activity during goal-directed attention.

    PubMed

    Enge, Sören; Fleischhauer, Monika; Lesch, Klaus-Peter; Reif, Andreas; Strobel, Alexander

    2014-05-01

    Recent evidence shows that genetic variations in key regulators of serotonergic (5-HT) signaling explain variance in executive tasks, which suggests modulatory actions of 5-HT on goal-directed selective attention as one possible underlying mechanism. To investigate this link, 130 volunteers were genotyped for the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) and for a variation (TPH2-703 G/T) of the TPH2 gene coding for the rate-limiting enzyme of 5-HT synthesis in the brain. Additionally, a functional polymorphism of the norepinephrine transporter gene (NET -3081 A/T) was considered, which was recently found to predict attention and working memory processes in interaction with serotonergic genes. The flanker-based Attention Network Test was used to assess goal-directed attention and the efficiency of attentional networks. Event-related gamma-band activity served to indicate selective attention at the intermediate phenotype level. The main findings were that 5-HTTLPR s allele and TPH2 G-allele homozygotes showed increased induced gamma-band activity during target processing when combined with the NET A/A genotype compared with other genotype combinations, and that gamma activity mediates the genotype-specific effects on task performance. The results further support a modulatory role of 5-HT and NE function in the top-down attentional selection of motivationally relevant over competing or irrelevant sensory input.

  17. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

    PubMed Central

    Cooke, Jennifer D.; Cavender, Hannah M.; Lima, Hope K.; Grover, Lawrence M.

    2014-01-01

    Rationale Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is up-regulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI) reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. Objectives We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BNDF by testing for region-specific changes in areas CA1, CA3 and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. Methods Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and western blotting. Results LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. Conclusions LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium-influx. PMID:24781518

  18. Role of transcription factor yin yang 1 in manganese-induced reduction of astrocytic glutamate transporters: Putative mechanism for manganese-induced neurotoxicity.

    PubMed

    Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook

    2015-09-01

    Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal glutamate levels in synapses. Regulation of glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST). Indeed, the dysregulation of these transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1. Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic glutamate transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic glutamate transporters in neurodegenerative diseases and Mn-induced neurotoxicity.

  19. Role of transcription factor yin yang 1 in manganese-induced reduction of astrocytic glutamate transporters: putative mechanism for manganese-induced neurotoxicity

    PubMed Central

    Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook

    2014-01-01

    Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal glutamate levels in synapses. Regulation of glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST). Indeed, the dysregulation of these transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1.Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic glutamate transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic glutamate transporters in neurodegenerative diseases and Mn-induced neurotoxicity. PMID:25128239

  20. Effects of Intraventricular Locus Coeruleus Transplants on Seizure Severity in Genetically Epilepsy-Prone Rats Following Depletion of Brain Norepinephrine

    PubMed Central

    Clough, R. W.; Browning, R. A.; Maring, M. L.; Statnick, M. A.; Wang, C.; Jobe, P. C.

    1994-01-01

    Audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR) of the moderateseizure substrain (GEPR-3s) were investigated to determine whether norepinephrine (NE) depletion induced by 6-hydroxydopalnine (6-OHDA) microinfusion into the locus coeruleus (LC) could alter the efficacy of intraventricular NE tissue grafts in promoting reductions in seizure severity in AGS. GEPR-3s were stereotaxically infused with 6-OHDA (4μg/side/rat), or vehicle into the region of the LC. Following 6-OHDA treatment all animals were subjected to 3 AGS tests. GEPR-3s seizure severities were increased in 39.5% of the animals after microinfusion of 6-OHDA into the region of the LC. Following the third AGS test, each rat was stereotaxicaily implanted with 17 gestational day rat fetal tissue obtained from the dorsal pons and containing the primordia of the LC or with tissue obtained from the neocortex or were sham-grafted. Subsequent to grafting, rats were subjected to 3 additional AGS tests. 53% (10/19) of 6-OHDA treated GEPRs showed a significant reduction in seizure severity following transplantation of fetal LC tissue. In contrast, only 20% (1/5) of GEPRs infused with saline rather than 6-OHDA showed, a reduction of seizure severity following fetal LC transplantation. NE content in the cortex and pons/medulla was decreased by 78% and 46% respectively following 6-OHDA microinfusion into the LC. Prominent grafts with numerous TH positive neurons and neurites were present within the third ventricle of grafted animals, while cortex grafts contained no TH immunostained structures. These findings suggest that the efficacy of fetal LC tissue to promote reductions in seizure severity in GEPRs is increased following depletion of central NE by microinfusion of 6-OHDA. PMID:7819373

  1. Adolescents and adults differ in the immediate and long-term impact of nicotine administration and withdrawal on cardiac norepinephrine.

    PubMed

    Slotkin, Theodore A; Stadler, Ashley; Skavicus, Samantha; Seidler, Frederic J

    2016-04-01

    Cardiovascular responses to smoking cessation may differ in adolescents compared to adults. We administered nicotine by osmotic minipump infusion for 17 days to adolescent and adult rats (30 and 90 days of age, respectively) and examined cardiac norepinephrine levels during treatment, after withdrawal, and for months after cessation. In adults, nicotine evoked a significant elevation of cardiac norepinephrine and a distinct spike upon withdrawal, after which the levels returned to normal; the effect was specific to males. In contrast, adolescents did not show significant changes during nicotine treatment or in the immediate post-withdrawal period. However, beginning in young adulthood, males exposed to adolescent nicotine showed sustained elevations of cardiac norepinephrine, followed by later-emerging deficits that persisted through six months of age. We then conducted adolescent exposure using twice-daily injections, a regimen that augments stress associated with inter-dose withdrawal episodes. With the injection route, adolescents showed an enhanced cardiac norepinephrine response, reinforcing the relationship between withdrawal stress and a surge in cardiac norepinephrine levels. The relative resistance of adolescents to the acute nicotine withdrawal response is likely to make episodic nicotine exposure less stressful or aversive than in adults. Equally important, the long-term changes after adolescent nicotine exposure resemble those known to be associated with risk of hypertension in young adulthood (elevated norepinephrine) or subsequent congestive heart disease (norepinephrine deficits). Our findings reinforce the unique responses and consequences of nicotine exposure in adolescence, the period in which most smokers commence tobacco use. PMID:26993795

  2. Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure.

    PubMed

    Kimura, Kensuke; Kanazawa, Hideaki; Ieda, Masaki; Kawaguchi-Manabe, Haruko; Miyake, Yoshiko; Yagi, Takashi; Arai, Takahide; Sano, Motoaki; Fukuda, Keiichi

    2010-08-25

    In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1+/-5.6 ng/ml at 28-day (control level was 0.39+/-0.1 ng/ml, p<0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine beta-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss

  3. Effects of exposure to simulated microgravity on neuronal catecholamine release and blood pressure responses to norepinephrine and angiotensin

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Ludwig, D. A.; Gray, B. D.; Vernikos, J.

    1998-01-01

    We tested the hypothesis that exposure to microgravity reduces the neuronal release of catecholamines and blood pressure responses to norepinephrine and angiotensin. Eight men underwent 30 days of 6 degrees head-down tilt (HDT) bedrest to simulate exposure to microgravity. Plasma norepinephrine and mean arterial blood pressure (MAP) were measured before and after a cold pressor test (CPT) and graded norepinephrine infusion (8, 16 and 32 ng/kg/min) on day 6 of a baseline control period (C6) and on days 14 and 27 of HDT. MAP and plasma angiotensin II (Ang-II) were measured during graded Ang-II infusion (1, 2 and 4 ng/kg/min) on C8 and days 16 and 29 of HDT. Baseline total circulating norepinephrine was reduced from 1017ng during the baseline control period to 610 ng at day 14 and 673ng at day 27 of HDT, confirming a hypoadrenergic state. An elevation of norepinephrine (+178 ng) to the CPT during the baseline control period was eliminated by HDT days 14 and 27. During norepinephrine infusion, similar elevations in plasma norepinephrine (7.7 pg/ml/ng/kg/min) caused similar elevations in MAP (0.12 mmHg/ng/kg/min) across all test days. Ang-II infusion produced higher levels of plasma Ang-II during HDT (47.3 pg/ml) than during baseline control (35.5 pg/ml), while producing similar corresponding elevations in blood pressure. While vascular responsiveness to norepinephrine appears unaffected, impaired neuronal release of norepinephrine and reduced vascular responsiveness to Ang-II might contribute to the lessened capacity to vasoconstrict after spaceflight. The time course of alterations indicates effects that occur within two weeks of exposure.

  4. Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings

    PubMed Central

    Silver, Randi B.; Poonwasi, Kumar S.; Seyedi, Nahid; Wilson, Sandy J.; Lovenberg, Timothy W.; Levi, Roberto

    2002-01-01

    Activation of presynatic histamine H3 receptors (H3R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of α2-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H3R-mediated antiexocytotic effects could result from a decreased Ca2+ influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H3R cDNA (SH-SY5Y-H3). We found that reducing Ca2+ influx in response to membrane depolarization by inhibiting N-type Ca2+ channels with ω-conotoxin (ω-CTX) greatly attenuated the exocytosis of [3H]norepinephrine from both SH-SY5Y and SH-SY5Y-H3 cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to ω-CTX, activation of H3R with the selective H3R-agonist imetit also reduced both the rise in intracellular Ca2+ concentration (Cai) and norepinephrine exocytosis in response to membrane depolarization. The selective H3R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H3R, imetit affected neither the rise in Cai nor [3H]norepinephrine exocytosis, demonstrating that the presence of H3R is a prerequisite for a decrease in Cai in response to imetit and that H3R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Cai. Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H3R agonists may offer a novel therapeutic approach to this condition. PMID:11752397

  5. Route and Regulation of Zinc, Cadmium, and Iron Transport in Rice Plants (Oryza sativa L.) during Vegetative Growth and Grain Filling: Metal Transporters, Metal Speciation, Grain Cd Reduction and Zn and Fe Biofortification.

    PubMed

    Yoneyama, Tadakatsu; Ishikawa, Satoru; Fujimaki, Shu

    2015-08-13

    Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and Fe concentrations in rice grains harvested under different levels of soil/hydroponic metals are known to change only within a small range, while Cd concentrations show greater changes. To clarify the mechanisms underlying such different metal contents, we synthesized information on the routes of metal transport and accumulation in rice plants by examining metal speciation, metal transporters, and the xylem-to-phloem transport system. At grain-filling, Zn and Cd ascending in xylem sap are transferred to the phloem by the xylem-to-phloem transport system operating at stem nodes. Grain Fe is largely derived from the leaves by remobilization. Zn and Fe concentrations in phloem-sap and grains are regulated within a small range, while Cd concentrations vary depending on xylem supply. Transgenic techniques to increase concentrations of the metal chelators (nicotianamine, 2'-deoxymugineic acid) are useful in increasing grain Zn and Fe concentrations. The elimination of OsNRAMP5 Cd-uptake transporter and the enhancement of root cell vacuolar Cd sequestration reduce uptake and root-to-shoot transport, respectively, resulting in a reduction of grain Cd accumulation.

  6. Route and Regulation of Zinc, Cadmium, and Iron Transport in Rice Plants (Oryza sativa L.) during Vegetative Growth and Grain Filling: Metal Transporters, Metal Speciation, Grain Cd Reduction and Zn and Fe Biofortification

    PubMed Central

    Yoneyama, Tadakatsu; Ishikawa, Satoru; Fujimaki, Shu

    2015-01-01

    Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and Fe concentrations in rice grains harvested under different levels of soil/hydroponic metals are known to change only within a small range, while Cd concentrations show greater changes. To clarify the mechanisms underlying such different metal contents, we synthesized information on the routes of metal transport and accumulation in rice plants by examining metal speciation, metal transporters, and the xylem-to-phloem transport system. At grain-filling, Zn and Cd ascending in xylem sap are transferred to the phloem by the xylem-to-phloem transport system operating at stem nodes. Grain Fe is largely derived from the leaves by remobilization. Zn and Fe concentrations in phloem-sap and grains are regulated within a small range, while Cd concentrations vary depending on xylem supply. Transgenic techniques to increase concentrations of the metal chelators (nicotianamine, 2′-deoxymugineic acid) are useful in increasing grain Zn and Fe concentrations. The elimination of OsNRAMP5 Cd-uptake transporter and the enhancement of root cell vacuolar Cd sequestration reduce uptake and root-to-shoot transport, respectively, resulting in a reduction of grain Cd accumulation. PMID:26287170

  7. Effects of dopamine, norepinephrine and dobutamine on gastric mucosal pH of septic shock patients

    PubMed Central

    Wu, Yifen; Zhang, Ning; Wu, Yifu; Zheng, Yanping; You, Xiaoen; Cao, Zhuo; Xu, Yaqi

    2016-01-01

    The effect of different vasoactive drugs on the pH [intracellular pH (pHi)] of gastric mucosa in patients with septic shock was evaluated in the present study. According to the vasoactive drugs applied, 48 patients with septic shock were divided into 3 groups: A, B and C, with 16 cases each. Cases of group A were treated with dopamine, those of group B with norepinephrine while those of group C were treated with norepinephrine plus dobutamine. The changes of pH of gastric mucosa were observed before treatment (baseline) and 6, 12, 24 and 48 h after treatment, and the hemodynamic indicators were observed before treatment (baseline) and 6 h after administration. The gastric mucosal pH was not significantly different between two of the three groups before treatment (each at P>0.05). The gastric mucosal pH of group A did not change 6, 12, 24 and 48 h after treatment with drugs compared with the baseline (all at P>0.05), while the gastric mucosal pH in groups B and C were each statistically higher at the time points of 6, 12, 24 and 48 h after treatment with drugs compared with the respective baselines (all at P<0.05). Following treatment with drugs, the gastric mucosal pH of group C at all the time points of 6, 12, 24 and 48 h after treatment were significantly higher than those of groups A and B at the same time points after treatment, while there were some statistical differences between groups A and B at these time points (6, 12, 24 and 48 h after treatment; P<0.05). The hemodynamic indicators of the patients before treatment were not significantly different between two of the three groups (all at P>0.05). Compared with the baseline values, the mean arterial pressure and the cardiac index of each group after treatment were significantly increased, the pulmonary capillary wedge pressure and the central venous pressure of groups B and C significantly increased (all at P<0.05) and the heart rate of group A was significantly increased (P<0.05). In conclusion, the

  8. Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

    PubMed

    Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

    2016-02-26

    Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. PMID:26806036

  9. Anaerobic humus and Fe(III) reduction and electron transport pathway by a novel humus-reducing bacterium, Thauera humireducens SgZ-1.

    PubMed

    Ma, Chen; Yu, Zhen; Lu, Qin; Zhuang, Li; Zhou, Shun-Gui

    2015-04-01

    In this study, an anaerobic batch experiment was conducted to investigate the humus- and Fe(III)-reducing ability of a novel humus-reducing bacterium, Thauera humireducens SgZ-1. Inhibition tests were also performed to explore the electron transport pathways with various electron acceptors. The results indicate that in anaerobic conditions, strain SgZ-1 possesses the ability to reduce a humus analog, humic acids, soluble Fe(III), and Fe(III) oxides. Acetate, propionate, lactate, and pyruvate were suitable electron donors for humus and Fe(III) reduction by strain SgZ-1, while fermentable sugars (glucose and sucrose) were not. UV-visible spectra obtained from intact cells of strain SgZ-1 showed absorption peaks at 420, 522, and 553 nm, characteristic of c-type cytochromes (cyt c). Dithionite-reduced cyt c was reoxidized by Fe-EDTA and HFO (hydrous ferric oxide), which suggests that cyt c within intact cells of strain SgZ-1 has the ability to donate electrons to extracellular Fe(III) species. Inhibition tests revealed that dehydrogenases, quinones, and cytochromes b/c (cyt b/c) were involved in reduction of AQS (9, 10-anthraquinone-2-sulfonic acid, humus analog) and oxygen. In contrast, only NADH dehydrogenase was linked to electron transport to HFO, while dehydrogenases and cyt b/c were found to participate in the reduction of Fe-EDTA. Thus, various different electron transport pathways are employed by strain SgZ-1 for different electron acceptors. The results from this study help in understanding the electron transport processes and environmental responses of the genus Thauera.

  10. Neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of (/sup 3/H)norepinephrine from rat cortical slices

    SciTech Connect

    Landa, M.E.; Rubio, M.C.; Jaim-Etcheverry, G.

    1984-10-01

    The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with (/sup 3/H)NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

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

    PubMed

    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.

  12. Urinary epinephrine and norepinephrine levels in women athletes during training and competition.

    PubMed

    Pierce, D; Kupprat, I; Harry, D

    1976-12-01

    Training and competitive epinephrine and norepinephrine levels and proportions were compared in two groups of women athletes to determine whether changes in catecholamine excretion reflect the added mental stress of athletic competition on physical effort. An intercollegiate basketball team and a group of track and field athletes volunteered as subjects. Competitive epinephrine urinary levels were significantly (P less than 0.01) higher than training levels. A concomitant rise in the norepinephrine with an increase in physical effort was observed in both groups of athletes following training sessions as well as after athletic competition. Track and field athletes trying to qualify for an international team exhibited significantly ( less than 0.01) higher epinephrine levels than the team members; thus suggesting that anticipation of competition imposes a mental stress on an athlete. Constant changes in the catecholamine pattern as against a normal work load have yet to be established.

  13. Continuous therapeutic epinephrine but not norepinephrine prolongs splanchnic IL-6 production in porcine endotoxic shock.

    PubMed

    Bergmann, Michael; Gornikiewicz, Alexander; Tamandl, Dietmar; Exner, Ruth; Roth, Erich; Függer, Reinhold; Götzinger, Peter; Sautner, Thomas

    2003-12-01

    Catecholamines play a central role in the treatment of sepsis-associated hypotension. However, these hormones have also been shown to modulate the lipopolysaccharide (LPS)-induced induction of cytokines such as tumor necrosis factor alpha, interleukin (IL)-10, and IL-6 in vitro and in human endotoxemia. We hypothesized that catecholamines applied therapeutically in septic shock also influence cytokine patterns. We studied the cytokine response in tissues of the splanchnic compartment in a porcine endotoxin shock model up to 4 h. Shock was induced by a short infusion of LPS, and animals were treated either with fluid resuscitation alone or in combination with continuous epinephrine or norepinephrine. Animals, receiving epinephrine therapy, showed a significantly prolonged upregulation of IL-6 mRNA expression at 4 h after LPS application in liver (P = 0.0014), spleen (P < 0.0001), and mesenteric lymph nodes (P = 0.0078) as compared with animals treated with norepinephrine or fluid resuscitation. Serum IL-6 increased over time in all groups. The total concentration of the cytokine (area under the curve) was significantly higher in the epinephrine group as compared with the norepinephrine and fluid resuscitation groups (P = 0.017). The peak of serum tumor necrosis factor alpha at 1 h after LPS application was already significantly reduced by epinephrine, which was only administered at a mean of less than 0.05 microg/kg/min at this time point (P < 0.01). None of the catecholamines had a significant effect on IL-10 serum levels when compared with animals receiving fluid resuscitation alone. Our data suggest that the therapeutic application of epinephrine but not of norepinephrine is associated with a profound effect on the IL-6 response of splanchnic reticuloendothelial tissues.

  14. Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure

    NASA Technical Reports Server (NTRS)

    Biaggioni, I.; Robertson, R. M.; Robertson, D.

    1994-01-01

    It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.

  15. The influence of age on dorsal hand vein responsiveness to norepinephrine.

    PubMed

    Martin, S A; Alexieva, S; Carruthers, S G

    1986-09-01

    The influence of age on the responsiveness of dorsal hand vein alpha-receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein alpha-receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.

  16. Cardiovascular alterations after injection of 2% lidocaine with norepinephrine 1:50,000 (xylestesin) in rats.

    PubMed

    Faraco, Fatima Neves; Armonia, Paschoal Laercio; Malamed, Stanley F

    2007-01-01

    The purpose of the present study is to determine the cardiovascular effects produced by intravascular injection of 2% lidocaine with 20 microg/mL of norepinephrine on systolic, diastolic, and mean arterial pressures and heart rate of rats at the following times: control period, during the injection (first 15 seconds), during the first minute, and at the end of 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after drug administration. The study was performed on 13 male Wistar rats with weights between 200 grams and 220 grams that were awake during the recording of these parameters. The dose administered was proportional to 1 cartridge of local anesthetic (1.8 mL) in an average-size human, which is equivalent to 0.51 mg/kg of lidocaine hydrochloride and 0.51 microg/kg of norepinephrine hydrochloride. The average time of injection was 15.7 seconds. The results of this study showed significant increases in systolic, diastolic, and mean arterial pressure and a noticeable decrease in heart rate. The greatest variation occurred in the systolic blood pressure. The greatest alterations occurred during injection and within the first minute following administration of the anesthetic solution. We would anticipate these changes in the parameters analyzed to be clinically significant. Thus, dentists using 2% lidocaine with norepinephrine 20 mug/mL should be very careful to avoid intravascular injection.

  17. Cardiovascular Alterations After Injection of 2% Lidocaine With Norepinephrine 1:50,000 (Xylestesin) in Rats

    PubMed Central

    Faraco, Fatima Neves; Armonia, Paschoal Laercio; Malamed, Stanley F

    2007-01-01

    The purpose of the present study is to determine the cardiovascular effects produced by intravascular injection of 2% lidocaine with 20 μg/mL of norepinephrine on systolic, diastolic, and mean arterial pressures and heart rate of rats at the following times: control period, during the injection (first 15 seconds), during the first minute, and at the end of 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after drug administration. The study was performed on 13 male Wistar rats with weights between 200 grams and 220 grams that were awake during the recording of these parameters. The dose administered was proportional to 1 cartridge of local anesthetic (1.8 mL) in an average-size human, which is equivalent to 0.51 mg/kg of lidocaine hydrochloride and 0.51 μg/kg of norepinephrine hydrochloride. The average time of injection was 15.7 seconds. The results of this study showed significant increases in systolic, diastolic, and mean arterial pressure and a noticeable decrease in heart rate. The greatest variation occurred in the systolic blood pressure. The greatest alterations occurred during injection and within the first minute following administration of the anesthetic solution. We would anticipate these changes in the parameters analyzed to be clinically significant. Thus, dentists using 2% lidocaine with norepinephrine 20 μg/mL should be very careful to avoid intravascular injection. PMID:17579502

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

    SciTech Connect

    Matsumura, Yasuo; Kawazoe, Shinka; Ichihara, Toshio; Shinyama, Hiroshi; Kageyama, Masaaki; Morimoto, Shiro )

    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.

  19. Dopamine and norepinephrine depletion in ring doves fed DDE, dieldrin, and Aroclor 1254

    USGS Publications Warehouse

    Heinz, G.H.; Hill, E.F.; Contrera, J.F.

    1980-01-01

    The levels of dopamine and norepinephrine were measured in one-half of the brain of ring doves fed a control diet or a diet containing 2, 20, or 200 ppm DDE; 1, 4, or 16 ppm dieldrin; or 1, 10, or 100 ppm Aroclor 1254. Levels of DDE, dieldrin, or Aroclor 1254 were determined in the other half of each brain. The intermediate and high levels of each chemical caused depletions in both neurotransmitters, and brain residues of each chemical were negatively correlated with levels of neurotransmitters. The highest concentrations of DDE, dieldrin, and Aroclor 1254 depressed averages of dopamine to 42.4, 41.4, and 45.2% of the control level and norepinephrine to 61.6, 62.0, and 56.9% of controls, respectively. Depletions of dopamine and norepinephrine could result in abnormal behavior of contaminated birds in the wild, and the detection of such depletions could become an important tool in assessing contaminant-induced behavioral aberrations in birds.

  20. Intra-amygdala injections of CREB antisense impair inhibitory avoidance memory: Role of norepinephrine and acetylcholine

    PubMed Central

    Canal, Clinton E.; Chang, Qing; Gold, Paul E.

    2008-01-01

    Infusions of CREB antisense into the amygdala prior to training impair memory for aversive tasks, suggesting that the antisense may interfere with CRE-mediated gene transcription and protein synthesis important for the formation of new memories within the amygdala. However, the amygdala also appears to modulate memory formation in distributed brain sites, through mechanisms that include the release of norepinephrine and acetylcholine within the amygdala. Thus, CREB antisense injections may affect memory by interfering with mechanisms of modulation, rather than storage, of memory. In the present experiment, rats received bilateral intra-amygdala infusions of CREB antisense (2 nmol/1 μL) 6 h prior to inhibitory avoidance training. In vivo microdialysis samples were collected from the right amygdala before, during, and following training. CREB antisense produced amnesia tested at 48 h after training. In addition, CREB antisense infusions dampened the training-related release of norepinephrine, and to a lesser extent of acetylcholine, in the amygdala. Furthermore, intra-amygdala infusions of the β-adrenergic receptor agonist clenbuterol administered immediately after training attenuated memory impairments induced by intra-amygdala injections of CREB antisense. These findings suggest that intra-amygdala treatment with CREB antisense may affect processes involved in modulation of memory in part through interference with norepinephrine and acetylcholine neurotransmission in the amygdala. PMID:18772255

  1. Morris water maze performance deficit produced by intermittent swim stress is partially mediated by norepinephrine.

    PubMed

    Warner, Timothy A; Drugan, Robert C

    2012-03-01

    Intermittent swim stress (ISS) exposes a rat to cold water and the effects of the procedure produce detrimental results on activity measures 24h later. The ISS model can be used with the Morris water maze (MWM) to investigate the impact of stress on a spatial learning and memory task, known to involve the hippocampus. We investigated if the ISS model produced performance deficits in the MWM (experiments 1 and 2). We also investigated the role of norepinephrine by using an alpha-2 adrenergic agonist (i.e., clonidine) to exacerbate ISS-induced deficits (experiment 3), and using antidepressants (i.e., desipramine and reboxetine) that enhance the synaptic availability of norepinephrine to reduce ISS-induced deficits (experiments 4 and 5). Results indicated a main effect for stress in all experiments, with the exception of experiment 2, as ISS did induce performance deficits in the MWM. Clonidine enhanced ISS-induced deficits only in the learning trials, while desipramine and reboxetine reduced ISS-induced deficits in the learning trials. Additionally, only reboxetine reduced memory deficits in the MWM. These findings provide evidence that norepinephrine may act as a partial mediator of ISS-induced deficits in MWM performance.

  2. Genetic marker of norepinephrine synthesis predicts individual differences in post-error slowing: a pilot study.

    PubMed

    Colzato, Lorenza S; de Rover, Mischa; van den Wildenberg, Wery P M; Nieuwenhuis, Sander

    2013-11-01

    When our brain detects the commission of an error, we slow down immediately thereafter: a phenomenon called post-error slowing (PES). Some researchers have speculated that slowing after unexpected errors or negative feedback is related to the activity of the neuromodulatory locus coeruleus-norepinephrine system. In the present pilot study, we tested whether individual differences in the size of PES are related to differences in genetic predisposition related to norepinephrine synthesis. In a sample of 100 healthy adults, we studied the dependency of an individual's size of PES on the DBH5'-ins/del polymorphism-a variation in the DBH gene associated with the production of the enzyme dopamine β-hydroxylase, which catalyzes the conversion of dopamine to norepinephrine. DBH5'-ins/del heterozygotes, who have intermediate levels of plasma DβH activity, showed increased PES in a Simon task compared to del/del homozygotes and ins/ins homozygotes, who have low and high levels of plasma DβH activity, respectively. This outcome pattern presents preliminary evidence that the size of PES varies with DβH activity and, presumably, NE release according to an inverted U-shape: intermediate levels of DβH activity and NE release are associated with larger post-error adjustments. PMID:23962674

  3. Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells.

    PubMed

    Nguyen, Hieu M; Mejia, Edgard M; Chang, Wenguang; Wang, Ying; Watson, Emily; On, Ngoc; Miller, Donald W; Hatch, Grant M

    2016-10-01

    Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. Cardiolipin is a mitochondrial phospholipid required for function of the electron transport chain and ATP generation. We examined the role of cardiolipin in maintaining mitochondrial function necessary to support barrier properties of brain microvessel endothelial cells. Knockdown of the terminal enzyme of cardiolipin synthesis, cardiolipin synthase, in hCMEC/D3 cells resulted in decreased cellular cardiolipin levels compared to controls. The reduction in cardiolipin resulted in decreased mitochondrial spare respiratory capacity, increased pyruvate kinase activity, and increased 2-deoxy-[(3) H]glucose uptake and glucose transporter-1 expression and localization to membranes in hCMEC/D3 cells compared to controls. The mechanism for the increase in glucose uptake was an increase in adenosine-5'-monophosphate kinase and protein kinase B activity and decreased glycogen synthase kinase 3 beta activity. Knockdown of cardiolipin synthase did not affect permeability of fluorescent dextran across confluent hCMEC/D3 monolayers grown on Transwell(®) inserts. In contrast, knockdown of cardiolipin synthase resulted in an increase in 2-deoxy-[(3) H]glucose transport across these monolayers compared to controls. The data indicate that in hCMEC/D3 cells, spare respiratory capacity is dependent on cardiolipin. In addition, reduction in cardiolipin in these cells alters their cellular energy status and this results in increased glucose transport into and across hCMEC/D3 monolayers. Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. In human adult brain endothelial cell hCMEC/D3 monolayers cultured on Transwell(®) plates, knockdown of cardiolipin synthase results in decrease in mitochondrial

  4. A Multimodel Assessment of the Influence of Regional Anthropogenic Emission Reductions on Aerosol Direct Radiative Forcing and the Role of Intercontinental Transport

    NASA Technical Reports Server (NTRS)

    Yu, Hongbin; Chin, Mian; West, Jason; Atherton, Cynthia S.; Bellouin, Nicolas; Bergmann, Dan; Bey, Isabelle; Bian, Huisheng; Diehl, Thomas; Forberth, Gerd; Hess, Peter; Schulz, Michael; Shindell, Drew; Takemura, Toshihiko; Tan, Qian

    2013-01-01

    In this study, we assess changes of aerosol optical depth (AOD) and direct radiative forcing (DRF) in response to the reduction of anthropogenic emissions in four major pollution regions in the Northern Hemisphere by using results from nine global models in the framework of the Hemispheric Transport of Air Pollution (HTAP). DRF at top of atmosphere (TOA) and surface is estimated based on AOD results from the HTAP models and AOD-normalized DRF (NDRF) from a chemical transport model. The multimodel results show that, on average, a 20% reduction of anthropogenic emissions in North America, Europe, East Asia, and South Asia lowers the global mean AOD (all-sky TOA DRF) by 9.2% (9.0%), 3.5% (3.0%), and 9.4% (10.0%) for sulfate, particulate organic matter (POM), and black carbon (BC), respectively. Global annual average TOA all-sky forcing efficiency relative to particle or gaseous precursor emissions from the four regions (expressed as multimodel mean +/- one standard deviation) is -3.5 +/-0.8, -4.0 +/- 1.7, and 29.5+/-18.1mW / sq m per Tg for sulfate (relative to SO2), POM, and BC, respectively. The impacts of the regional emission reductions on AOD and DRF extend well beyond the source regions because of intercontinental transport (ICT). On an annual basis, ICT accounts for 11 +/- 5% to 31 +/- 9% of AOD and DRF in a receptor region at continental or subcontinental scale, with domestic emissions accounting for the remainder, depending on regions and species. For sulfate AOD, the largest ICT contribution of 31 +/- 9% occurs in South Asia, which is dominated by the emissions from Europe. For BC AOD, the largest ICT contribution of 28 +/- 18% occurs in North America, which is dominated by the emissions from East Asia. The large spreads among models highlight the need to improve aerosol processes in models, and evaluate and constrain models with observations.

  5. Coupled Vortex-Lattice Flight Dynamic Model with Aeroelastic Finite-Element Model of Flexible Wing Transport Aircraft with Variable Camber Continuous Trailing Edge Flap for Drag Reduction

    NASA Technical Reports Server (NTRS)

    Nguyen, Nhan; Ting, Eric; Nguyen, Daniel; Dao, Tung; Trinh, Khanh

    2013-01-01

    This paper presents a coupled vortex-lattice flight dynamic model with an aeroelastic finite-element model to predict dynamic characteristics of a flexible wing transport aircraft. The aircraft model is based on NASA Generic Transport Model (GTM) with representative mass and stiffness properties to achieve a wing tip deflection about twice that of a conventional transport aircraft (10% versus 5%). This flexible wing transport aircraft is referred to as an Elastically Shaped Aircraft Concept (ESAC) which is equipped with a Variable Camber Continuous Trailing Edge Flap (VCCTEF) system for active wing shaping control for drag reduction. A vortex-lattice aerodynamic model of the ESAC is developed and is coupled with an aeroelastic finite-element model via an automated geometry modeler. This coupled model is used to compute static and dynamic aeroelastic solutions. The deflection information from the finite-element model and the vortex-lattice model is used to compute unsteady contributions to the aerodynamic force and moment coefficients. A coupled aeroelastic-longitudinal flight dynamic model is developed by coupling the finite-element model with the rigid-body flight dynamic model of the GTM.

  6. Reaction-Based Transport Modeling of Iron Reduction and Uranium Immobilization at Area 2 of the NABIR Field Research Center

    SciTech Connect

    Yeh, Gour-Tsyh

    2006-06-01

    This research project (started Fall 2004) was funded by a grant to The Pennsylvania State University, University of Central Florida, and The University of Alabama in the Integrative Studies Element of the NABIR Program (DE-FG04-ER63914/63915/63196). Dr. Eric Roden, formerly at The University of Alabama, is now at the University of Wisconsin - Madison. Our project focuses on the development of a mechanistic understanding and quantitative models of coupled Fe(III)/U(VI) reduction in FRC Area 2 sediments. This work builds on our previous studies of microbial Fe(III) and U(VI) reduction, and is directly aligned with the Scheibe et al. NABIR FRC Field Project at Area 2.

  7. Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake.

    PubMed

    Shobo, M; Kondo, Y; Yamada, H; Mihara, T; Yamamoto, N; Katsuoka, M; Harada, K; Ni, K; Matsuoka, N

    2010-06-01

    The antipsychotic drug zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP; N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7- to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamine-induced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3beta,16beta,17alpha,18beta,20alpha)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in

  8. Reaction-Based Reactive Transport Modeling of Iron Reduction and Uranium Immobilization at Area 2 of the NABIR Field Research Center

    SciTech Connect

    Burgos, W.D.

    2009-09-02

    This report summarizes research conducted in conjunction with a project entitled “Reaction-Based Reactive Transport Modeling of Iron Reduction and Uranium Immobilization at Area 2 of the NABIR Field Research Center”, which was funded through the Integrative Studies Element of the former NABIR Program (now the Environmental Remediation Sciences Program) within the Office of Biological and Environmental Research. Dr. William Burgos (The Pennsylvania State University) was the overall PI/PD for the project, which included Brian Dempsey (Penn State), Gour-Tsyh (George) Yeh (Central Florida University), and Eric Roden (formerly at The University of Alabama, now at the University of Wisconsin) as separately-funded co-PIs. The project focused on development of a mechanistic understanding and quantitative models of coupled Fe(III)/U(VI) reduction in FRC Area 2 sediments. The work builds on our previous studies of microbial Fe(III) and U(VI) reduction, and was directly aligned with the Scheibe et al. ORNL FRC Field Project at Area 2.

  9. Aluminium-induced reduction of plant growth in alfalfa (Medicago sativa) is mediated by interrupting auxin transport and accumulation in roots.

    PubMed

    Wang, Shengyin; Ren, Xiaoyan; Huang, Bingru; Wang, Ge; Zhou, Peng; An, Yuan

    2016-01-01

    The objective of this study was to investigate Al(3+)-induced IAA transport, distribution, and the relation of these two processes to Al(3+)-inhibition of root growth in alfalfa. Alfalfa seedlings with or without apical buds were exposed to 0 or 100 μM AlCl3 and were foliar sprayed with water or 6 mg L(-1) IAA. Aluminium stress resulted in disordered arrangement of cells, deformed cell shapes, altered cell structure, and a shorter length of the meristematic zone in root tips. Aluminium stress significantly decreased the IAA concentration in apical buds and root tips. The distribution of IAA fluorescence signals in root tips was disturbed, and the IAA transportation from shoot base to root tip was inhibited. The highest intensity of fluorescence signals was detected in the apical meristematic zone. Exogenous application of IAA markedly alleviated the Al(3+)-induced inhibition of root growth by increasing IAA accumulation and recovering the damaged cell structure in root tips. In addition, Al(3+) stress up-regulated expression of AUX1 and PIN2 genes. These results indicate that Al(3+)-induced reduction of root growth could be associated with the inhibitions of IAA synthesis in apical buds and IAA transportation in roots, as well as the imbalance of IAA distribution in root tips. PMID:27435109

  10. Aluminium-induced reduction of plant growth in alfalfa (Medicago sativa) is mediated by interrupting auxin transport and accumulation in roots

    PubMed Central

    Wang, Shengyin; Ren, Xiaoyan; Huang, Bingru; Wang, Ge; Zhou, Peng; An, Yuan

    2016-01-01

    The objective of this study was to investigate Al3+-induced IAA transport, distribution, and the relation of these two processes to Al3+-inhibition of root growth in alfalfa. Alfalfa seedlings with or without apical buds were exposed to 0 or 100 μM AlCl3 and were foliar sprayed with water or 6 mg L−1 IAA. Aluminium stress resulted in disordered arrangement of cells, deformed cell shapes, altered cell structure, and a shorter length of the meristematic zone in root tips. Aluminium stress significantly decreased the IAA concentration in apical buds and root tips. The distribution of IAA fluorescence signals in root tips was disturbed, and the IAA transportation from shoot base to root tip was inhibited. The highest intensity of fluorescence signals was detected in the apical meristematic zone. Exogenous application of IAA markedly alleviated the Al3+-induced inhibition of root growth by increasing IAA accumulation and recovering the damaged cell structure in root tips. In addition, Al3+ stress up-regulated expression of AUX1 and PIN2 genes. These results indicate that Al3+-induced reduction of root growth could be associated with the inhibitions of IAA synthesis in apical buds and IAA transportation in roots, as well as the imbalance of IAA distribution in root tips. PMID:27435109

  11. Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain.

    PubMed

    Kourtesis, Ioannis; Kasparov, Sergey; Verkade, Paul; Teschemacher, Anja G

    2015-01-01

    The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas-nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine-containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension.

  12. Role of nitric oxide in modulating the long-term renal and hypertensive actions of norepinephrine.

    PubMed

    Granger, J; Schnackenberg, C; Novak, J; Tucker, B; Miller, T; Morgan, S; Kassab, S

    1997-01-01

    We have previously reported that nitric oxide (NO) plays an important role in protecting the renal vasculature from acute norepinephrine-induced vasoconstriction. The purpose of this study was to determine the importance of this interaction between NO and norepinephrine in long-term control of renal hemodynamics and arterial pressure. To achieve this goal, we examined the effects of an intrarenal infusion of norepinephrine (NE) (0.1 microgram.kg-1.min-1) for 7 days in conscious, chronically instrumented control dogs and in dogs pretreated with a synthesis inhibitor, L-NAME (3 micrograms.kg-1.min-1 intrarenally). Both groups of dogs also received captopril (15 micrograms.kg-1.min-1) plus angiotensin I] intravenously to clamp the renin-angiotensin system throughout the protocol. In control dogs (n = 6), intrarenal infusion of NE decreased renal plasma flow by 9% (134 +/- 10 to 122 +/- 14 mL/min) and glomerular filtration rate by 16% (49 +/- 4 to 41 +/- 5 mL/min) while having no effect on mean arterial pressure (100 +/- 3 to 98 +/- 4 mm Hg). In marked contrast, in dogs pretreated with intrarenal L-NAME (n = 9), NE decreased renal plasma flow by 37% (129 +/- 8 to 81 +/- 16 mL/min) and glomerular filtration rate by 32% (47 +/- 3 to 32 +/- 5 mL/min) while increasing mean arterial pressure from 104 +/- 5 to 113 +/- 6 mm Hg. The results of this study demonstrate that NO plays an important role in modulating the long-term actions of NE on renal function and arterial pressure.

  13. Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain.

    PubMed

    Kourtesis, Ioannis; Kasparov, Sergey; Verkade, Paul; Teschemacher, Anja G

    2015-01-01

    The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas-nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine-containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension. PMID

  14. Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain

    PubMed Central

    Kourtesis, Ioannis; Kasparov, Sergey; Verkade, Paul

    2015-01-01

    The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas—nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine-containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension. PMID

  15. The role of norepinephrine and insulin resistance in an early stage of hypertension.

    PubMed

    Penesova, Adela; Radikova, Zofia; Cizmarova, Eva; Kvetnanský, Richard; Blazicek, Pavel; Vlcek, Miroslav; Koska, Juraj; Vigas, Milan

    2008-12-01

    The interrelationship between activity of sympathetic nervous system and metabolic risk factors in youth with hypertension (HT) has been poorly studied. The aim of our present study was to assess the interrelationship between metabolic risk factors, such as insulin resistance, concentration of plasminogen activator inhibitor (PAI)-1, and catecholamines in an early stage of HT onset. An oral glucose tolerance test was performed in 17 young males with early-diagnosed nontreated HT grade 1 and 16 gender-, age-, and BMI-matched normotensive controls. Concentrations of glucose, insulin, epinephrine, norepinephrine, PAI-1, and plasma renin activity (PRA) were determined in venous plasma. Insulin sensitivity indices (ISIs) proposed by Cederholm, Matsuda, and Gutt were calculated. HT had higher baseline levels of norepinephrine, insulin (P= 0.02), and PAI-1 (P= 0.04). ISIs were lower in HT subjects (P < 0.001). Baseline concentrations of epinephrine were negatively associated with HDL cholesterol (r=-0.415, P= 0.02), ISI Matsuda (r=-0.361, P= 0.04), ISI Cederholm (r=-0.354, P= 0.04), and ISI Gutt (r=-0.429, P= 0.01), and positively with PRA (r= 0.609, P < 0.0001). Positive association was found between baseline concentrations of norepinephrine and PAI-1 (r= 0.418, P= 0.02). The sympathetic overactivity, which occurs in the early stage of HT may contribute to reduced insulin sensitivity even in young patients and intensify the undesirable development of metabolic cardiovascular risk factors and progress of the disease. PMID:19120146

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

    SciTech Connect

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

    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.

  17. Deep Reductions in Greenhouse Gas Emissions from the California Transportation Sector: Dynamics in Vehicle Fleet and Energy Supply Transitions to Achieve 80% Reduction in Emissions from 1990 Levels by 2050

    NASA Astrophysics Data System (ADS)

    Leighty, Wayne Waterman

    California's "80in50" target for reducing greenhouse gas emissions to 80 percent below 1990 levels by the year 2050 is based on climate science rather than technical feasibility of mitigation. As such, it raises four fundamental questions: is this magnitude of reduction in greenhouse gas emissions possible, what energy system transitions over the next 40 years are necessary, can intermediate policy goals be met on the pathway toward 2050, and does the path of transition matter for the objective of climate change mitigation? Scenarios for meeting the 80in50 goal in the transportation sector are modelled. Specifically, earlier work defining low carbon transport scenarios for the year 2050 is refined by incorporating new information about biofuel supply. Then transition paths for meeting 80in50 scenarios are modelled for the light-duty vehicle sub-sector, with important implications for the timing of action, rate of change, and cumulative greenhouse gas emissions. One aspect of these transitions -- development in the California wind industry to supply low-carbon electricity for plug-in electric vehicles -- is examined in detail. In general, the range of feasible scenarios for meeting the 80in50 target is narrow enough that several common themes are apparent: electrification of light-duty vehicles must occur; continued improvements in vehicle efficiency must be applied to improving fuel economy; and energy carriers must de-carbonize to less than half of the carbon intensity of gasoline and diesel. Reaching the 80in50 goal will require broad success in travel demand reduction, fuel economy improvements and low-carbon fuel supply, since there is little opportunity to increase emission reductions in one area if we experience failure in another. Although six scenarios for meeting the 80in50 target are defined, only one also meets the intermediate target of reducing greenhouse gas emissions to 1990 levels by the year 2020. Furthermore, the transition path taken to reach any

  18. Altered baseline blood volume and the norepinephrine response to stress in humans

    NASA Technical Reports Server (NTRS)

    Vernikos, J.; Convertino, V. A.

    1992-01-01

    A hypothesis is proposed that a primary physiological purpose of the neural and endocrine response to stressors is the preservation of the blood volume/blood pressure relationship. Changes in blood volume caused by an adaptation to the environmental challenge serve to modulate the neural and endocrine responsiveness to stress. Relationships between changes in vascular volume, vasoconstriction, and norepinephrine (NE) responses during acute and chronic exposure to various stressors are examined. It is noted that the hypothesis is based on numerous observations rather than definitive cause-effect experiments and further investigation is required to prove it.

  19. Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia.

    PubMed

    Hatta, E; Yasuda, K; Levi, R

    1997-11-01

    During protracted myocardial ischemia, ATP depletion promotes Na+ accumulation in sympathetic terminals and prevents vesicular storage of norepinephrine (NE). This forces the reversal of the neuronal uptake1 transporter, and NE is massively released (carrier-mediated release). We had shown that histamine H3 receptors (H3Rs) modulate ischemic NE release in animals. We have now used a human model of protracted myocardial ischemia to investigate whether H3Rs may control carrier-mediated NE release. Surgical specimens of human atrium were incubated in anoxic conditions. NE release increased approximately 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ independent and inhibited by the uptake1 inhibitor desipramine. Furthermore, the Na+/H+ exchanger (NHE) inhibitors ethyl-isopropyl-amiloride and HOE 642, and the Na+ channel blocker tetrodotoxin inhibited NE release, whereas the Na+ channel activator aconitine potentiated it. The selective H3R agonist imetit decreased NE release, an effect that was blocked by each of the H3R antagonists thioperamide and clobenpropit. Notably, imetit acted synergistically with ethyl-isopropyl-amiloride, HOE 642 and tetrodotoxin to reduce anoxic NE release. Thus, activation of H3R appears to result in an inhibition of both NHE- and voltage-dependent Na+ channels. Most importantly, endogenous histamine was released from the anoxic human heart, and thioperamide and clobenpropit each alone increased NE release, indicating that H3R become activated in myocardial ischemia. Our findings indicate that H3Rs are likely to mitigate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with myocardial ischemia.

  20. Innovative Techniques of Multiphase Flow in Pipeline System for Oil-Gas Gathering and Transportation with Energy-Saving and Emission-Reduction

    NASA Astrophysics Data System (ADS)

    Bai, Bofeng; Guo, Liejin; Zhang, Shaojun; Zhang, Ximin; Gu, Hanyang

    2010-03-01

    Multiphase flow measurement, desanding, dehumidification and heat furnace are critical techniques for the oil and gas gathering and transportation, which influnce intensively the energy-saving and emission-reduction in the petroleum industry. Some innovative techniques were developed for the first time by the present research team, including an online recognation instrument of multiphase flow regime, a water fraction instrument for multuphase flow, a coiled tube desanding separator with low pressure loss and high efficiency, a supersonic swirling natural gas dehumifier, and a vacuum phase-change boiler. With an integration of the above techniques, a new oil gas gathering and transpotation system was proposed, which reduced the establishment of one metering station and several transfer stations compared with the tranditional system. The oil and gas mixture transpotation in single pipes was realized. The improved techniques were applied in the oilfields in China and promoted the productivity of the oilfields by low energy consumption, low emissions, high efficiency and great security.

  1. Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials.

    PubMed

    Rojo, Miguel Muñoz; Martín, Jaime; Grauby, Stéphane; Borca-Tasciuc, Theodorian; Dilhaire, Stefan; Martin-Gonzalez, Marisol

    2014-07-21

    To date, there is no experimental characterization of thermal conductivity of semiconductor polymeric individual nanowires embedded in a matrix. This work reports on scanning thermal microscopy measurements in a 3ω configuration to determine how the thermal conductivity of individual nanowires made of a model conjugated polymer (P3HT) is modified when decreasing their diameters. We observe a reduction of thermal conductivity, from λNW = 2.29 ± 0.15 W K(-1) m(-1) to λNW = 0.5 ± 0.24 W K(-1) m(-1), when the diameter of nanowires is reduced from 350 nm to 120 nm, which correlates with the polymer crystal orientation measured by WAXS. Through this work, the foundations for future polymer thermal transport engineering are presented. PMID:24933655

  2. Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials.

    PubMed

    Rojo, Miguel Muñoz; Martín, Jaime; Grauby, Stéphane; Borca-Tasciuc, Theodorian; Dilhaire, Stefan; Martin-Gonzalez, Marisol

    2014-07-21

    To date, there is no experimental characterization of thermal conductivity of semiconductor polymeric individual nanowires embedded in a matrix. This work reports on scanning thermal microscopy measurements in a 3ω configuration to determine how the thermal conductivity of individual nanowires made of a model conjugated polymer (P3HT) is modified when decreasing their diameters. We observe a reduction of thermal conductivity, from λNW = 2.29 ± 0.15 W K(-1) m(-1) to λNW = 0.5 ± 0.24 W K(-1) m(-1), when the diameter of nanowires is reduced from 350 nm to 120 nm, which correlates with the polymer crystal orientation measured by WAXS. Through this work, the foundations for future polymer thermal transport engineering are presented.

  3. Reduction of intracellular pH by tenidap. Involvement of cellular anion transporters in the pH change.

    PubMed

    McNiff, P; Robinson, R P; Gabel, C A

    1995-10-26

    Tenidap [5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide], a novel antirheumatic agent, produces a rapid and sustained intracellular acidification when applied to cells in culture. To investigate the mechanism by which this change in ionic homeostasis is achieved, the acidification activities of structural analogs of tenidap were determined, and the movements of [14C]tenidap into and out of cells were explored. The acidification activity of tenidap was enhanced by lowering extracellular pH, suggesting that the free acid species was required for this process. Consistent with this requirement, a non-acidic analog of tenidap did not produce a change in intracellular pH (pHi). In contrast, multihalogenated derivatives of tenidap produced greater changes in pHi than did tenidap, and one analog produced a transient acidification from which the cell recovered; this recovery, however, was blocked by an inhibitor of the Na+/H+ antiporter. Fibroblasts incubated with [14C]tenidap achieved within 5 min a level of cell-associated drug that remained constant during longer incubations. Simultaneous addition of the electrogenic ionophore valinomycin or the P-glycoprotein inhibitor 4-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-N-[2-(3,4-dimethoxyphe nyl) ethyl]-6,7-dimethoxy-2-quinazolinamine (CP-100,356) caused a time- and concentration-dependent increase in the level of cell-associated [14C]tenidap; other agents tested did not promote this enhanced cellular accumulation. [14C]Tenidap accumulated by fibroblasts in the presence of CP-100,356 subsequently was released when these cells were placed in a tenidap- and CP-100,356-free medium. Importantly, several agents that are known to inhibit anion transport processes, including alpha-cyano-beta-(1-phenylindol-3-yl) acrylate, 5-nitro-2(3-phenylpropylamino)-benzoic acid, and meclofenamic acid, inhibited efflux of [14C]tenidap. In contrast, ethacrynic acid and 4,4'-diisothiocyanatostilbene-2

  4. FW-CADIS Method for Global and Semi-Global Variance Reduction of Monte Carlo Radiation Transport Calculations

    SciTech Connect

    Wagner, John C; Peplow, Douglas E.; Mosher, Scott W

    2014-01-01

    This paper presents a new hybrid (Monte Carlo/deterministic) method for increasing the efficiency of Monte Carlo calculations of distributions, such as flux or dose rate distributions (e.g., mesh tallies), as well as responses at multiple localized detectors and spectra. This method, referred to as Forward-Weighted CADIS (FW-CADIS), is an extension of the Consistent Adjoint Driven Importance Sampling (CADIS) method, which has been used for more than a decade to very effectively improve the efficiency of Monte Carlo calculations of localized quantities, e.g., flux, dose, or reaction rate at a specific location. The basis of this method is the development of an importance function that represents the importance of particles to the objective of uniform Monte Carlo particle density in the desired tally regions. Implementation of this method utilizes the results from a forward deterministic calculation to develop a forward-weighted source for a deterministic adjoint calculation. The resulting adjoint function is then used to generate consistent space- and energy-dependent source biasing parameters and weight windows that are used in a forward Monte Carlo calculation to obtain more uniform statistical uncertainties in the desired tally regions. The FW-CADIS method has been implemented and demonstrated within the MAVRIC sequence of SCALE and the ADVANTG/MCNP framework. Application of the method to representative, real-world problems, including calculation of dose rate and energy dependent flux throughout the problem space, dose rates in specific areas, and energy spectra at multiple detectors, is presented and discussed. Results of the FW-CADIS method and other recently developed global variance reduction approaches are also compared, and the FW-CADIS method outperformed the other methods in all cases considered.

  5. [Involvement of calmodulin in realization of vasoconstrictive effects of serotonin and norepinephrin].

    PubMed

    Kozhevnikova, L M; Avdonin, P V

    2012-01-01

    Possible involvement ofcalmodulin in adrenergic and serotoninergic regulation of vascular contractility has been studied. Calmodulin inhibitors trifluoperazine and W-13 suppress vasoconstriction of the rat aorta in response to norepinephrine, serotonin, and serotonin 5HT1A- and 5HT2A-receptor agonists (8-OH-DPAT and DOI, respectively) and do not affect the vasodilatory effect of 5HT1B-, 5HT2B-, and 5HT4-receptors. The force of aorta contraction in response to 8-OH-DPAT increases after the activation of calcium entry through voltage-gated Ca2+-channels. This effect is not related to non-specific activation of alpha1-adrenoceptors, since it is realized in the presence of prazosin. The inhibitor of calmodulin-dependent myosin light chain kinase KN93 decreases the vasoconstrictive response in response to norepinephrine and serotonin by only 20%. Calmodulin inhibitors slightly decrease aortic constriction in response to endothelin-1, vasopressin, angiotensin II, and KCl. Trifluoperazine does not suppress vasoconstriction induced by the G-protein activator AlF4(-). It is assumed that the target of trifluoperazine and W-13 is calmodulin interacting directly with alpha1-adrenoceptors and serotonin 5HT1A- and 5HT2A-receptors.

  6. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way.

    PubMed

    Wang, Shan; Wang, Xiuchao; Ye, Zichen; Xu, Chengming; Zhang, Ming; Ruan, Banjun; Wei, Ming; Jiang, Yinghao; Zhang, Ying; Wang, Li; Lei, Xiaoying; Lu, Zifan

    2015-10-16

    Brown adipose tissue converts energy from food into heat via the mitochondrial uncoupling protein UCP1, defending against cold. In some conditions, inducible 'brown-like' adipocytes, also known as beige adipocytes, can develop within white adipose tissue (WAT). These beige adipocytes have characteristics similar to classical brown adipocytes and thus can burn lipids to produce heat. In the current study, we demonstrated that curcumin (50 or 100 mg/kg/day) decreased bodyweight and fat mass without affecting food intake in mice. We further demonstrated that curcumin improves cold tolerance in mice. This effect was possibly mediated by the emergence of beige adipocytes and the increase of thermogenic gene expression and mitochondrial biogenesis in inguinal WAT. In addition, curcumin promotes β3AR gene expression in inguinal WAT and elevates the levels of plasma norepinephrine, a hormone that can induce WAT browning. Taken together, our data suggest that curcumin can potentially prevent obesity by inducing browning of inguinal WAT via the norepinephrine-β3AR pathway.

  7. Sleep allostasis in chronic sleep restriction: the role of the norepinephrine system

    PubMed Central

    Kim, Youngsoo; Chen, Lichao; McCarley, Robert W.; Strecker, Robert E.

    2013-01-01

    Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the α1- adrenergic receptor in the basal forebrain as well as α2- and β1-adrenergic receptor in the anterior cingulate cortex only on the first sleep restriction day. On the other hand, the frontal cortex α1-, α2-, and β1- adrenergic receptor mRNA levels were reduced throughout the period of sleep restriction. Combined with our earlier findings on EEG that sleep time and intensity significantly increased only on the first sleep restriction days, these results suggest that alterations in the brain norepinephrine system in the basal forebrain and cingulate cortex may mediate allostatic changes in sleep time and intensity observed during chronic sleep restriction. PMID:23916734

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

    PubMed Central

    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

  9. Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder.

    PubMed

    Saraceni, Megan M; Venci, Jineane V; Gandhi, Mona A

    2014-08-01

    In July 2013, the US Food and Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotonin-norepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy. PMID:24381243

  10. Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*

    PubMed Central

    Yuen, Eunice Y.; Qin, Luye; Wei, Jing; Liu, Wenhua; Liu, Aiyi; Yan, Zhen

    2014-01-01

    The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of Gi protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons. PMID:25056951

  11. Insulin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    PubMed

    Garcia, Rodrigo Antonio Peliciari; Afeche, Solange Castro; Scialfa, Julieta Helena; do Amaral, Fernanda Gaspar; dos Santos, Sabrina Heloísa José; Lima, Fabio Bessa; Young, Martin Elliot; Cipolla-Neto, José

    2008-01-01

    The mammalian pineal gland synthesizes melatonin in a circadian manner, peaking during the dark phase. This synthesis is primarily regulated by sympathetic innervations via noradrenergic fibers, but is also modulated by many peptidergic and hormonal systems. A growing number of studies reveal a complex role for melatonin in influencing various physiological processes, including modulation of insulin secretion and action. In contrast, a role for insulin as a modulator of melatonin synthesis has not been investigated previously. The aim of the current study was to determine whether insulin modulates norepinephrine (NE)-mediated melatonin synthesis. The results demonstrate that insulin (10(- 8)M) potentiated norepinephrine-mediated melatonin synthesis and tryptophan hydroxylase (TPOH) activity in ex vivo incubated pineal glands. When ex vivo incubated pineal glands were synchronized (12h NE-stimulation, followed by 12h incubation in the absence of NE), insulin potentiated NE-mediated melatonin synthesis and arylalkylamine-N-acetyltransferase (AANAT) activity. Insulin did not affect the activity of hydroxyindole-O-methyltranferase (HIOMT), nor the gene expression of tpoh, aanat, or hiomt, under any of the conditions investigated. We conclude that insulin potentiates NE-mediated melatonin synthesis in cultured rat pineal gland, potentially through post-transcriptional events.

  12. Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

    PubMed Central

    Fox, Megan E; Studebaker, R Isaac; Swofford, Nathaniel J; Wightman, R Mark

    2015-01-01

    Previous work has demonstrated the importance of genetic factors and stress-sensitive circuits in the development of affective disorders. Anxiety and numerous psychological disorders are comorbid with substance abuse, and noradrenergic signaling in the bed nucleus of the stria terminalis (BNST) is thought to be a source of this convergence. Here, we examined the effects of different stressors on behavior and norepinephrine dynamics in the BNST of rat strains known to differ in their HPA-axis function. We compared the effects of acute morphine dependence and social isolation in non-anxious Sprague Dawley (SD) rats, and a depression model, Wistar-Kyoto (WKY) rats. We found a shared phenotype in drug-dependent and singly housed SD rats, characterized by slowed norepinephrine clearance, decreased autoreceptor function, and elevated anxiety. WKY rats exhibited changes in anxiety and autoreceptor function only following morphine dependence. To ascertain the influence of LC inhibition on this plasticity, we administered the LC-terminal-selective toxin DSP-4 to SD and WKY rats. DSP-4-treated SD rats demonstrated a dependence-like phenotype, whereas WKY rats were unchanged. Overall, our findings suggest that individuals with varying stress susceptibilities have different noradrenergic signaling changes in response to stress. These changes may establish conditions that favor stress-induced reinstatement and increase the risk for addiction. PMID:25601230

  13. Marked changes in endogenous antioxidant expression precede vitamin A-, C-, and E-protectable, radiation-induced reductions in small intestinal nutrient transport.

    PubMed

    Roche, Marjolaine; Kemp, Francis W; Agrawal, Amit; Attanasio, Alicia; Neti, Prasad V S V; Howell, Roger W; Ferraris, Ronaldo P

    2011-01-01

    Rapidly proliferating epithelial crypt cells of the small intestine are susceptible to radiation-induced oxidative stress, yet there is a dearth of data linking this stress to expression of antioxidant enzymes and to alterations in intestinal nutrient absorption. We previously showed that 5-14 days after acute γ-irradiation, intestinal sugar absorption decreased without change in antioxidant enzyme expression. In the present study, we measured antioxidant mRNA and protein expression in mouse intestines taken at early times postirradiation. Observed changes in antioxidant expression are characterized by a rapid decrease within 1h postirradiation, followed by dramatic upregulation within 4h and then downregulation a few days later. The cell type and location expressing the greatest changes in levels of the oxidative stress marker 4HNE and of antioxidant enzymes are, respectively, epithelial cells responsible for nutrient absorption and the crypt region comprising mainly undifferentiated cells. Consumption of a cocktail of antioxidant vitamins A, C, and E, before irradiation, prevents reductions in transport of intestinal sugars, amino acids, bile acids, and peptides. Ingestion of antioxidants may blunt radiation-induced decreases in nutrient transport, perhaps by reducing acute oxidative stress in crypt cells, thereby allowing the small intestine to retain its absorptive function when those cells migrate to the villus days after the insult.

  14. Na(+) doping induced changes in the reduction and charge transport characteristics of Al2O3-stabilized, CuO-based materials for CO2 capture.

    PubMed

    Imtiaz, Q; Abdala, P M; Kierzkowska, A M; van Beek, W; Schweiger, S; Rupp, J L M; Müller, C R

    2016-04-28

    Chemical looping combustion (CLC) and chemical looping with oxygen uncoupling (CLOU) are emerging CO2 capture technologies that could reduce appreciably the costs associated with the capture of CO2. In CLC and CLOU, the oxygen required to combust a hydrocarbon is provided by a solid oxygen carrier. Among the transition metal oxides typically considered for CLC and CLOU, copper oxide (CuO) stands out owing to its high oxygen carrying capacity, exothermic reduction reactions and fast reduction kinetics. However, the low Tammann (sintering) temperature of CuO is a serious drawback. In this context, it has been proposed to support CuO on high Tammann temperature and low cost alumina (Al2O3), thus, reducing the morphological changes occurring over multiple CLC or CLOU redox cycles and stabilizing, in turn, the high activity of CuO. However, in CuO-Al2O3 systems, phase stabilization and avoiding the formation of the CuAl2O4 spinel is key to obtaining a material with a high redox stability and activity. Here, we report a Na(+) doping strategy to phase stabilize Al2O3-supported CuO, yielding in turn an inexpensive material with a high redox stability and CO2 capture efficiency. We also demonstrate that doping CuO-Al2O3 with Na(+) improves the oxygen uncoupling characteristics and coke resistance of the oxygen carriers. Utilizing in situ and ex situ X-ray absorption spectroscopy (XAS), the local structure of Cu and the reduction pathways of CuO were determined as a function of the Na(+) content and cycle number. Finally, using 4-point conductivity measurements, we confirm that doping of Al2O3-supported CuO with Na(+) lowers the activation energy for charge transport explaining conclusively the improved redox characteristics of the new oxygen carriers developed. PMID:27080470

  15. Na(+) doping induced changes in the reduction and charge transport characteristics of Al2O3-stabilized, CuO-based materials for CO2 capture.

    PubMed

    Imtiaz, Q; Abdala, P M; Kierzkowska, A M; van Beek, W; Schweiger, S; Rupp, J L M; Müller, C R

    2016-04-28

    Chemical looping combustion (CLC) and chemical looping with oxygen uncoupling (CLOU) are emerging CO2 capture technologies that could reduce appreciably the costs associated with the capture of CO2. In CLC and CLOU, the oxygen required to combust a hydrocarbon is provided by a solid oxygen carrier. Among the transition metal oxides typically considered for CLC and CLOU, copper oxide (CuO) stands out owing to its high oxygen carrying capacity, exothermic reduction reactions and fast reduction kinetics. However, the low Tammann (sintering) temperature of CuO is a serious drawback. In this context, it has been proposed to support CuO on high Tammann temperature and low cost alumina (Al2O3), thus, reducing the morphological changes occurring over multiple CLC or CLOU redox cycles and stabilizing, in turn, the high activity of CuO. However, in CuO-Al2O3 systems, phase stabilization and avoiding the formation of the CuAl2O4 spinel is key to obtaining a material with a high redox stability and activity. Here, we report a Na(+) doping strategy to phase stabilize Al2O3-supported CuO, yielding in turn an inexpensive material with a high redox stability and CO2 capture efficiency. We also demonstrate that doping CuO-Al2O3 with Na(+) improves the oxygen uncoupling characteristics and coke resistance of the oxygen carriers. Utilizing in situ and ex situ X-ray absorption spectroscopy (XAS), the local structure of Cu and the reduction pathways of CuO were determined as a function of the Na(+) content and cycle number. Finally, using 4-point conductivity measurements, we confirm that doping of Al2O3-supported CuO with Na(+) lowers the activation energy for charge transport explaining conclusively the improved redox characteristics of the new oxygen carriers developed.

  16. Effects of 2-substituted-4-phenylquinolines on uptake of serotonin and norepinephrine by isolated brain synaptosomes

    SciTech Connect

    Alhaider, A.A.; Lein, E.J.; Ransom, R.W.; Bolger, M.B.

    1987-03-02

    In this present communication, the in vitro inhibition of the uptake of (/sup 3/H)-L-norepinephrine ((/sup 3/H) NE) and (/sup 3/H)-Serotonin ((/sup 3/H) 5-HT) by eleven synthesized 2-substituted-4-phenylquionlines were studied using rate brain synaptosomal preparations. Compounds with an open side chain were relatively weak inhibitors of the synaptosomal uptake of (/sup 3/H) NE and (/sup 3/H) 5HT. Compounds having a distance of three atoms between the terminal basic nitrogen of the side chain and the quinoline ring were better inhibitors of serotonin uptake than those compounds having a four-atom distance. The replacement of the side chain with a piperazine ring produced compounds which were more potent and selective inhibitors of the uptake of either (/sup 3/H) 5-HT or (/sup 3/H) NE. Further structure-activity relationships are also discussed. 13 references, 1 table.

  17. Norepinephrine turnover in heart and spleen of 7-, 22-, and 34 C-acclimated hamsters

    NASA Technical Reports Server (NTRS)

    Jones, S. B.; Musacchia, X. J.

    1976-01-01

    The relationship of norepinephrine (NE) concentration and endogenous turnover rates in both myocardial and spleen tissues in the golden hamster is examined as a function of chronic exposure to either high or low ambient temperatures. Changes in myocardial and spleen NE turnover values are discussed in terms of functional alterations in sympathetic nerve activity and the importance of such changes in temperature acclimation. It is found that acclimation of hamsters to 7 C for 7-10 weeks results in decreased myocardial NE concentration and an apparent increase in myocardial NE turnover. In contrast, exposure to 34 C for 6-8 weeks results in increased myocardial NE concentration and an apparent decrease in NE turnover in both myocardial and spleen tissues. The implication of altered NE synthesis is that sympathetic nerve activity is reduced with heat acclimation and is enhanced with cold acclimation.

  18. Norepinephrine alterations under stress conditions following the regular practice of meditation.

    PubMed

    Morrell, E M; Hollandsworth, J G

    1986-01-01

    The present study reexamined an investigation that found enhanced plasma norepinephrine (NE) levels during isometric handgrip after 30 days of meditation practice. Since hemodynamic activity did not show corresponding increases, it was suggested that meditation had down regulated the cardiovascular response to sympathetic stimulation. The present study assessed response to venipuncture as well as isometric stress. At posttest, meditators showed a trend towards higher plasma NE levels than controls during isometric handgrip. However, in contrast to previous speculation, this did not appear to represent cardiovascular down-regulation. At the same time, meditators produced the greater NE levels during venipuncture, accompanied by marginally lower heart rate. The results support the association between regular meditation and noradrenergic hyperactivation, but suggest the need for further investigation of underlying mechanisms.

  19. Thermal effects of injecting norepinephrine into hypothalamus of the rat during rest and exercise

    SciTech Connect

    Gisolfi, C.V.; Christman, J.V.

    1980-12-01

    Norepinephrine (NE) was injected bilaterally through implanted guide cannulas into the anterior hypothalamus (AH) of male Sprague-Dawley rats at rest and before treadmill exercise. Colonic (T sub c), tail-skin (T sub s), and ambient (T sub a) temperatures were monitored by a telethermometer. Intrahypothalamic injections of NE produced a dose-dependent hypothermia with a 3-5 C rise in T sub s at rest, but NE injected 2 min before exercise raised the T sub s and reduced the T sub c by 0.9 C below resting levels during exercise. The results show that (1) 0.5-40.0 microgram amounts of NE injected into the AH produce only hypothermia, (2) alpha-adrenergic receptors in the AH play a role in heat dissipation when the thermoregulatory system is subjected to the endogenous stress of exercise, and (3) exercise provides a nonthermal input to the temperature regulatory system which increases heat dissipation.

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

    PubMed

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

    2015-01-01

    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. PMID:26374985

  1. Insulation for Daydreams: A Role for Tonic Norepinephrine in the Facilitation of Internally Guided Thought

    PubMed Central

    Smallwood, Jonathan; Brown, Kevin S.; Baird, Benjamin; Mrazek, Michael D.; Franklin, Michael S.; Schooler, Jonathan W.

    2012-01-01

    Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment. PMID:22493672

  2. A highly sensitive radioenzymatic assay for simultaneous estimation of norepinephrine, dopamine, and epinephrine

    SciTech Connect

    Cheng, C.H.; Wotten, G.F.

    1980-06-01

    We have developed a radioenzymatic assay for simultaneous estimation of norepinephrine (NE), dopamine (DA) and epinephrine (E) that was the result of the integration of several unique features of previously described assay procedures. Catecholamines in sera or tissue homogenates were enzymatically 0-methylated in the presence of partially purified catechol-0-methyltransferase with S-(methyl-/sup 3/H) adenosyl methionine serving as the methyl donor. The 0-methylated products were then separated by thin-layer chromatography, eluted from the gel, and their tritium content determined. The assay allows measurement of catecholamines with a sensitivity in the ranges of 15-20 pg. In addition, the assay is highly specific, reproducible, relatively rapid and simple, and inexpensive.

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

    ERIC Educational Resources Information Center

    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…

  4. Effects of norepinephrine infusion on myocardial high-energy phosphate content and turnover in the living rat.

    PubMed Central

    Bittl, J A; Balschi, J A; Ingwall, J S

    1987-01-01

    Using 31P-nuclear magnetic resonance, we studied the relationship between myocardial high-energy phosphate content and flux values for the creatine kinase reaction in the living rat under inotropic states achieved during norepinephrine infusion and halothane anesthesia. Under 2% halothane anesthesia (n = 4), 1% halothane anesthesia (n = 5) and norepinephrine infusion (n = 4), rats developed rate-pressure products of 19.5 +/- 1.6, 32.0 +/- 3.5, and 48.5 +/- 2.0 X 1,000 mmHg/min, respectively. Adenosine triphosphate content was not affected by inotropic state, ranging from 24.3 +/- 1.1 to 25.6 +/- 1.1 mumol/g dry weight, but creatine phosphate content varied inversely and reversibly with cardiac performance from 45.6 +/- 6.0 under 2% halothane to 26.0 +/- 6.5 mumol/g dry weight during norepinephrine infusion. The flux values for the creatine kinase reaction were 15.4 +/- 4.6, 20.5 +/- 2.0, and 30.1 +/- 7.9 mumol/g dry weight per s under 2% halothane, 1% halothane, and 1% halothane with norepinephrine, respectively. These results suggest that the turnover of myocardial high-energy phosphate compounds, not their tissue contents, matches cardiac performance during inotropic stimulation. Images PMID:3584473

  5. Dietary Zinc Reduction, Pyruvate Supplementation, or Zinc Transporter 5 Knockout Attenuates β-Cell Death in Nonobese Diabetic Mice, Islets, and Insulinoma Cells123

    PubMed Central

    Sheline, Christian T.; Shi, Chunxiao; Takata, Toshihiro; Zhu, Julia; Zhang, Wenlan; Sheline, P. Joshua; Cai, Ai-Li; Li, Li

    2012-01-01

    Pancreatic zinc (Zn2+) concentrations are linked to diabetes and pancreatic dysfunction, but Zn2+ is also required for insulin processing and packaging. Zn2+ released with insulin increases β-cell pancreatic death after streptozotocin toxin exposure in vitro and in vivo. Triosephosphate accumulation, caused by NAD+ loss and glycolytic enzyme dysfunction, occur in type-1 diabetics (T1DM) and animal models. We previously showed these mechanisms are also involved in Zn2+ neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD+ concentrations, Zn2+ restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn2+- and NAD+-mediated mechanisms are involved in β-cell toxicity in models of ongoing T1DM using mouse insulinoma cells, islets, and nonobese diabetic (NOD) mice. Zn2+, streptozotocin, and cytokines caused NAD+ loss and death in insulinoma cells and islets, which were attenuated by Zn2+ restriction, pyruvate, nicotinamide, NAD+, and inhibitors of Sir2 proteins. We measured diabetes incidence and mortality in NOD mice and demonstrated that pyruvate supplementation, or genetic or dietary Zn2+ reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn2+ staining, and β-cell loss increased with time in islets of NOD mice. Dietary Zn2+ restriction or Zn2+ transporter 5 knockout reduced pancreatic Zn2+ staining and increased β-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn2+ supplementation had the opposite effects. Pancreatic Zn2+ reduction or NAD+ restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM. PMID:23096014

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

    SciTech Connect

    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.

  7. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression.

    PubMed

    Bangasser, D A; Reyes, B A S; Piel, D; Garachh, V; Zhang, X-Y; Plona, Z M; Van Bockstaele, E J; Beck, S G; Valentino, R J

    2013-02-01

    Stress-related psychiatric disorders are more prevalent in women than men. As hypersecretion of the stress neuromediator, corticotropin-releasing factor (CRF) has been implicated in these disorders, sex differences in CRF sensitivity could underlie this disparity. Hyperarousal is a core symptom that is shared by stress-related disorders and this has been attributed to CRF regulation of the locus ceruleus (LC)-norepinephrine arousal system. We recently identified sex differences in CRF(1) receptor (CRF(1)) signaling and trafficking that render LC neurons of female rats more sensitive to CRF and potentially less able to adapt to excess CRF compared with male rats. The present study used a genetic model of CRF overexpression to test the hypothesis that females would be more vulnerable to LC dysregulation by conditions of excess CRF. In both male and female CRF overexpressing (CRF-OE) mice, the LC was more densely innervated by CRF compared with wild-type controls. Despite the equally dense CRF innervation of the LC in male and female CRF-OE mice, LC discharge rates recorded in slices in vitro were selectively elevated in female CRF-OE mice. Immunoelectron microscopy revealed that this sex difference resulted from differential CRF(1) trafficking. In male CRF-OE mice, CRF(1) immunolabeling was prominent in the cytoplasm of LC neurons, indicative of internalization, a process that would protect cells from excessive CRF. However, in female CRF-OE mice, CRF(1) labeling was more prominent on the plasma membrane, suggesting that the compensatory response of internalization was compromised. Together, the findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking. As excessive LC activation has been implicated in the arousal components of stress-related psychiatric disorders, this may be a cellular mechanism that contributes to the increased incidence of

  8. Dual effect of digitalis glycosides on norepinephrine release from human atrial tissue and bovine adrenal chromaffin cells: differential dependence on [Na+]i and [Ca2+]i.

    PubMed

    Haass, M; Serf, C; Gerber, S H; Krüger, C; Haunstetter, A; Vahl, C F; Nobiling, R; Kübler, W

    1997-06-01

    It was the aim of the present study (1) to characterize the influence of Na+/K(+)-ATPase inhibition by the digitalis glycoside ouabain on both spontaneous and nicotine-evoked norepinephrine release from the human heart; and (2) to further investigate the role of glycoside-induced changes in [Na+]i and [Ca2+]i (determined by microfluorimetry) for catecholamine release. The latter experiments were performed in bovine adrenal medullary chromaffin cells (BCC), an established cell culture model for sympathetic nerves. Ouabain (1-1000 mumol/l) exerted a dual effect on norepinephrine release (determined by HPLC) from incubated human atrial tissue: (I) Ouabain induced a concentration-dependent increase in norepinephrine release, that was calcium-independent and almost completely prevented by blockade of the uptake1-carrier by desipramine (1 mumol/l). The characteristics of this release process are consistent with a non-exocytotic mechanism. (II) In addition, ouabain augmented the nicotine-evoked (1-100 mumol/l) calcium-dependent norepinephrine release, which can be considered to be exocytotic. Na+/K(+)-ATPase inhibition also reduced the threshold concentration of nicotine from 10 to 1 mumol/l and it delayed the rapid tachyphylaxis of its norepinephrine releasing effect in human atrial tissue. In BCC, ouabain increased [Na+]i, [Ca2+]i and [3H]-norepinephrine release in parallel. Under calcium-free conditions, not only the ouabain-induced increase in [Na+]i, but also [3H]-norepinephrine release were enhanced. The ouabain-induced [3H]-norepinephrine release was always closely related to changes in [Na+]i, indicating a key role of [Na+]i for this calcium-independent non-exocytotic norepinephrine release. In addition, pretreatment with ouabain (1 mmol/l) augmented the nicotine-evoked (0.1-10 mumol/l) increments in [Na+]i, [Ca2+]i and [3H]-norepinephrine release. As nicotine-induced norepinephrine release depends on an increase in both [Na+]i and [Ca2+]i, these findings are

  9. Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain.

    PubMed

    Friess, Stuart H; Bruins, Benjamin; Kilbaugh, Todd J; Smith, Colin; Margulies, Susan S

    2015-02-15

    Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO2), and cerebral microdialysis 30 min to 6 h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP>70 mm Hg for 5 h. Animals were euthanized 6 h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO2 than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6 h post-injury, p<0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6 h post-injury, p<0.05). Augmentation of CPP to 70 mm Hg with PE resulted in significantly smaller cell injury volumes at 6 h post-injury than CPP support with NE (0.4% vs. 1.4%, p<0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted.

  10. U.S. onroad transportation CO2 emissions analysis comparing highly resolved CO2 emissions and a national average approach : mitigation options and uncertainty reductions

    NASA Astrophysics Data System (ADS)

    Mendoza, D. L.; Gurney, K. R.

    2011-12-01

    The transportation sector is the second largest CO2 emitting economic sector in the United States, accounting for 32.3% of the total U.S. emissions in 2002. Within the transportation sector, the largest component (80%) is made up of onroad emissions. In order to accurately quantify future emissions and evaluate emissions regulation strategies, analysis must account for spatially-explicit fleet distribution, driving patterns, and mitigation strategies. Studies to date, however, have either focused on one of these three components, have been only completed at the national scale, or have not explicitly represented CO2 emissions instead relying on the use of vehicle miles traveled (VMT) as an emissions proxy. We compare a high resolution onroad emissions data product (Vulcan) to a national averaging of the Vulcan result. This comparison is performed in four groupings: light duty (LD) and heavy duty (HD) vehicle classes, and rural and urban road classes. Two different bias metrics are studied: 1) the state-specific, group-specific bias and 2) the same bias when weighted by the state share of the national group-specific emissions. In the first metric, we find a spread of positive and negative biases for the LD and HD vehicle groupings and these biases are driven by states having a greater/lesser proportion of LD/HD vehicles within their total state fleet than found from a national average. The standard deviation of these biases is 2.01% and 0.75% for the LD and HD groupings, respectively. These biases correlate with the road type present in a state, so that biases found in the urban and LD groups are both positive or both negative, with a similar relationship found between biases of the rural and HD groups. Additionally, the road group bias is driven by the distribution of VMT on individual road classes within the road groupings. When normalized by national totals, the state-level group-specific biases reflect states with large amounts of onroad travel that deviate

  11. Increases in norepinephrine release and ovarian cyst formation during ageing in the rat

    PubMed Central

    Acuña, Eric; Fornes, Romina; Fernandois, Daniela; Garrido, Maritza P; Greiner, Monika; Lara, Hernan E; Paredes, Alfonso H

    2009-01-01

    Background Depletion of ovarian follicles is associated with the end of reproductive function in ageing females. Recently, it has been described that this process parallels increases in the concentration of norepinephrine (NE) in the rat ovary. In sexually mature rats, experimentally-induced increases in the sympathetic tone of the ovary is causally related to ovarian cyst formation and deranged follicular development. Thus, there is a possibility that increased ovarian NE concentrations represent changes in the activity of sympathetic nerves, which consequently participate in the process of ovarian cyst formation observed during ageing in the human and experimental animal models. Methods Sprague-Dawley rats between 6 and 14 months old were used to analyse the capacity of the ovary to release 3H-NE recently incorporated under transmural depolarisation in relation to changes in the ovarian follicular population. Morphometric analysis of ovarian follicles and real time PCR for Bcl2 and Bax mRNA were used to assess follicular atresia. Results From 8 months old, the induced release of recently incorporated 3H-norepinephrine (3H-NE) from the ovary and ovarian NE concentrations increased, reaching their peak values at 12 months old and remained elevated up to 14 months old. Increases in sympathetic nerve activity paralleled changes in the follicular population, as well as disappearance of the corpus luteum. In contrast, luteinised follicles, precystic follicles, and cystic follicles increased. During this period, the relationship between Bax and Bcl2 mRNAs (the proapoptotic/antiapoptotic signals) increased, suggesting atresia as the principal mechanism contributing to the decreased follicular population. When NE tone was increased, the mRNA ratio favoured Bcl2 to Bax and antiapoptotic signals dominated this period of development. Thus, these changing ratios could be responsible for the increase in luteinised follicles, as well as precystic and cystic follicles

  12. Cloning of the cocaine-sensitive bovine dopamine transporter

    SciTech Connect

    Usdin, T.B.; Chen, C.; Brownstein, M.J.; Hoffman, B.J. ); Mezey, E. )

    1991-12-15

    A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat {gamma}-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. ({sup 3}H)Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transports, including GBR12909.

  13. Diabetes-related changes in brain beta adrenoreceptors in rats as assessed by quantitative autoradiography: relationship to hypothalamic norepinephrine metabolism and pituitary-gonadal hormone secretion.

    PubMed

    Bitar, M S; DeSouza, E B

    1990-09-01

    Streptozotocin (STZ)-induced diabetes produced significant and selective alterations in brain beta adrenoreceptor subtypes, norepinephrine (NE) metabolism and pituitary-testicular hormone in male rats. The densities of beta-1 but not beta-2 adrenoreceptors were increased in hypothalamus (anterior and lateral nuclei), thalamus (ventral posterior nucleus) and amygdala (basolateral nucleus) of the STZ diabetic rats. In contrast, a decrease in the rate of metabolism of NE (estimated by the concentration of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol) was observed in these STZ-treated animals. Serum concentrations of luteinizing hormone and testosterone were lower in the STZ diabetic rats. Pretreatment of rats with nicotinamide prevented the induction of hyperglycemia, upregulation of brain beta-1 adrenoreceptors, decreases in NE metabolism and reduction in serum levels of luteinizing hormone and testosterone seen in STZ-treated rats. These data suggest that derangements in the hypothalamic-pituitary-testicular axis seen in uncontrolled diabetes may be secondary to decreases in NE metabolism and compensatory upregulation of beta-1 adrenoreceptors in brain.

  14. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency

    NASA Technical Reports Server (NTRS)

    Kim, Chun-Hyung; Zabetian, Cyrus P.; Cubells, Joseph F.; Cho, Sonhae; Biaggioni, Italo; Cohen, Bruce M.; Robertson, David; Kim, Kwang-Soo

    2002-01-01

    Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.

  15. Aircraft noise exposure affects rat behavior, plasma norepinephrine levels, and cell morphology of the temporal lobe.

    PubMed

    Di, Guo-Qing; Zhou, Bing; Li, Zheng-Guang; Lin, Qi-Li

    2011-12-01

    In order to investigate the physiological effects of airport noise exposure on organisms, in this study, we exposed Sprague-Dawley rats in soundproof chambers to previously recorded aircraft-related noise for 65 d. For comparison, we also used unexposed control rats. Noise was arranged according to aircraft flight schedules and was adjusted to its weighted equivalent continuous perceived noise levels (L(WECPN)) of 75 and 80 dB for the two experimental groups. We examined rat behaviors through an open field test and measured the concentrations of plasma norepinephrine (NE) by high performance liquid chromatography-fluorimetric detection (HPLC-FLD). We also examined the morphologies of neurons and synapses in the temporal lobe by transmission electron microscopy (TEM). Our results showed that rats exposed to airport noise of 80 dB had significantly lower line crossing number (P<0.05) and significantly longer center area duration (P<0.05) than control animals. After 29 d of airport noise exposure, the concentration of plasma NE of exposed rats was significantly higher than that of the control group (P<0.05). We also determined that the neuron and synapsis of the temporal lobe of rats showed signs of damage after aircraft noise of 80 dB exposure for 65 d. In conclusion, exposing rats to long-term aircraft noise affects their behaviors, plasma NE levels, and cell morphology of the temporal lobe.

  16. Norepinephrine uptake by hypothalamic tissue from the rat related to feeding.

    PubMed

    Van Der Gugten, J; Slangen, J L

    1975-01-01

    Norepinephrine (NE) uptake by rat hypothalamus in vitro was studied in relation to food intake. Significant daily variations in NE uptake were observed in caudal hypothalamus from freely feeding rats. A maximal elevation occurred at the beginning of the night when food intake is also increasing to a maximum. NE uptake by caudal hypothalamus from relatively hungry rats previously adjusted to restricted feeding during the daytime was enhanced in afternoon and evening when compared with uptake by tissue from ad lib feeding animals. Determination of NE uptake by caudal hypothalamus from freely feeding individual rats and registration of individual meals taken by these rats revealed a relation between hypothalamic neuronal activity and the feeding pattern of the rat. A positive correlation was observed between NE uptake in vitro and feeding rate during a 2- to 4-hr interval. It also appeared that NE uptake by caudal hypothalamus is dependent on the time elapsed after the last meal. The data were evaluated in view of physiological studies concerning the onset of feeding and the hypothesis of hypothalamic adrenergic control of food intake.

  17. Catheter-Based Radiofrequency Renal Denervation: Location Effects on Renal Norepinephrine

    PubMed Central

    Zhang, Yongxing; Hata, Cary; Narciso, Irvin; Hall, Michael E.; Hall, John E.

    2015-01-01

    BACKGROUND Clinical studies indicate that blood pressure (BP)-lowering effects of radiofrequency (RF) renal denervation (RD) are sustained for up to 2 years, although a recent clinical trial failed to find a major effect compared to sham treatment. In most previous studies, the efficacy of RD has not been assessed. The current study determined whether RD in different regions of the renal artery causes different degrees of RD as assessed with renal norepinephrine (NE) levels. METHODS AND RESULTS Unilateral RD was performed on 14 pigs divided into 3 groups: RD near the ostium, in the main renal artery near the bifurcation, and in extrarenal branches of the renal artery. After 2 weeks post-RD, the pigs were euthanized, renal cortex tissue was collected for NE measurement, and renal arteries were prepared for histological analysis. Renal NE decreased by 12% with RD at the ostium, 45% with RD near the bifurcation in the main renal artery, and 74% when RD was performed in extrarenal artery branches. The number of renal nerves was greatest in extrarenal branches and in the main artery compared to the ostium and the average distance from the lumen was greatest for nerves at the ostium and least at the branches. CONCLUSIONS RF RD lowers renal NE more significantly when performed in branches of the renal artery closer to the kidney. Increased efficacy of RF RD in extrarenal arterial branches may be due to the greater number of nerves in close proximity to the artery lumen in the branches. PMID:25576624

  18. Drinking-Induced Plasma Vasopressin and Norepinephrine Changes in Dehydrated Humans

    NASA Technical Reports Server (NTRS)

    Geelen, Ghislaine; Greenleaf, John E.; Keil, Lanny C.

    1996-01-01

    After 24-h water deprivation, five men (23-41 yr; 78 +/- 3.6 kg) consumed, within 4.0-6.2 min, 12 mL/kg of one of six fluid formulations (16.5 C) once a week over a period of 6 weeks: water, hypotonic saline (0.045% Na(+)), isotopic saline (0.36%, Na(+)), hypertonic glucose 9 7%, glucose), and two commercial mildly hypertonic 9.7% carbohydrate drinks. Blood samples were drawn 5 min before and: 3, 9, 15, 30, and 70 min after completion of drinking. Ingestion induced no significant change in plasma Na(+), K(+), osmotic, or protein concentrations, blood pressure; or heart rate. Plasma volume (PV) was increases (P <0.05) between 30-70 min with isotonic saline and the two commercial drinks. Ingestion induced a decrease in plasma AVP (PAVP) at 3 min, which was maximal (P < 0.05) at 15 min with all drinks. Thus, the act of drinking, independent of the composition or osmolality of the fluid absorbed, leads to a prompt inhibition of PAVP secretion in man. With the exception of rehydration with isotonic saline, this prompt response was followed by a long lasting inhibition of PAVP. There was no change in PRA, plasma aldosterone, atrial natriuretic peptide, or epinephrine, but an increase in plasma norepinephrine occurred immediately after ingestion, which suggests, like that for PAVP depression, a drinking-stimulate neural mechanism.

  19. Norepinephrine and acetylcholine changes during electrically-induced atrial fibrillation episodes in canine models.

    PubMed

    Zhang, X; Zhang, Y; Gao, F; Zhang, F; Yang, Z; Ouyang, S; Rao, M; Hou, Y

    2016-01-01

    Atrial fibrillation (AF) is the most prevalent heart rhythm disorder, and autonomic nervous system (ANS) is important to AF. This study aims to identify whether changes in transmitters released by ANS could reflect their activities. The right atrium (RA) groups (1-40V) included RA500 and RA1000. While ANS groups received high-frequency electrical stimulation (1-8V, 20 Hz, 2 ms), including left stellate ganglion stimulation (LSGS) andleft cervical vagus trunk stimulation (LVTS). The induced rate of AF, duration and atrial effective refractory period (AERP) were measured. The blood was drawn for evaluation of norepinephrine (NE) and acetylcholine (Ach) concentrations. At 12-hours, RA tissue was dissected and compared against un-stimulated controls. While AF was induced by all groups, duration and AERP were significantly different between RA pacing groups and ANS-stimulated groups, respectively (P<0.05). Specific changes in profile of NE and Ach were associated with modality of stimulation. RA1000 tended to display most significant changes (P<0.05) compared to other groups while variables concentration levels were observed in other groups. In conclusion, electrically-induced AF initiated by various modalities of stimulation showed different changes in serum and RA tissues. Fast frequency pacing caused significant atrial electrical remodeling, including ANS activity change. PMID:27453277

  20. Estrogen prevents norepinephrine alpha-2a receptor reversal of stress-induced working memory impairment

    PubMed Central

    SHANSKY, REBECCA M.; BENDER, GENEVIEVE; ARNSTEN, A. F. T.

    2011-01-01

    Understanding effects of estrogen on the medial prefrontal cortex (PFC) may help to elucidate the increased prevalence of depression and post-traumatic stress disorder in women of ovarian cycling age. Estrogen replacement in ovariectomized (OVX) young rats amplifies the detrimental effects of stress on working memory (a PFC-mediated task), but the mechanisms by which this occurs have yet to be identified. In male rats, stimulation of norepinephrine alpha-2 adrenoceptors protects working memory from stress-induced impairments. However, this effect has not been studied in females, and has not been examined for sensitivity to estrogen. The current study asked whether OVX females with estrogen replacement (OVX + Est) and without replacement (OVX + Veh) responded differently to stimulation of alpha-2 adrenoceptors after administration of the benzodiazepine inverse agonist FG7142, a pharmacological stressor. The alpha-2 agonist, guanfacine, protected working memory from the impairing effects of FG7142 in OVX + Veh, but not in OVX + Est rats. Western Blot analysis for alpha-2 receptors was performed on PFC tissue from each group, but no changes in expression were found, indicating that the behavioral effects observed were likely not due to changes in receptor expression. These findings point to possible mechanisms by which estrogen may enhance the stress response, and hold implications for the gender discrepancy in the prevalence of stress-related mental illness. PMID:19005873

  1. Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate

    PubMed Central

    Haile, Colin N.; Mahoney, James J.; Newton, Thomas F.; De La Garza, Richard

    2012-01-01

    Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine. PMID:22327234

  2. Spectrophotometric determination of norepinephrine with sodium iodate and determination of its acidity constants

    NASA Astrophysics Data System (ADS)

    Hashem, E. Y.; Youssef, A. K.

    2013-05-01

    A spectrophotometric method is proposed for the determination of norepinephrine (NE) and its bitartrate salts. The method was based on the development of a red color (λmax = 495 nm) with sodium iodate in aqueous alcoholic medium at pH 5. The color was stable for at least 4 hrs. The molar reacting ratio of NE to sodium iodate was 1:4. A linear relationship was obtained between the absorption intensity and NE concentration in the range of 3.384-37.224 μg/ml with detection limit of 0.067 μg/ml and correlation coefficient of 0.9972. The present work facilitated the determination of the three acidity constants, 7.564 ± 0.02, 9.036 ± 0.034, and 10.761 ± 0.023. The reaction mechanism was also described. The proposed method was successfully applied for the determination of NE in pharmaceutical formulations. Results for analysis of bulk drugs and injections agree with those of official methods.

  3. Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis

    PubMed Central

    Uehara, Akihito; Motegi, Sei-ichiro; Yamada, Kazuya; Uchiyama, Akihiko; Perera, Buddhini; Toki, Sayaka; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Ishikawa, Osamu

    2016-01-01

    Raynaud’s phenomenon is frequently observed in systemic sclerosis (SSc) patients, and cold- or stress-induced norepinephrine (NE) has been speculated to be associated with vasoconstriction. Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)β agonist, isoproterenol, but not ARα agonist, oxymetazoline. ARβ blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via ARβ enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1/2 via ARα inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts, and both propranolol and SB203580 inhibited NE-induced collagen production. These results suggest that cold exposure and/or emotional stress-induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc. PMID:27650973

  4. Norepinephrine does not alter NPY and POMC mRNA expression in neonatal chicks.

    PubMed

    Katayama, Sachiko; Tomonaga, Shozo; Sato, Momoka; Yamane, Haruka; Tsuneyoshi, Yousuke; Denbow, D Michael; Furuse, Mitsuhiro

    2010-05-01

    Norepinephrine (NE), synthesized in both the central and peripheral nervous system, is involved in food intake regulation of both mammals and chickens. Neuropeptide Y (NPY), a potent orexigenic peptide, is colocalized with NE neurons in the central and peripheral nervous system, suggesting an interaction. Proopiomelanocortin (POMC) is the precursor of alpha-melanocyte stimulating hormone, a potent anorexigenic peptide synthesized in the hypothalamus. In this study, two experiments were conducted to examine the effect of intracerebroventricular (ICV) injection of NE on appetite mediators in neonatal chicks (Gallus gallus). Experiment 1 was done to confirm the effect of centrally administered NE (0, 25, 50, and 100 microg) on food intake following a 3h fast, and to determine the change in NPY mRNA expression in the central nervous system (CNS). In Experiment 2, chicks fed ad libitum were treated ICV with NE (50 microg) to determine if changes occurred in brain NPY and POMC mRNA levels. In Experiment 1, the ICV injection of NE dose-dependently reduced food intake, but there was no change in NPY mRNA expression in the CNS. In Experiment 2, there was no significant change in NPY and POMC mRNA expression between the control and NE-treated group, indicating that ICV injection of NE may not be associated with changes in NPY or POMC gene expression.

  5. Effect of Uptake-one inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine

    SciTech Connect

    Tobes, M.C.; Jaques, S. Jr.; Wieland, D.M.; Sisson, J.C.

    1985-08-01

    The mechanisms underlying the uptake of the radiopharmaceutical metaiodobenzylguanidine (MIBG) and the catecholamine norepinephrine (NE) were studied using cultured bovine adrenomedullary cells as an in vitro model system. Sodium-dependent and sodium-independent uptake systems have been identified and characterized for both MIBG and NE. The sodium-dependent uptake of Ne and MIBG was inhibited by the selective Uptake-one inhibitors, desmethylimipramine (DMI) and cocaine, whereas the sodium-independent uptake for NE and MIBG was much less sensitive to inhibition by these agents. The sodium-dependent uptake system fulfills the criteria for the neuronal Uptake-one system, and the sodium-independent uptake system fulfills the criteria for a passive diffusion mechanism. Arterial concentrations proximal to the dog adrenal were very small suggesting that the sodium-dependent (Uptake-one) system is predominant in vivo. Consistent with the in vitro observations, the in vivo uptake of MIBG and NE into dog adrenal medullae was effectively blocked by pretreatment with DMI or cocaine. Therefore, iodine-131 MIBG scintigraphy of the adrenal appears to reflect uptake by way of the Uptake-one system.

  6. Impact of methylene blue in addition to norepinephrine on the intestinal microcirculation in experimental septic shock.

    PubMed

    Nantais, Jordan; Dumbarton, Tristan C; Farah, Nizam; Maxan, Alexander; Zhou, Juan; Minor, Samuel; Lehmann, Christian

    2014-01-01

    Methylene blue (MB) has been used with some success as a treatment for the vasoplegia of vasopressor-refractory septic shock. The putative mechanism of action of MB is the inhibition of endothelial nitric oxide within the microvasculature and improved responsiveness to endogenous catecholamines (norepinephrine (NE)). However, to date, no study has demonstrated the microcirculatory effect of methylene blue in septic shock. The objective of this randomized, controlled, animal study was to show, in an experimentally-induced, septic shock model in rats, the effects of MB and NE on global hemodynamics and the microcirculation. Mean arterial pressure (MAP) was drastically reduced following bacterial endotoxin (lipopolysaccharide, LPS) administration in animals not receiving vasopressors. Only the combination of NE + MB restored MAP to control levels by the end of the three hour experiment. Intravital microscopy of the microcirculation was performed in the terminal ileum in order to examine functional capillary density in intestinal muscle layers and the mucosa, as well as leukocyte activation in venules (rolling, adhesion to the endothelium). Untreated LPS animals showed a significant increase in leukocyte adhesion and a decrease in capillary perfusion in the intestinal microcirculation. In groups receiving NE or NE+MB, we observed a significant decrease in leukocyte adhesion and improved functional capillary density, indicating that microvasculature function was improved. This study suggests that methylene blue may be able to improve hemodynamics while preserving microvascular function in septic shock.

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

    PubMed Central

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

    2015-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.07000.001 PMID:26374985

  8. Norepinephrine is necessary for experience-dependent plasticity in the developing mouse auditory cortex.

    PubMed

    Shepard, Kathryn N; Liles, L Cameron; Weinshenker, David; Liu, Robert C

    2015-02-11

    Critical periods are developmental windows during which the stimuli an animal encounters can reshape response properties in the affected system to a profound degree. Despite this window's importance, the neural mechanisms that regulate it are not completely understood. Pioneering studies in visual cortex initially indicated that norepinephrine (NE) permits ocular dominance column plasticity during the critical period, but later research has suggested otherwise. More recent work implicating NE in experience-dependent plasticity in the adult auditory cortex led us to re-examine the role of NE in critical period plasticity. Here, we exposed dopamine β-hydroxylase knock-out (Dbh(-/-)) mice, which lack NE completely from birth, to a biased acoustic environment during the auditory cortical critical period. This manipulation led to a redistribution of best frequencies (BFs) across auditory cortex in our control mice, consistent with prior work. By contrast, Dbh(-/-) mice failed to exhibit the expected redistribution of BFs, even though NE-deficient and NE-competent mice showed comparable auditory cortical organization when reared in a quiet colony environment. These data suggest that while intrinsic tonotopic patterning of auditory cortical circuitry occurs independently from NE, NE is required for critical period plasticity in auditory cortex. PMID:25673838

  9. Neurotensin-produced antinociception in the rostral ventromedial medulla is partially mediated by spinal cord norepinephrine

    PubMed Central

    Buhler, A. V.; Proudfit, H. K.; Gebhart, G. F.

    2008-01-01

    Microinjection of neurotensin (NT) into the rostral ventromedial medulla (RVM) produces dose-dependent antinociception. Here we show that antinociception produced by intra RVM microinjection of neurotensin (NT) or the selective NT receptor subtype 1 (NTR1) agonist PD149163 can be partially blocked by intrathecal (i.t.) yohimbine, an α2-adrenoceptor antagonist and by methysergide, a serotonin receptor antagonist. Antinociception produced by the NTR2 agonist beta-lactotensin (β-LT) is blocked by intrathecal (i.t.) yohimbine, but not by methysergide i.t.. It is not known which noradrenergic cell group is involved in this newly identified noradrenergic component of NTR-mediated antinociception. These experiments provide the first evidence that selective activation of NTR2 in the RVM produces antinociception. These results also provide evidence that activation of NTR1 in the RVM produces antinociception through spinal release of norepinephrine (NE) and serotonin, and that activation of NTR2 in the RVM produces antinociception mediated by spinal release of NE. PMID:17664042

  10. Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span.

    PubMed

    Wang, Lucy Y; Murphy, Richard R; Hanscom, Brett; Li, Ge; Millard, Steven P; Petrie, Eric C; Galasko, Douglas R; Sikkema, Carl; Raskind, Murray A; Wilkinson, Charles W; Peskind, Elaine R

    2013-10-01

    Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21-100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.

  11. Increase in norepinephrine-induced formation of phosphatidic acid in rat vas deferens after denervation.

    PubMed

    Takenawa, T; Masaki, T; Goto, K

    1983-01-01

    Surgical denervation of rat vas deferens causes supersensitivity in that the tissue sensitivity and the maximum response to a variety of agonists increase. To understand the molecular mechanism of supersensitivity in smooth muscle, norepinephrine(NE)-induced alteration in phospholipid metabolism was studied using control and denervated vasa deferentia. When the tissue was stimulated by NE, only [32P]Pi incorporation into phosphatidic acid(PA) was increased in proportion to the increase in NE concentration without any significant effect on that into other phospholipids. This PA labeling was significantly accelerated by denervation. In the denervated tissue, PA labeling was stimulated by lower concentrations of NE and the maximum response to NE was increased compared to the control. The breakdown of phosphatidylinositol 4-monophosphate(DPI) and phosphatidylinositol 4,5-diphosphate (TPI) was also accelerated by NE. But the influence of denervation on this NE-induced DPI and TPI was not marked. Therefore, it is likely that denervation clearly enhanced NE-induced PA labeling without an appreciable effect on that of the other phospholipids. Furthermore, the absolute amount of PA was also increased by NE, and this increase was exaggerated by denervation. Considering that PA can behave as a Ca2+ ionophore in the plasma membrane, these results suggest that the stimulated accumulation of PA plays an important role in receptor-linked supersensitivity in smooth muscle.

  12. Hypothalamic Norepinephrine Mediates Acupunctural Effects on Hypothalamic-Pituitary-Adrenal Axis During Ethanol Withdrawal.

    PubMed

    Zhao, Zheng Lin; Kim, Sang Chan; Zhang, Jie; Liu, Hong Feng; Lee, Bong Hyo; Jang, Eun Young; Lee, Chul Won; Cho, Il Je; An, Won G; Yang, Chae Ha; Kim, Young Woo; Zhao, Rong Jie; Wu, Yi Yan

    2016-02-01

    A previous study demonstrated that acupuncture at ST36 (Zu-San-Li) attenuates ethanol withdrawal (EW)-induced hyperactivation of the hypothalamic-pituitary-adrenal axis in rats. The current study investigated the involvement of hypothalamic norepinephrine (NE) in that process. Rats were intraperitoneally treated with 3 g/kg/d of ethanol or saline for 28 days. After 24 hours of EW, acupuncture was applied to rats at bilateral ST36 points or at nonacupoints (tail) for 1 minute. A high-performance liquid chromatography analysis showed that EW significantly increased both the NE and the 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels in the hypothalamic paraventricular nucleus (PVN). Western blot analysis also revealed that EW markedly elevated the phosphorylation rates of tyrosine hydroxylase (TH), but spared TH protein expression in the PVN. However, acupuncture at ST36, but not at nonacupoints, greatly inhibited the increase in the hypothalamic NE, MHPG, and phosphorylation rates of TH. Additionally, postacupuncture infusion of NE into the PVN significantly attenuated the inhibitory effects of acupuncture at ST36 on the oversecretion of plasma corticosterone during EW. These results suggest that acupuncture at ST36 inhibits EW-induced hyperactivation of the hypothalamic NEergic system to produce therapeutic effects on the hypothalamic-pituitary-adrenal axis.

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

    SciTech Connect

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

    1987-02-01

    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 (/sup 3/H)NE, (/sup 3/H)DA, or endogenous Epi. The (/sup 3/H)NE corrected renal NE overflow to plasma increased from 144 +/- 40 to 243 +/- 64 pmol-min/sup -1/ during BCO, which, when compared with a previous study of the (/sup 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 approx. 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.

  14. Behavioral and sleep/wake characteristics of mice lacking norepinephrine and hypocretin.

    PubMed

    Hunsley, M S; Curtis, W R; Palmiter, R D

    2006-08-01

    We investigated the interaction between norepinephrine (NE) and orexin/hypocretin (Hcrt) in the control of sleep behavior and narcoleptic symptoms by creating mice that were deficient in both neurotransmitters. Mice with a targeted disruption of the dopamine beta-hydroxylase (Dbh) gene (deficient in NE and epinephrine) or the Hcrt gene were bred to generate double knockouts (DKOs), each single KO (Dbh-KO and Hcrt-KO), and control mice. The duration of wake, non-rapid eye movement (NREM) and REM sleep were monitored by electroencephalogram (EEG)/electromyogram (EMG) recording over a 24-h period, and the occurrence of behavioral arrests was monitored by video/EEG recording for 4 h. Overall, there was very little interaction between the two genes; for most parameters that were measured, the DKO mice resembled either Dbh-KO or Hcrt-KO mice. REM sleep was increased in both DKO and Hcrt-KO mice at night relative to the other groups, but DKO mice had significantly more REM sleep during the day than the other three groups. Sleep latency in response to saline or amphetamine injections was reduced in Dbh-KO and DKO mice relative to other groups. Behavioral arrests, that are frequent in Hcrt-KO mice, were not exacerbated in DKO mice.

  15. CO2 asphyxia increases plasma norepinephrine in rats via sympathetic nerves.

    PubMed

    Borovsky, V; Herman, M; Dunphy, G; Caplea, A; Ely, D

    1998-01-01

    The objective of this study was to determine whether the plasma norepinephrine (NE) increase in rats exposed to CO2 asphyxia was due to adrenal gland release or sympathetic nerve ending (SNS) release. Plasma NE was measured by high-performance liquid chromatography in hypertensive and normotensive rats using the following protocol: control session, CO2 exposure, N2 exposure, reserpine + CO2, and adrenalectomy + CO2. Four strains of male and female rats were used: spontaneously hypertensive rats, Wistar-Kyoto rats, and two congenic strains with different Y chromosomes. The same rats were used throughout the experiment (n = 80). Blood pressure measured by aortic telemetry increased approximately 50-60 mmHg in response to CO2 in all strains. CO2 increased NE 6-10x in all strains and both genders. N2 produced a significant increase in NE (73% of CO2 response). Reserpine significantly decreased (67%) plasma NE after CO2. Adrenalectomy did not significantly reduce the NE response to CO2. In conclusion, the increase in plasma NE after CO2 was associated with SNS release and not adrenal medullary release, was mainly due to hypoxia, and was not a specific response to CO2.

  16. Improved radioenzymatic assay for plasma norepinephrine using purified phenylethanolamine n-methyltransferase

    SciTech Connect

    Bowsher, R.R.; Henry, D.P.

    1986-03-01

    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.

  17. Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis.

    PubMed

    Uehara, Akihito; Motegi, Sei-Ichiro; Yamada, Kazuya; Uchiyama, Akihiko; Perera, Buddhini; Toki, Sayaka; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Ishikawa, Osamu

    2016-01-01

    Raynaud's phenomenon is frequently observed in systemic sclerosis (SSc) patients, and cold- or stress-induced norepinephrine (NE) has been speculated to be associated with vasoconstriction. Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)β agonist, isoproterenol, but not ARα agonist, oxymetazoline. ARβ blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via ARβ enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1/2 via ARα inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts, and both propranolol and SB203580 inhibited NE-induced collagen production. These results suggest that cold exposure and/or emotional stress-induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc. PMID:27650973

  18. Recall performance, plasma cortisol and plasma norepinephrine in normal human subjects.

    PubMed

    Bemelmans, Karel J; Goekoop, Jaap G; de Rijk, Roel; van Kempen, Godfried M J

    2003-01-01

    This study investigated hypothalamic-pituitary-adrenal (HPA)-axis and sympathetic nervous system (SNS) correlates of recall performance in normal human subjects. Twenty-two normal human subjects were given one memory task: short-term recall of unrelated non-organizable lists of neutral words, in immediate recall conditions. Two types of memory were individualized: measures reflecting effortful processing and measures reflecting automatic processing, which were related to 3 daytime plasma cortisol (CORT) and plasma NE values, and assessed after venipuncture. It was hypothesized that plasma CORT is positively related and plasma norepinephrine (NE) is negatively related to effortful processing. Pearson correlation was computed and regression analysis was performed. Positive correlation appeared between plasma CORT values and negative correlation appeared between plasma NE values and measures reflecting effortful processing. However, stepwise multiple regression analysis showed that only morning plasma CORT values are functionally positively and afternoon plasma NE values are functionally negatively related to effortful processing. This suggests that morning HPA-axis activities enhance and afternoon SNS activities inhibit effortful processing.

  19. The norepinephrine reuptake inhibitor reboxetine is more potent in treating murine narcoleptic episodes than the serotonin reuptake inhibitor escitalopram.

    PubMed

    Schmidt, Christian; Leibiger, Judith; Fendt, Markus

    2016-07-15

    One of the major symptoms of narcolepsy is cataplexy, a sudden loss of muscle tone. Despite the advances in understanding the neuropathology of narcolepsy, cataplexy is still treated symptomatically with antidepressants. Here, we investigate in a murine narcolepsy model the hypothesis that the antidepressants specifically blocking norepinephrine reuptake are more potent in treating narcoleptic episodes than the antidepressants blocking of serotonin reuptake. Furthermore, we tested the effects of α1 receptor stimulation and blockade, respectively, on narcoleptic episodes. Orexin-deficient mice were treated with different doses of the norepinephrine reuptake inhibitor reboxetine, the serotonin reuptake inhibitor escitalopram, the α1 receptor agonist cirazoline or the α1 receptor antagonist prazosin. The effect of these treatments on narcoleptic episodes was tested. Additionally, potential treatment effects on locomotor activity in an open-field were tested. Reboxetine (doses ≥0.55mg/kg) as well as escitalopram (doses ≥3.0mg/kg) dose-dependently reduced the number of narcoleptic episodes in orexin-deficient mice. The ED50 for reboxetine (0.012mg/kg) was significantly lower than for escitalopram (0.44mg/kg). Cirazoline and prazosin did not affect narcoleptic episodes. Furthermore, cirazoline but not the other compounds reduced locomotor activity of the mice. The present study strongly supports the hypothesis that a specific blockade of norepinephrine reuptake is more potent in treating cataplexy than a specific blockade of serotonin reuptake. This argues for the development of more specific norepinephrine reuptake inhibitors for the treatment of narcolepsy. PMID:27118715

  20. Regulation of Monoamine Transporters: Role of Transporter Phosphorylation

    PubMed Central

    Ramamoorthy, Sammanda; Shippenberg, Toni S.; Jayanthi, Lankupalle D.

    2010-01-01

    Presynaptic biogenic amine transporters mediate reuptake of released amines from the synapse, thus regulating serotonin, dopamine and norepinephrine neurotransmission. Medications utilized in the treatment of depression, attention deficit-hyperactivity disorder and other psychiatric disorders possess high affinity for amine transporters. In addition, amine transporters are targets for psychostimulants. Altered expression of biogenic amine transporters has long been implicated in several psychiatric and degenerative disorders. Therefore, appropriate regulation and maintenance of biogenic amine transporter activity is critical for the maintenance of normal amine homoeostasis. Accumulating evidence suggests that cellular protein kinases and phosphatases regulate amine transporter expression, activity, trafficking and degradation. Amine transporters are phosphoproteins that undergo dynamic control under the influence of various kinase and phosphatase activities. This review presents a brief overview of the role of amine transporter phosphorylation in the regulation of amine transport in the normal and diseased brain. Understanding the molecular mechanisms by which phosphorylation events affect amine transporter activity is essential for understanding the contribution of transporter phosphorylation to the regulation of monoamine neurotransmission and for identifying potential new targets for the treatment of various brain diseases. PMID:20951731

  1. Stimulation of nonshivering thermogenesis in the Syrian hamster by norepinephrine and beta-selective adrenergic agents: a phenomenon of refractoriness.

    PubMed

    Dicker, A; Cannon, B; Nedergaard, J

    1996-01-01

    The ability of different adrenergic agents to stimulate nonshivering thermogenesis in Syrian hamsters was investigated. The hamsters were cold-acclimated to 6 degrees C and their thermogenic response was investigated in an open-circuit system at 24 degrees C. Both norepinephrine and the beta 3-specific adrenergic agonist CGP-12177 induced a high rate of nonshivering thermogenesis. However, neither CGP-12177 nor other beta 3-selective agonists (BRL-37344, ICI-D7114) could induce nonshivering thermogenesis fully to the extent induced by norepinephrine. It was further observed that an apparent "thermogenic refractoriness" was induced by certain adrenergic agents (isoprenaline, CGP-12177) but not by others (norepinephrine, BRL-37344, ICI-D7114). It is discussed whether the refractoriness could be secondary to effects of these agents on the vascular system. It is pointed out that the thermogenic response to adrenergic stimulation observed in the intact animal does not always fully correspond to what would be predicted from corresponding studies with isolated brown-fat cells. PMID:8665400

  2. Dual regulation by opioids of 3H-norepinephrine release in the human neuroblastoma cell-line SK-N-SH.

    PubMed

    Keren, O; Garty, M; Sarne, Y

    1994-05-23

    Depolarization-evoked 3H-norepinephrine release from SK-N-SH cells was found to be regulated by opioid ligands. Opioids exerted either inhibition or augmentation of 3H-norepinephrine release. Both effects were mediated by opioid receptors. In addition, a nonopioid inhibitory effect of opiates on release was observed. The SK-N-SH cell-line provides a suitable model for studying the various mechanisms underlying the opioid regulatory pathways within single cells.

  3. A Selective V1A Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock*

    PubMed Central

    He, Xinrong; Su, Fuhong; Taccone, Fabio Silvio; Laporte, Régent; Kjølbye, Anne Louise; Zhang, Jing; Xie, Keliang; Moussa, Mouhamed Djahoum; Reinheimer, Torsten Michael

    2016-01-01

    Objective: Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Forty-six adult female sheep. Interventions: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 μg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70–80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. Measurements and Main Results: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower

  4. Influence of Reactive Transport on the Reduction of U(VI) in the Presence of Fe(III) and Nitrate: Implications for U(VI) Immobilization by Bioremidation/Biobarriers

    SciTech Connect

    Wood, Brian; Chongxuan Liu; John Zachara

    2004-03-17

    The purposes of this report are to: (1) to determine how flow and transport influence the distribution of U(VI) under field-relevant conditions and the transfer of reductive equivalents to the aqueous and solid phases by DMRB; and (2) to examine the solid-phase stability of bioreduced uranium phases--effects of mass transfer on reoxidation of U(IV) by O{sub 2} and other oxidants (e.g., NO{sub 3}{sup -}, denitrification products).

  5. Influence of Reactive Transport on the Reduction of U(VI) in the Presence of Fe(III) and Nitrate: Implications for U(VI) Immobilization by Bioremediation / Biobarriers- Final Report

    SciTech Connect

    B.D. Wood

    2007-01-01

    Subsurface contamination by metals and radionuclides represent some of the most challenging remediation problems confronting the Department of Energy (DOE) complex. In situ remediation of these contaminants by dissimilatory metal reducing bacteria (DMRB) has been proposed as a potential cost effective remediation strategy. The primary focus of this research is to determine the mechanisms by which the fluxes of electron acceptors, electron donors, and other species can be controlled to maximize the transfer of reductive equivalents to the aqueous and solid phases. The proposed research is unique in the NABIR portfolio in that it focuses on (i) the role of flow and transport in the initiation of biostimulation and the successful sequestration of metals and radionuclides [specifically U(VI)], (ii) the subsequent reductive capacity and stability of the reduced sediments produced by the biostimulation process, and (iii) the potential for altering the growth of biomass in the subsurface by the addition of specific metabolic uncoupling compounds. A scientifically-based understanding of these phenomena are critical to the ability to design successful bioremediation schemes. The laboratory research will employ Shewanella putrefaciens (CN32), a facultative DMRB that can use Fe(III) oxides as a terminal electron acceptor. Sediment-packed columns will be inoculated with this organism, and the reduction of U(VI) by the DMRB will be stimulated by the addition of a carbon and energy source in the presence of Fe(III). Separate column experiments will be conducted to independently examine: (1) the importance of the abiotic reduction of U(VI) by biogenic Fe(II); (2) the influence of the transport process on Fe(III) reduction and U(VI) immobilization, with emphasis on methods for controlling the fluxes of aqueous species to maximize uranium reduction; (3) the reductive capacity of biologically-reduced sediments (with respect to re-oxidation by convective fluxes of O2 and NO3-) and

  6. Segregation of the classical transmitters norepinephrine and acetylcholine and the neuropeptide Y in sympathetic neurons: modulation by ciliary neurotrophic factor or prolonged growth in culture.

    PubMed

    Vega, A; Luther, J A; Birren, S J; Morales, M A

    2010-12-01

    Recent evidence has demonstrated that cotransmission from mammalian neurons is not uniquely achieved by costorage and corelease of transmitters and cotransmitters from single varicosities, but also by the concurrent release of mediators segregated in separate synapses of individual neurons. An important question to be addressed is whether neurons show defined patterns of segregation or whether this is a plastic feature. We addressed this question by exploring the segregation pattern of the classical sympathetic transmitters norepinephrine (NE) and acetylcholine (ACh) and the cotransmitter neuropeptide Y (NPY) in sympathetic ganglionic neurons cocultured with cardiac myocytes. Using antibodies against NPY and the vesicular NE and ACh transporters VMAT2 and vesicular acetylcholine transporter (VAChT), we investigated the effect of ciliary neurotrophic factor (CNTF) or long (three weeks) culture periods on the segregation of VMAT2, VAChT, and NPY to separate varicosities. We found that although ganglionic neurons showed cell body coexpression of all the markers examined after three days, VMAT2 was segregated from VAChT in 43% of the VAChT-positive varicosities. In contrast, VMAT2 was only segregated from NPY in 16.3% of the NPY-positive varicosities. Cotransmitter segregation and VAChT expression was potentiated by both CNTF and longer times in culture. We also found two types of varicosities: one was smaller and located further from neuronal somata, and the other was larger, proximal to neuronal somata and had a higher level of segregation. These data demonstrate segregation of classical transmitters in sympathetic neurons and plasticity of neurotransmitter segregation. Finally, we discuss a possible functional correlate of segregation in sympathetic neurons.

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

    PubMed Central

    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. PMID:25414697

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

    NASA Technical Reports Server (NTRS)

    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%, P<0.02). After tyramine, NE spillover did not change significantly in patients but increased 50+/-10% in control subjects (P<0.001). The dose of isoproterenol required to increase heart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, P<0.005), and the dose of phenylephrine required to increase systolic blood pressure 25 mm Hg was lower in patients than control subjects (105+/-11 versus 210+/-12 microg, P<0.001). Baroreflex sensitivity was lower in patients (12+/-1 versus 18+/-2 ms/mm Hg, P<0.02), but the intrinsic heart 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.

  9. Electrocatalytic oxidation of Epinephrine and Norepinephrine at metal oxide doped phthalocyanine/MWCNT composite sensor.

    PubMed

    Mphuthi, Ntsoaki G; Adekunle, Abolanle S; Ebenso, Eno E

    2016-01-01

    Glassy carbon electrode (GCE) was modified with metal oxides (MO = Fe3O4, ZnO) nanoparticles doped phthalocyanine (Pc) and functionalized MWCNTs, and the electrocatalytic properties were studied. Successful synthesis of the metal oxide nanoparticles and the MO/Pc/MWCNT composite were confirmed using FTIR, Raman and SEM techniques. The electrodes were characterized using cyclic voltammetry (CV) technique. The electrocatalytic behaviour of the electrode towards epinephrine (EP) and norepinephrine (NE) oxidation was investigated using CV and DPV. Result showed that GCE-MWCNT/Fe3O4/2,3-Nc, GCE-MWCNT/Fe3O429H,31H-Pc, GCE-MWCNT/ZnO/2,3-Nc and GCE-MWCNT/ZnO/29H,31H-Pc electrodes gave enhanced EP and NE current response. Stability study indicated that the four GCE-MWCNT/MO/Pc modified electrodes were stable against electrode fouling effect with the percentage NE current drop of 5.56-5.88% after 20 scans. GCE-MWCNT/Fe3O4/29H,31H-Pc gave the lowest limit of detection (4.6 μM) towards EP while MWCNT/ZnO/29H,31H-Pc gave the lowest limit of detection (1.7 μM) towards NE. The limit of detection and sensitivity of the electrodes compared well with literature. Electrocatalytic oxidation of EP and NE on GCE-MWCNT/MO/Pc electrodes was diffusion controlled with some adsorption of electro-oxidation reaction intermediates products. The electrodes were found to be electrochemically stable, reusable and can be used for the analysis of EP and NE in real life samples. PMID:27245690

  10. Mitochondrial Superoxide Signaling Contributes to Norepinephrine-Mediated T-Lymphocyte Cytokine Profiles

    PubMed Central

    Roessner, Colton T.; Tian, Jun; Zimmerman, Matthew C.

    2016-01-01

    Norepinephrine (NE) produces multifaceted regulatory patterns in T-lymphocytes. Recently, we have shown that NE utilizes redox signaling as evidenced by increased superoxide (O2●-) causally linked to the observed changes in these cells; however, the source of this reactive oxygen species (ROS) remains elusive. Herein, we hypothesized that the source of increased O2●- in NE-stimulated T-lymphocytes is due to disruption of mitochondrial bioenergetics. To address this hypothesis, we utilized purified mouse splenic CD4+ and CD8+ T-lymphocytes stimulated with NE and assessed O2●- levels, mitochondrial metabolism, cellular proliferation, and cytokine profiles. We demonstrate that the increase in O2●- levels in response to NE is time-dependent and occurs at later points of T-lymphocyte activation. Moreover, the source of O2●- was indeed the mitochondria as evidenced by enhanced MitoSOX Red oxidation as well as abrogation of this signal by the addition of the mitochondrial-targeted O2●--scavenging antioxidant MitoTempol. NE-stimulated T-lymphocytes also demonstrated decreased mitochondrial respiratory capacity, which suggests disruption of mitochondrial metabolism and the potential source of increased mitochondrial O2●-. The effects of NE in regards to redox signaling appear to be adrenergic receptor-dependent as specific receptor antagonists could reverse the increase in O2●-; however, differential receptors regulating these processes were observed in CD4+ versus CD8+ T-lymphocytes. Finally, mitochondrial O2●- was shown to be mechanistic to the NE-mediated T-lymphocyte phenotype as supplementation of MitoTempol could reverse specific changes in cytokine expression observed with NE treatment. Overall, these studies indicate that mitochondrial metabolism and O2●--mediated redox signaling play a regulatory role in the T-lymphocyte response to NE. PMID:27727316

  11. Angiotensin II and norepinephrine activate specific calcineurin-dependent NFAT transcription factor isoforms in cardiomyocytes.

    PubMed

    Lunde, Ida G; Kvaløy, Heidi; Austbø, Bjørg; Christensen, Geir; Carlson, Cathrine R

    2011-11-01

    Norepinephrine (NE) and angiotensin II (ANG II) are primary effectors of the sympathetic adrenergic and the renin-angiotensin-aldosterone systems, mediating hypertrophic, apoptotic, and fibrotic events in the myocardium. As NE and ANG II have been shown to affect intracellular calcium in cardiomyocytes, we hypothesized that they activate the calcium-sensitive, prohypertrophic calcineurin-nuclear factor of activated T-cell (NFATc) signaling pathway. More specifically, we have investigated isoform-specific activation of NFAT in NE- and ANG II-stimulated cardiomyocytes, as it is likely that each of the four calcineurin-dependent isoforms, c1-c4, play specific roles. We have stimulated neonatal ventriculocytes from C57/B6 and NFAT-luciferase reporter mice with ANG II or NE and quantified NFAT activity by luciferase activity and phospho-immunoblotting. ANG II and NE increased calcineurin-dependent NFAT activity 2.4- and 1.9-fold, measured as luciferase activity after 24 h of stimulation, and induced protein synthesis, measured by radioactive leucine incorporation after 24 and 72 h. To optimize measurements of NFAT isoforms, we examined the specificity of NFAT antibodies on peptide arrays and by immunoblotting with designed blocking peptides. Western analyses showed that both effectors activate NFATc1 and c4, while NFATc2 activity was regulated by NE only, as measured by phospho-NFAT levels. Neither ANG II nor NE activated NFATc3. As today's main therapies for heart failure aim at antagonizing the adrenergic and renin-angiotensin-aldosterone systems, understanding their intracellular actions is of importance, and our data, through validating a method for measuring myocardial NFATs, indicate that ANG II and NE activate specific NFATc isoforms in cardiomyocytes.

  12. Norepinephrine Reduces Reactive Oxygen Species (ROS) and DNA Damage in Ovarian Surface Epithelial Cells

    PubMed Central

    Patel, Pooja R; Hegde, Muralidhar L; Theruvathu, Jacob; Mitra, Sankar A; Boldogh, Istvan; Sowers, Lawrence

    2015-01-01

    Objective To determine the role of norepinephrine (NE) on DNA damage and reactive oxygen species (ROS) generation in ovarian surface epithelial cells. Method Non-tumorigenic, immortalized ovarian surface epithelial cells were treated with NE, bleomycin, and bleomycin followed by NE. The comet assay was performed on each treatment group to determine the amount of single and double-strand breaks induced by treatments. ROS levels for each treatment group were measured using the H2DCF-DA fluorescence assay. Finally, RNA transcripts were measured for each treatment group with regards to the expression of DNA repair and oxidative stress genes. Results The mean tail moment of untreated cells was significantly greater than that of cells treated with NE (p=0.02). The mean tail moment of cells treated with bleomycin was significantly greater than that of cells treated with bleomycin followed by NE (p<0.01). Treatment with NE resulted in significantly less ROS generation than in untreated cells (p<0.01). NE treatment after hydrogen peroxide treatment resulted in a noticeable decrease in ROS generation. Genes associated with oxidative stress were upregulated in cells treated with bleomycin, however this upregulation was blunted when bleomycin-treated cells were treated subsequently with NE. Conclusion NE is associated with decreased DNA damage and ROS production in ovarian surface epithelial cells. This effect is protective in the presence of the oxidative-damaging agent bleomycin. These results suggest an additional physiologic role for the stress hormone NE, in protecting ovarian surface epithelial cells from oxidative stress. PMID:26167254

  13. Electrocatalytic oxidation of Epinephrine and Norepinephrine at metal oxide doped phthalocyanine/MWCNT composite sensor

    PubMed Central

    Mphuthi, Ntsoaki G.; Adekunle, Abolanle S.; Ebenso, Eno E.

    2016-01-01

    Glassy carbon electrode (GCE) was modified with metal oxides (MO = Fe3O4, ZnO) nanoparticles doped phthalocyanine (Pc) and functionalized MWCNTs, and the electrocatalytic properties were studied. Successful synthesis of the metal oxide nanoparticles and the MO/Pc/MWCNT composite were confirmed using FTIR, Raman and SEM techniques. The electrodes were characterized using cyclic voltammetry (CV) technique. The electrocatalytic behaviour of the electrode towards epinephrine (EP) and norepinephrine (NE) oxidation was investigated using CV and DPV. Result showed that GCE-MWCNT/Fe3O4/2,3-Nc, GCE-MWCNT/Fe3O429H,31H-Pc, GCE-MWCNT/ZnO/2,3-Nc and GCE-MWCNT/ZnO/29H,31H-Pc electrodes gave enhanced EP and NE current response. Stability study indicated that the four GCE-MWCNT/MO/Pc modified electrodes were stable against electrode fouling effect with the percentage NE current drop of 5.56–5.88% after 20 scans. GCE-MWCNT/Fe3O4/29H,31H-Pc gave the lowest limit of detection (4.6 μM) towards EP while MWCNT/ZnO/29H,31H-Pc gave the lowest limit of detection (1.7 μM) towards NE. The limit of detection and sensitivity of the electrodes compared well with literature. Electrocatalytic oxidation of EP and NE on GCE-MWCNT/MO/Pc electrodes was diffusion controlled with some adsorption of electro-oxidation reaction intermediates products. The electrodes were found to be electrochemically stable, reusable and can be used for the analysis of EP and NE in real life samples. PMID:27245690

  14. Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline.

    PubMed

    Mei, Yufei; Jiang, Chun; Wan, You; Lv, Jihui; Jia, Jianping; Wang, Xiaomin; Yang, Xu; Tong, Zhiqian

    2015-08-01

    A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer's disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging-associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age-related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6-hydroxydopamine (6-OHDA, a NE depletor) can mimic age-related NE deficiency, long-term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age-related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence-accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age-matched, senescence-resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging-associated NE depletion and cognitive decline.

  15. Social Isolation is associated with Elevated Tumor Norepinephrine in Ovarian Carcinoma Patients

    PubMed Central

    Lutgendorf, Susan K.; DeGeest, Koen; Dahmoush, Laila; Farley, Donna; Penedo, Frank; Bender, David; Goodheart, Michael; Buekers, Thomas E.; Mendez, Luis; Krueger, Gina; Clevenger, Lauren; Lubaroff, David M.; Sood, Anil K.; Cole, Steve W.

    2011-01-01

    Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (β = −0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β=−0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values > 0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer. PMID:20955777

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

    SciTech Connect

    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 ..mu..Ci of (/sup 3/H)NE, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 ..mu..l/min over successive intervals of 5.0 min. When 0.05 or 0.1 ..mu..g/..mu..l 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.

  17. Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs.

    PubMed

    Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G; Nguyen, Peter V

    2015-10-01

    Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (β)-adrenergic receptors (β-ARs). Previous studies demonstrated that a β-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 µM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (>4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required β1-AR activation, as coapplication of the β1-receptor antagonist CGP-20712A (1 µM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translation- and transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NE-induced metaplasticity. Thus, activation of β-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories. PMID:26373828

  18. Lack of limb or sex differences in the cutaneous vascular responses to exogenous norepinephrine

    PubMed Central

    Stanhewicz, Anna E.; Kenney, W. Larry; Alexander, Lacy M.

    2014-01-01

    The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women (protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women (protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10−12 to 10−2 M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10−12 to 10−2 M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10−12 to 10−10 M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE. PMID:25342706

  19. Differential phosphorylation, desensitization, and internalization of α1A-adrenoceptors activated by norepinephrine and oxymetazoline.

    PubMed

    Akinaga, Juliana; Lima, Vanessa; Kiguti, Luiz Ricardo de Almeida; Hebeler-Barbosa, Flávia; Alcántara-Hernández, Rocío; García-Sáinz, J Adolfo; Pupo, André Sampaio

    2013-04-01

    Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an α1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that α1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the α1B and α1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent α1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of α1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native α1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed α1A-AR regulation. OXY shows functional selectivity relative to NE and PE at α1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by α1A-ARs.

  20. Layer- and area-specific actions of norepinephrine on cortical synaptic transmission.

    PubMed

    Salgado, Humberto; Treviño, Mario; Atzori, Marco

    2016-06-15

    The cerebral cortex is a critical target of the central noradrenergic system. The importance of norepinephrine (NE) in the regulation of cortical activity is underscored by clinical findings that involve this catecholamine and its receptor subtypes in the regulation of a large number of emotional and cognitive functions and illnesses. In this review, we highlight diverse effects of the LC/NE system in the mammalian cortex. Indeed, electrophysiological, pharmacological, and behavioral studies in the last few decades reveal that NE elicits a mixed repertoire of excitatory, inhibitory, and biphasic effects on the firing activity and transmitter release of cortical neurons. At the intrinsic cellular level, NE can produce a series of effects similar to those elicited by other monoamines or acetylcholine, associated with systemic arousal. At the synaptic level, NE induces numerous acute changes in synaptic function, and ׳gates' the induction of long-term plasticity of glutamatergic synapses, consisting in an enhancement of engaged and relevant cortical synapses and/or depression of unengaged synapses. Equally important in shaping cortical function, in many cortical areas NE promotes a characteristic, most often reversible, increase in the gain of local inhibitory synapses, whose extent and temporal properties vary between different areas and sometimes even between cortical layers of the same area. While we are still a long way from a comprehensive theory of the function of the LC/NE system, its cellular, synaptic, and plastic effects are consistent with the hypothesis that noradrenergic modulation is critical in coordinating the activity of cortical and subcortical circuits for the integration of sensory activity and working memory. This article is part of a Special Issue entitled SI: Noradrenergic System.

  1. Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion.

    PubMed

    León-Velarde, F; Bourin, M C; Germack, R; Mohammadi, K; Crozatier, B; Richalet, J P

    2001-01-01

    Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg. kg(-1). h(-1)) for 21 days. Because NE treatment resulted in left ventricular (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, alpha(1)-adrenergic receptors (AR) density increased by 35%, only in the LV. In NE, alpha(1)-AR density decreased by 43% in the RV. Both hypoxia and NE decreased beta-AR density. No difference was found in receptor apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of G(i) and G(s) proteins in cardiac membranes were assessed by incubation with pertussis toxin (PT) and cholera toxin (CT). PT had an important effect in abolishing the decrease in isoproterenol-induced stimulation of adenylate cyclase in hypoxia; however, pretreatment of the NE ventricle cells with PT failed to restore this stimulation. Although CT attenuates the basal activity of adenylate cyclase in the RV and the isoproterenol-stimulated activity in the LV, pretreatment of NE or hypoxic cardiac membranes with CT has a less clear effect on the adenylate cyclase pathway. The present study has demonstrated that 1) NE does not mimic the effects of hypoxia at the cellular level, i.e., hypoxia has specific effects on cardiac adrenergic signaling, and 2) changes in alpha- and beta-adrenergic pathways are chamber specific and may depend on the type of stimulation (hypoxia or adrenergic).

  2. Effects of hypocretin and norepinephrine interaction in bed nucleus of the stria terminalis on arterial pressure.

    PubMed

    Ciriello, J; Caverson, M M; Li, Z

    2013-01-01

    Forebrain neuronal circuits containing hypocretin-1 (hcrt-1) and norepinephrine (NE) are important components of central arousal-related processes. Recently, these two systems have been shown to have an overlapping distribution within the bed nucleus of the stria terminalis (BST), a limbic structure activated by stressful challenges, and which functions to adjust arterial pressure (AP) and heart rate (HR) to the stressor. However, whether hcrt-1 and NE interact in BST to alter cardiovascular function is unknown. Experiments were done in urethane-α-chloralose anesthetized, paralyzed, and artificially ventilated male Wistar rats to investigate the effect of hcrt-1 and NE on the cardiovascular responses elicited by l-glutamate (Glu) stimulation of BST neurons. Microinjections of hcrt-1, NE or tyramine into BST attenuated the decrease in AP and HR to Glu stimulation of BST. Additionally, combined injections of hcrt-1 with NE or tyramine did not elicit a greater attenuation than either compound alone. Furthermore, injections into BST of the α2-adrenergic receptor (α2-AR) antagonist yohimbine, but not the α1-AR antagonist 2-{[β-(4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone hydrochloride, blocked both the hcrt-1 and NE-induced inhibition of the BST cardiovascular depressors responses. Finally, injections into BST of the GABAA receptor antagonist bicuculline, but not the GABAB receptor antagonist phaclofen, blocked the hcrt-1 and NE attenuation of the BST Glu-induced depressor and bradycardia responses. These data suggest that hcrt-1 effects in BST are mediated by NE neurons, and hcrt-1 likely acts to facilitate the synaptic release of NE. NE neurons, acting through α2-AR may activate Gabaergic neurons in BST, which in turn through the activation of GABAA receptors inhibit a BST sympathoinhibitory pathway. Taken together, these data suggest that hcrt-1 pathways to BST through their interaction with NE and Gabaergic neurons may function in the coordination of

  3. Metabolism of D, L-/sup 3/H-norepinephrine in essential hypertension

    SciTech Connect

    Gitlow, S.; Dziedzic, S.; Dziedzic, L.; Roubein, I.

    1981-01-01

    Defective control of the cardiovascular system by the sympathetic nerves continues to be incriminated as the potential primary physiologic defect in essential hypertension (EH). The need to measure sympathetic tone has progressed from physiologic mensuration by assessment of reflex and pharmacological responses to the recent assay of norepinephrine (NE) and its congeners in both urine and plasma. The way in which the body handles D,L-B-/sup 3/H-NE represents yet another technique by which to evaluate sympathetic function. Previous studies of EH by this method demonstrated more rapid plasma disappearance of /sup 3/H-NE as well as elevated 24 hour tritium accumulation in the urine following D,L-B-/sup 3/H-NE injection. The present study of 7 normotensive subjects and 7 patients with EH was designed to depict more precisely these abnormalities in /sup 3/H-NE-metabolism. Following a one minute injection of 8 micrograms D,L-B-/sup 3/H-NE, (200 microCi) intravenously, the excretion of unlabeled endogenous metabolites and their labeled congeners was assayed. By these means one could estimate catecholamine synthesis, turnover of the labeled pools, and by comparison of relative specific activities of the metabolites, gain some insight into the distribution of the injected material. Alternative catabolic pathways were evaluated by measurement of the excretion of /sup 3/H/sub 2/O. Patients with EH excreted more label per 24 hours, revealed a more rapid decline of /sup 3/H2O excretion and lower specific activity of normetanephrine (NM). These findings are compatible with changes in pool dynamics and distribution of administered label which gave additional support to the concept of adrenergic dysfunction in association with essential hypertension.

  4. Curcumin Suppresses Gelatinase B Mediated Norepinephrine Induced Stress in H9c2 Cardiomyocytes

    PubMed Central

    Kohli, Shrey; Chhabra, Aastha; Jaiswal, Astha; Rustagi, Yashika; Sharma, Manish; Rani, Vibha

    2013-01-01

    Background Extracellular matrix (ECM) remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE), on cardiac muscle cells. Matrix metalloproteinases (MMPs) are the key proteases involved in degradation of the ECM in heart. Objectives The present study focuses on studying the effect of curcumin on Gelatinase B (MMP-9), an ECM remodeling regulatory enzyme, in NE-induced cardiac stress. Curcumin, a bioactive polyphenol found in the spice turmeric, has been studied for its multi-fold beneficial properties. This study focuses on investigating the role of curcumin as a cardio-protectant. Methods H9c2 cardiomyocytes were subjected to NE and curcumin treatments to study the response in stress conditions. Effect on total collagen content was studied using Picrosirus red staining. Gelatinase B activity was assessed through Gel-Diffusion Assay and Zymographic techniques. RT-PCR, Western Blotting and Immunocytochemistry were performed to study effect on expression of gelatinase B. Further, the effect of curcumin on the localization of NF-κB, known to regulate gelatinase B, was also examined. Results Curcumin suppressed the increase in the total collagen content under hypertrophic stress and was found to inhibit the in-gel and in-situ gelatinolytic activity of gelatinase B. Moreover, it was found to suppress the mRNA and protein expression of gelatinase B. Conclusions The study provides an evidence for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling. PMID:24116115

  5. Electrocatalytic oxidation of Epinephrine and Norepinephrine at metal oxide doped phthalocyanine/MWCNT composite sensor

    NASA Astrophysics Data System (ADS)

    Mphuthi, Ntsoaki G.; Adekunle, Abolanle S.; Ebenso, Eno E.

    2016-06-01

    Glassy carbon electrode (GCE) was modified with metal oxides (MO = Fe3O4, ZnO) nanoparticles doped phthalocyanine (Pc) and functionalized MWCNTs, and the electrocatalytic properties were studied. Successful synthesis of the metal oxide nanoparticles and the MO/Pc/MWCNT composite were confirmed using FTIR, Raman and SEM techniques. The electrodes were characterized using cyclic voltammetry (CV) technique. The electrocatalytic behaviour of the electrode towards epinephrine (EP) and norepinephrine (NE) oxidation was investigated using CV and DPV. Result showed that GCE-MWCNT/Fe3O4/2,3-Nc, GCE-MWCNT/Fe3O429H,31H-Pc, GCE-MWCNT/ZnO/2,3-Nc and GCE-MWCNT/ZnO/29H,31H-Pc electrodes gave enhanced EP and NE current response. Stability study indicated that the four GCE-MWCNT/MO/Pc modified electrodes were stable against electrode fouling effect with the percentage NE current drop of 5.56–5.88% after 20 scans. GCE-MWCNT/Fe3O4/29H,31H-Pc gave the lowest limit of detection (4.6 μM) towards EP while MWCNT/ZnO/29H,31H-Pc gave the lowest limit of detection (1.7 μM) towards NE. The limit of detection and sensitivity of the electrodes compared well with literature. Electrocatalytic oxidation of EP and NE on GCE-MWCNT/MO/Pc electrodes was diffusion controlled with some adsorption of electro-oxidation reaction intermediates products. The electrodes were found to be electrochemically stable, reusable and can be used for the analysis of EP and NE in real life samples.

  6. Monoamine Transporters: Vulnerable and Vital Doorkeepers

    PubMed Central

    Lin, Zhicheng; Canales, Juan J.; Björgvinsson, Thröstur; Thomsen, Morgane M.; Qu, Hong; Liu, Qing-Rong; Torres, Gonzalo E.; Caine, S. Barak

    2012-01-01

    Transporters of dopamine, serotonin and norepinephrine have been empirically used as medication targets for several mental illnesses for the last decades. These protein-targeted medications are effective only for subpopulations of patients with transporter-related brain disorders. Since the cDNA clonings in early 1990’s, molecular studies of these transporters have revealed a wealth of information about the transporters’ structure activity relationship (SAR), neuropharmacology, cell biology, biochemistry, pharmacogenetics and the diseases related to the human genes encoding these transporters among related regulators. Such new information creates a unique opportunity to develop transporter-specific medications based on SAR, mRNA, DNA and perhaps transporter trafficking regulation, for a list of highly relevant diseases including substance abuse, depression, schizophrenia and Parkinson’s disease. PMID:21199769

  7. Green tea catechins enhance norepinephrine-induced lipolysis via a protein kinase A-dependent pathway in adipocytes.

    PubMed

    Chen, Shu; Osaki, Noriko; Shimotoyodome, Akira

    2015-05-22

    Green tea catechins have been shown to attenuate obesity in animals and humans. The catechins activate adenosine monophosphate-activated protein kinase (AMPK), and thereby increase fatty acid oxidation in liver and skeletal muscles. Green tea catechins have also been shown to reduce body fat in humans. However, the effect of the catechins on lipolysis in adipose tissue has not been fully understood. The aim of this study was to clarify the effect of green tea catechins on lipolysis in adipocytes and to elucidate the underlying mechanism. Differentiated mouse adipocyte cell line (3T3-L1) was stimulated with green tea catechins in the presence or absence of norepinephrine. Glycerol and free fatty acids in the media were measured. Phosphorylation of hormone-sensitive lipase (HSL) was determined by Western blotting, and the mRNA expression levels of HSL, adipose triglyceride lipase (ATGL), and perilipin were determined by quantitative RT-PCR. The cells were treated with inhibitors of protein kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG), or mitogen-activated protein kinase (MAPK) to determine the responsible pathway. Treatment of 3T3-L1 adipocytes with green tea catechins increased the level of glycerol and free fatty acids released into the media in the presence, but not absence, of norepinephrine, and increased the level of phosphorylated HSL in the cells. The catechins also increased mRNA and protein levels of HSL and ATGL. PKA inhibitor (H89) attenuated the catechin-induced increase in glycerol release and HSL phosphorylation. The results demonstrate that green tea catechins enhance lipolysis in the presence of norepinephrine via a PKA-dependent pathway in 3T3-L1 adipocytes, providing a potential mechanism by which green tea catechins could reduce body fat. PMID:25849890

  8. Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

    PubMed

    Atzori, Marco; Cuevas-Olguin, Roberto; Esquivel-Rendon, Eric; Garcia-Oscos, Francisco; Salgado-Delgado, Roberto C; Saderi, Nadia; Miranda-Morales, Marcela; Treviño, Mario; Pineda, Juan C; Salgado, Humberto

    2016-01-01

    Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented-in order of decreasing affinity for the catecholamine-by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing-in turn-a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large

  9. Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

    PubMed Central

    Zhang, Ting-ting; Xue, Rui; Zhu, Lei; Li, Juan; Fan, Qiong-yin; Zhong, Bo-hua; Li, Yun-feng; Ye, Cai-ying; Zhang, You-zhi

    2016-01-01

    Aim: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. Results: Oral administration of ammoxetine (0.625–10 mg/kg) or duloxetine (2.5–40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5–10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex

  10. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    SciTech Connect

    Mosaddeghi, M.

    1989-01-01

    The function of {alpha}{sub 1}-adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with ({sup 3}H)inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 {mu}M potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC{sub 50} was decreased from 3.93 {plus minus} 0.42 to 1.91 {plus minus} 0.31 {mu}M NE. Concentrations of 0.1-100 {mu}M and 0.1-10 {mu}M cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 {mu}M NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 {mu}M prazosin. Cocaine (10 {mu}M) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 {mu}M prazosin. ({sup 3}H)Prazosin saturation and NE ({sup 3}H)prazosin competition binding studies using crude membrane preparations showed that 10 {mu}M cocaine did not alter binding parameters B{sub max}, K{sub d}, Hill slope, and IC{sub 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.

  11. Effect of norepinephrine dosage and calibration frequency on accuracy of pulse contour-derived cardiac output

    PubMed Central

    2011-01-01

    Introduction Continuous cardiac output monitoring is used for early detection of hemodynamic instability and guidance of therapy in critically ill patients. Recently, the accuracy of pulse contour-derived cardiac output (PCCO) has been questioned in different clinical situations. In this study, we examined agreement between PCCO and transcardiopulmonary thermodilution cardiac output (COTCP) in critically ill patients, with special emphasis on norepinephrine (NE) administration and the time interval between calibrations. Methods This prospective, observational study was performed with a sample of 73 patients (mean age, 63 ± 13 years) requiring invasive hemodynamic monitoring on a non-cardiac surgery intensive care unit. PCCO was recorded immediately before calibration by COTCP. Bland-Altman analysis was performed on data subsets comparing agreement between PCCO and COTCP according to NE dosage and the time interval between calibrations up to 24 hours. Further, central artery stiffness was calculated on the basis of the pulse pressure to stroke volume relationship. Results A total of 330 data pairs were analyzed. For all data pairs, the mean COTCP (±SD) was 8.2 ± 2.0 L/min. PCCO had a mean bias of 0.16 L/min with limits of agreement of -2.81 to 3.15 L/min (percentage error, 38%) when compared to COTCP. Whereas the bias between PCCO and COTCP was not significantly different between NE dosage categories or categories of time elapsed between calibrations, interchangeability (percentage error <30%) between methods was present only in the high NE dosage subgroup (≥0.1 μg/kg/min), as the percentage errors were 40%, 47% and 28% in the no NE, NE < 0.1 and NE ≥ 0.1 μg/kg/min subgroups, respectively. PCCO was not interchangeable with COTCP in subgroups of different calibration intervals. The high NE dosage group showed significantly increased central artery stiffness. Conclusions This study shows that NE dosage, but not the time interval between calibrations, has an

  12. Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

    PubMed Central

    Atzori, Marco; Cuevas-Olguin, Roberto; Esquivel-Rendon, Eric; Garcia-Oscos, Francisco; Salgado-Delgado, Roberto C.; Saderi, Nadia; Miranda-Morales, Marcela; Treviño, Mario; Pineda, Juan C.; Salgado, Humberto

    2016-01-01

    Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented—in order of decreasing affinity for the catecholamine—by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing—in turn—a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a

  13. Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

    PubMed Central

    Atzori, Marco; Cuevas-Olguin, Roberto; Esquivel-Rendon, Eric; Garcia-Oscos, Francisco; Salgado-Delgado, Roberto C.; Saderi, Nadia; Miranda-Morales, Marcela; Treviño, Mario; Pineda, Juan C.; Salgado, Humberto

    2016-01-01

    Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented—in order of decreasing affinity for the catecholamine—by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing—in turn—a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a

  14. Extracellular Electron Transport-Mediated Fe(III) Reduction by a Community of Alkaliphilic Bacteria That Use Flavins as Electron Shuttles

    PubMed Central

    Fuller, Samuel J.; McMillan, Duncan G. G.; Renz, Marc B.; Schmidt, Martin

    2014-01-01

    The biochemical and molecular mechanisms used by alkaliphilic bacterial communities to reduce metals in the environment are currently unknown. We demonstrate that an alkaliphilic (pH > 9) consortium dominated by Tissierella, Clostridium, and Alkaliphilus spp. is capable of using iron (Fe3+) as a final electron acceptor under anaerobic conditions. Iron reduction is associated with the production of a freely diffusible species that, upon rudimentary purification and subsequent spectroscopic, high-performance liquid chromatography, and electrochemical analysis, has been identified as a flavin species displaying properties indistinguishable from those of riboflavin. Due to the link between iron reduction and the onset of flavin production, it is likely that riboflavin has an import role in extracellular metal reduction by this alkaliphilic community. PMID:24141133

  15. The role of adenosine A2A and A3 receptors on the differential modulation of norepinephrine and neuropeptide Y release from peripheral sympathetic nerve terminals.

    PubMed

    Donoso, M Verónica; Aedo, Felipe; Huidobro-Toro, J Pablo

    2006-03-01

    The pre-synaptic sympathetic modulator role of adenosine was assessed by studying transmitter release following electrical depolarization of nerve endings from the rat mesenteric artery. Mesentery perfusion with exogenous adenosine exclusively inhibited the release of norepinephrine (NA) but did not affect the overflow of neuropeptide Y (NPY), establishing the basis for a differential pre-synaptic modulator mechanism. Several adenosine structural analogs mimicked adenosine's effect on NA release and their relative order of potency was: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride = 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-d-ribofuranuronamide = 5'-(N-ethylcarboxamido)adenosine > adenosine > N(6)-cyclopentyladenosine. The use of selective receptor subtype antagonists confirmed the involvement of A(2A) and A(3) adenosine receptors. The modulator role of adenosine is probably due to the activation of both receptors; co-application of 1 nM 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride plus 1 nM 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide caused additive reductions in NA released. Furthermore, while 1 nM of an A(2A) or A(3) receptor antagonist only partially reduced the inhibitory action of adenosine, the combined co-application of the two antagonists fully blocked the adenosine-induced inhibition. Only the simultaneous blockade of the adenosine A(2A) plus A(3) receptors with selective antagonists elicited a significant increase in NA overflow. H 89 reduced the release of both NA and NPY. We conclude that pre-synaptic A(2A) and A(3) adenosine receptor activation modulates sympathetic co-transmission by exclusively inhibiting the release of NA without affecting immunoreactive (ir)-NPY and we suggest separate mechanisms for vesicular release modulation.

  16. Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM

    PubMed Central

    Yeh, Yi-Wei; Ho, Pei-Shen; Kuo, Shin-Chang; Chen, Chun-Yen; Liang, Chih-Sung; Yen, Che-Hung; Huang, Chang-Chih; Ma, Kuo-Hsing; Shiue, Chyng-Yann; Huang, Wen-Sheng; Shyu, Jia-Fwu; Wan, Fang-Jung; Lu, Ru-Band

    2015-01-01

    Background: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. Methods: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. Results: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. Conclusions: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD. PMID:25568284

  17. A New Family of Membrane Electron Transporters and Its Substrates, Including a New Cell Envelope Peroxiredoxin, Reveal a Broadened Reductive Capacity of the Oxidative Bacterial Cell Envelope

    PubMed Central

    Cho, Seung-Hyun; Parsonage, Derek; Thurston, Casey; Dutton, Rachel J.; Poole, Leslie B.; Collet, Jean-Francois; Beckwith, Jon

    2012-01-01

    ABSTRACT The Escherichia coli membrane protein DsbD functions as an electron hub that dispatches electrons received from the cytoplasmic thioredoxin system to periplasmic oxidoreductases involved in protein disulfide isomerization, cytochrome c biogenesis, and sulfenic acid reduction. Here, we describe a new class of DsbD proteins, named ScsB, whose members are found in proteobacteria and Chlamydia. ScsB has a domain organization similar to that of DsbD, but its amino-terminal domain differs significantly. In DsbD, this domain directly interacts with substrates to reduce them, which suggests that ScsB acts on a different array of substrates. Using Caulobacter crescentus as a model organism, we searched for the substrates of ScsB. We discovered that ScsB provides electrons to the first peroxide reduction pathway identified in the bacterial cell envelope. The reduction pathway comprises a thioredoxin-like protein, TlpA, and a peroxiredoxin, PprX. We show that PprX is a thiol-dependent peroxidase that efficiently reduces both hydrogen peroxide and organic peroxides. Moreover, we identified two additional proteins that depend on ScsB for reduction, a peroxiredoxin-like protein, PrxL, and a novel protein disulfide isomerase, ScsC. Altogether, our results reveal that the array of proteins involved in reductive pathways in the oxidative cell envelope is significantly broader than was previously thought. Moreover, the identification of a new periplasmic peroxiredoxin indicates that in some bacteria, it is important to directly scavenge peroxides in the cell envelope even before they reach the cytoplasm. PMID:22493033

  18. Assessing the Cr(VI) reduction efficiency of a permeable reactive barrier using Cr isotope measurements and 2D reactive transport modeling.

    PubMed

    Wanner, Christoph; Zink, Sonja; Eggenberger, Urs; Mäder, Urs

    2012-04-01

    In Thun, Switzerland, a permeable reactive barrier (PRB) for Cr(VI) reduction by gray cast iron was installed in May 2008. The PRB is composed of a double array of vertical piles containing iron shavings and gravel. The aquifer in Thun is almost saturated with dissolved oxygen and the groundwater flow velocities are ca. 10-15m/day. Two years after PRB installation Cr(VI) concentrations still permanently exceed the Swiss threshold value for contaminated sites downstream of the barrier at selected localities. Groundwater δ(53/52)Cr(SRM979) measurements were used to track Cr(VI) reduction induced by the PRB. δ(53/52)Cr(SRM979) values of two samples downstream of the PRB showed a clear fractionation towards more positive values compared to four samples from the hotspot, which is clear evidence of Cr(VI) reduction induced by the PRB. Another downstream sample did not show a shift to more positive δ(53/52)Cr(SRM979) values. Because this latter location correlates with the highest downstream Cr(VI) concentration it is proposed that a part of the Cr(VI) plume is bypassing the barrier. Using a Rayleigh fractionation model a minimum present-day overall Cr(VI) reduction efficiency of ca. 15% was estimated. A series of 2D model simulations, including the fractionation of Cr isotopes, confirm that only a PRB bypass of parts of the Cr(VI) plume can lead to the observed values. Additionally, the simulations revealed that the proposed bypass occurs due to an insufficient permeability of the individual PRB piles. It is concluded that with this type of PRB a complete and long-lasting Cr(VI) reduction is extremely difficult to achieve for Cr(VI) contaminations located in nearly oxygen and calcium carbonate saturated aquifer in a regime of high groundwater velocities. Additional remediation action would limit the environmental impact and allow to reach target concentrations.

  19. The catecholamine stress hormones norepinephrine and dopamine increase the virulence of pathogenic Vibrio anguillarum and Vibrio campbellii.

    PubMed

    Pande, Gde Sasmita J; Suong, Nguyen Thao; Bossier, Peter; Defoirdt, Tom

    2014-12-01

    Obtaining a better understanding of mechanisms involved in bacterial infections is of paramount importance for the development of novel agents to control disease caused by (antibiotic resistant) pathogens in aquaculture. In this study, we investigated the impact of catecholamine stress hormones on growth and virulence factor production of pathogenic vibrios (i.e. two Vibrio campbellii strains and two Vibrio anguillarum strains). Both norepinephrine and dopamine (at 100 μM) significantly induced growth in media containing serum. The compounds also increased swimming motility of the tested strains, whereas they had no effect on caseinase, chitinase, and hemolysin activities. Further, antagonists for eukaryotic catecholamine receptors were able to neutralize some of the effects of the catecholamines. Indeed, the dopaminergic receptor antagonist chlorpromazine neutralized the effect of dopamine, and the α-adrenergic receptor antagonists phentolamine and phenoxybenzamine neutralized the effect of norepinephrine, whereas the β-adrenergic receptor antagonist propranolol had limited to no effect. Finally, pretreatment of pathogenic V. campbellii with catecholamines significantly increased its virulence toward giant freshwater prawn larvae. However, the impact of catecholamine receptor antagonists on in vivo virulence was less clear-cut when compared to the in vitro experiments. In summary, our results show that—similar to enteric pathogens—catecholamines also increase the virulence of vibrios that are pathogenic to aquatic organisms by increasing motility and growth in media containing serum.

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

    SciTech Connect

    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.

  1. Superlattice assembly of graphene oxide (GO) and titania nanosheets: fabrication, in situ photocatalytic reduction of GO and highly improved carrier transport

    NASA Astrophysics Data System (ADS)

    Cai, Xingke; Ma, Renzhi; Ozawa, Tadashi C.; Sakai, Nobuyuki; Funatsu, Asami; Sasaki, Takayoshi

    2014-11-01

    Two different kinds of two-dimensional (2D) materials, graphene oxide (GO) and titanium oxide nanosheets (Ti0.87O20.52-), were self-assembled layer-by-layer using a polycation as a linker into a superlattice film. Successful construction of an alternate molecular assembly was confirmed by atomic force microscopy and UV-visible absorption spectroscopy as well as X-ray diffraction analysis. Exposure of the resulting film to UV light effectively promoted photocatalytic reduction of GO as well as decomposition of the polycation, which are due to their intimate molecular-level contact. The reduction completed within 3 hours, bringing about a decrease of the sheet resistance by ~106. This process provides a clean and mild route to reduced graphene oxide (rGO), showing advantages over other chemical and thermal reduction processes. A field-effect-transistor device was fabricated using the resulting superlattice assembly of rGO/Ti0.87O20.52- as a channel material. The rGO in the film was found to work as a unipolar n-type conductor, which is in contrast to ambipolar or unipolar p-type behavior mostly reported for rGO films. This unique property may be associated with the electron doping effect from Ti0.87O20.52- nanosheets. A significant improvement in the conductance and electron carrier mobility by more than one order of magnitude was revealed, which may be accounted for by the heteroassembly with Ti0.87O20.52- nanosheets with a high dielectric constant as well as the better 2D structure of rGO produced via the soft photocatalytic reduction.Two different kinds of two-dimensional (2D) materials, graphene oxide (GO) and titanium oxide nanosheets (Ti0.87O20.52-), were self-assembled layer-by-layer using a polycation as a linker into a superlattice film. Successful construction of an alternate molecular assembly was confirmed by atomic force microscopy and UV-visible absorption spectroscopy as well as X-ray diffraction analysis. Exposure of the resulting film to UV light

  2. Advanced computer technology - An aspect of the Terminal Configured Vehicle program. [air transportation capacity, productivity, all-weather reliability and noise reduction improvements

    NASA Technical Reports Server (NTRS)

    Berkstresser, B. K.

    1975-01-01

    NASA is conducting a Terminal Configured Vehicle program to provide improvements in the air transportation system such as increased system capacity and productivity, increased all-weather reliability, and reduced noise. A typical jet transport has been equipped with highly flexible digital display and automatic control equipment to study operational techniques for conventional takeoff and landing aircraft. The present airborne computer capability of this aircraft employs a multiple computer simple redundancy concept. The next step is to proceed from this concept to a reconfigurable computer system which can degrade gracefully in the event of a failure, adjust critical computations to remaining capacity, and reorder itself, in the case of transients, to the highest order of redundancy and reliability.

  3. Reduction of Nitrate in Shewanella oneidensis depends on atypical NAP and NRF systems with NapB as a preferred electron transport protein from CymA to NapA

    SciTech Connect

    Gao, Haichun; Yang, Zamin; Barua, Soumitra; Reed, Samantha B.; Romine, Margaret F.; Nealson, Kenneth H.; Fredrickson, Jim K.; Tiedje, James M.; Zhou, Jizhong

    2009-04-23

    In the genome of Shewanella oneidensis, a napDAGHB gene cluster encoding periplasmic nitrate reductase (NapA) and accessory proteins and an nrfA gene encoding periplasmic nitrite reductase (NrfA) have been identified. These two systems seem to be atypical because the genome lacks genes encoding cytoplasmic membrane electron transport proteins, NapC for NAP and NrfBCD/NrfH for NRF, respectively. Here, we present evidence that reduction of nitrate to ammonium in S. oneidensis is carried out by these atypical systems in a two-step manner. Transcriptional and mutational analyses suggest that CymA, a cytoplasmic membrane electron transport protein, is likely to be the functional replacement of both NapC and NrfH in S. oneidensis. Surprisingly, a strain devoid of napB encoding the small subunit of nitrate reductase exhibited the maximum cell density sooner than the wild type. Further characterization of this strain showed that nitrite was not detected as a free intermediate in its culture and NapB provides a fitness gain for S. oneidensis to compete for nitrate in the environments. On the basis results from mutational analyses of napA, napB, nrfA and napBnrfA in-frame deletion mutants, we propose that NapB is able to favor nitrate reduction by routing electrons to NapA exclusively.

  4. Neurogenic Hyperadrenergic Orthostatic Hypotension – A Newly-recognized Variant of Orthostatic Hypotension in Older Adults with Elevated Norepinephrine

    PubMed Central

    Mar, Philip L; Shibao, Cyndya A.; Garland, Emily M; Black, Bonnie K; Biaggioni, Italo; Diedrich, André; Paranjape, Sachin Y; Robertson, David; Raj, Satish R

    2015-01-01

    Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine. We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma norepinephrine. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based upon standing norepinephrine, patients were dichotomized into a hyperadrenergic orthostatic hypotension group (hyperOH: upright NE ≥3.55 nmol/L [600 pg/mL], n=19) or a non-hyperadrenergic orthostatic hypotension group (nOH: upright NE < 3.55 nmol/L [600 pg/mL], n=64). Medical history and data from autonomic testing, including the Valsalva maneuver (VM), were analyzed. HyperOH patients had profound orthostatic falls in blood pressure, but less severe than in nOH (change in SBP: −53±31 mmHg vs. −68±33 mmHg, P=0.050; change in DBP: −18±23 mmHg vs. −30±17 mmHg, P=0.01). The expected compensatory increase in standing heart rate was similarly blunted in both hyperOH and nOH groups (84±15 bpm vs. 82±14 bpm; P=0.6). HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM, and a shorter VM phase 4 blood pressure recovery time (16.5±8.9 sec vs. 31.6±16.6 sec; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic orthostatic hypotension, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand if hyperOH patients will progress to nOH or if this represents a different disorder. PMID:25706983

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

    SciTech Connect

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

    1987-11-30

    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 (/sup 3/H-NE) was metabolized mainly to tritiated 3,4-dihydroxyphenylethylene glycol (/sup 3/HDOPEG) and 3,4-dihydroxy mandelic acid (/sup 3/HDOMA), whereas after denervation it was metabolized mainly to tritiated normetanephrine (/sup 3/HNMN). In the denervated mucosa, cocaine(30umol/l) inhibited /sup 3/HNMN formation by 50-60%. Cocaine also inhibited /sup 3/HNMN formation by 60% in the denervated lingual gingiva. It is concluded that the tissues metabolize /sup 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.

  6. Differential effects of chronic lead intoxication on circadian rhythm of ambulatory activity and on regional brain norepinephrine levels in rats

    SciTech Connect

    Shafiq-ur-Rehman; Khushnood-ur-Rehman; Kabir-ud-Din; Chandra, O.

    1986-01-01

    Changes in biochemical mechanisms and amine concentrations in the brain have been manifested in the form of varying disorders and abnormalities in behavior, including motor-activity, which has been proved with a number of psychoactive drugs. It has been reported that increased level of cerebral norepinephrine (NE) has been shown to be associated with motor hyper-activity, and in lead exposed rats. No study is available which could account for the pattern of changes in spontaneous ambulatory responses in an open field situation together with the steady state regional levels of NE in the brain of chronically lead exposed rats. Therefore, it seemed to be worthwhile to study the circadian rhythm of ambulatory activity and its association with NE levels in various brain regions of rats exposed to lead.

  7. Norepinephrine content in discrete brain areas and neurohypophysial vasopressin in rats after a 9-d spaceflight (SLS-1)

    NASA Technical Reports Server (NTRS)

    Fareh, Jeannette; Cottet-Emard, Jean-Marie; Pequignot, Jean-Marc; Jahns, Gary; Meylor, John; Viso, Michel; Vassaux, Didier; Gauquelin, Guillemette; Gharib, Claude

    1993-01-01

    The norepinephrine (NE) content in discrete brain areas and the vasopressin content in the neurohypophysial system were assessed in rats after a 9-d spaceflight and after a recovery period. The NE content in the locus coeruleus decreased significantly in spaceflight rats, but showed no difference between control and flight animals after a 9-d recovery. These findings were probably due to an acute stress undergone during landing. The NE content was unchanged in the A2 and A5 cell groups. In rats flown aboard SLS-1, the vasopressin content was increased in the posterior pituitary, and was significantly decreased in the hypothalamus. We conclude that the NE depletion in the locus coeruleus and the alteration in vasopressin release were consistent with an acute stress, likely occurring during and/or after landing. These changes tend to mask the actual neuroendocrine modifications caused by microgravity.

  8. The role of QseC quorum-sensing sensor kinase in colonization and norepinephrine-enhanced motility of Salmonella enterica serovar Typhirmurium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transcriptional analysis of Salmonella enterica serovar Typhimurium in the presence of the mammalian hormone Norepinephrine (NE) revealed up-regulation of chemotaxis and motility genes. Motility assays confirmed enhanced motility of wild-type S. Typhimurium in the presence of NE that could be block...

  9. Plasma cortisol and norepinephrine concentrations in pigs: automated sampling of freely moving pigs housed in the PigTurn versus manually sampled and restrained pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Minimizing effects of restraint and human interaction on the endocrine physiology of animals is essential for collection of accurate physiological measurements. Our objective was to compare stress-induced cortisol (CORT) and norepinephrine (NE) responses in automated versus manual blood sampling. A ...

  10. Hypothalamic norepinephrine turnover response to a single low protein, high carbohydrate meal in the male Wistar rat

    SciTech Connect

    Raum, W.; Glick, Z.

    1986-03-01

    A single meal stimulates norepinephrine turnover (NET) by approximately 4-fold in the brown adipose tissue (BAT). In this experiment the role of the hypothalamus in regulating this response was examined. NET was measured in the cortex (C), ventro-medial (VMH), and the lateral hypothalamus (LH). A total of 48 male Wistar rats (200 g body weight) 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 hours. NET was determined by the synthesis inhibition method using alpha-methyltyrosine (AMT) injected within one hour after the meal. Norepinephrine (NE) content in each brain section was measured by radioimmunoassay at 4 time points (0, 1, 2, 3 hours) after AMT. The turnover rate (TR) was calculated as the slope of the decline in NE content over time (ng/mg protein/hr) following AMT. The fraction of the total pool of NE released/hr (k) was calculated by dividing the slope (TR) by the Y intercept (NE content at zero time). NET (TR) increased significantly (p < .05) in the VMH following a meal (9.36 +/- .67 vs 8.04 +/- .98 ng/hr; fed vs deprived). There was no change in TR in the C or LH, or in k in any brain section. The marked (4-fold) increase in BAT NET and minimal increase in VMH NET suggests that the meal has a direct effect on BAT with the VMH playing a secondary or modulatory role.

  11. Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats.

    PubMed

    Alfinito, Peter D; Huselton, Christine; Chen, Xiaohong; Deecher, Darlene C

    2006-07-01

    Desvenlafaxine succinate (DVS) is a novel serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) that is currently in clinical development for the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Previous studies have documented the pharmacokinetic and pharmacodynamic profiles of DVS in male rats. Similar studies, however, have not been performed in ovariectomized (OVX) rats, a model that mimics the loss of ovarian hormones that occurs at menopause. The goal of the present study, therefore, was to characterize the pharmacokinetic and pharmacodynamic properties of DVS in OVX rats. Desvenlafaxine levels peaked in plasma, brain (total brain minus hypothalamus) and hypothalamus at concentrations of 7.0, 10.8 and 9.5 microM (assuming 1 g = 1 ml), respectively, 30 min post-dosing DVS (30 mg/kg, oral). The apparent terminal half-lives of desvenlafaxine in plasma, brain and hypothalamus were 3.0, 2.1 and 2.5 h, respectively. Based on AUC(0-last), brain to plasma and hypothalamus to plasma ratios were 1.7 and 1.3, respectively. Microdialysis experiments in the medial preoptic area of the hypothalamus showed that DVS (30 mg/kg, s.c.), in the presence of WAY-100635 (5-HT(1A) antagonist), increased 5-HT levels 225% at 1 h post-dosing. Norepinephrine levels increased 44% at 3 h post-dosing while dopamine levels were unchanged. Thus, in OVX rats, DVS has good pharmacokinetic properties, rapid brain penetration, excellent brain penetrability and selectively increases 5-HT and NE levels in the hypothalamus. This work supports the notion that DVS could have utility for treating disorders in menopausal women in which changes in 5-HT and/or NE have been implicated.

  12. Early adolescence as a critical window during which social stress distinctly alters behavior and brain norepinephrine activity.

    PubMed

    Bingham, Brian; McFadden, Kile; Zhang, Xiaoyan; Bhatnagar, Seema; Beck, Sheryl; Valentino, Rita

    2011-03-01

    Many neural programs that shape behavior become established during adolescence. Adverse events at this age can have enduring consequences for both adolescent and adult mental health. Here we show that repeated social stress at different stages of adolescent development differentially affects rat behavior and neuronal activity. Early-adolescent (PND 28, EA), mid-adolescent (PND 42, MA), and adult (PND 63) rats were subjected to resident-intruder social stress (7 days) and behavior was examined 24-72 h later. In EA rats selectively, resident-intruder stress increased proactive responses in the defensive burying and forced swim tests. In adult rats, resident-intruder stress decreased burying behavior regardless of whether the animal was stressed as an adult or during early adolescence. As the locus coeruleus (LC)-norepinephrine system has been implicated in proactive defense behaviors, LC neuronal activity was quantified in separate cohorts. Stressed EA rats had elevated spontaneous LC discharge rates and diminished responses to sensory stimuli compared with controls. Microinjection of a CRF antagonist into the LC selectively inhibited neurons of stressed EA rats, suggesting that EA social stress induces tonic CRF release onto LC neurons, shifting the mode of discharge to an activated state that promotes active defensive behaviors. In all adult groups, resident-intruder stress resulted in an increased phasic response to sensory stimuli with no change in spontaneous rates. MA was a transition period during which social stress did not affect behavior or LC activity. The results suggest that social stress interacts with the brain norepinephrine system to regulate defensive strategies in an age-dependent manner.

  13. Mechanism of norepinephrine release elicited by renal nerve stimulation, veratridine and potassium chloride in the isolated rat kidney

    SciTech Connect

    el-Din, M.M.; Malik, K.U.

    1987-10-01

    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 (/sup 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.

  14. Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

    PubMed

    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.

  15. Elevated blood plasma levels of epinephrine, norepinephrine, tyrosine hydroxylase, TGFβ1, and TNFα associated with high-altitude pulmonary edema in an Indian population.

    PubMed

    Pandey, Priyanka; Ali, Zahara; Mohammad, Ghulam; Pasha, M A Qadar

    2016-01-01

    Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) against adapted highlanders (HLs) and healthy sojourners, HAPE-controls (HAPE-c). For this, seven circulatory biomarkers, namely, epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor beta 1, tumor necrosis factor alpha (TNFα), platelet-derived growth factor beta beta, and C-reactive protein (CRP), were measured in blood plasma of the three study groups. All the subjects were recruited at ~3,500 m, and clinical features such as arterial oxygen saturation (SaO2), body mass index, and mean arterial pressure were measured. Increased levels of epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor-beta 1, and TNFα were observed in HAPE-p against the healthy groups, HAPE-c, and HLs (P<0.0001). CRP levels were decreased in HAPE-p against HAPE-c and HLs (P<0.0001). There was no significant difference or very marginal difference in the levels of these biomarkers in HAPE-c and HLs (P>0.01). Correlation analysis revealed a negative correlation between epinephrine and norepinephrine (P=4.6E-06) in HAPE-p and positive correlation in HAPE-c (P=0.004) and HLs (P=9.78E-07). A positive correlation was observed between TNFα and CRP (P=0.004) in HAPE-p and a negative correlation in HAPE-c (P=4.6E-06). SaO2 correlated negatively with platelet-derived growth factor beta beta (HAPE-p; P=0.05), norepinephrine (P=0.01), and TNFα (P=0.005) and positively with CRP (HAPE-c; P=0.02) and norepinephrine (HLs; P=0.04). Body mass index correlated negatively with epinephrine (HAPE-p; P=0.001) and positively with norepinephrine and tyrosine hydroxylase in HAPE-c (P<0.05). Mean arterial pressure correlated positively with TNFα in HAPE-p and norepinephrine in HLs (P

  16. Elevated blood plasma levels of epinephrine, norepinephrine, tyrosine hydroxylase, TGFβ1, and TNFα associated with high-altitude pulmonary edema in an Indian population

    PubMed Central

    Pandey, Priyanka; Ali, Zahara; Mohammad, Ghulam; Pasha, M A Qadar

    2016-01-01

    Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) against adapted highlanders (HLs) and healthy sojourners, HAPE-controls (HAPE-c). For this, seven circulatory biomarkers, namely, epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor beta 1, tumor necrosis factor alpha (TNFα), platelet-derived growth factor beta beta, and C-reactive protein (CRP), were measured in blood plasma of the three study groups. All the subjects were recruited at ~3,500 m, and clinical features such as arterial oxygen saturation (SaO2), body mass index, and mean arterial pressure were measured. Increased levels of epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor-beta 1, and TNFα were observed in HAPE-p against the healthy groups, HAPE-c, and HLs (P<0.0001). CRP levels were decreased in HAPE-p against HAPE-c and HLs (P<0.0001). There was no significant difference or very marginal difference in the levels of these biomarkers in HAPE-c and HLs (P>0.01). Correlation analysis revealed a negative correlation between epinephrine and norepinephrine (P=4.6E−06) in HAPE-p and positive correlation in HAPE-c (P=0.004) and HLs (P=9.78E−07). A positive correlation was observed between TNFα and CRP (P=0.004) in HAPE-p and a negative correlation in HAPE-c (P=4.6E−06). SaO2 correlated negatively with platelet-derived growth factor beta beta (HAPE-p; P=0.05), norepinephrine (P=0.01), and TNFα (P=0.005) and positively with CRP (HAPE-c; P=0.02) and norepinephrine (HLs; P=0.04). Body mass index correlated negatively with epinephrine (HAPE-p; P=0.001) and positively with norepinephrine and tyrosine hydroxylase in HAPE-c (P<0.05). Mean arterial pressure correlated positively with TNFα in HAPE-p and norepinephrine in

  17. Intrahypothalamic injections of norepinephrine facilitate feline affective aggression via alpha 2-adrenoceptors.

    PubMed

    Barrett, J A; Edinger, H; Siegel, A

    1990-08-20

    The purpose of this study was to investigate the effects of noradrenergic agents infused into the anterior hypothalamus on feline affective defense responses elicited by electrical stimulation of the ventromedial hypothalamus. Anterior hypothalamic sites which are known to receive inputs from both the ventromedial hypothalamus and ascending noradrenergic pathways were selected for pharmacological analysis. Intracerebral infusions of NE (1.2-2.4 nmol) into the anterior hypothalamus significantly reduced the threshold current required to elicit the hissing component of affective defense via electrical stimulation of the ventromedial hypothalamus. Maximal threshold reductions (17 +/- 3% to 20 +/- 3%) were observed 30 min following infusion. Anterior hypothalamic infusions of clonidine facilitated feline affective defense by reducing hissing current thresholds by 18 +/- 4%. Clonidine-induced changes in response thresholds parallel those obtained with NE. Both NE-induced and clonidine-induced reductions in current thresholds were reversible by pre- and post-treatment of the anterior hypothalamic sites with yohimbine. These results demonstrate that the reductions in response thresholds are mediated by post-synaptic alpha 2-adrenoceptors located within the anterior hypothalamus. Thus the noradrenergic system may play an important role in the regulation of affective aggressive behavior. PMID:2174712

  18. Regional transportation network blocked by snowdrifts: assessment of risk reduction strategies by the example of the wind event of February 2015 in the Canton of Vaud, Switzerland

    NASA Astrophysics Data System (ADS)

    Voumard, Jérémie; Jaboyedoff, Michel; Derron, Marc-Henri

    2016-04-01

    The 5-8th February, a meteorological situation characterized by a strong wind coming from the North generated many snowdrifts on roads and railways in the Canton of Vaud, Switzerland. The affected region, about 900 km2, is located on the Swiss Plateau. More than thirty roads and few railways were blocked during the event. On some areas, too many roads and railways tracks were closed to assure the school transports making obligatory the total closure of seven schools and the partial closure of three schools affecting 8'000 students, which is almost 10% of students of the Canton of Vaud. Over hundred vehicles blocked in the snowdrifts had to be unobstructed. Over 150 snowplows drivers were requisitioned but the wind with gusts of over 80 km/h was too strong to release the roads from the snow accumulation. The boat transport on the Lake Geneva was interrupted during three days because of the danger generated by the strong wind during the berths. This interruption generated up to 100 km deviation for commuting traffic. The county police recommended to the population to limit their travels on the road. The last roads closures due to snowdrifts in the Canton of Vaud occurred ten years ago, in 2005. This particular event that affected considerably the accessibility of a large area of the Canton of Vaud is interesting because results of a "simple" meteorological situation that strongly reduced the accessibility during four days of an area with a population of about 340'000. It raises several questions as for examples: how the emergency services accessibility is assured; what are the tools that can reduce the roads closures; what is the best road management to follow during such an event (which roads must be priority cleaned, which roads can be left covered by snow); how to prevent such an event, are snow fences enough to avoid snowdrifts or is there another way to limit their creation? To try obtaining answers to those questions, we assess the most critical infrastructures

  19. Pu(V) transport through Savannah River Site soils - an evaluation of a conceptual model of surface- mediated reduction to Pu (IV).

    PubMed

    Powell, Brian A; Kaplan, Daniel I; Serkiz, Steven M; Coates, John T; Fjeld, Robert A

    2014-05-01

    Over the last fifteen years the Savannah River Site (SRS) in South Carolina, USA, was selected as the site of three new plutonium facilities: the Mixed Oxide Fuel Fabrication Facility, Pit Disassembly and Conversion Facility, and the Pu Immobilization Plant. In order to assess the potential human and environmental risk associated with these recent initiatives, improved understanding of the fate and transport of Pu in the SRS subsurface environment is necessary. The hypothesis of this study was that the more mobile forms of Pu, Pu(V) and Pu(VI), would be reduced to the less mobile Pu(III/IV) oxidation states under ambient SRS subsurface conditions. Laboratory-scale dynamic flow experiments (i.e., column studies) indicated that Pu(V) was very mobile in SRS sediments. At higher pH values the mobility of Pu decreased and the fraction of Pu that became irreversibly sorbed to the sediment increased, albeit, only slightly. Conversely, these column experiments showed that Pu(IV) was essentially immobile and was largely irreversibly sorbed to the sediment. More than 100 batch sorption experiments were also conducted with four end-member sediments, i.e., sediments that include the chemical, textural, and mineralogical properties likely to exist in the SRS. These tests were conducted as a function of initial Pu oxidation state, pH, and contact time and consistently demonstrated that although Pu(V) sorbed initially quite weakly to sediments, it slowly, over the course of <33 days, sorbed very strongly to sediments, to approximately the same degree as Pu(IV). This is consistent with our hypothesis that Pu(V) is reduced to the more strongly sorbing form of Pu, Pu(IV). These studies provide important experimental support for a conceptual geochemical model for dissolved Pu in a highly weathered subsurface environment. That is that, irrespective of the initial oxidation state of the dissolved Pu introduced into a SRS sediment system, Pu(IV) controls the environmental transport

  20. Use of a reactive transport model to describe reductive dechlorination (RD) as a remediation design tool: application at a CAH-contaminated site.

    PubMed

    Viotti, Paolo; Di Palma, Paolo Roberto; Aulenta, Federico; Luciano, Antonella; Mancini, Giuseppe; Papini, Marco Petrangeli

    2014-01-01

    In this paper, a numerical model is presented that is capable of describing the complex set of biochemical processes that occur in chlorinated aliphatic hydrocarbon (CAH)-contaminated groundwater when an exogenous electron donor is added. The reactive pattern is based on the degradation pathways of both chlorinated ethanes and ethenes, and it includes electron donor production (H2 and acetate) from the fermentation of an organic substrate as well as rate-limiting processes related to electron acceptor competition. Coupling of the kinetic model to a convection-dispersion module is described. The calibration phase was carried out using data obtained at a real CAH-contaminated site in the north of Italy. Model simulations of different application scenarios are presented to draw general conclusions on the effectiveness of reductive dechlorination (RD) as a possible cleanup strategy. Early outcomes indicate that cleanup targets can only be achieved if source longevity is reduced. Therefore, metabolic RD is expected to produce beneficial effects because it is known to induce bioenhanced degradation and transformation of CAHs.

  1. The Use of a Lidar Forward-Looking Turbulence Sensor for Mixed-Compression Inlet Unstart Avoidance and Gross Weight Reduction on a High Speed Civil Transport

    NASA Technical Reports Server (NTRS)

    Soreide, David; Bogue, Rodney K.; Ehernberger, L. J.; Seidel, Jonathan

    1997-01-01

    Inlet unstart causes a disturbance akin to severe turbulence for a supersonic commercial airplane. Consequently, the current goal for the frequency of unstarts is a few times per fleet lifetime. For a mixed-compression inlet, there is a tradeoff between propulsion system efficiency and unstart margin. As the unstart margin decreases, propulsion system efficiency increases, but so does the unstart rate. This paper intends to first, quantify that tradeoff for the High Speed Civil Transport (HSCT) and second, to examine the benefits of using a sensor to detect turbulence ahead of the airplane. When the presence of turbulence is known with sufficient lead time to allow the propulsion system to adjust the unstart margin, then inlet un,starts can be minimized while overall efficiency is maximized. The NASA Airborne Coherent Lidar for Advanced In-Flight Measurements program is developing a lidar system to serve as a prototype of the forward-looking sensor. This paper reports on the progress of this development program and its application to the prevention of inlet unstart in a mixed-compression supersonic inlet. Quantified benefits include significantly reduced takeoff gross weight (TOGW), which could increase payload, reduce direct operating costs, or increase range for the HSCT.

  2. Reduction of the dark current in a P3HT-based organic photodiode with a ytterbium-fluoride buffer layer for electron transport

    NASA Astrophysics Data System (ADS)

    Lim, Seong Bin; Ji, Chan Hyuk; Kim, Kee Tae; Oh, Se Young

    2016-08-01

    Photodiodes are widely used to convert light into electrical signals. The conventional silicon (Si) based photodiodes boast high photoelectric conversion efficiency and detectivity. However, in general, inorganic-based photodiodes have low sensitivity at visible wavelengths due to their absorption of infrared wavelengths. Recently, electrical conducting polymer-based photodiodes have received significant attention due to their flexibility, low cost of production and high sensitivity at visible wavelength ranges. In the present work, we fabricated an organic photodiode (OPD) with a consisting of ITO/ NiO x / P3HT:PC60BM/ YbF3/Al structure. In the OPD, a yitterbium fluoride (YbF3) buffer layer was used as the electron transport layer. The OPD was analyzed by using optical-electrical measurements to determine its J-V, detectivity, and dynamic characteristics. We investigated the physical effects of the YbF3 buffer layer on the performance of OPD such as its carrier extraction, leakage current and ohmic characteristics.

  3. Development of a SMA-Based Slat-Cove Filler for Reduction of Aeroacoustic Noise Associated With Transport-Class Aircraft Wings

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Kidd, Reggie T.; Hartl, Darren J.; Scholten, William D.

    2013-01-01

    Airframe noise is a significant part of the overall noise produced by typical, transport-class aircraft during the approach and landing phases of flight. Leading-edge slat noise is a prominent source of airframe noise. The concept of a slat-cove filler was proposed in previous work as an effective means of mitigating slat noise. Bench-top models were deployed at 75% scale to study the feasibility of producing a functioning slat-cove filler. Initial results from several concepts led to a more-focused effort investigating a deformable structure based upon pseudoelastic SMA materials. The structure stows in the cavity between the slat and main wing during cruise and deploys simultaneously with the slat to guide the aerodynamic flow suitably for low noise. A qualitative parametric study of SMA-enabled, slat-cove filler designs was performed on the bench-top. Computational models were developed and analyses were performed to assess the displacement response under representative aerodynamic load. The bench-top and computational results provide significant insight into design trades and an optimal design.

  4. Microbial reduction of uranium

    USGS Publications Warehouse

    Lovley, D.R.; Phillips, E.J.P.; Gorby, Y.A.; Landa, E.R.

    1991-01-01

    REDUCTION of the soluble, oxidized form of uranium, U(VI), to insoluble U(IV) is an important mechanism for the immobilization of uranium in aquatic sediments and for the formation of some uranium ores1-10. U(VI) reduction has generally been regarded as an abiological reaction in which sulphide, molecular hydrogen or organic compounds function as the reductant1,2,5,11. Microbial involvement in U(VI) reduction has been considered to be limited to indirect effects, such as microbial metabolism providing the reduced compounds for abiological U(VI) reduction and microbial cell walls providing a surface to stimulate abiological U(VI) reduction1,12,13. We report here, however, that dissimilatory Fe(III)-reducing microorganisms can obtain energy for growth by electron transport to U(VI). This novel form of microbial metabolism can be much faster than commonly cited abiological mechanisms for U(VI) reduction. Not only do these findings expand the known potential terminal electron acceptors for microbial energy transduction, they offer a likely explanation for the deposition of uranium in aquatic sediments and aquifers, and suggest a method for biological remediation of environments contaminated with uranium.

  5. Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology.

    PubMed

    Yohn, Samantha E; Errante, Emily E; Rosenbloom-Snow, Aaron; Somerville, Matthew; Rowland, Margaret; Tokarski, Kristin; Zafar, Nadia; Correa, Merce; Salamone, John D

    2016-10-01

    Deficits in behavioral activation, exertion of effort, and other psychomotor/motivational symptoms are frequently seen in people with depression and other disorders. Depressed people show a decision bias towards selection of low effort activities, and animal tests of effort-related decision making are being used as models of motivational dysfunctions seen in psychopathology. The present studies investigated the ability of drugs that block dopamine transport (DAT), norepinephrine transport (NET), and serotonin transport (SERT) to modulate work output in rats responding on a test of effort-related decision making (i.e., a progressive ratio (PROG)/chow feeding choice task). With this task, rats choose between working for a preferred food (high carbohydrate pellets) by lever pressing on a PROG schedule vs. obtaining a less preferred lab chow that is freely available in the chamber. The present studies focused on the effects of the selective DAT inhibitor GBR12909, the selective SERT inhibitor fluoxetine, and the selective NET inhibitors desipramine and atomoxetine. Acute and repeated administration of GBR12909 shifted choice behavior, increasing measures of PROG lever pressing but decreasing chow intake. In contrast, fluoxetine, desipramine and atomoxetine failed to increase lever pressing output, and actually decreased it at higher doses. In the behaviorally effective dose range, GBR12909 elevated extracellular dopamine levels in accumbens core as measured by microdialysis, but fluoxetine, desipramine and atomoxetine decreased extracellular dopamine. Thus, blockade of DAT increases selection of the high effort instrumental activity, while inhibition of SERT or NET does not. These results have implications for the use of monoamine uptake inhibitors for the treatment of effort-related psychiatric symptoms in humans. PMID:27329556

  6. Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology.

    PubMed

    Yohn, Samantha E; Errante, Emily E; Rosenbloom-Snow, Aaron; Somerville, Matthew; Rowland, Margaret; Tokarski, Kristin; Zafar, Nadia; Correa, Merce; Salamone, John D

    2016-10-01

    Deficits in behavioral activation, exertion of effort, and other psychomotor/motivational symptoms are frequently seen in people with depression and other disorders. Depressed people show a decision bias towards selection of low effort activities, and animal tests of effort-related decision making are being used as models of motivational dysfunctions seen in psychopathology. The present studies investigated the ability of drugs that block dopamine transport (DAT), norepinephrine transport (NET), and serotonin transport (SERT) to modulate work output in rats responding on a test of effort-related decision making (i.e., a progressive ratio (PROG)/chow feeding choice task). With this task, rats choose between working for a preferred food (high carbohydrate pellets) by lever pressing on a PROG schedule vs. obtaining a less preferred lab chow that is freely available in the chamber. The present studies focused on the effects of the selective DAT inhibitor GBR12909, the selective SERT inhibitor fluoxetine, and the selective NET inhibitors desipramine and atomoxetine. Acute and repeated administration of GBR12909 shifted choice behavior, increasing measures of PROG lever pressing but decreasing chow intake. In contrast, fluoxetine, desipramine and atomoxetine failed to increase lever pressing output, and actually decreased it at higher doses. In the behaviorally effective dose range, GBR12909 elevated extracellular dopamine levels in accumbens core as measured by microdialysis, but fluoxetine, desipramine and atomoxetine decreased extracellular dopamine. Thus, blockade of DAT increases selection of the high effort instrumental activity, while inhibition of SERT or NET does not. These results have implications for the use of monoamine uptake inhibitors for the treatment of effort-related psychiatric symptoms in humans.

  7. The co-occurrence of zinc deficiency and social isolation has the opposite effects on mood compared with either condition alone due to changes in the central norepinephrine system.

    PubMed

    Mitsuya, Hironori; Omata, Naoto; Kiyono, Yasushi; Mizuno, Tomoyuki; Murata, Tetsuhito; Mita, Kayo; Okazawa, Hidehiko; Wada, Yuji

    2015-05-01

    Nutritional and social environmental problems during the early stages of life are closely associated with the pathophysiology of mood disorders such as depression. Disruption or dysfunction of the central norepinephrine (NE) system is also considered to play a role in mood disorders. Therefore, we evaluated the effects of zinc deficiency and/or social isolation on mood and changes in the central NE system using rats. Compared with the controls, the rats subjected to zinc deficiency or social isolation alone exhibited increased anxiety-related behavior in the elevated plus maze and greater depression-like behavior in the forced swim test. However, the co-occurrence of zinc deficiency and social isolation resulted in decreased anxiety-related behavior and control levels of depression-like behavior. Social isolation alone decreased the rats' cerebral NE concentrations. The expression of the NE transporter was not affected by social isolation alone, but its expression in the locus coeruleus was markedly decreased by the co-occurrence of social isolation and zinc deficiency, and this change was accompanied by an increase in the blood concentration of 3-methoxy-4-hydroxyphenylglycol, which is a marker of central NE system activity. These findings suggest that zinc deficiency or social isolation alone induce anxious or depressive symptoms, but the presence of both conditions has anxiolytic or antidepressive effects. Furthermore, these opposing effects of mood-related behaviors were found to be associated with changes in the central NE system.

  8. The in vitro maintenance of clock genes expression within the rat pineal gland under standard and norepinephrine-synchronized stimulation.

    PubMed

    Andrade-Silva, Jéssica; Cipolla-Neto, José; Peliciari-Garcia, Rodrigo A

    2014-01-01

    Although the norepinephrine (NE) synchronization protocol was proved to be an important procedure for further modulating in vitro pineal melatonin synthesis, the maintenance of clock genes under the same conditions remained to be investigated. The aim of this study was to investigate the maintenance of the clock genes expression in pineal gland cultures under standard and NE-synchronized stimulation. The glands were separated into three experimental groups: Control, Standard (acute NE-stimulation), and NE-synchronized. The expression of Bmal1, Per2, Cry2, Rev-erbα, the clock controlled gene Dbp and Arylalkylamine-N-acetyltransferase were investigated, as well as melatonin content. No oscillations were observed in the expression of the investigated genes from the control group. Under Standard NE stimulation, the clock genes did not exhibit a rhythmic pattern of expression. However, in the NE-synchronized condition, a rhythmic expression pattern was observed in all cases. An enhancement in pineal gland responsiveness to NE stimulation, reflected in an advanced synthesis of melatonin was also observed. Our results reinforce our previous hypothesis that NE synchronization of pineal gland culture mimics the natural rhythmic release of NE in the gland, increasing melatonin synthesis and keeping the pineal circadian clock synchronized, ensuring the fine adjustments that are relied in the clockwork machinery.

  9. Chemotaxis of Escherichia coli to norepinephrine (NE) requires conversion of NE to 3,4-dihydroxymandelic acid.

    PubMed

    Pasupuleti, Sasikiran; Sule, Nitesh; Cohn, William B; MacKenzie, Duncan S; Jayaraman, Arul; Manson, Michael D

    2014-12-01

    Norepinephrine (NE), the primary neurotransmitter of the sympathetic nervous system, has been reported to be a chemoattractant for enterohemorrhagic Escherichia coli (EHEC). Here we show that nonpathogenic E. coli K-12 grown in the presence of 2 μM NE is also attracted to NE. Growth with NE induces transcription of genes encoding the tyramine oxidase, TynA, and the aromatic aldehyde dehydrogenase, FeaB, whose respective activities can, in principle, convert NE to 3,4-dihydroxymandelic acid (DHMA). Our results indicate that the apparent attractant response to NE is in fact chemotaxis to DHMA, which was found to be a strong attractant for E. coli. Only strains of E. coli K-12 that produce TynA and FeaB exhibited an attractant response to NE. We demonstrate that DHMA is sensed by the serine chemoreceptor Tsr and that the chemotaxis response requires an intact serine-binding site. The threshold concentration for detection is ≤5 nM DHMA, and the response is inhibited at DHMA concentrations above 50 μM. Cells producing a heterodimeric Tsr receptor containing only one functional serine-binding site still respond like the wild type to low concentrations of DHMA, but their response persists at higher concentrations. We propose that chemotaxis to DHMA generated from NE by bacteria that have already colonized the intestinal epithelium may recruit E. coli and other enteric bacteria that possess a Tsr-like receptor to preferred sites of infection.

  10. Sensorimotor recovery from cortical injury is accompanied by changes on norepinephrine and serotonin levels in the dentate gyrus and pons.

    PubMed

    Ramos-Languren, Laura E; González-Piña, Rigoberto; Montes, Sergio; Chávez-García, Norma; Ávila-Luna, Alberto; Barón-Flores, Verónica; Ríos, Camilo

    2016-01-15

    Monoamines such as norepinephrine (NE) and serotonin (5-HT) have shown to play an important role in motor recovery after brain injury. The effects elicited by these neurotransmitters have been reported as distal from the area directly affected. Remote changes may take place over minutes to weeks and play an important role in post-stroke recovery. However, the mechanisms involved in spontaneous recovery have not been thoroughly delineated. Therefore, we determined the NE and 5-HT content, in the pons and hippocampal dentate gyrus (DG) as well as motor deficit and spontaneous activity in rats after 3, 10 and 20 days cortical iron injection. Three days post-lesion the pontine NE content diminished, this effect was accompanied by deficient spontaneous activity and impaired sensorimotor evaluation. Ten and twenty days after lesion the NE levels were similar to those of control group, and animals also showed behavioral recovery. Monoamines content on DG 3 days post-lesion showed no differences as compared to controls. Interestingly, ten and twenty days after cortical injury, animals showed increased NE and 5-HT. These results suggest that behavioral recovery after brain damage involve changes on monoamines levels on DG, an important structure to plastic processes. In addition, the results herein support evidence to propose these neurotransmitters as key molecules to functional recovery in the central nervous system.

  11. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion.

    PubMed

    Bialik, R J; Pappas, B A; Pusztay, W

    1982-02-01

    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females.

  12. Effect of epinephrine, norepinephrine and(or) GnRH on serum LH in prepuberal beef heifers.

    PubMed

    Hardin, D R; Randel, R D

    1983-09-01

    Forty prepuberal Simmental X Brahman-Hereford heifers were utilized to determine the effects of epinephrine (E), norepinephrine (NE), gonadotropin releasing hormone (GnRH) or combinations of GnRH + E and GnRH + NE on serum luteinizing hormone (LH) concentrations. Animals were assigned randomly to one of five treatments with four replicates/treatment. Treatments consisted of I) 100 micrograms GnRH at time 0 (n = 8); II) 50 mg NE at time -15 and 0 (n = 8); III) 50 mg E at time -15 and 0 (n = 8); IV) 100 micrograms GnRH at time 0, plus 50 mg NE at time -15 and 0 (n = 8) and V) 100 micrograms GnRH at time 0, plus 50 mg E at time -15 and 0 (n = 8). All treatment compounds were administered im in 2 ml physiological saline and blood samples were collected via tail vessel puncture at -30, -15, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min from GnRH injection. Treatment with NE or E alone had no effect (P greater than .10) on serum LH during the sampling period. The initial LH release to GnRH was altered (P less than .05) by concomitant treatment with NE (treatment IV) or E (treatment V). Magnitude of the LH release was reduced (P less than .01) by treatment V. Area under the LH surge was reduced (P less than .05) by treatment IV (NE) and V (E). PMID:6355042

  13. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats.

    PubMed

    Xue, Rui; He, Xin-Hua; Yuan, Li; Chen, Hong-Xia; Zhang, Li-Ming; Yong, Zheng; Yu, Gang; Fan, Shi-Yong; Li, Yun-Feng; Zhong, Bo-Hua; Zhang, You-Zhi

    2016-01-01

    Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  14. Excimer emission in norepinephrine and epinephrine drugs with α- and β-cyclodextrins: spectral and molecular modeling studies.

    PubMed

    Rajendiran, N; Mohandoss, T; Thulasidasan, J

    2014-07-01

    The inclusion complexation behavior of norepinephrine (NORE) and epinephrine (EPIN) with native cyclodextrins (α-CD and β-CD) were investigated by UV-visible, fluorimetry, time-resolved fluorescence, SEM, TEM, FT-IR, (1)H NMR, DSC, powder XRD and PM3 methods. Single emission was observed in aqueous solution where as dual emission (excimer) noticed in the CD solutions. Both drugs form 1:1 drug-CD complexes in lower CD concentrations and 1:2 CD-drug2 complexes in the higher CD concentrations. Time-resolved fluorescence studies indicated that both drugs showed single exponential decay in water and biexponential decay in CD. Nano-sized self-aggregated particles of drug-CD were found by TEM studies. Molecular modeling studies indicated that aliphatic chain part of the drug was entrapped in the CD cavity. Thermodynamic parameters and binding affinity of complex formation of the CD were determined according to PM3 method. The PM3 results were in good agreement with the experimental results.

  15. The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn.

    PubMed

    Lee, Hyung Gon; Choi, Jeong Il; Yoon, Myung Ha; Obata, Hideaki; Saito, Shigeru; Kim, Woong Mo

    2014-11-01

    The purpose of this study was to validate the effects of tianeptine on serotonergic and noradrenergic neurotransmission in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of intrathecally administered tianeptine on mechanical allodynia were assessed. Dihydroergocristine or yohimbine, a serotonergic or α-2 adrenergic receptor antagonists, respectively, were intrathecally administered 10min before tianeptine to investigate its mechanism of action. Additionally microdialysis studies were performed to measure the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the spinal dorsal horn following tianeptine administration. Intrathecal tianeptine significantly increased the paw withdrawal thresholds in a dose-dependent manner and the antiallodynic effect was antagonized by dihydroergocristine and yohimbine. Microdialysis studies revealed that tianeptine increased the levels of 5-HT and NE in the spinal dorsal horn. These findings suggest that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level.

  16. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion.

    PubMed

    Bialik, R J; Pappas, B A; Pusztay, W

    1982-02-01

    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females. PMID:7071081

  17. Reversal of aging-related emotional memory deficits by norepinephrine via regulating the stability of surface AMPA receptors.

    PubMed

    Luo, Yi; Zhou, Jun; Li, Ming-Xing; Wu, Peng-Fei; Hu, Zhuang-Li; Ni, Lan; Jin, You; Chen, Jian-Guo; Wang, Fang

    2015-04-01

    Aging-related emotional memory deficit is a well-known complication in Alzheimer's disease and normal aging. However, little is known about its molecular mechanism. To address this issue, we examined the role of norepinephrine (NE) and its relevant drug desipramine in the regulation of hippocampal long-term potentiation (LTP), surface expression of AMPA receptor, and associative fear memory in rats. We found that there was a defective regulation of NE content and AMPA receptor trafficking during fear conditioning, which were accompanied by impaired emotional memory and LTP in aged rats. Furthermore, we also found that the exogenous upregulation of NE ameliorated the impairment of LTP and emotional memory via enhancing AMPA receptor trafficking in aged rats, and the downregulation of NE impaired LTP in adult rats. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory in aged rats. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in aging rats and suggest that desipramine is a potential candidate for treating aging-related emotional memory deficit.

  18. Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats.

    PubMed

    Liu, Liangming; Tian, Kunlun; Xue, Mingying; Zhu, Yu; Lan, Dan; Peng, Xiaoyong; Wu, Yue; Li, Tao

    2013-11-01

    Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.

  19. Comparison of the effects of spaceflight and hindlimb-suspension on rat pituitary vasopressin and brainstem norepinephrine content

    NASA Astrophysics Data System (ADS)

    Fareh, J.; Fagette, S.; Cottet-Emard, J. M.; Allevard, A. M.; Viso, M.; Gauquelin, G.; Gharib, C.

    1994-08-01

    To compare actual spaceflight to ground-based simulation (hindlimb-suspension), we measured the norepinephrine (NE) content in A1, A2, A5 and A6 (locus coeruleus) and the vasopressin content in the neurohypophysial system. The experimental period was of 9 days' duration. The NE content in the locus coeruleus decreased significantly in rats flown for 9 days (67 %,p<0.001), but showed no significant changes after hindlimb-suspension. These results demonstrated that suspended rats adapted better to weightlessness-simulation than flown rats to actual microgravity. In rats flown aboard SLS-1, the vasopressin content was significantly increased in the posterior pituitary (71 %,p<0.01), and was decreased in the hypothalamus (49 %, p<0.05). In 9-day suspended rats pituitary vasopressin levels were unchanged, while in the hypothalamus a significant decrease was noted (21 %, p<0.05). It was concluded that spaceflight changes in pituitary vasopressin levels and in the locus coeruleus NE content were consistent with a stress reaction, occurring during and/or after landing. These results confirmed that hindlimb-suspension model constitutes a valid and lesstressful ground-based simulation of microgravity in rats.

  20. The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn.

    PubMed

    Lee, Hyung Gon; Choi, Jeong Il; Yoon, Myung Ha; Obata, Hideaki; Saito, Shigeru; Kim, Woong Mo

    2014-11-01

    The purpose of this study was to validate the effects of tianeptine on serotonergic and noradrenergic neurotransmission in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of intrathecally administered tianeptine on mechanical allodynia were assessed. Dihydroergocristine or yohimbine, a serotonergic or α-2 adrenergic receptor antagonists, respectively, were intrathecally administered 10min before tianeptine to investigate its mechanism of action. Additionally microdialysis studies were performed to measure the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the spinal dorsal horn following tianeptine administration. Intrathecal tianeptine significantly increased the paw withdrawal thresholds in a dose-dependent manner and the antiallodynic effect was antagonized by dihydroergocristine and yohimbine. Microdialysis studies revealed that tianeptine increased the levels of 5-HT and NE in the spinal dorsal horn. These findings suggest that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level. PMID:25233863

  1. Effect of epinephrine, norepinephrine and(or) GnRH on serum LH in prepuberal beef heifers.

    PubMed

    Hardin, D R; Randel, R D

    1983-09-01

    Forty prepuberal Simmental X Brahman-Hereford heifers were utilized to determine the effects of epinephrine (E), norepinephrine (NE), gonadotropin releasing hormone (GnRH) or combinations of GnRH + E and GnRH + NE on serum luteinizing hormone (LH) concentrations. Animals were assigned randomly to one of five treatments with four replicates/treatment. Treatments consisted of I) 100 micrograms GnRH at time 0 (n = 8); II) 50 mg NE at time -15 and 0 (n = 8); III) 50 mg E at time -15 and 0 (n = 8); IV) 100 micrograms GnRH at time 0, plus 50 mg NE at time -15 and 0 (n = 8) and V) 100 micrograms GnRH at time 0, plus 50 mg E at time -15 and 0 (n = 8). All treatment compounds were administered im in 2 ml physiological saline and blood samples were collected via tail vessel puncture at -30, -15, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min from GnRH injection. Treatment with NE or E alone had no effect (P greater than .10) on serum LH during the sampling period. The initial LH release to GnRH was altered (P less than .05) by concomitant treatment with NE (treatment IV) or E (treatment V). Magnitude of the LH release was reduced (P less than .01) by treatment V. Area under the LH surge was reduced (P less than .05) by treatment IV (NE) and V (E).

  2. Chemotaxis of Escherichia coli to norepinephrine (NE) requires conversion of NE to 3,4-dihydroxymandelic acid.

    PubMed

    Pasupuleti, Sasikiran; Sule, Nitesh; Cohn, William B; MacKenzie, Duncan S; Jayaraman, Arul; Manson, Michael D

    2014-12-01

    Norepinephrine (NE), the primary neurotransmitter of the sympathetic nervous system, has been reported to be a chemoattractant for enterohemorrhagic Escherichia coli (EHEC). Here we show that nonpathogenic E. coli K-12 grown in the presence of 2 μM NE is also attracted to NE. Growth with NE induces transcription of genes encoding the tyramine oxidase, TynA, and the aromatic aldehyde dehydrogenase, FeaB, whose respective activities can, in principle, convert NE to 3,4-dihydroxymandelic acid (DHMA). Our results indicate that the apparent attractant response to NE is in fact chemotaxis to DHMA, which was found to be a strong attractant for E. coli. Only strains of E. coli K-12 that produce TynA and FeaB exhibited an attractant response to NE. We demonstrate that DHMA is sensed by the serine chemoreceptor Tsr and that the chemotaxis response requires an intact serine-binding site. The threshold concentration for detection is ≤5 nM DHMA, and the response is inhibited at DHMA concentrations above 50 μM. Cells producing a heterodimeric Tsr receptor containing only one functional serine-binding site still respond like the wild type to low concentrations of DHMA, but their response persists at higher concentrations. We propose that chemotaxis to DHMA generated from NE by bacteria that have already colonized the intestinal epithelium may recruit E. coli and other enteric bacteria that possess a Tsr-like receptor to preferred sites of infection. PMID:25182492

  3. Comparative effects of epinephrine, norepinephrine, and a gentle handling stress on plasma lactate, glucose, and hematocrit levels in the American bullfrog (Rana catesbeiana).

    PubMed

    MbangKollo, D; deRoos, R

    1983-02-01

    The effects of a single infusion of epinephrine or norepinephrine and of a 2-min handling stress on plasma lactate, glucose, and hematocrit levels were compared in the American bullfrog (Rana catesbeiana). The catecholamines were administered, and serial blood samples were collected, via a cannula placed in the truncus arteriosus. Plasma lactate was estimated by the lactate dehydrogenase method and glucose by the glucose oxidase method. Dose-dependent increases occurred in plasma lactate, glucose, and hematocrit levels after the infusion of 50 and 500 micrograms/kg body weight of epinephrine. Norepinephrine infusion resulted in dose-dependent increases in hematocrit levels, but plasma lactate and glucose levels were not increased significantly by 50 micrograms/kg body weight of norepinephrine. The infusion of 500 micrograms/kg body weight of norepinephrine caused a lactacidemia that was similar to that which occurred with the same dose of epinephrine, but the hyperglycemia was less. The plasma lactate increases after handling were similar to those that occurred after treatment with 500 micrograms/kg body weight of the catecholamines; however, the hematocrit elevations were less and the glucose levels were not increased significantly. In addition, the plasma lactate and hematocrit responses to handling were more rapid than those that occurred after the catecholamines. The results suggest that immediate physiological adjustments to a sudden threat are mediated in the bullfrog by direct nervous stimulation of the relevant organs. Catecholamines and corticoids secreted by the adrenal glands probably function synergistically and sequentially when a stress is more severe and/or more prolonged than the brief, gentle handling employed in this study.

  4. Prepuberal subchronic methylphenidate and atomoxetine induce different long-term effects on adult behaviour and forebrain dopamine, norepinephrine and serotonin in Naples high-excitability rats.

    PubMed

    Ruocco, L A; Carnevale, U A Gironi; Treno, C; Sadile, A G; Melisi, D; Arra, C; Ibba, M; Schirru, C; Carboni, E

    2010-06-26

    The psychostimulant methylphenidate and the non-stimulant atomoxetine are two approved drugs for attention-deficit hyperactivity disorder (ADHD) therapy. The aim of this study was to investigate the long-term effects of prepuberal subchronic methylphenidate and atomoxetine on adult behaviour and the forebrain neurotransmitter and metabolite content of Naples High-Excitability (NHE) rats, a genetic model for the mesocortical variant of ADHD. Male NHE rats were given a daily intraperitoneal injection (1.0mg/kg) of methylphenidate, atomoxetine or vehicle from postnatal day 29 to 42. At postnatal day 70-75, rats were exposed to spatial novelty in the Làt and radial (Olton) mazes. Behavioural analysis for indices of horizontal, vertical, non-selective (NSA) and selective spatial attention (SSA) indicated that only methylphenidate significantly reduced horizontal activity to a different extent, i.e., 39 and 16% respectively. Moreover methylphenidate increased NSA as assessed by higher leaning duration. The high-performance liquid chromatography (HPLC) tissue content assessment of dopamine, norepinephrine, serotonin and relative metabolites in the prefrontal cortex (PFC), cortical motor area (MC), dorsal striatum (DS), ventral striatum (VS), hippocampus and mesencephalon indicated that methylphenidate decreased (i) dopamine, DOPAC, norepinephrine, MHPG, 5-HT and 5-HIAA in the PFC, (ii) dopamine, DOPAC, HVA, serotonin, 5-HIAA in the DS, (iii) dopamine, DOPAC, HVA and MHPG (but increased norepinephrine) in the VS and (iv) norepinephrine, MHPG, serotonin and 5-HIAA in the hippocampus. Atomoxetine increased dopamine and decreased MHPG in the PFC. Like methylphenidate, atomoxetine decreased dopamine, DOPAC, HVA, serotonin and 5-HIAA in the DS, but decreased MHPG in the VS. These results suggest that methylphenidate determined long-term effects on behavioural and neurochemical parameters, whereas atomoxetine affected only the latter.

  5. Bioartificial Therapy of Sepsis: Changes of Norepinephrine-Dosage in Patients and Influence on Dynamic and Cell Based Liver Tests during Extracorporeal Treatments

    PubMed Central

    Altrichter, Jens; Haubner, Cristof; Pertschy, Annette; Wild, Thomas; Doß, Fanny; Thomsen, Maren; Ehler, Johannes; Henschel, Jörg; Doß, Sandra; Koch, Stephanie; Richter, Georg; Mitzner, Steffen R.

    2016-01-01

    Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A granulocyte bioreactor for the extracorporeal treatment of sepsis was tested in a prospective clinical study focusing on the dosage of norepinephrine in patients and influence on dynamic and cell based liver tests during extracorporeal therapies. Methods and Patients. Ten patients with severe sepsis were treated twice within 72 h with the system containing granulocytes from healthy donors. Survival, physiologic parameters, extended hemodynamic measurement, and the indocyanine green plasma disappearance rate (PDR) were monitored. Plasma of patients before and after extracorporeal treatments were tested with a cell based biosensor for analysis of hepatotoxicity. Results. The observed mortality rate was 50% during stay in hospital. During the treatments, the norepinephrine-dosage could be significantly reduced while mean arterial pressure was stable. In the cell based analysis of hepatotoxicity, the viability and function of sensor-cells increased significantly during extracorporeal treatment in all patients and the PDR-values increased significantly between day 1 and day 7 only in survivors. Conclusion. The extracorporeal treatment with donor granulocytes showed promising effects on dosage of norepinephrine in patients, liver cell function, and viability in a cell based biosensor. Further studies with this approach are encouraged. PMID:27433475

  6. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.

    PubMed

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2011-12-01

    Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration. PMID:22015808

  7. Issues in Pupil Transportation.

    ERIC Educational Resources Information Center

    Association of School Business Officials International, Reston, VA.

    The primary purpose of this book is to present the critical issues in pupil transportation that will confront pupil transportation supervisors in local school districts. The following issues are discussed: (1) demands for extended service from community pressure groups; (2) reductions in budget requests by governing bodies; (3) unrest among driver…

  8. Physical And Technical Energy Problems. Factors of Greenhouse Gas Emissions Reduction in the Road Transport of Latvia / Siltumnīcefekta Gāzu Emisiju Samazināšanas Faktori Autotransportā Latvijā

    NASA Astrophysics Data System (ADS)

    Grackova, L.; Klavs, G.

    2013-02-01

    The admissible scenarios are considered as related to reduction in the greenhouse gas emissions from the road transport in Latvia by 2020. All of the scenarios are analysed, and the proofs are presented for the possibility to reduce such emissions as well as the energy consumption through a more extensive use of efficient cars and biofuel. Izmantojot scenāriju modelēšanas pieeju un COPERT IV modeli, novērtēts siltumnīcefekta gāzu emisiju samazināšanas potenciāls autotransportā Latvijā līdz 2020. gadam. Modelēšanas rezultāti un analīze ļauj secināt, ka neskatoties uz sagaidāmo automašīnu skaita palielināšanos, jaunu energoefektīvu automašīnu ar augstākiem izmešu standartiem izmantošana un biodegvielas piemaisījuma palielināšana autotransportā izmantojamā degvielā ļauj ierobežot siltumnīcefekta gāzu emisiju pieaugumu.

  9. Neuropeptide Y as a presynaptic modulator of norepinephrine release from the sympathetic nerve fibers in the pig pineal gland.

    PubMed

    Ziółkowska, N; Lewczuk, B; Przybylska-Gornowicz, B

    2015-01-01

    Norepinephrine (NE) released from the sympathetic nerve endings is the main neurotransmitter controlling melatonin synthesis in the mammalian pineal gland. Although neuropeptide Y (NPY) co-exists with NE in the pineal sympathetic nerve fibers it also occurs in a population of non-adrenergic nerve fibers located in this gland. The role of NPY in pineal physiology is still enigmatic. The present study characterizes the effect of NPY on the depolarization-evoked 3H-NE release from the pig pineal explants. The explants of the pig pineal gland were loaded with 3H-NE in the presence of pargyline and superfused with Tyrode medium. They were exposed twice to the modified Tyrode medium containing 60 mM of K+ to evoke the 3H-NE release via depolarization. NPY, specific agonists of Y1- and Y2- receptors and pharmacologically active ligands of α2-adrenoceptors were added to the medium before and during the second depolarization. The radioactivity was measured in medium fractions collected every 2 minutes during the superfusion. NPY (0.1-10 μM) significantly decreased the depolarization-induced 3H-NE release. Similar effect was observed after the treatment with Y2-agonist: NPY13-36, but not with Y1-agonist: [Leu31,Pro34]-NPY. The tritium overflow was lower in the explants exposed to the 5 μM NPY and 1 μM rauwolscine than to rauwolscine only. The effects of 5 μM NPY and 0.05 μM UK 14,304 on the depolarization-evoked 3H-NE release were additive. The results show that NPY is involved in the regulation of NE release from the sympathetic terminals in the pig pineal gland, inhibiting this process via Y2-receptors.

  10. Elevated corticosterone in the dorsal hindbrain increases plasma norepinephrine and neuropeptide Y, and recruits a vasopressin response to stress

    PubMed Central

    Daubert, Daisy L.; Looney, Benjamin M.; Clifton, Rebekah R.; Cho, Jake N.

    2014-01-01

    Repeated stress and chronically elevated glucocorticoids cause exaggerated cardiovascular responses to novel stress, elevations in baseline blood pressure, and increased risk for cardiovascular disease. We hypothesized that elevated corticosterone (Cort) within the dorsal hindbrain (DHB) would: 1) enhance arterial pressure and neuroendocrine responses to novel and repeated restraint stress, 2) increase c-Fos expression in regions of the brain involved in sympathetic stimulation during stress, and 3) recruit a vasopressin-mediated blood pressure response to acute stress. Small pellets made of 10% Cort were implanted on the surface of the DHB in male Sprague-Dawley rats. Blood pressure was measured by radiotelemetry. Cort concentration was increased in the DHB in Cort-treated compared with Sham-treated rats (60 ± 15 vs. 14 ± 2 ng Cort/g of tissue, P < 0.05). DHB Cort significantly increased the integrated arterial pressure response to 60 min of restraint stress on days 6, 13, and 14 following pellet implantation (e.g., 731 ± 170 vs. 1,204 ± 68 mmHg/60 min in Sham- vs. Cort-treated rats, day 6, P < 0.05). Cort also increased baseline blood pressure by day 15 (99 ± 2 vs. 108 ± 3 mmHg for Sham- vs. Cort-treated rats, P < 0.05) and elevated baseline plasma norepinephrine and neuropeptide Y concentrations. Cort significantly enhanced stress-induced c-Fos expression in vasopressin-expressing neurons in the paraventricular nucleus of the hypothalamus, and blockade of peripheral vasopressin V1 receptors attenuated the effect of DHB Cort to enhance the blood pressure response to restraint. These data indicate that glucocorticoids act within the DHB to produce some of the adverse cardiovascular consequences of chronic stress, in part, by a peripheral vasopressin-dependent mechanism. PMID:24829502

  11. The effect of endomorphins on the release of 3H-norepinephrine from rat nucleus tractus solitarii slices.

    PubMed

    Al-Khrasani, Mahmoud; Elor, Guy; Yusuf Abbas, Mamode; Rónai, András Z

    2003-03-28

    We used two, 3-min field stimulation cycles 30 min apart (S1, S2) in 3H-norepinephrine-loaded, superfused rat nucleus tractus solitarii-dorsal motor vagal nucleus (NTS-DVN) slices. The stimulation-induced release was expressed as the area above the baseline. Drugs were introduced 12 min before S2 and drug actions were characterized in terms of alterations of S2/S1 ratios. The S2/S1 ratio was 1.047 (0.946-1.159, n = 4, geometric mean and 95% confidence interval) in controls and 0.336 (0.230-0.490, n = 3), 0.726 (0.590-0.892, n = 4), 0.613 (0.594-0.683, n = 4) and 0.665 (0.500-0.886, n = 4) in the presence of 10(-6) M clonidine, D-Ala(2),MePhe(4),Gly(5)-ol-enkephalin (DAMGO), endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) [the latter two in the presence of 10(-4) M diprotin A, an inhibitor of dipeptidyl-aminopeptidase IV (DAP-IV) enzyme]. The effect of DAMGO at 10(-5) M was significantly higher than at 10(-6) M, whereas the effect of endomorphins did not differ at the two concentration levels. Diprotin A potentiated only very modestly the action of endomorphins. These data (a) confirm the presence of functional mu-opioid receptors in the vagal complex, (b) render it likely that the enzymic degradation of endomorphins is not a highly effective process in brain slices and (c) may suggest that the apparent ceiling in the effect of endomorphins might be related to their partial agonist property. PMID:12609755

  12. Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models.

    PubMed

    Deecher, Darlene C; Alfinito, Peter D; Leventhal, Liza; Cosmi, Scott; Johnston, Grace H; Merchenthaler, Istvan; Winneker, Richard

    2007-03-01

    Hot flushes and night sweats, referred to as vasomotor symptoms (VMS), are presumed to be a result of declining hormone levels and are the principal menopausal symptoms for which women seek medical treatment. To date, estrogens and/or some progestins are the most effective therapeutics for alleviating VMS; however, these therapies may not be appropriate for all women. Therefore, nonhormonal therapies are being evaluated. The present study investigated a new reuptake inhibitor, desvenlafaxine succinate (DVS), in animal models of temperature dysfunction. Both models used are based on measuring changes in tail-skin temperature (TST) in ovariectomized (OVX) rats. The first relies on naloxone-induced withdrawal in morphine-dependent (MD) OVX rats, resulting in an acute rise in TST. The second depends on an OVX-induced loss of TST decreases during the dark phase as measured by telemetry. An initial evaluation demonstrated abatement of the rise in TST with long-term administration of ethinyl estradiol or with a single oral dose of DVS (130 mg/kg) in the MD model. Further evaluation showed that orally administered DVS acutely and dose dependently (10-100 mg/kg) abated a naloxone-induced rise in TST of MD rats and alleviated OVX-induced temperature dysfunction in the telemetry model. Oral administration of DVS to OVX rats caused significant increases in serotonin and norepinephrine levels in the preoptic area of the hypothalamus, a key region of the brain involved in temperature regulation. These preclinical studies provide evidence that DVS directly impacts thermoregulatory dysfunction in OVX rats and may have utility in alleviating VMS associated with menopause.

  13. Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone

    PubMed Central

    Poletini, Maristela O.; Leite, Cristiane M.; Bernuci, Marcelo P.; Kalil, Bruna; Mendonça, Leonardo B.D.; Carolino, Ruither O. G.; Helena, Cleyde V. V.; Bertram, Richard; Franci, Celso R.; Anselmo-Franci, Janete A.

    2013-01-01

    The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids. PMID:23150494

  14. Norepinephrine stimulates progesterone production in highly estrogenic bovine granulosa cells cultured under serum-free, chemically defined conditions

    PubMed Central

    2012-01-01

    Background Since noradrenergic innervation was described in the ovarian follicle, the actions of the intraovarian catecholaminergic system have been the focus of a variety of studies. We aimed to determine the gonadotropin-independent effects of the catecholamine norepinephrine (NE) in the steroid hormone profile of a serum-free granulosa cell (GC) culture system in the context of follicular development and dominance. Methods Primary bovine GCs were cultivated in a serum-free, chemically defined culture system supplemented with 0.1% polyvinyl alcohol. The culture features were assessed by hormone measurements and ultrastructural characteristics of GCs. Results GCs produced increasing amounts of estradiol and pregnenolone for 144h and maintained ultrastructural features of healthy steroidogenic cells. Progesterone production was also detected, although it significantly increased only after 96h of culture. There was a highly significant positive correlation between estradiol and pregnenolone production in high E2-producing cultures. The effects of NE were further evaluated in a dose–response study. The highest tested concentration of NE (10 (−7) M) resulted in a significant increase in progesterone production, but not in estradiol or pregnenolone production. The specificity of NE effects on progesterone productio n was further investigated by incubating GCs with propranolol (10 (−8) M), a non-selective beta-adrenergic antagonist. Conclusions The present culture system represents a robust model to study the impact of intrafollicular factors, such as catecholamines, in ovarian steroidogenesis and follicular development. The results of noradrenergic effects in the steroidogenesis of GC have implications on physiological follicular fate and on certain pathological ovarian conditions such as cyst formation and anovulation. PMID:23171052

  15. Hindbrain medulla catecholamine cell group involvement in lactate-sensitive hypoglycemia-associated patterns of hypothalamic norepinephrine and epinephrine activity.

    PubMed

    Shrestha, P K; Tamrakar, P; Ibrahim, B A; Briski, K P

    2014-10-10

    Cell-type compartmentation of glucose metabolism in the brain involves trafficking of the oxidizable glycolytic end product, l-lactate, by astrocytes to fuel neuronal mitochondrial aerobic respiration. Lactate availability within the hindbrain medulla is a monitored function that regulates systemic glucostasis as insulin-induced hypoglycemia (IIH) is exacerbated by lactate repletion of that brain region. A2 noradrenergic neurons are a plausible source of lactoprivic input to the neural gluco-regulatory circuit as caudal fourth ventricular (CV4) lactate infusion normalizes IIH-associated activation, e.g. phosphorylation of the high-sensitivity energy sensor, adenosine 5'-monophosphate-activated protein kinase (AMPK), in these cells. Here, we investigated the hypothesis that A2 neurons are unique among medullary catecholamine cells in directly screening lactate-derived energy. Adult male rats were injected with insulin or vehicle following initiation of continuous l-lactate infusion into the CV4. Two hours after injections, A1, C1, A2, and C2 neurons were collected by laser-microdissection for Western blot analysis of AMPKα1/2 and phosphoAMPKα1/2 proteins. Results show that AMPK is expressed in each cell group, but only a subset, e.g. A1, C1, and A2 neurons, exhibit increased sensor activity in response to IIH. Moreover, hindbrain lactate repletion reversed hypoglycemic augmentation of pAMPKα1/2 content in A2 and C1 but not A1 cells, and normalized hypothalamic norepinephrine and epinephrine content in a site-specific manner. The present evidence for discriminative reactivity of AMPK-expressing medullary catecholamine neurons to the screened energy substrate lactate implies that that lactoprivation is selectively signaled to the hypothalamus by A2 noradrenergic and C1 adrenergic cells.

  16. A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis.

    PubMed

    Jiang, Lulu; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Shi-Jun; Oyarzabal, Esteban; Wilson, Belinda; Sanders, Virginia; Xie, Keqin; Wang, Qingshan; Hong, Jau-Shyong

    2015-06-01

    Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti-inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS)-induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose-dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from β2-adrenergic receptor (β2-AR)-deficient mice, suggesting that novel pathways other than β2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism. PMID:25740080

  17. Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model

    PubMed Central

    2009-01-01

    Introduction The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain. Methods Seventy SD-rats (280-310 g) were divided into 1 control and 6 sepsis groups. Sepsis groups received 1 or 5 mg/kg lipopolysaccharide (LPS) intravenously to induce a moderate or severe sepsis syndrome. Thirty minutes later rats were further randomized into subgroups receiving moderate volume therapy alone or additionally continuous norepinephrine (NE) or 1400W infusion. Separately, effects of 1400W on neurofunctional parameters were investigated in 3 rats without sepsis induction. Performing electric forepaw-stimulation evoked potentials (N2-P1 amplitude, P1-latency) and local hemodynamic responses were recorded with surface electrodes and laser Doppler over the somatosensory cortex at baseline and repeatedly after LPS administration. Cytokine levels (tumor necrosis factor-alpha (TNFα), interleukin-6 (IL6), interferon-gamma (IFNγ)) and cell destruction markers (neuron-specific enolase (NSE), S-100 calcium binding protein B (S100B)) were obtained at the end of experiments. Results During sepsis progression resting cerebral blood flow increased and functionally activated hemodynamic responses decreased in a dose-dependent manner. Whereas 1400W and NE improved blood pressure, only 1400W stabilized resting flow levels. However, both regimens were ineffective on the functionally coupled flow responses and destruction markers were similar between groups. Conclusions NE and 1400W appeared to be ineffective in mitigating the effects of sepsis on the neurovascular coupling. Other regimens are needed to protect the cerebral microcirculation under septic conditions. PMID:19709421

  18. Differential visualization of dopamine and norepinephrine uptake sites in rat brain using (/sup 3/H)mazindol autoradiography

    SciTech Connect

    Javitch, J.A.; Strittmatter, S.M.; Snyder, S.H.

    1985-06-01

    Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using (/sup 3/H)mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits (/sup 3/H)mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific (/sup 3/H) mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific (/sup 3/H)mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific (/sup 3/H)mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific (/sup 3/H)mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases (/sup 3/H)mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce (/sup 3/H)mazindol binding to either the ipsilateral or contralateral caudate-putamen.

  19. Waste Reduction.

    ERIC Educational Resources Information Center

    Bray, Marilyn; And Others

    1996-01-01

    Presents activities that focus on waste reduction in the school and community. The ideas are divided into grade level categories. Sample activities include Techno-Trash, where children use tools to take apart broken appliances or car parts, then reassemble them or build new creations. Activities are suggested for areas including language arts and…

  20. The vesicular monoamine transporter 2: an underexplored pharmacological target

    PubMed Central

    Bernstein, Alison I.; Stout, Kristen A.; Miller, Gary W.

    2016-01-01

    Active transport of neurotransmitters into synaptic vesicles is required for their subsequent exocytotic release. In the monoamine system, this process is carried out by the vesicular monoamine transporters (VMAT1 and VMAT2). These proteins are responsible for vesicular packaging of dopamine, norepinephrine, serotonin, and histamine. These proteins are essential for proper neuronal function; however, compared to their plasma membrane counterparts, there are few drugs available that target these vesicular proteins. This is partly due to the added complexity of crossing the plasma membrane, but also to the technical difficulty of assaying for vesicular uptake in high throughput. Until recently, reagents to enable high throughput screening for function of these vesicular neurotransmitter transporters have not been available. Fortunately, novel compounds and methods are now making such screening possible; thus, a renewed focus on these transporters as potential targets is timely and necessary. PMID:24398404

  1. Nitrate reduction

    DOEpatents

    Dziewinski, Jacek J.; Marczak, Stanislaw

    2000-01-01

    Nitrates are reduced to nitrogen gas by contacting the nitrates with a metal to reduce the nitrates to nitrites which are then contacted with an amide to produce nitrogen and carbon dioxide or acid anions which can be released to the atmosphere. Minor amounts of metal catalysts can be useful in the reduction of the nitrates to nitrites. Metal salts which are formed can be treated electrochemically to recover the metals.

  2. Single-file diffusion and neurotransmitter transporters: Hodgkin and Keynes model revisited.

    PubMed

    DeFelice, L J; Adams, S V; Ypey, D L

    2001-01-01

    Norepinephrine transporters (NETs) use the Na gradient to remove norepinephrine (NE) from the synaptic cleft of adrenergic neurons following NE release from the presynaptic terminal. By coupling NE to the inwardly directed Na gradient, it is possible to concentrate NE inside cells. This mechanism, which is referred to as co-transport or secondary transport (Läuger, 1991, Electrogenic Ion Pumps, Sinauer Associates) is apparently universal: Na coupled transport applies to serotonin transporters (SERTs), dopamine transporters (DATs), glutamate transporters, and many others, including transporters for osmolites, metabolites and substrates such as sugar. Recently we have shown that NETs and SERTs transport norepinephrine or serotonin as if Na and the transmitter permeated through an ion channel together 'Galli et al., 1998, PNAS 95, 13260-13265; Petersen and DeFelice, 1999, Nature Neurosci. 2, 605-610'. These data are paradoxical because it has been difficult to envisage how NE, for example, would couple to Na if these ions move passively through an open pore. An 'alternating access' model is usually evoked to explain coupling: in such models NE and Na bind to NET, which then undergoes a conformational change to release NE and Na on the inside. The empty transporter then turns outward to complete the cycle. Alternating-access models never afford access to an open channel. Rather, substrates and co-transported ions are occluded in the transporter and carried across the membrane. The coupling mechanism we propose is fundamentally different than the coupling mechanism evoked in the alternating access model. To explain coupling in co-transporters, we use a mechanism first evoked by 'Hodgkin and Keynes (1955) J. Physiol. 128, 61-88' to explain ion interactions in K-selective channels. In the Hodgkin and Keynes model, K ions move single-file through a long narrow pore. Their model accounted for the inward/outward flux ratio if they assumed that two K ions queue within the

  3. Industrial Waste Reduction Program

    SciTech Connect

    Not Available

    1991-10-24

    US industry generates over 12 billion tons of wastes each year. These wastes consist of undesirable by-products of industrial production that are discarded into our environment. Energy is an integral part of these wastes; it is found in the embodied energy of industrial feedstocks not optimally used, in the energy content of the wastes themselves, and in the energy needed to transport, treat, and dispose of wastes. Estimates of the potential energy savings from reducing industrial wastes range from three to four quadrillion Btu per year -- enough to meet the annual energy needs of 30 million American homes. This document presents a plan for the Industrial Waste Reduction Program, which has been designed to help achieve national goals for energy efficiency and waste minimization. The objective of the program is to improve the energy efficiency of industrial processes through cost-effective waste reduction. The initial program focus is on waste reduction opportunities in the production and use of chemicals, due to the significant amount of energy used in these activities and the large amounts of hazardous and toxic wastes they generate. The chemical industry will be the initial subject of a series of waste reduction opportunity assessments conducted as part of the program. Assessments of other industries and waste problems will follow.

  4. Intracellular chromium reduction.

    PubMed

    Arslan, P; Beltrame, M; Tomasi, A

    1987-10-22

    Two steps are involved in the uptake of Cr(VI): (1) the diffusion of the anion CrO4(2-) through a facilitated transport system, presumably the non-specific anion carrier and (2) the intracellular reduction of Cr(VI) to Cr(III). The intracellular reduction of Cr(VI), keeping the cytoplasmic concentration of Cr(VI) low, facilitates accumulation of chromate from extracellular medium into the cell. In the present paper, a direct demonstration of intracellular chromium reduction is provided by means of electron paramagnetic (spin) resonance (EPR) spectroscopy. Incubation of metabolically active rat thymocytes with chromate originates a signal which can be attributed to a paramagnetic species of chromium, Cr(V) or Cr(III). The EPR signal is originated by intracellular reduction of chromium since: (1) it is observed only when cells are incubated with chromate, (2) it is present even after extensive washings of the cells in a chromium-free medium; (3) it is abolished when cells are incubated with drugs able to reduce the glutathione pool, i.e., diethylmaleate or phorone; and (4) it is abolished when cells are incubated in the presence of a specific inhibitor of the anion carrier, 4-acetamido-4'-isothiocyanatostilbene-2-2'-disulfonic acid. PMID:2820507

  5. The effect of altered sodium balance upon renal vascular reactivity to angiotensin II and norepinephrine in the dog. Mechanism of variation in angiotensin responses.

    PubMed Central

    Oliver, J A; Cannon, P J

    1978-01-01

    The mechanism whereby the vasoconstrictor response to angiotensin II (AII) is influenced by sodium balance or disease is unclear. To explore this question, the renal vascular responses (RVR) to intrarenal injections of subpressor doses of AII and norepinephrine were studied in dogs with an electromagnetic flowmeter. Acute and chronic sodium depletion increased plasma renin activity (PRA) and blunted the RVR to AII, while acute sodium repletion and chronic sodium excess plus desoxycorticosterone acetate decreased PRA and enhanced the RVR to AII. The magnitude of the RVR to AII was inversely related to PRA. The RVR to norepinephrine was unaffected by sodium balance and was not related to PRA. Inhibition of the conversion of angiotensin I to AII by SQ 20,881 during sodium depletion lowered mean arterial blood pressure (MABP), increased renal blood flow (RBF), and enhanced the RVR to AII but not to norepinephrine. Administration of bradykinin to chronically sodium-depleted dogs also lowered the MABP and increased RBF but had no effect on the RVR to AII. SQ 20,881 had no effect on MABP, RBF, or the RVR to AII in the dogs with chronic sodium excess and desoxycorticosterone acetate. Administration of indomethacin to chronically sodium-depleted dogs lowered RBF but did not influence the RVR to AII. The results indicate that the RVR to AII is selectively influenced by sodium balance and that the magnitude of the response is inversely related to the availability of endogenous AII. The data did not suggest that the variations in the RVR to AII were because of direct effects of sodium on vascular contraction, changes in the number of vascular AII receptors, or the renal prostaglandins. The results are consistent with the hypothesis that the vasoconstrictor effect of AII in the renal vasculature is primarily dependent upon the degree to which the AII vascular receptors are occupied by endogenous hormone. PMID:641142

  6. Transmembrane segment five serines of the D4 dopamine receptor uniquely influence the interactions of dopamine, norepinephrine, and Ro10-4548.

    PubMed

    Cummings, David F; Ericksen, Spencer S; Goetz, Angela; Schetz, John A

    2010-06-01

    Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with alpha(1)- and alpha(2)-adrenergic, beta(2)-adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2'-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines. PMID:20215412

  7. Effects of chronic treatment with losartan and enalaprilat on [3H]-norepinephrine release from isolated atria of Wistar-Kyoto and spontaneously hypertensive rats.

    PubMed

    Foucart, S; Patrick, S K; Oster, L; de Champlain, J

    1996-01-01

    The present study was designed to evaluate the effect of chronic treatment with losartan, an AT1 angiotensin II receptor antagonist, and enalaprilat, an angiotensin converting enzyme inhibitor, on the presynaptic modulation of [3H]-norepinephrine release from isolated atria of spontaneously hypertensive rats (SHR) and their respective control, the Wistar-Kyoto rats (WKY). The rats received either losartan (5 mg/kg/day) or enalaprilat (1 mg/kg/day) for 12 days by means of osmotic minipumps. The atria were isolated and incubated with [3H]-norepinephrine and the release of radioactivity was used as an index of norepinephrine release. The experimental protocol consisted of two electrical stimulations and the drugs were administered 20 min before the second stimulation. The modulatory action of angiotensin II (0.01 and 1 mumol/L), the alpha 2-adrenoceptor agonist, oxymetazoline (1 mumol/L), the alpha 2-adrenoceptor antagonist, idazoxan (1 mumol/L) and the beta 2-adrenoceptor agonist fenoterol (1 mumol/L) were tested. The results show that losartan or enalaprilat both similarly reduced the blood pressure in SHR. However, only the chronic losartan treatment, and not enalaprilat, abolished the facilitatory effect of exogenously administered angiotensin II on the release of radioactivity. The prejunctional alpha 2- and beta 2-adrenoceptor modulatory mechanisms were not altered by either chronic treatments. Similarly, the facilitatory effect of angiotensin II was blocked by acute administration of losartan but not by enalaprilat. Finally, the facilitatory action of bradykinin on the release of radioactivity was unchanged by chronic enalaprilat treatment. These results confirm the presence of facilitatory AT1 angiotensin II receptors on sympathetic nerve terminals of rat atria. These results also confirm that sympathetic nerve terminal blockade by losartan or the blockade of endogenous angiotensin II formation by enalaprilat are likely to participate in the antihypertensive

  8. Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.

    PubMed

    Stoetzer, Carsten; Papenberg, Bastian; Doll, Thorben; Völker, Marc; Heineke, Joerg; Stoetzer, Marcus; Wegner, Florian; Leffler, Andreas

    2016-07-15

    Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na(+)-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na(+)-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na(+)-channels. Effects of duloxetine, venlafaxine and amitriptyline were examined on endogenous Na(+)-channels in neuroblastoma ND7/23 cells and on the α-subunits Nav1.5, Nav1.7 and Nav1.8 with whole-cell patch clamp recordings. Tonic block of the cardiac Na(+)-channel Nav1.5 and rat-cardiomyocytes (CM) revealed a higher potency for duloxetine (Nav 1.5 IC50 14±1µM, CM IC50 27±3µM) as compared to venlafaxine (Nav 1.5 IC50 671±26µM, CM IC50 452±34µM). Duloxetine was as potent as the cardiotoxic antidepressant amitriptyline (IC50 13±1µM). While venlafaxine almost failed to induce use-dependent block on Nav1.5 and cardiomyocytes, low concentrations of duloxetine (1, 10µM) induced prominent use-dependent block similar to amitriptyline. Duloxetine, but not venlafaxine stabilized fast and slow inactivation and delayed recovery from inactivation. Duloxetine induced an unselective inhibition of neuronal Na(+)-channels (IC50 ND7/23 23±1µM, Nav1.7 19±2µM, Nav1.8 29±2). Duloxetine, but not venlafaxine inhibits cardiac Na(+)-channels with a potency similar to amitriptyline. These data indicate that an inhibition of Na(+)-channels does not predict a clinically relevant cardiotoxicity. PMID:27130441

  9. Norepinephrine regulates prophenoloxidase system-related parameters and gene expressions via α- and β-adrenergic receptors in Litopenaeus vannamei.

    PubMed

    Chang, Chin-Chyuan; Lee, Pai-Po; Cheng, Winton

    2012-10-01

    The total (THC) and differential haemocyte counts (DHC), phenoloxidase (PO) activity, and prophenoloxidase (proPO) system-related genes were investigated in haemocytes of Litopenaeus vannamei that received saline, norepinephrine (NE), and NE co-treated with various adrenergic receptor (AR) antagonists both in vivo and in vitro. Results showed that semi-granular and granular cells of shrimp which received NE, NE + phentolamine (Phe), NE + prazosin (Pra), NE + propanolol (Pro) and NE + metoprolol (Met) significantly decreased, while the PO activity of the shrimp received NE + Phe in vivo was significant higher than all the other treatments. PO activities of haemocytes exposed to saline, Pra + NE, and Met + NE were significantly higher than those of haemocytes exposed to NE, Phe + NE, and Pro + NE in vitro. Similar phenomena in lipopolysaccharide- and β-1,3-glucan-binding protein (LGBP), proPO-I, proPO-II, serine proteinases (SP), and peroxinectin (PE) messenger (m)RNA expressions of haemocytes exposed to saline, NE, and NE co-treated with various AR antagonists were observed both in vivo and in vitro. No significant differences were observed for LGBP and proPO-II mRNA expressions between haemocytes treated with saline and Pra + NE, for proPO-I mRNA expression between haemocytes treated with saline and Met + NE; or for SP and PE mRNA expressions among haemocytes treated with saline, Pra + NE, and Met + NE. These results suggest that stress-induced NE may promote the migration of circulating granulocytes to the site of the injection and the existing proPO mRNA translation which had been stored in granulocytes. NE downregulated the LGBP, proPO-I, proPO-II, SP, and PE gene transcription by haemocytes via α1-, β1-, α1-, α1- and β1-, and α1- and β1-ARs, respectively, which subsequently decreased the PO activity by α1- and β1-ARs in haemocytes of L. vannamei.

  10. Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats.

    PubMed

    Walsh, Kathryn R; Kuwabara, Jill T; Shim, Joon W; Wainford, Richard D

    2016-01-15

    Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension. PMID:26608659

  11. Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats.

    PubMed

    Walsh, Kathryn R; Kuwabara, Jill T; Shim, Joon W; Wainford, Richard D

    2016-01-15

    Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

  12. Norepinephrine content in the paraventicular nucleus of the hypothalamus as a function of photoperiod and dopaminergic tone.

    PubMed

    Woods, K A; Buechi, K A; Illig, A M; Badura, L L

    1998-02-01

    The decline in the release of various anterior pituitary hormones, particularly prolactin (PRL), as a result of exposure to inhibitory, short-day photoperiods in long-day breeders is a well-documented phenomenon. This alteration in the hypothalamic-hypophyseal-gonadal axis is largely controlled by changes in the duration of the nocturnal melatonin pulse secreted by the pineal gland. Increased duration of melatonin secretion serves to increase the inhibitory activity of the tuberoinfundibular dopaminergic (TIDA) neurons, which in turn suppress PRL release and synthesis. However, other hypothalamic factors also appear to stimulate anterior pituitary function, working in concert with changes in TIDA activity to modulate circulating PRL levels under different photoperiod conditions. Past work from this laboratory has suggested that neurochemical changes at the level of the hypothalamic paraventricular nuclei (PVN), particularly changes in norepinephrine (NE) activity, may represent one of these modulatory influences. The current study investigated potential alterations in NF, content within the PVN during the early stages of short-day exposure in Siberian hamsters. In addition, the interaction of NE content with the modulatory dopamine (DA) system was investigated via administration of a DA agonist (CD154) or antagonist (pimozide). Hamsters received CB 154 (500 micrograms), pimozide (45 micrograms), or control solution via the drinking water under either long days (16L:8D) or short days (10L:14D), and were sacrificed at 1, 3, or 5 wk of photoperiod and drug treatment. The brains were removed, and the PVN microdissected from the hypothalamus and analyzed for catecholamine content using high-pressure liquid chromatography with electrochemical detection (HPLC-EC). The results revealed the expected stimulation of circulating PRL under both photoperiods following pimozide administration, as well as the expected trend toward an accelerated suppression of PRL under short days

  13. Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-β₂-agonist for the treatment of chronic obstructive pulmonary disease.

    PubMed

    Osborne, Rachel; Clarke, Nick; Glossop, Paul; Kenyon, Amy; Liu, Hao; Patel, Sheena; Summerhill, Susan; Jones, Lyn H

    2011-10-13

    Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity. PMID:21863888

  14. A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants.

    PubMed

    Larsen, Mads B; Fontana, Andréia C K; Magalhães, Lizandra G; Rodrigues, Vanderlei; Mortensen, Ole V

    2011-05-01

    The trematode Schistosoma mansoni is the primary cause of schistosomiasis, a devastating neglected tropical disease that affects 200 million individuals. Identifying novel therapeutic targets for the treatment of schistosomiasis is therefore of great public interest. The catecholamines norepinephrine (NE) and dopamine (DA) are essential for the survival of the parasite as they cause muscular relaxation and a lengthening in the parasite and thereby control movement. Here we characterize a novel dopamine/norepinephrine transporter (SmDAT) gene transcript, from S. mansoni. The SmDAT is expressed in the adult form and in the sporocyst form (infected snails) of the parasite, and also in the egg and miracidium stage. It is absent in the cercariae stage but curiously a transcript missing the exon encoding transmembrane domain 8 was identified in this stage. Heterologous expression of the cDNA in mammalian cells resulted in saturable, dopamine transport activity with an apparent affinity for dopamine comparable to that of the human dopamine transporter. Efflux experiments reveal notably higher substrate selectivity compared with its mammalian counterparts as amphetamine is a much less potent efflux elicitor against SmDAT compared to the human DAT. Pharmacological characterization of the SmDAT revealed that most human DAT inhibitors including psychostimulants such as cocaine were significantly less potent in inhibiting SmDAT. Like DATs from other simpler organisms the pharmacology for SmDAT was more similar to the human norepinephrine transporter. We were not able to identify other dopamine transporting carriers within the completed parasite genome and we hypothesize that the SmDAT is the only catecholamine transporter in the parasite and could be responsible for not only clearing DA but also NE. PMID:21251927

  15. A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants

    PubMed Central

    Larsen, Mads B.; Fontana, Andréia C. K.; Magalhães, Lizandra G.; Rodrigues, Vanderlei; Mortensen, Ole V.

    2011-01-01

    The trematode Schistosoma mansoni is the primary cause of schistosomiasis, a devastating neglected tropical disease that affects 200 million individuals. Identifying novel therapeutic targets for the treatment of schistosomiasis is therefore of great public interest. The catecholamines norepinephrine (NE) and dopamine (DA) are essential for the survival of the parasite as they cause muscular relaxation and a lengthening in the parasite and thereby control movement. Here we characterize a novel dopamine/norepinephrine transporter (SmDAT) gene transcript, from Schistosoma mansoni. The SmDAT is expressed in the adult form and in the sporocyst form (infected snails) of the parasite, and also in the egg and miracidium stage. It is absent in the cercaria stage but curiously a transcript missing the exon encoding transmembrane domain 8 was identified in this stage. Heterologous expression of the cDNA in mammalian cells resulted in saturable, dopamine transport activity with an apparent affinity for dopamine comparable to that of the human dopamine transporter. Efflux experiments reveal notably higher substrate selectivity compared with its mammalian counterparts as amphetamine is a much less potent efflux elicitor against SmDAT compared to the human DAT. Pharmacological characterization of the SmDAT revealed that most human DAT inhibitors including psychostimulants such as cocaine were significantly less potent in inhibiting SmDAT. Like DATs from other simpler organisms the pharmacology for SmDAT was more similar to the human norepinephrine transporter. We were not able to identify other dopamine transporting carriers within the completed parasite genome and we hypothesize that the SmDAT is the only catecholamine transporter in the parasite and could be responsible for not only clearing DA but also NE. PMID:21251927

  16. Selective reduction.

    PubMed

    Evans, Mark I; Krivchenia, Eric L; Gelber, Shari E; Wapner, Ronald J

    2003-03-01

    Multifetal pregnancy reduction continues to be controversial. Attitudes about MFPR have not, in our experience, followed a simple "pro-choice/pro-life" dichotomy. As far back as the mid to late 1980s, opinions about the subject were varied. Even then, when much less was known about the subject, opinions did not always parallel the usual pro-choice/theological boundaries. We believe that the real debate over the next 5 to 10 years will not be whether or not MFPR should be performed with triplets or more. The fact is that MFPR does improve those outcomes. A serious debate will emerge over whether or not it is appropriate to offer MFPR routinely for twins, even natural ones, for whom the outcome is commonly considered "good enough." Our data suggest that reduction of twins to a singleton improves the outcome of the remaining fetus. No consensus on appropriateness of routine 2-1 reductions is ever likely to emerge. The ethical issues surrounding MFPR will always be controversial. Over the years, much has been written on the subject. Opinions will always vary from outraged condemnation to complete acceptance. No short paragraph could do justice to the subject other than to state that most proponents do not believe this is a frivolous procedure but do believe in the principle of proportionality ie, therapy to achieve the most good for the least harm). Over the past 15 years, MFPR has become a well-established and integral part of infertility therapy and attempts to deal with the sequelae of aggressive infertility management. In the mid 1980s, the risks and benefits of the procedure could only be guessed. We now have clear and precise data on the risks and benefits of the procedure and an understanding that the risks increase substantially with the starting and finishing number of fetuses in multifetal pregnancies. The collaborative loss rate numbers (ie, 4.5% for triplets, 8% for quadruplets. 11% for quintuplets, and 15% for sextuplets or more) seem reasonable to present

  17. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

    PubMed Central

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-01-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  18. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

    PubMed

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-10-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  19. Methylone and Monoamine Transporters: Correlation with Toxicity

    PubMed Central

    Sogawa, Chiharu; Sogawa, Norio; Ohyama, Kazumi; Kikura-Hanajiri, Ruri; Goda, Yukihiro; Sora, Ichiro; Kitayama, Shigeo

    2011-01-01

    Methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propane-1-one) is a synthetic hallucinogenic amphetamine analog, like MDMA (3,4-methylenedioxy- methamphetamine), considered to act on monoaminergic systems. However, the psychopharmacological profile of its cytotoxicity as a consequence of monoaminergic deficits remains unclear. We examined here the effects of methylone on the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using a heterologous expression system in CHO cells, in association with its cytotoxicity. Methylone inhibited the activities of DAT, NET, and SERT, but not GABA transporter-1 (GAT1), in a concentration-dependent fashion with a rank order of NET > DAT > SERT. Methylone was less effective at inhibiting DAT and NET, but more effective against SERT, than was methamphetamine. Methylone alone was not toxic to cells except at high concentrations, but in combination with methamphetamine had a synergistic effect in CHO cells expressing the monoamine transporters but not in control CHO cells or cells expressing GAT1. The ability of methylone to inhibit monoamine transporter function, probably by acting as a transportable substrate, underlies the synergistic effect of methylone and methamphetamine. PMID:21886563

  20. SLC6 Transporters: Structure, Function, Regulation, Disease Association and Therapeutics

    PubMed Central

    Bala, Pramod Akula; Foster, James; Carvelli, Lucia; Henry, L. Keith

    2012-01-01

    The SLC6 family of secondary active transporters are integral membrane solute carrier proteins characterized by the Na+-dependent translocation of small amino acid or amino acid-like substrates. SLC6 transporters, which include the serotonin, dopamine, norepinephrine, GABA, taurine, creatine, as well as amino acid transporters, are associated with a number of human diseases and disorders making this family a critical target for therapeutic development. In addition, several members of this family are directly involved in the action of drugs of abuse such as cocaine, amphetamines, and ecstasy. Recent advances providing structural insight into this family have vastly accelerated our ability to study these proteins and their involvement in complex biological processes. PMID:23506866