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David Robertson - One of the best experts on this subject based on the ideXlab platform.
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Synergistic Effect of Norepinephrine Transporter Blockade and α-2 Antagonism on Blood Pressure in Autonomic Failure
Hypertension (Dallas Tex. : 1979), 2012Co-Authors: Luis E. Okamoto, Bonnie K Black, David Robertson, André Diedrich, Cyndya A. Shibao, Alfredo Gamboa, Leena Choi, Satish R. Raj, Italo BiaggioniAbstract:Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine Transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic Norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of Norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of Norepinephrine Transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance ( P P =0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of Norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced Norepinephrine clearance by Norepinephrine Transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.
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Norepinephrine Transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension.
Neuroscience, 2006Co-Authors: Nancy R. Keller, Randy D Blakely, André Diedrich, Martin Appalsamy, Marc G. Caron, L. C. Miller, Michael P. Mcdonald, Richard C. Shelton, David RobertsonAbstract:The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific Transporter blockade. The Norepinephrine Transporter is crucial in limiting catecholaminergic signaling. Norepinephrine Transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced Norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, Norepinephrine Transporter-deficient (Norepinephrine Transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in Norepinephrine Transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in Norepinephrine Transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in Norepinephrine Transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, Norepinephrine Transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, Norepinephrine Transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in Norepinephrine Transporter-/- mice, Norepinephrine Transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic Norepinephrine Transporter blockade with Transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.
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Norepinephrine Transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.
Circulation, 2004Co-Authors: Nancy R. Keller, André Diedrich, Martin Appalsamy, Sunti Tuntrakool, Suzanna Lonce, Charlene Finney, Marc G. Caron, David RobertsonAbstract:Background— Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the Norepinephrine Transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. Methods and Results— We telemetrically monitored NET-deficient (NET−/−) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET−/− mice compared with NET+/+ controls (103±0.6 versus 99±0.4 mm Hg; P
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orthostatic intolerance and tachycardia associated with Norepinephrine Transporter deficiency
The New England Journal of Medicine, 2000Co-Authors: John R Shannon, Nancy Flattem, Jens Jordan, Giris Jacob, Bonnie K Black, Randy D Blakely, Italo Biaggioni, David RobertsonAbstract: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 states that lead to orthostatic intolerance.
Marc G. Caron - One of the best experts on this subject based on the ideXlab platform.
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Norepinephrine Transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension.
Neuroscience, 2006Co-Authors: Nancy R. Keller, Randy D Blakely, André Diedrich, Martin Appalsamy, Marc G. Caron, L. C. Miller, Michael P. Mcdonald, Richard C. Shelton, David RobertsonAbstract:The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific Transporter blockade. The Norepinephrine Transporter is crucial in limiting catecholaminergic signaling. Norepinephrine Transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced Norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, Norepinephrine Transporter-deficient (Norepinephrine Transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in Norepinephrine Transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in Norepinephrine Transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in Norepinephrine Transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, Norepinephrine Transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, Norepinephrine Transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in Norepinephrine Transporter-/- mice, Norepinephrine Transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic Norepinephrine Transporter blockade with Transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.
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Norepinephrine Transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.
Circulation, 2004Co-Authors: Nancy R. Keller, André Diedrich, Martin Appalsamy, Sunti Tuntrakool, Suzanna Lonce, Charlene Finney, Marc G. Caron, David RobertsonAbstract:Background— Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the Norepinephrine Transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. Methods and Results— We telemetrically monitored NET-deficient (NET−/−) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET−/− mice compared with NET+/+ controls (103±0.6 versus 99±0.4 mm Hg; P
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Genetic approaches to studying Norepinephrine function: knockout of the mouse Norepinephrine Transporter gene.
Biological psychiatry, 1999Co-Authors: Yan-min Wang, Raul R. Gainetdinov, Marc G. CaronAbstract:Norepinephrine is an important chemical messenger in the nervous system. It regulates affective states, learning and memory, endocrine and autonomic functions. It has been implicated in depression, aggression, and addiction, as well as cardiac and thermal dysregulation. The Norepinephrine Transporter functions by uptaking Norepinephrine back into the cell for cyclic use, and is a direct target of a number of antidepressants and psychostimulants. Functional deletion (knockout) of monamine Transporters results in increases in extracellular levels of neurotransmitters, thereby prolonging their actions. For the Norepinephrine Transporter knockout mice, this altered state of the Norepinephrine system should simulate the therapeutic effects of Norepinephrine selective antidepressants and some of the effects of psychostimulants. Careful use of such an animal model can hopefully provide valuable insight into the multiple roles Norepinephrine plays in normal and pathological physiology.
James F. Padbury - One of the best experts on this subject based on the ideXlab platform.
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Cloning and sequence analysis of the rat Norepinephrine Transporter promoter
Molecular Brain Research, 2000Co-Authors: James F. Padbury, B Mcgonnigal, T T Nguyen, Yi T. Tseng, J P StabilaAbstract:Abstract We isolated a 2.5-kb fragment of the promoter for the rat Norepinephrine Transporter (NET) gene. The transcription start site was identified ∼200 base pairs upstream from the translation start site. Several potential regulatory elements were identified by sequence analysis. The structure of the rat NET promoter was compared to mouse and human. Expression studies in placental and neuroblastoma cells suggested the presence of a ‘repressor’ element more than 500 base pairs upstream from the transcription start site. These studies provide the basis for examination of transcriptional regulation of this gene and for understanding its temporal and tissue-specific modes of regulation.
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Expression of a pulmonary endothelial Norepinephrine Transporter.
Journal of Neural Transmission, 1998Co-Authors: Y.-t. Tseng, James F. PadburyAbstract:To determine whether pulmonary endothelial cells express the plasma membrane Norepinephrine Transporter (NET), an ovine-specific riboprobe was prepared from a partial NET cDNA clone isolated by PCR from a placental cDNA library. Northern hybridization detected a predominant 5.8 kb and a weaker transcript at 3.6 kb in RNAs isolated from near-term ovine fetal pulmonary endothelial cells. These data should be useful for future studies examining the molecular mechanisms underlying pulmonary endothelial NET expression and regulation.
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Human placental Norepinephrine Transporter mRNA: expression and correlation with fetal condition at birth.
Placenta, 1997Co-Authors: Lisanne Bzoskie, Julian Yen, Yi-tang Tseng, Leslie Blount, Kent Kashiwai, James F. PadburyAbstract:The purpose of this study was to determine the primary form of human placental Norepinephrine Transporter (hNET) mRNA expressed in the human placenta and to compare the level of expression in normal pregnancies and in pregnancies complicated by drug exposure or other forms of physiological derangement. We used the hNET cDNA to measure RNA extracted from placenta and examined placental RNA following complicated and uncomplicated pregnancies. To compare Transporter expression and its relation to fetal condition at birth, umbilical arterial plasma catecholamine levels, umbilical arterial blood gases and placental Transporter mRNA level were compared by linear regression analysis. Uncomplicated pregnancies had a higher level of placental Norepinephrine Transporter mRNA than complicated pregnancies. An inverse relationship between umbilical cord Norepinephrine level and Transporter expression was demonstrated. We conclude that placental Transporter expression represents an important and newly described metabolic function of the placenta. Placental catecholamine clearance mediated via the placental NET may be important in the pathophysiology of disorders associated with placental dysfunction, impaired placental blood flow or intrauterine growth retardation. This may also explain the adverse effects of drugs, such as cocaine, which block catecholamine transport.
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Placental Norepinephrine Transporter development in the ovine fetus
Placenta, 1997Co-Authors: I. Bzoskie, I. Blount, Kent Kashiwai, James Humme, James F. PadburyAbstract:The placenta has been shown to be a site of expression of several of the monoamine membrane uptake Transporters. However, the development and relative contribution of transport-dependent mechanisms to placental catecholamine clearance in vivo have not been demonstrated. These studies were designed to determine the development of the placental Norepinephrine Transporter (NET) and the relative contribution of transport dependent mechanisms to whole body and placental catecholamine clearance. Norepinephrine clearance and production rate were determined in 122 ± 1 day gestation chronically catheterized fetal sheep. Placental clearance was shown to account for over 40 per cent of total intrauterine clearance and, of the clearance in the placenta, nearly 50 per cent was uptake, transport-dependent as shown by specific pharmacologic blockade. NET transport expression was examined by measurement nisoxetine binding in placenta and compared with binding in the frontal cortex of fetal, newborn and adult animals. Nisoxetine is a selective ligand for the Norepinephrine Transporter. Nisoxetine binding was 20-fold greater in placenta than in frontal cortex. Placental Transporter binding decreased modestly in between 99 days gestation and term (145 days) but did not change in frontal cortex. These results suggest that expression of the Norepinephrine Transporter in the placenta is associated with a significant capacity for neurotransmitter re-uptake in utero. Given the high fetal Norepinephrine production rate, this capacity is important for fetal homeostasis. This site of Transporter expression may be important in the pathogenesis of derangements in catecholamine production in the fetus and in the adverse effects on the fetus of drugs, such as cocaine, which block catecholamine re-uptake.
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PLACENTAL Norepinephrine Transporter: EXPRESSION AND REGULATION. † 331
Pediatric Research, 1996Co-Authors: Lisanne Bzoskie, Julian Yen, Yi-tang Tseng, Leslie Blount, Kent Kahiwai, James F. PadburyAbstract:The placenta has recently been shown to express the Transporters for catecholamines and serotonin. In previous studies of catheterized fetal sheep, we used isotope tracer methods to show that the placenta contributes to>50% of total (fetal+placental) clearance of Norepinephrine. Using Norepinephrine transport blockers, we demonstrated that more than 50% of placental clearance is Norepinephrine Transporter dependent. The factors which regulate expression of these proteins in the placenta are not known. To compare placental Transporter expression with alterations in placental function during pregnancy, we used the human Norepinephrine cDNA to examine RNA extracted from the placenta of 35 patients following complicated and uncomplicated pregnancies. To compare Transporter expression and its relation to fetal condition at birth, we collected both placentas and umbilical arterial cord blood for catecholamines and blood gases. Transporter expression was measured by Northern analysis and RNase protection. Quantitative Norepinephrine Transporter expression was compared to umbilical plasma Norepinephrine by regression analysis. Uncomplicated pregnancies had a higher level of placental Norepinephrine Transporter expression than complicated pregnancies. An inverse relationship between umbilical cord Norepinephrine level and Transporter expression was demonstrated. That is, if Transporter expression was high, umbilical plasma Norepinephrine levels were low (r=0.54, p
André Diedrich - One of the best experts on this subject based on the ideXlab platform.
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Synergistic Effect of Norepinephrine Transporter Blockade and α-2 Antagonism on Blood Pressure in Autonomic Failure
Hypertension (Dallas Tex. : 1979), 2012Co-Authors: Luis E. Okamoto, Bonnie K Black, David Robertson, André Diedrich, Cyndya A. Shibao, Alfredo Gamboa, Leena Choi, Satish R. Raj, Italo BiaggioniAbstract:Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine Transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic Norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of Norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of Norepinephrine Transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance ( P P =0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of Norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced Norepinephrine clearance by Norepinephrine Transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.
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Hormonal Influences on Cardiovascular Norepinephrine Transporter Responses in Healthy Women
Hypertension (Dallas Tex. : 1979), 2008Co-Authors: Iryna Moldovanova, Giris Jacob, André Diedrich, Christoph Schroeder, Christoph Hiemke, Friedrich C. Luft, Jens JordanAbstract:Gender differences in human cardiovascular Norepinephrine Transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25+/-1 years) during the early follicular phase (day 5+/-0) and midluteal phase (day 22+/-0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective Norepinephrine Transporter inhibitor reboxetine or placebo. We monitored heart rate, blood pressure, and thoracic bioimpedance at rest and during standard autonomic function tests, including head-up tilt. Venous estradiol and progesterone concentrations were higher in the luteal than in the follicular phase but did not differ between placebo and Norepinephrine Transporter inhibition testing days. On placebo, hemodynamics at rest and in response to different stressors were mostly identical between cycle phases. In the supine position, Norepinephrine Transporter inhibition increased blood pressure and stroke volume to a greater extent during the follicular than during the luteal phase. Conversely, the increase in heart rate and cardiac output with Norepinephrine Transporter inhibition was augmented in the luteal compared with the follicular phase. During head-up tilt with Norepinephrine Transporter inhibition, blood pressure and stroke volume decreased to a greater extent in the follicular than in the luteal phase. The tachycardic response to head-up tilt with Norepinephrine Transporter inhibition was augmented in the follicular phase. Our study suggests that sex hormones alter the hemodynamic response to Norepinephrine Transporter inhibition in women. The phenomenon may be explained by an effect of female sex hormones on Norepinephrine Transporter function, on compensatory cardiovascular responses, or both.
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Norepinephrine Transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension.
Neuroscience, 2006Co-Authors: Nancy R. Keller, Randy D Blakely, André Diedrich, Martin Appalsamy, Marc G. Caron, L. C. Miller, Michael P. Mcdonald, Richard C. Shelton, David RobertsonAbstract:The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific Transporter blockade. The Norepinephrine Transporter is crucial in limiting catecholaminergic signaling. Norepinephrine Transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced Norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, Norepinephrine Transporter-deficient (Norepinephrine Transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in Norepinephrine Transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in Norepinephrine Transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in Norepinephrine Transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, Norepinephrine Transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, Norepinephrine Transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in Norepinephrine Transporter-/- mice, Norepinephrine Transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic Norepinephrine Transporter blockade with Transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.
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Norepinephrine Transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.
Circulation, 2004Co-Authors: Nancy R. Keller, André Diedrich, Martin Appalsamy, Sunti Tuntrakool, Suzanna Lonce, Charlene Finney, Marc G. Caron, David RobertsonAbstract:Background— Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the Norepinephrine Transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. Methods and Results— We telemetrically monitored NET-deficient (NET−/−) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET−/− mice compared with NET+/+ controls (103±0.6 versus 99±0.4 mm Hg; P
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Phenotypical evidence for a gender difference in cardiac Norepinephrine Transporter function
American journal of physiology. Regulatory integrative and comparative physiology, 2004Co-Authors: Christoph Schroeder, Italo Biaggioni, André Diedrich, Friedrich C. Luft, Frauke Adams, Michael Boschmann, Jens Tank, Sebastian Haertter, Jens JordanAbstract:Norepinephrine Transporter (NET) function has a central role in the regulation of synaptic Norepinephrine concentrations. Clinical observations in orthostatic intolerance patients suggest a gender ...
Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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Venlafaxine ER Blocks the Norepinephrine Transporter in the Brain of Patients with Major Depressive Disorder: a PET Study Using [18F]FMeNER-D2.
The international journal of neuropsychopharmacology, 2019Co-Authors: Ryosuke Arakawa, Akihiro Takano, Christer Halldin, Per Stenkrona, Jonas Svensson, Max Andersson, Sangram Nag, Yuko Asami, Yoko Hirano, Johan LundbergAbstract:BACKGROUND The in vivo binding of clinical dose of venlafaxine on Norepinephrine Transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin Transporter than that to Norepinephrine Transporter. Although serotonin Transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of Norepinephrine Transporter occupancy in the human brain. METHODS This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine Transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of Norepinephrine Transporter were also estimated. RESULTS The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P = .0004 < .05/2). The Norepinephrine Transporter occupancy (8-61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. CONCLUSIONS This study demonstrates that clinically relevant doses of venlafaxine extended-release block the Norepinephrine Transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin Transporter and Norepinephrine Transporter blockades.
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Serotonin and Norepinephrine Transporter Occupancy of Tramadol in Nonhuman Primate Using Positron Emission Tomography.
The international journal of neuropsychopharmacology, 2018Co-Authors: Ryosuke Arakawa, Akihiro Takano, Christer HalldinAbstract:Background Tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin Transporter and Norepinephrine Transporter in addition to μ-opioid receptor. Based on this characteristic, tramadol is expected to have an antidepressant effect. Methods Positron emission tomography measurements with [11C]MADAM and [18F]FMeNER-D2 were performed at baseline and after i.v. administration of 3 different doses (1, 2, and 4 mg/kg) of tramadol using 6 cynomolgus monkeys. The relationship between dose and occupancy for serotonin Transporter and Norepinephrine Transporter was estimated. Results Tramadol occupied similarly both serotonin Transporter (40%-72%) and Norepinephrine Transporter (7%-73%) in a dose-dependent manner. The Kd was 2.2 mg/kg and 2.0 mg/kg for serotonin Transporter and Norepinephrine Transporter, respectively. Conclusions Both serotonin Transporter and Norepinephrine Transporter of in vivo brain were blocked at >70% at a clinically relevant high dose of tramadol. This study suggests tramadol has potential antidepressant effects through the inhibition of serotonin Transporter and Norepinephrine Transporter in the brain.
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Norepinephrine Transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2.
Psychopharmacology, 2010Co-Authors: Mizuho Sekine, Harumasa Takano, Ryosuke Arakawa, Christer Halldin, Masaki Okumura, Hiroshi Ito, Hidehiko Takahashi, Yoshiro Okubo, Takeshi Sasaki, Tetsuya SuharaAbstract:Rationale Central Norepinephrine Transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive.
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Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-18F-FMeNER-D2
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2008Co-Authors: Ryosuke Arakawa, Harumasa Takano, Masaki Okumura, Hiroshi Ito, Chie Seki, Hidehiko Takahashi, Ryuji Nakao, Kazutoshi Suzuki, Yoshiro Okubo, Christer HalldinAbstract:(S,S)-18F-FMeNER-D2 was recently developed as a radioligand for the measurement of Norepinephrine Transporter imaging with PET. In this study, a Norepinephrine Transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-18F-FMeNER-D2. Binding potential relative to nondisplaceable binding (BPND) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120–180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BPND values by the indirect kinetic method were 0.54 ± 0.19 and 0.35 ± 0.25 in the thalamus and locus coeruleus, respectively. BPND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r = 0.81–0.92). Conclusion: The regional distribution of (S,S)-18F-FMeNER-D2 in our study agreed with that demonstrated by previous PET and postmortem studies of Norepinephrine Transporter in the human brain. The ratio method with a time integration interval of 120–180 min will be useful for clinical research of psychiatric disorders for estimation of Norepinephrine Transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.
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biodistribution and radiation dosimetry of the Norepinephrine Transporter radioligand s s 18f fmener d2 a human whole body pet study
European Journal of Nuclear Medicine and Molecular Imaging, 2008Co-Authors: Akihiro Takano, Christer Halldin, Nils Sjoholm, Magnus Schou, James B. Stubbs, Andrea Varrone, Per Karlsson, Anu J Airaksinen, Johannes Tauscher, Balázs GulyásAbstract:Purpose (S,S)-[18F]FMeNER-D2 is a recently developed positron-emission tomography (PET) radioligand for in vivo quantification of the Norepinephrine Transporter system. The aim of this study was to provide dosimetry estimates for (S,S)-[18F]FMeNER-D2 based on human whole-body PET measurements.
