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Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations., (© 2021. The Author(s).)

Catecholamine (CA) function has been widely implicated in cognitive functions that are tied to the prefrontal cortex and striatal areas. The present study investigated the effects of methylphenidate, which is a CA agonist, on the electroencephalogram (EEG) response related to semantic processing using a double-blind, placebo-controlled, randomized, crossover, within-subject design. Forty-eight healthy participants read semantically congruent or incongruent sentences after receiving 20-mg methylphenidate or a placebo while their brain activity was monitored with EEG. To probe whether the catecholaminergic modulation is task-dependent, in one condition participants had to focus on comprehending the sentences, while in the other condition, they only had to attend to the font size of the sentence. The results demonstrate that methylphenidate has a task-dependent effect on semantic processing. Compared to placebo, when semantic processing was task-irrelevant, methylphenidate enhanced the detection of semantic incongruence as indexed by a larger N400 amplitude in the incongruent sentences; when semantic processing was task-relevant, methylphenidate induced a larger N400 amplitude in the semantically congruent condition, which was followed by a larger late positive complex effect. These results suggest that CA-related neurotransmitters influence language processing, possibly through the projections between the prefrontal cortex and the striatum, which contain many CA receptors., (© The Author(s) 2020. Published by Oxford University Press.)

Catecholaminergic neural transmission plays an important role during the inhibition of prepotent responses. Methylphenidate (MPH) is an important drug that modulates the catecholaminergic system. However, theoretical considerations suggest that the effects of drugs (e.g. MPH) on cognitive control may depend on prior learning effects. Here we investigate this in a conflict-modulated Go/Nogo task and evaluate neurophysiological processes associated with this dynamic using EEG signal decomposition methods and source localization analysis. The behavioral data show that prior learning experiences eliminate effects of MPH on response inhibition processes. On a neurophysiological level, we show that MPH modulates specific processes in medial frontal brain regions. Although MPH seems to consistently modulate neurophysiological processes associated with response inhibition, this is no longer sufficient to modulate behavioral performance once learning or task familiarization processes have taken place. An important consequence of this study finding is that it may be important to adjust MPH dosage depending on learning effects in a specific setting to constantly increase cognitive control functions in that setting. This has important implications for clinical practice, since MPH is the first-line pharmacological therapy in attention-deficit hyperactivity disorder (ADHD). Cross-over study designs with constant doses of MPH can mask effects on cognitive functions. The impact of learning needs careful consideration in cross-over study designs examining catecholaminergic drug effects., Competing Interests: Conflict of interest MM has nothing to disclose. V. Roessner has received payment for consulting and writing activities from Lilly, Novartis, and Shire Pharmaceuticals, lecture honoraria from Lilly, Novartis, Shire Pharmaceuticals, and Medice Pharma, and support for research from Shire and Novartis. He has carried out clinical trials in cooperation with the Novartis, Shire, and Otsuka companies. C. Beste has received payment for consulting from GlaxoSmithKline, Novartis, Teva, Biogen, Celgene, Bayer and Genzyme. He is carrying out clinical research for Genzyme., (Copyright © 2020. Published by Elsevier B.V.)

Lung cancer results in more patient deaths each year than any other cancer type. Additional treatment strategies are needed to improve clinical responses to approved treatment modalities and prevent the emergence of resistant disease. Catecholamines including norepinephrine and epinephrine are elevated as a result of chronic stress and mediate their physiological effects through activation of adrenergic receptors on target tissues. Lung cancer cells express β-adrenergic receptors (β-ARs), and numerous preclinical studies indicate that β2-AR signaling on lung cancer cells facilities cellular programs including proliferation, motility, apoptosis resistance, epithelial-to-mesenchymal transition, metastasis, and the acquisition of an angiogenic and immunosuppressive phenotype. Here, we review the preclinical and clinical evidence supporting a potential role for beta-blockers in improving the clinical outcome of lung cancer patients. Graphical Abstract Catecholamines including norepinephrine and epinephrine act of β-ARs expressed on NSCLC tumor cells and activate pathways regulating tumor progression.

The release of [ 3 H]dopamine ([ 3 H]DA) and [ 3 H]noradrenaline ([ 3 H]NA) in acutely perfused rat striatal and cortical slice preparations was measured at 37 °C and 17 °C under ischemic conditions. The ischemia was simulated by the removal of oxygen and glucose from the Krebs solution. At 37 °C, resting release rates in response to ischemia were increased; in contrast, at 17 °C, resting release rates were significantly reduced, or resting release was completely prevented. The removal of extracellular Ca 2+ further increased the release rates of [ 3 H]DA and [ 3 H]NA induced by ischemic conditions. This finding indicated that the Na + /Ca 2+ exchanger (NCX), working in reverse in the absence of extracellular Ca 2+ , fails to trigger the influx of Ca 2+ in exchange for Na + and fails to counteract ischemia by further increasing the intracellular Na + concentration ([Na + ] i ). KB-R7943, an inhibitor of NCX, significantly reduced the cytoplasmic resting release rate of catecholamines under ischemic conditions and under conditions where Ca 2+ was removed. Hypothermia inhibited the excessive release of [ 3 H]DA in response to ischemia, even in the absence of Ca 2+ . These findings further indicate that the NCX plays an important role in maintaining a high [Na + ] i , a condition that may lead to the reversal of monoamine transporter functions; this effect consequently leads to the excessive cytoplasmic tonic release of monoamines and the reversal of the NCX. Using HPLC combined with scintillation spectrometry, hypothermia, which enhances the stimulation-evoked release of DA, was found to inhibit the efflux of toxic DA metabolites, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL). In slices prepared from human cortical brain tissue removed during elective neurosurgery, the uptake and release values for [ 3 H]NA did not differ from those measured at 37 °C in slices that were previously maintained under hypoxic conditions at 8 °C for 20 h. This result indicates that hypothermia preserves the functions of the transport and release mechanisms, even under hypoxic conditions. Oxidative stress (H 2 O 2 ), a mediator of ischemic brain injury enhanced the striatal resting release of [ 3 H]DA and its toxic metabolites (DOPAL, quinone). The study supports our earlier findings that during ischemia transmitters are released from the cytoplasm. In addition, the major findings of this study that hypothermia of brain slice preparations prevents the extracellular calcium concentration ([Ca 2+ ] o )-independent non-vesicular transmitter release induced by ischemic insults, inhibiting Na + /Cl - -dependent membrane transport of monoamines and their toxic metabolites into the extracellular space, where they can exert toxic effects.

Parkinson's disease (PD) presents with a constellation of non-motor symptoms, notably increased anxiety, which are currently poorly treated and underrepresented in animal models of the disease. Human post-mortem studies report loss of catecholaminergic neurons in the pre-symptomatic phases of PD when anxiety symptoms emerge, and a large literature from rodent and human studies indicate that catecholamines are important mediators of anxiety via their modulatory effects on limbic regions such as the amygdala. On the basis of these observations, we hypothesized that anxiety in PD could result from an early loss of catecholaminergic inputs to the amygdala and/or other limbic structures. To interrogate this hypothesis, we bilaterally injected the neurotoxin 6-OHDA in the mouse basolateral amygdala (BL). This produced a restricted pattern of catecholaminergic (tyrosine-hydroxylase-labeled) denervation in the BL, intercalated cell masses and ventral hippocampus, but not the central amygdala or prefrontal cortex. We found that this circuit-specific lesion did not compromise performance on multiple measures of motor function (home cage, accelerating rotarod, beam balance, pole climbing), but did increase anxiety-like behavior in the elevated plus-maze and light-dark exploration tests. Fear behavior in the pavlovian cued conditioning and passive avoidance assays was, by contrast, unaffected; possibly due to preservation of catecholamine innervation of the central amygdala from the periaqueductal gray. These data provide some of the first evidence implicating loss of catecholaminergic neurotransmission in midbrain-amygdala circuits to increased anxiety-like behavior. Our findings offer an initial step towards identifying the neural substrates for pre-motor anxiety symptoms in PD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The psychostimulant methylphenidate (MPH) is the primary drug treatment for attention deficit hyperactivity disorder (ADHD) in children. MPH is well known to acutely block the dopamine (DAT) and noradrenaline (NET) transporters. Its effect on additional catecholamine targets is however less known. This study was aimed at comparing the effects of acute (2 mg/kg, i.p.) and chronic (2 mg/kg twice daily for 2 weeks) MPH treatment to young rats on key catecholamine protein targets in brain regions implicated in the symptoms and treatment of ADHD. For this purpose, the density of DAT, NET, the vesicular monoamine transporter 2 (VMAT2), the rate limiting enzyme for catecholamine synthesis tyrosine hydroxylase (TH) and the dopamine D 1 receptor were measured in frontal (FC), parietal cortex (PCx) and the dorsal (DS) and ventral (VS) striatum. The data demonstrate that the effects of MPH depend on duration of treatment and brain region investigated. With the exception of DAT in the VS our results indicate that chronic but not acute administration of MPH increases levels of DAT, NET, TH, VMAT2 and D 1 . These effects were further more prominent in the VS over DS and in the PCx compared to the FC. In addition, chronic MPH enhanced DAT levels in the left DS but not in right side. To summarize, this study shows new evidence that chronic MPH to young rats preferentially alters catecholamine targets in PCx and VS over DS and FC. The effect of chronic MPH to increase levels of DAT, NET and VMAT2 suggests that the drug might long-term loose some of its acute action to increase extracellular levels of dopamine and noradrenaline. In conclusion, these findings provide novel insights into the mechanism of action by MPH in the treatment of ADHD and further suggest that the long-term effectiveness of the stimulant drug could be limited., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases 1-5 . Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.

Background and Purpose: Antiarrhythmic β-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized that β-blockers do not prevent ventricular fibrillation (VF) but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness., Experimental Approach: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized study. Ischaemic zone (IZ) size was deliberately made small or large., Key Results: In rat hearts with large IZs, ischaemia-induced VF incidence was high in controls. Atenolol, butoxamine and trimazosin did not affect VF at concentrations with β 1 -, β 2 - or α 1 - adrenoceptor specificity and selectivity (confirmed in separate rat aortae myography experiments). In hearts with small IZs and low baseline incidence of ischaemia-induced VF, CATs, delivered to the uninvolved zone (UZ), increased ischaemia-induced VF incidence. This effect was not mimicked by atrial pacing, hence, not due to sinus tachycardia. However, the CATs-facilitated increase in ischaemia-induced VF was inhibited by atenolol and butoxamine (but not trimazosin), indicative of β 1 - and β 2 - but not α 1 -adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). CATs did not facilitate VF in low-flow globally ischaemic hearts, which have no UZ., Conclusions and Implications: Catecholamines facilitated ischaemia-induced VF when risk was low, acting via β 1 - and β 2 - adrenoceptors located in the UZ. There was no scope for facilitation when VF risk was high (large IZ), which may explain why β-blockers have equivocal effectiveness in humans., (© 2018 The British Pharmacological Society.)

We investigated the influence of simvastatin, a statin, on the secretion of catecholamines (CA) in rat adrenal glands, and clarified its action mechanism. Simvastatin suppressed acetylcholine (ACh)-evoked CA release in a dose- and time-dependent fashion. In the presence of simvastatin, CA secretion evoked by 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP), angiotensin II, high K + , veratridine, and Bay-K-8644 was time-dependently inhibited. However, in the simultaneous presence of simvastatin and Nω-nitro-L-arginine methyl ester hydrochloride, CA secretion evoked by angiotensin II and DMPP recovered to control levels. Adrenal NO release was increased by simvastatin-treatment. Simvastatin-inhibited CA secretion was not affected by treatment with mevalonate. Pravastatin did not influence ACh-evoked CA secretion, while atorvastatin reduced it. In the simultaneous presence of simvastatin and fimasartan, ACh-induced CA release was markedly reduced compared to that of fimasartan-treatment alone. We present the first evidence that simvastatin reduces adrenal CA secretion induced by stimulation of nicotinic and AT 1 -receptors. Simvastatin-induced inhibition seems to involve reducing the influx of both Ca 2+ and Na + into adrenochromaffin cells, partly via the elevation of NO production by NO synthase activation, without inhibition of 3-hydroxy-methylglutaryl coenzyme A reductase. Co-administration of simvastatin and fimasartan may be clinically helpful for the treatment of cardiovascular diseases.

The genus Passiflora is popularly used to treat anxiety. Recent studies showed antidepressant-like effects of two varieties of P. edulis (edulis and flavicarpa) in mice. However, the mechanisms of antidepressant actions are still unknown. Here, the effects of P. edulis fo. edulis aqueous extract (AE, 100-300mg/kg, po), and ethyl acetate (AcOEt, 25-50mg/kg, po), butanol (BuOH, 25-50mg/kg, po) and residual aqueous (25-100mg/kg, po) fractions were investigated in the mouse forced swimming test. In addition, the involvement of monoamines in the P. edulis fractions-induced antidepressant actions was approached. HPLC analyses showed that AcOEt and BuOH, but not residual, fractions shared with AE the main peaks between 25 and 70min (UV 340nm), which are suggestive of flavonoids. Nortriptyline and fluoxetine reduced the immobility time and similar results were observed for AE, AcOEt and BuOH but not residual fractions. PCPA (inhibitor of 5-HT synthesis), AMPT (inhibitor of catecholamine synthesis) and sulpiride (selective D2 receptor antagonist), but not DSP-4 (noradrenergic neurotoxin), blocked the antidepressant actions of AcOEt and BuOH. In conclusion, AcOEt and BuOH fractions shared with AE similar phytochemical composition and antidepressant actions. Preserved 5-HT and dopamine transmissions were required for the antidepressant effects of P. edulis fractions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca 2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT 1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca 2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca 2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca 2+ entry via nAChRs., (© 2017 International Society for Neurochemistry.)

Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A human study of the effects on hemodynamics of caffeine and epigallocatechin-3-O-gallate (EGCG) was performed. Caffeine tablets (200 mg) were orally administered to healthy males aged between 25 and 35 years 30 min after oral administration of EGCG tablets (100 and 200 mg). The increase in BP induced by caffeine was inhibited when co-administrated with EGCG. We found that caffeine slightly decreased heart rate (HR) in the volunteers. Although EGCG enhanced HR reduction, the effect was not significant. In addition, caffeine increased blood catecholamine levels, but EGCG inhibited the increase in noradrenaline, adrenaline and dopamine levels induced by caffeine. Whether EGCG decreases the elevated HR and systolic perfusion pressure, and ventricular contractility induced by adrenergic agonists in the isolated rat heart was investigated. The modified Krebs-Henseleit solution was perfused through a Langendorff apparatus to the isolated hearts of rats. HR, systolic perfusion pressure, and developed maximal rates of contraction (+dP/dtmax) and relaxation (-dP/dtmax) were increased by epinephrine (EP) and isoproterenol (IP). In contrast, EGCG decreased the elevated HR, systolic perfusion pressure, and left ventricular ±dp/dtmax induced by EP and/or IP. In conclusion, EGCG could attenuate the hemodynamics stimulated by caffeine through decreasing catecholamine release.

We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and β-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The pretreatment of cultured pheochromocytoma (PC12) cells with cis-diamminedichloroplatinum (cisplatin), an anti-cancer drug, influences the exocytotic ability of the cells in a dose-dependent manner. Low concentrations of cisplatin stimulate catecholamine release whereas high concentrations inhibit it. Single-cell amperometry reflects that 2 μm cisplatin treatment increases the frequency of exocytotic events and reduces their duration, whereas 100 μm cisplatin treatment decreases the frequency of exocytotic events and increases their duration. Furthermore, the stability of the initial fusion pore that is formed in the lipid membrane during exocytosis is also regulated differentially by different cisplatin concentrations. This study thus suggests that cisplatin influences exocytosis by multiple mechanisms., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 μM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 μM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3β4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 μM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 μM and 10-100 μM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

Rationale: Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine., Objectives: The current studies investigated the effects of tetrabenazine on effort-based decision making using the T-maze barrier task., Methods: Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4-2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4-0 barrier)., Results: Tetrabenazine (0.25-0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4-0 barrier conditions. The effects of tetrabenazine on barrier climbing in the 4-2 condition were reversed by the adenosine A2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion., Conclusions: These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders.

Currently, propranolol is the preferred treatment for problematic proliferating infantile haemangiomas (IHs). The rapid action of propranolol has been shown to be especially dramatic in IHs involving dyspnoea, haemodynamic compromise, palpebral occlusion or ulceration. Another remarkable aspect of propranolol treatment revealed that the growth of the IHs was not only stabilized, but also that the improvement continued until complete involution was achieved, leading to a considerable shortening of the natural course of IH. However, the mechanisms underlying the effects of propranolol have not been fully elucidated. Recent studies have offered evidence of a variety of mechanisms. These include the promotion of pericyte-mediated vasoconstriction, the inhibition of vasculogenesis and catecholamine-induced angiogenesis, the disruption of haemodynamic force-induced cell survival, and the inactivation of the renin-angiotensin system. This review summarizes these mechanisms and the new concepts that are emerging in this area of research. Moreover, several molecular mechanisms by which propranolol may modify neovascularization in IH have also been proposed. The antihaemangioma effect of propranolol may not be attributable to a single mechanism, but rather to a combination of events that have not yet been elucidated or understood. Further studies are needed to evaluate and verify these mechanisms to gain a greater understanding of the effects of the intake of propranolol on haemangioma involution., (© 2014 British Association of Dermatologists.)

Using embryonic chickens (Gallus gallus domesticus), we examined the role of the renin-angiotensin system (RAS) in cardiovascular and osmotic homeostasis through chronic captopril, an angiotensin-converting enzyme (ACE) inhibitor. Captopril (5 mg kg⁻¹ embryo wet mass) or saline (control) was delivered via the egg air cell daily from embryonic day 5-18. Mean arterial pressure (MAP), heart rate (ƒ(H)), fluid osmolality and ion concentration, and embryonic and organ masses were measured on day 19. Exogenous angiotensin I (ANG I) injection did not change MAP or ƒ(H) in captopril-treated embryos, confirming ACE inhibition. Captopril-treated embryos were significantly hypotensive, with MAP 15% lower than controls, which we attributed to the loss of vasoconstrictive ANG II action. Exogenous ANG II induced a relatively greater hypertensive response in captopril-treated embryos compared to controls. Changes in response to ANG II following pre-treatment with phentolamine (α-adrenergic antagonist) indicated a portion of the ANG II response was due to circulating catecholamines in captopril-treated embryos. An increase in MAP and ƒ(H) in response to hexamethonium indicated vagal tone was also increased in the absence of ACE activity. Captopril-treated embryos had lower osmolality, lower Na⁺ and higher K⁺ concentration in the blood, indicating osmoregulatory changes. Larger kidney mass in captopril-treated embryos suggests disrupting the RAS may stimulate kidney growth by decreasing resistance at the efferent arteriole and increasing the fraction of cardiac output to the kidneys. This study suggests that the RAS, most likely through ANG II action, influences the development of the cardiovascular and osmoregulatory systems., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Taurine, a ubiquitous endogenous sulfur-containing amino acid, possesses numerous pharmacological and physiological actions, including antioxidant activity, modulation of calcium homeostasis and antiapoptotic effects. There is mounting evidence supporting the utility of taurine as a pharmacological agent against heart disease, including chronic heart failure (CHF). In the past decade, angiotensin II blockade and β-adrenergic inhibition have served as the mainstay in the treatment of CHF. Both groups of pharmaceutical agents decrease mortality and improve the quality of life, a testament to the critical role of the sympathetic nervous system and the renin--angiotensin system in the development of CHF. Taurine has also attracted attention because it has beneficial actions in CHF, in part by its demonstrated inhibition of the harmful actions of the neurohumoral factors. In this review, we summarize the beneficial actions of taurine in CHF, focusing on its antagonism of the catecholamines and angiotensin II.

Ethnopharmacological Relevance: Traditional Chinese Medicine (TCM) operates on the general principle that compatible components of different herbal decoction may work together to synergistically enhance therapeutic efficacy or reduce adverse effects. Cortex Periplocae is an herb that has been used in TCM clinics for a long time in the treatment of chronic heart failure. However, recently, the use of this herb has been restricted because of widespread abuse and misapplications. Radix Notoginseng is another herb that is used in TCM because of its protective role on cardiomyocytes. From our previous studies on these two herbs in a mouse model, we observed an increased LD50 after oral administration of Cortex Periplocae extract (CPE) and Panax notoginseng saponins (PNS) in a ratio of 1:1 compared with Cortex Periplocae extract used alone., Aim of the Study: This study aimed to investigate whether there are mutual synergistic effects of the two herbal extracts, CPE and PNS, on catecholamines (CAs) secretion, and their possible underlying mechanism(s) for such effects., Materials and Methods: CPE and PNS were quantified by the LC-MS/MS method. HPLC-ECD was used to determine the CAs secreted into the medium by bovine adrenal medulla cells (BAMCs) and calcium influx was measured using a Calcium 4 reagent kit., Results: We found that the stimulatory effect of CPE on CAs secretion was inhibited when used together with PNS. For a better clarification of the different constituents of the extracts, a quantitative analysis was carried out. Periplocin was found to be the main active component of CPE valued as 0.99% and saponins were the principal constituents of PNS. These results also showed that CPE increased the secretion of CAs in a dose-dependent manner while the actions of PNS were seen to be inhibitory. Periplocin monomer of CPE could be implicated for the actions of CPE since it plays the role of increasing the ACh-induced CAs secretion in a calcium-dependent manner. We therefore conclude that; CPE and PNS exert antagonistic effects in regulating the concentration of intracellular calcium., Conclusions: PNS inhibits CPE-induced CAs secretion by suppressing calcium influx in bovine adrenal medulla cells while periplocin, one of the main components of CPE has the same secretagogue effect as CPE., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

In efforts to assess baroreflex and cardiovascular responses in rats in which substance P (SP) or catecholamine transmission had been eliminated we studied animals after bilateral injections into the nucleus tractus solitarii (NTS) of SP or stabilized SP (SSP) conjugated to saporin (SP-SAP or SSP-SAP respectively) or SAP conjugated to an antibody to dopamine-β-hydroxylase (anti-DBH-SAP). We found that SP- and SSP-SAP eliminated NTS neurons that expressed the SP neurokinin-1 receptor (NK1R) while anti-DBH-SAP eliminated NTS neurons expressing tyrosine hydroxylase (TH) and DBH. The toxins were selective. Thus SP- or SSP-SAP did not eliminate TH/DBH neurons and anti-DBH-SAP did not eliminate NK1R neurons in the NTS. Each toxin, however, led to chronic lability of arterial blood pressure, diminished baroreflex function, cardiac ventricular irritability, coagulation necrosis of cardiac myocytes and, in some animals, sudden death associated with asystole. However, when TH/DBH neurons were targeted and eliminated by injection of 6-hydroxydopamine (6-OHDA), none of the cardiovascular or cardiac changes occurred. The studies reviewed here reveal that selective lesions of the NTS lead to altered baroreflex control and to cardiac changes that may lead to sudden death. Though the findings could support a role for SP or catecholamines in baroreflex transmission neither is proven in that NK1R colocalizes with glutamate receptors. Thus neurons with both are lost when treated with SP- or SSP-SAP. In addition, loss of catecholamine neurons after treatment with 6-OHDA does not affect cardiovascular control. Thus, the effect of the toxins may depend on an action of SAP independent of the effects of the SAP conjugates on targeted neuronal types., (Published by Elsevier B.V.)

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous β-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period., (©2012 AACR.)

Background: Gabapentin is most commonly prescribed for chronic pain, but acute perioperative effects, including preemptive analgesia and hemodynamic stabilization, have been reported. Adrenal chromaffin cells are a widely used model to investigate neurosecretion, and adrenal catecholamines play important physiologic roles and contribute to the acute stress response. However, the effects of gabapentin on adrenal catecholamine release have never been tested., Methods: Primary cultures of bovine adrenal chromaffin cells were treated with gabapentin or vehicle for 18-24 h. The authors quantified catecholamine secretion from dishes of cells using high-performance liquid chromatography and resolved exocytosis of individual secretory vesicles from single cells using carbon fiber amperometry. Voltage-gated calcium channel currents were recorded using patch clamp electrophysiology and intracellular [Ca2+] using fluorescent imaging., Results: Gabapentin produced statistically significant reductions in catecholamine secretion evoked by cholinergic agonists (24 ± 3%, n = 12) or KCl (16 ± 4%, n = 8) (mean ± SEM) but did not inhibit Ca2+ entry or calcium channel currents. Amperometry (n = 51 cells) revealed that gabapentin inhibited the number of vesicles released upon stimulation, with no change in quantal size or kinetics of these unitary events., Conclusions: The authors show Ca2+ entry was not inhibited by gabapentin but was less effective at triggering vesicle fusion. The work also demonstrates that chromaffin cells are a useful model for additional investigation of the cellular mechanism(s) by which gabapentin controls neurosecretion. In addition, it identifies altered adrenal catecholamine release as a potential contributor to some of the beneficial perioperative effects of gabapentin.

Effects of a sympatholytic drug on bone marrow stromal and hemopoietic precursors were studied on the model of cyclophosphamide-induced myelosuppression. Sympatholytic treatment increased the content of hemopoietic stem cells of different classes in the bone marrow. Selective stimulation of differentiation of polypotent precursors into granulocyte-macrophage precursors was noted. Acceleration of proliferation and maturation of granulocytic precursors was observed at later terms during regeneration of the hemopoietic tissue. The sympatholytic inhibited proliferation of stromal precursors and reduced feeder activity of fibroblasts for granulocyte precursors.

The effects of catecholamines on longitudinal displacements and intramural shear strain of the arterial wall are unexplored. Therefore, the common carotid artery of five anaesthetized pigs was investigated using an in-house developed noninvasive ultrasonic technique. The study protocol included intravenous infusion of low-dose epinephrine (β-adrenoceptor activation), as well as intravenous boluses of norepinephrine (α-adrenoceptor activation). Further, the effects of β-blockade (metoprolol) were studied. There were significant positive correlations between pulse pressure and longitudinal displacement of the intima-media complex (r = 0.72; P < 0.001), as well as between pulse pressure and intramural shear strain (r = 0.48; P < 0.001). Following administration of norepinephrine, the longitudinal displacement of the intima-media complex and intramural shear strain profoundly increased (median 190%, range 102-296%, and median 141%, range 101-182%, respectively, compared with baseline), also when given during β-blockade (median 228%, range 133-266%, and median 158%, range 152-235%, respectively). During infusion of low-dose epinephrine, the longitudinal displacement of the intima-media complex and intramural shear strain decreased (median 88%, range 69-122%, and median 69%, range 47-117%, respectively, compared with baseline). In conclusion, the present study shows, for the first time, that the longitudinal displacement and intramural shear strain of the porcine carotid artery undergo profound changes in response to catecholamines. Increase in longitudinal displacements seems to be strongly related to α-adrenoceptor activation. Thus metoprolol is insufficient to counteract a profound increase in longitudinal displacement and intramural shear strain following a surge of norepinephrine.

Catecholamines are stress hormones and sympathetic neurotransmitters essential for control of cardiac function and metabolism. However, pathologically increased catecholamine levels may be cardiotoxic by mechanism that includes iron-catalyzed formation of reactive oxygen species. In this study, five iron chelators used in clinical practice were examined for their potential to protect cardiomyoblast-derived cell line H9c2 from the oxidative stress and toxicity induced by catecholamines epinephrine and isoprenaline and their oxidation products. Hydroxamate iron chelator desferrioxamine (DFO) significantly reduced oxidation of catecholamines to more toxic products and abolished redox activity of the catecholamine-iron complex at pH 7.4. However, due to its hydrophilicity and large molecule, DFO was able to protects cells only at very high and clinically unachievable concentrations. Two newer chelators, deferiprone (L1) and deferasirox (ICL670A), showed much better protective potential and were effective at one or two orders of magnitude lower concentrations as compared to DFO that were within their clinically relevant plasma levels. Ethylenediaminetetraacetic acid (EDTA), dexrazoxane (ICRF-187, clinically approved cardioprotective agent against anthracycline-induced cardiotoxicity) as well as selected beta adrenoreceptor antagonists and calcium channel blockers exerted no effect. Hence, results of the present study indicate that small, lipophilic and iron-specific chelators L1 and ICL670A can provide significant protection against the oxidative stress and cardiomyocyte damage exerted by catecholamines and/or their reactive oxidation intermediates. This potential new application of the clinically approved drugs L1 and ICL670A warrants further investigation, preferably using more complex in vivo animal models., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Ketosis is found in various pathophysiological conditions, including diabetes and starvation, that are accompanied by suppression of gonadal activity. The aim of the present study was to determine the role of ketone body in the brain in regulating pulsatile luteinizing hormone (LH) secretion in female rats. Injection of 3-hydroxybutyrate (3HB), a ketone body, into the fourth cerebroventricle (4V) induced suppression of pulsatile LH secretion in a dose-dependent manner in ovariectomized (OVX) rats with an estradiol (E2) implant producing diestrus plasma E2 levels. Plasma glucose and corticosterone levels increased immediately after the 4V 3HB injection, suggesting that the treatment caused a hunger response. The 3HB-induced suppression of LH pulses might be mediated by noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) because a local injection of α-methyl- p-tyrosine, a catecholamine synthesis inhibitor, into the PVN blocked 3HB-induced suppression of LH pulses and PVN noradrenaline release was increased by 4V 3HB injection in E2-primed OVX rats. These results suggest that ketone body sensed by a central energy sensor in the hindbrain may suppress gonadotropin release via noradrenergic inputs to the PVN under ketosis.

One of the major enzymatic cell defenses providing protection from oxidative injury is the TrxR-Trx system. It consists of NADPH and thioredoxin reductase (TrxR), which maintain thioredoxin (Trx) in a reduced state. Perturbing the TrxR-Trx system with the selective TrxR inhibitor auranofin (AuF; 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S-(triethylphosphine) gold) induces oxidative stress by keeping Trx in its oxidized state. We have prepared a family of tri- and tetra-oligopeptides derived from the canonical CxxC motif of the Trx active site and a modified CxC motif. These Trx-mimetic compounds are N- and C-terminal-blocked peptides that consist of two cysteine residues that flank the two-amino-acid CxxC motif (CB4 and CB6) or the single-amino-acid CxC motif (CB3). Catecholamine (CA) secretion in bovine chromaffin cells, which is a highly redox sensitive process, is abolished by AuF. The Trx-mimetic peptides effectively restore CA secretion, as monitored by amperometry in single cells. They also prevent the AuF-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase. In PC12 cells, the alleviation of AuF-induced ERK1/2-MAPK phosphorylation by Trx-like peptides parallels their effect of restoring CA secretion. CB3, CB4, and CB6 act intracellularly and are significantly more potent than the traditional antioxidants NAC, GSH, DTT, AD4 (NAC-amide), and ascorbic acid. Taken together, the CxxC and CxC peptides represent a new family of potent and selective redox compounds that could serve as potential candidates for prevention and treatment of oxidative-stress-related disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by noradrenergic inputs to the PVN.

The cardiovascular protecting effects of resveratrol, an antioxidant polyphenol present in grapes and wine, have been attributed to its vasorelaxing effects and to its anti-inflammatory, antioxidant, and antiplatelet actions. Inhibition of adrenal catecholamine release has also been recently implicated in its cardioprotecting effects. Here, we have studied the effects of nanomolar concentrations of resveratrol on quantal single-vesicle catecholamine release in isolated bovine adrenal chromaffin cells. We have found that 30 to 300 nM concentrations of resveratrol blocked the acetylcholine (ACh) and high K(+)-evoked quantal catecholamine release, amperometrically measured with a carbon fiber microelectrode. At these concentrations, resveratrol did not affect the whole-cell inward currents through nicotinic receptors or voltage-dependent sodium and calcium channels, neither the ACh- or K(+)-elicited transients of cytosolic Ca(2+). Blockade by nanomolar resveratrol of secretion in ionomycin- or digitonin-treated cells suggests an intracellular site of action beyond Ca(2+)-dependent exocytotic steps. The fact that nanomolar resveratrol augmented cGMP is consistent with the view that resveratrol could be blocking the quantal secretion of catecholamine through a nitric oxide-linked mechanism. Because this effect occurs at nanomolar concentrations, our data are relevant in the context of the low circulating levels of resveratrol found in moderate consumers of red wines, which could afford cardioprotection by mitigating the catecholamine surge occurring during stress.

Stress impairs cutaneous wound healing; however, it is unclear how beta-adrenoceptors participates in alterations induced by stress on skin wound repair. Therefore, the aim of this study was to investigate the effects of propranolol, a non-selective beta-blocker, administration on cutaneous wound healing of chronically stressed mice. Male mice were spun at 115 rpm for 15 min every hour from three days before wounding until euthanasia. Control animals were not submitted to stress. Stressed and control animals were treated with propranolol dissolved in water; controls received only water. Propranolol administration began one day before wounding and was continued daily until euthanasia. A full-thickness excisional lesion was performed. Seven and fourteen days later, animals were killed, and lesions were formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin-eosin and immunostained against F4/80 to quantify macrophages, alpha-smooth muscle actin to quantify the myofibroblast density and proliferating cell nuclear antigen to quantify the cell proliferation. Furthermore, matrix metalloproteinases (MMP)-2 and MMP-9 activity, nitrite and hydroxyproline levels and tumor necrosis factor-alpha (TNF-alpha) expression were measured in wound. Stress and control + propranolol groups presented a delay in wound contraction, re-epithelialization, F4/80-positive macrophages, neutrophils and mast cells infiltration, cellular proliferation, angiogenesis, myofibroblastic differentiation, MMP-2 and MMP-9 activation and TNF-alpha expression, whereas an increase in the nitrite levels. Stress + propranolol group presented results similar to control group. In conclusion, stress impairs cutaneous wound healing in mice through beta1- adrenoceptors and beta2-adrenoceptors activation.

Background: A unique opportunity to eradicate cancer is presented immediately after the excision of the primary tumor, but surgical procedures often induce the release of immunosuppressing factors that render cell mediated immunity ineffective. Here we tested the hypothesis that integration of peri-operative immunostimulation and blockade of immunosuppression could synergistically improve post-operative anti-metastatic immunity and long-term survival., Methods: Two syngeneic tumor models in F344 rats were employed, studying post-operative tumor progression. In the first model, survival following laparotomy and CRNK-16 leukemia was studied. Rats were peri-operatively treated with the immuno-stimulant poly I-C (5x0.2 mg/kg/inj), with catecholamine- and prostaglandin-blockers (shown to prevent post-operative immunosuppression: 4.5 mg/kg nadolol, 4 mg/kg indomethacin), with both interventions, or with neither. Long-term survival was assessed thereafter. The second model used the MADB106 mammary adenocarcinoma, assessing its lung tumor retention (LTR) following i.v. inoculation, as well as host marginating-pulmonary NK numbers and activity against this tumor. IL-12 was employed for immunostimulation (4x1.5 microg/kg/inj), with and without the above blockers., Results: Post-operative CRNK-16 survival rates were significantly improved only by the integrated approach of immune stimulation and endocrine blockers. Post-operative MADB106 LTR was additively reduced by the two interventions. Importantly, while IL-12 increased pulmonary NK cytotoxicity against MADB106, surgery markedly suppressed this cytotoxicity in both IL-12 and vehicle treated animals. The blockers prevented this suppression per lung and per single NK cell., Conclusions: Immunostimulation could be rendered ineffective post-operatively due to immunosuppression; therefore integrating endocrine-blocker therapies into the realm of peri-operative immunotherapy could optimize immune control over residual disease, potentially improving clinical outcomes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Nobiletin, a compound of polymethoxy flavones found in citrus fruits, possesses a wide range of pharmacological activities. Here we report the effects of nobiletin on catecholamine secretion in cultured bovine adrenal medullary cells. Nobiletin (1.0-100 microM) concentration-dependently stimulated catecholamine secretion and (45)Ca(2+) influx. Its stimulatory effect of nobiletin on catecholamine secretion was abolished by deprivation of extracellular Ca(2+) and partially inhibited by specific inhibitors of voltage-dependent Ca(2+) channels and Na(+)/Ca(2+) exchangers. On the other hand, nobiletin suppressed catecholamine secretion and (22)Na(+) and (45)Ca(2+) influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner. It also inhibited catecholamine secretion, (22)Na(+) influx and/or (45)Ca(2+) influx induced by veratridine, an activator of voltage-dependent Na(+) channels, and 56 mM K(+), an activator of voltage-dependent Ca(2+) channels. In Xenopus oocytes expressing alpha3beta4 neuronal acetylcholine receptors, nobiletin directly inhibited the current evoked by acetylcholine in a concentration-dependent manner similar to that observed in catecholamine secretion. The present findings suggest that nobiletin, by itself, stimulates catecholamine secretion via activation of voltage-dependent Ca(2+) channels or Na(+)/Ca(2+) exchangers, whereas it inhibits catecholamine secretion induced by acetylcholine through the suppression of Na(+) influx and Ca(2+) influx in cultured bovine adrenal medullary cells.

We studied the effect of blockade of neurotransmitter monoamine reuptake and inhibition of catecholamine synthesis on heart rate variability in outbred albino rats at rest and during acute stress. Amitriptyline increased, while α-methyltyrosine reduced the power of VLF waves in heart rate variability spectrum. The effect of amitriptyline manifested at rest and was most striking under stressful conditions, while the effect of α-methyltyrosine was observed only under conditions of acute stress. This suggests that VLF-band waves in the heart rate variability spectrum have catecholaminergic nature and are determined by activity of the central monoaminergic systems; the role of peripheral adrenergic influences mediated by humoral and nervous regulation in the formation of these waves cannot also be excluded.

Background and Purpose: Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction., Experimental Approach: Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration., Key Results: Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia., Conclusions and Implications: A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Objective: Circulating catecholamines and adrenal steroids are significantly increased following traumatic brain injury, and elevations in plasma catecholamines and cortisol portend a poor outcome. We hypothesize that an increase in the generation of reactive oxygen species from the synthesis of adrenal steroids and catecholamines is responsible for neuronal injury following traumatic brain injury. As a first step in testing this hypothesis, we sought to determine whether or not inhibition of catecholamine synthesis would decrease neuronal damage., Methods and Results: Using PC12 cells as a model of catecholamine synthesizing neurons, and serum deprivation as a method to induce neuronal damage, we show (1) adrenal corticosteroids increase reactive oxygen species formation and apoptosis induced by serum deprivation; (2) the inhibitor of catecholamine synthesis, alpha-methyltyrosine, reduces reactive oxygen species formation and apoptosis in PC12 cells; and (3) that acetazolamide, chlorthalidone, and the neurosteroid, allopregnanolone, which inhibits chloride transport, protect PC12 cells from apoptosis., Conclusions: It may be possible to protect catecholaminergic neurons from reactive oxygen species-induced apoptotic death by not only blocking catecholamine synthesis, but also, by inhibiting carbonic anhydrase-dependent chloride/bicarbonate exchange with acetazolamide or chlorthalidone. These agents may prove salutary in reducing cell death in patients with traumatic brain injury or stroke.

Although the antidepressant mechanism of ECT is unknown, there are data to support noradrenergic involvement. Patients who had been recently successfully treated with ECT for major depression were studied in a randomized double-blind cross-over design comparing catecholamine depletion using alpha-methyl-para-tyrosine to a placebo procedure. Mean MADRS scores at baseline (4.2 SD 2.7) and following depletion (4.6 SD 1.1) were similar, despite a 57.7% decrease in serum homovanillic acid (HVA) and a 61.5% decrease in 3-methoxy-4-hydroxyenylethyleneglycol (MHPG). These data suggest that catecholamine availability may not be necessary for acutely maintaining an antidepressant response to ECT.

High levels of catecholamines are cardiotoxic and may trigger acute myocardial infarction (AMI). Similarly, the synthetic catecholamine isoprenaline (ISO) evokes a pathological state similar to AMI. During AMI there is a marked increase of free iron and copper which are crucial catalysts of reactive oxygen species formation. Rutin, a natural flavonoid glycoside possessing free radical scavenging and iron/copper chelating activity, may therefore be potentially useful in reduction of catecholamine cardiotoxicity as was previously demonstrated after its long-term peroral administration. Male Wistar:Han rats received rutin (46 or 11.5 mg kg(-1) i.v.) alone or with necrogenic dose of ISO (100 mg kg(-1) s.c.). Haemodynamic parameters were measured 24h after drug application together with analysis of blood, myocardial content of elements and histological examination. Results were confirmed by cytotoxicity studies using cardiomyoblast cell line H9c2. Rutin in a dose of 46 mg kg(-1) aggravated ISO-cardiotoxicity while the dose of 11 mg kg(-1) had no effect. These unexpected results were in agreement with in vitro experiments, where co-incubation with larger concentrations of rutin significantly augmented ISO cytotoxicity. Our results, in contrast to previous studies in the literature, suggest that the reported positive effects of peroral administration of rutin were unlikely to have been mediated by rutin per se but probably by its metabolite(s) or by some other, at this moment, unknown adaptive mechanism(s), which merit further investigation.

Iron (Fe) chelators are used clinically for the treatment of Fe overload disease. Iron also plays a role in the pathology of many other conditions, and these potentially include the cardiotoxicity induced by catecholamines such as isoprenaline (ISO). The current study examined the potential of Fe chelators to prevent ISO cardiotoxicity. This was done as like other catecholamines, ISO contains the classical catechol moiety that binds Fe and may form redox-active and cytotoxic Fe complexes. Studies in vitro used the cardiomyocyte cell line, H9c2, which was treated with ISO in the presence or absence of the chelator, desferrioxamine (DFO), or the lipophilic ligand, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH). Both of these chelators were not cardiotoxic and significantly reduced ISO cardiotoxicity in vitro. However, PCTH was far more effective than DFO, with the latter showing activity only at a high, clinically unachievable concentration. Further studies in vitro showed that interaction of ISO with Fe(II)/(III) did not increase cytotoxic radical generation, suggesting that this mechanism was not involved. Studies in vivo were initiated using rats pretreated intravenously with DFO or PCTH before subcutaneous administration of ISO (100 mg/kg). DFO at a clinically used dose (50 mg/kg) failed to reduce catecholamine cardiotoxicity, while PCTH at an equimolar dose totally prevented catecholamine-induced mortality and reduced cardiotoxicity. This study demonstrates that PCTH reduced ISO-induced cardiotoxicity in vitro and in vivo, demonstrating that Fe plays a role, in part, in the pathology observed.

Rationale: Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life., Objectives: To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice., Results: 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.5- to 11.7-fold increases in SERT-/- mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT-/-, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT-/- mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT-/- mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/- mice with no effect in SERT-/- mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT-/- mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT+/- and -/- mice., Conclusions: These studies demonstrate that SERT-/- mice have exaggerated neurochemical, behavioral, and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT-/- mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice.

beta-Adrenoceptor blocking agents (beta-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant beta-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (beta(1H)AR), but cause cardiostimulation mainly through a low-affinity site (beta(1L)AR) of the myocardial beta(1)-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca(2+) current density and Ca(2+) transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca(2+) transients and arrhythmic cardiocyte contractions. Other beta-blockers, which do not cause cardiostimulation, consistently have lower affinity for beta(1L)AR than beta(1H)AR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant beta(1)-adrenoceptors and on beta(1)-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of beta(1H)AR but left intact the pharmacology of beta(1L)AR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

Context: The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD)., Objectives: To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD., Design: Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial., Setting: Psychiatric outpatient clinic., Participants: Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls., Intervention: Induction of CD by oral administration of alpha-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose., Main Outcome Measures: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia)., Results: Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms., Conclusions: This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Angiotensin (AT) II and noradrenaline play major roles in hypertension, stroke and coronary heart disease, which are themselves interlinked. Harmful effects of AT II are not blocked solely by angiotensin-converting enzyme inhibitors, as it is now evident that AT II is generated by other enzymes such as chymase. Angiotensin II also stimulates noradrenaline release modulated by presynaptic receptors on sympathetic nerves. Numerous studies have defined the action of the AT II type 1 receptor blocker (ARB) eprosartan as controlling noradrenergic and adrenergic effects, resulting from actions on the renin-angiotensin-aldosterone system and the sympathetic nervous system. Clinical studies have been carried out to assess the effects of ARBs on morbidity and mortality. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial compared the effects of valsartan and the calcium channel blocker (CCB) amlodipine in over 15,000 patients at high risk of a cardiac event. Results showed that blood pressure was reduced by both treatments and cardiac mortality/morbidity was similar in both groups. By contrast, the Morbidity and mortality after Stroke, Eprosartan compared with nitrendipine for Secondary prevention (MOSES) study (n = 1405) generated results which differed from the VALUE study, in that blood pressure was reduced by both eprosartan and nitrendipine, but eprosartan reduced all cardiovascular and cerebrovascular events to a greater extent than nitrendipine. It is also possible that any delayed clinical benefit of eprosartan could be due to reverse cardiac remodelling. Eprosartan, by blocking AT II receptors, reducing noradrenaline release and blocking catecholamine actions, may, therefore, provide greater protection against vascular events than CCBs or other ARBs.

Neuropathic pain is a personally devastating and costly condition affecting 3-8% of the population. Existing treatments have limited effectiveness and produce relatively frequent adverse effects. Preclinical research has identified many promising pharmacological targets; however, reliable predictors of success in humans remain elusive. At least 50 new molecular entities have reached clinical development including: glutamate antagonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, opioids, cannabinoids, COX inhibitors, acteylcholine modulators, adenosine receptor agonists and several miscellaneous drugs. Eight drugs are in Phase III trials at present. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations and, in future, gene-related therapies. Recent years have heralded an explosion of pharmaceutical development in neuropathic pain, reflecting advanced knowledge of neurobiology and a heightened perception of the commercial value of neuropathic pain therapeutics. In the interest of improving patient care, the authors recommend implementing comparative studies throughout the development process in order to demonstrate the increased value of novel agents.

Background: The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s) to which catecholamines (norepinephrine, epinephrine and dopamine) may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species., Results: Use of specific catecholamine receptor antagonists revealed that only alpha, and not beta, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake., Conclusion: The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

Dysphoria is an integral part of the symptomatology of a variety of clinical states, though there is little empirical data available on the qualitative and quantitative aspects of this phenomenon. The purpose of the study was to administer alphamethyl paratyrosine (AMPT), a catecholamine depleting agent as a chemical probe to induce dysphoria, and document the ensuing changes in mental status. AMPT (4-5 g/day) was administered to a group of medication-free schizophrenic patients (n=13) over a 48 hour period, and changes in their mental status were monitored at 12 hour intervals with the Profile of Mood States (POMS), Addiction Research Center Inventory (ARCI), Drug Attitude Inventory (DAI) and other standardized rating scales. All of the subjects experienced dysphoric responses of variable severity. The profile of changes included blunted pleasure responsivity, clouded thinking, loss of motivation and lowered vigilance. Subtle subjective changes were experienced soon after the first dose of AMPT and the dysphoria steadily worsened, resulting in social withdrawal and personal distress. Subjective responses were the earliest to manifest, followed by akathisia, akinesia and rigidity. We conclude that AMPT induced dopamine depletion is a safe, rapid, reliable and reversible method of studying dysphoric states in humans. The technique is helpful in examining the phenomenology of dysphoria, the temporal relationship between subjective and behavioural consequences of dopamine depletion, and the role of dopamine in mediating subtle aspects of pleasure responsivity, which is in turn crucial to the understanding of treatment non-adherence in schizophrenia and the origins of comorbid substance abuse.