Reduction Of Norepinephrine Research Articles

Adrenergic chromaffin cells are adrenergic even in the absence of epinephrine.

Adrenal chromaffin cells release epinephrine (EPI) and norepinephrine (NE) into the bloodstream as part of the homeostatic response to situations like stress. Here we utilized EPI-deficient mice generated by knocking out (KO) the phenylethanolamine N-methyltransferase (Pnmt) gene. These Pnmt-KO mice were bred to homozygosis but displayed no major phenotype. The lack of EPI was partially compensated by an increase in NE, suggesting that EPI storage was optimized in adrenergic cells. Electron microscopy showed that despite the lack of EPI, chromaffin granules retain their shape and general appearance. This indicate that granules from adrenergic or noradrenergic cells preserve their characteristics even though they contain only NE. Acute insulin injection largely reduced the EPI content in wild-type animals, with a minimal reduction in NE, whereas there was only a partial reduction in NE content in Pnmt-KO mice. The analysis of exocytosis by amperometry revealed a reduction in the quantum size (-30%) and Imax (-21%) of granules in KO cells relative to the wild-type granules, indicating a lower affinity of NE for the granule matrix of adrenergic cells. As amperometry cannot distinguish between adrenergic or noradrenergic cells, it would suggest even a larger reduction in the affinity for the matrix. Therefore, our results demonstrate that adrenergic cells retain their structural characteristics despite the almost complete absence of EPI. Furthermore, the chromaffin granule matrix from adrenergic cells is optimized to accumulate EPI, with NE being a poor substitute. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.

1196Transvascular pace-capture of aorticorenal ganglia provides a testable procedural endpoint for transcatheter renal artery denervation and identifies a novel therapeutic ablation target for denervation

Abstract Background Transcatheter renal denervation procedures often produces incomplete renal denervation and inconsistent antihypertensive effect. The lack of an intraprocedural method for renal sympathetic nerve function assessment has precluded a rational and physiologically based approach to ensure adequate denervation has been achieved at the time of the procedure. Purpose To demonstrate that it is possible to localise aorticorenal ganglia via transvascular pacing to provide: 1) a testable procedural endpoint for transcatheter renal denervation and, 2) a novel ablation target for renal denervation. Methods High frequency pacing in the inferior vena cava and aorta, invasive blood pressure measurements and renal angiography was performed in sheep (N=19) to identify ARG pace-capture sites by concurrent hypertensive and renal vasoconstrictive responses. Group A (N=5) underwent ink injection labelling at the ARG pace-capture site for histological verification; Group B (N=6) received unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1week post-procedure; and Group C (N=8) had ARG pacing performed prior to and 2–3 weeks after unilateral transcatheter microwave renal denervation. Results ARG pace-capture responses were observed at paired discrete sites in the posterior IVC and anterolateral aorta approximately 40mm above the ipsilateral renal artery. Pacing elicited a mean arterial blood pressure change of 22.2 [IQR 15.5–34.3] mmHg, p<0.001, together with ipsilateral renal vasoconstriction with main renal artery calibre change of −0.42mm [IQR −0.64mm to −0.24mm] measured with quantitative coronary analysis (QCA), p<0.0001, and branch renal artery median pixel density index change −10.4% [IQR −22.7% to −3.0%], p=0.003. Contralateral renal arterial vasoconstriction was not observed consistently at either the main or branch renal artery level. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation caused significant ipsilateral renal denervation with a median hilar functional sympathetic nerve area reduction of 51% [IQR 24%–52%], p=0.043, and renal cortical norepinephrine reduction of 54% [IQR 36%–59%], p=0.043. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing induced renal vasoconstriction and significant ipsilateral renal denervation. Conclusion Localisation of ARG using transvascular pacing is feasible with pace-capture demonstrated by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing induced renal arterial vasoconstriction may indicate successful renal sympathetic denervation, providing a physiological procedural endpoint to guide transcatheter renal denervation. Additionally, ablation of ARG could provide an alternative or adjunctive method for renal denervation. Acknowledgement/Funding University of Sydney; Western Sydney Local health District; National Health and Medical Research Council of Australia; National Heart Foundation (Au)

Clinical Implications

HomeHypertensionVol. 74, No. 3Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published7 Aug 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.13545Hypertension. 2019;74:431is related toProcedural and Anatomical Determinants of Multielectrode Renal Denervation EfficacyAssociation of Blood Pressure Level With Left Ventricular Mass in AdolescentsEdoxaban Versus Warfarin Stratified by Average Blood Pressure in 19 679 Patients With Atrial Fibrillation and a History of Hypertension in the ENGAGE AF-TIMI 48 TrialDeterminants of Biomarker Reduction in Denervation (page 546)Download figureDownload PowerPointCatheter-based radiofrequency renal denervation reduces sympathetic activity and blood pressure with variable success. Among the reasons cited for variability in response was suboptimal procedural performance with incomplete nerve ablation. Further optimization of renal denervation systems and understanding of the dependence of efficacy on the pattern of ablations is necessary. The coupling of quantitative preclinical experiments and computational models provided a comprehensive understanding of the procedural dependence of renal norepinephrine reduction as a biomarker of efficacy. Biomarker effects were shown to track with the percentage of affected nerves in the treated artery segment, such that half-maximal norepinephrine reduction was achieved when >46% of nerves were affected. For 15 W/30 s treatments, threshold effects were only attained when ≥4 electrodes were powered. The total fractions of ablation area and annular coverage were the prime determinants of renal denervation efficacy. Hence, all else being equal, efficacy decreased with increasing vessel diameter owing to an increase in the target area, or when radiofrequency electrodes directed their energy at blood vessels owing to efficient heat clearance and reduced ablation area. Design of new renal denervation therapies should focus on strategies for maximizing total ablation area and arc rather than depth of ablation. In particular, strategies for delivering multiple helically staggered ablations and abrogating the heat clearance effects of periarterial blood vessels seem promising.Association of BP With LV Mass in Adolescents (page 590)Download figureDownload PowerPointHypertension is associated with left ventricular hypertrophy, a risk factor for cardiovascular events. The current guidelines on management of blood pressure (BP) in children recommend evaluation for left ventricular hypertrophy at the time of starting medication to treat hypertension, usually when BP is persistently above the 95th percentile of the normal BP distribution in healthy children. However, the optimal BP percentile associated with left ventricular hypertrophy in youth is unknown. In this multicenter study of 303 adolescents, we found that the 90th percentile for systolic BP resulted in the best balance between sensitivity and specificity for predicting left ventricular hypertrophy. Therefore, our findings indicate that many youths with lower levels of BP than currently recommended for medication treatment may be at risk for BP-related target organ damage. Validation of our findings in other cohorts and examination of other measures of target organ damage are needed to provide additional evidence to inform future BP guidelines on pediatrics.BP and Anticoagulation in Atrial Fibrillation (page 597)Download figureDownload PowerPointHypertension is the most common comorbid condition with atrial fibrillation and is associated with increased risks of stroke and bleeding. Because uncontrolled hypertension is a known risk factor for stroke, cardiovascular mortality, and bleeding in anticoagulated patients, there are concerns that the benefits of direct oral anticoagulants may be modified by blood pressure (BP). Although direct oral anticoagulants compare favorably to warfarin in preventing cardiovascular events and reducing the risk of major bleeding, including intracranial hemorrhage, the relationship between on-treatment BP and the efficacy and safety of direct oral anticoagulants is not fully known. In this post hoc analysis of the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), we examined the efficacy and safety of edoxaban relative to warfarin stratified by average BP during the trial among 19 679 patients with atrial fibrillation, a history of hypertension, and elevated stroke risk. The efficacy and safety of high dose edoxaban relative to warfarin were consistent across the full range of average systolic BP. Further, the superior safety of edoxaban was most pronounced among patients with elevated diastolic BP. As direct oral anticoagulants continue to be underused in patients with atrial fibrillation perceived to be at elevated bleeding risk, including those with uncontrolled hypertension, these findings emphasize the importance of this class of medications in the management of this high-risk patient population. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesProcedural and Anatomical Determinants of Multielectrode Renal Denervation EfficacyAbraham R. Tzafriri, et al. Hypertension. 2019;74:546-554Association of Blood Pressure Level With Left Ventricular Mass in AdolescentsElaine M. Urbina, et al. Hypertension. 2019;74:590-596Edoxaban Versus Warfarin Stratified by Average Blood Pressure in 19 679 Patients With Atrial Fibrillation and a History of Hypertension in the ENGAGE AF-TIMI 48 TrialSungha Park, et al. Hypertension. 2019;74:597-605 September 2019Vol 74, Issue 3 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.119.13545 Originally publishedAugust 7, 2019 PDF download Advertisement

Selective Renal Denervation Guided by Renal Nerve Stimulation in Canine.

Renal nerve stimulation (RNS) can result in substantial blood pressure (BP) elevation, and the change was significantly blunted when repeated stimulation after ablation. However, whether RNS could provide a meaningful renal nerve mapping for identification of optimal ablation targets in renal denervation (RDN) is not fully clear. Here, we compared the antihypertensive effects of selective RDN guided by two different BP responses to RNS and explored the nerve innervations at these sites in Kunming dogs. Our data indicated that ablation at strong-response sites showed a more systolic BP-lowering effect than at weak-response sites (P=0.002), as well as lower levels of tyrosine hydroxylase and norepinephrine in kidney and a greater reduction in plasma norepinephrine (P=0.004 for tyrosine hydroxylase, P=0.002 for both renal and plasma norepinephrine). Strong-response sites showed a greater total area and mean number of renal nerves than weak-response sites (P=0.012 for total area and P<0.001 for mean number). Systolic BP-elevation response to RNS before RDN and blunted systolic BP-elevation to RNS after RDN were correlated with systolic BP changes at 4 weeks follow-up (R=0.649; P=0.012 and R=0.643; P=0.013). Changes of plasma norepinephrine and renal norepinephrine levels at 4 weeks were also correlated with systolic BP changes at 4 weeks (R=0.837, P<0.001 and R=0.927, P<0.001). These data suggest that selective RDN at sites with strong BP-elevation response to RNS could lead to a more efficient RDN. RNS is an effective method to identify the nerve-enriched area during RDN procedure and improve the efficacy of RDN.

Procedural and Anatomical Determinants of Multielectrode Renal Denervation Efficacy.

Radiofrequency renal denervation is under investigation for treatment of hypertension with variable success. We developed preclinical models to examine the dependence of ablation biomarkers on renal denervation treatment parameters and anatomic variables. One hundred twenty-nine porcine renal arteries were denervated with an irrigated radiofrequency catheter with multiple helically arrayed electrodes. Nerve effects and ablation geometries at 7 days were characterized histomorphometrically and correlated with associated renal norepinephrine levels. Norepinephrine exhibited a threshold dependence on the percentage of affected nerves across the range of treatment durations (30-60 s) and power set points (6-20 W). For 15 W/30 s treatments, norepinephrine reduction and percentage of affected nerves tracked with number of electrode treatments, confirming additive effects of helically staggered ablations. Threshold effects were only attained when ≥4 electrodes were powered. Histomorphometry and computational modeling both illustrated that radiofrequency treatments directed at large neighboring veins resulted in subaverage ablation areas and, therefore, contributed suboptimally to efficacy. Account for measured nerve distribution patterns and the annular geometry of the artery revealed that, regardless of treatment variables, total ablation area and circumferential coverage were the prime determinants of renal denervation efficacy, with increased efficacy at smaller diameters.

A Study of the Effect of Derivative of Oximes Pyridine (GIZh-298) on the Contents of Monoamines and Their Metabolites in the Rat Brain during Seizures Induced by Maximal Electroshock

Abstract—We studied the effects of the potential antiepileptic agent GIZh-298 and a comparison drug, topiramate, on the concentration of monoamines and their metabolites in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus in the rat brain after generalized tonic–clonic seizure caused by electroshock (MES). We found that GIZh-298 (60 mg/kg, i.p.) exhibits a pronounced anticonvulsant effect in the test of MES antagonism and prevents the increase in functional activity of the dopaminergic system and the reduction of the norepinephrine (NE) content in the same structure. Topiramate (100 mg/kg, i.p.), as well as the GIZh-298, prevented the emergence of MES-induced seizures and stimulated an increase in the NA level in the striatum to the normal values but did not affect the MES-induced changes in the functional activity of the dopaminergic system of the nigrostriatal system. Therefore, it may be concluded that the modulation of the noradrenergic neurotransmission in the striatum is one of the mechanisms of the anticonvulsant effect of both GIZh-298 and topiramate in the test of MES antagonism and, in addition, GIZh-298, unlike topiramate, contributes to the reduction of the functional activity of the dopaminergic system in this structure in response to MES.

Magnetic resonance imaging of noradrenergic neurons

Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T1-weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R1) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T1-shortening paramagnetic ions in active cells rather than to specific T1-shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(−/−) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(−/−) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(−/−) mice, a transgenic model of Alzheimer’s disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60–75% reduction of noradrenaline is responsible for a reduction of N-acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer’s disease accelerates pathologic processes such as inflammation and neuron loss.

Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland

ABSTRACTBackground and Objective: Evaluate the activity of dopamine-β-hydroxylase (DβH) as well as the effect of the DβH inhibitor nepicastat upon enzyme activity and levels of dopamine (DA) and norepinephrine (NE) in the rat left ventricle, kidney, and adrenal glands.Methods: DβH assay consisted of the enzymatic hydroxylation of tyramine into octopamine, and DA and NE tissues levels were quantified by HPLC-ED.Results: Nepicastat (30 mg/kg, p.o.) reduced DβH activity by 93% and 80% in the adrenals at 4 h and 8 h postdrug administration, accompanied by significant reductions in NE and epinephrine tissue levels and an increase in DA levels and of DA/NE tissue ratios, with similar findings for NE, DA and of DA/NE tissue ratios in left ventricle and kidney. DβH activity in the left ventricle and kidney showed a high degree of variability, which does not allow corroboration of the effects of nepicastat upon catecholamine tissue levels.Conclusion: The assay of DβH activity in heart and kidney lacks the necessary robustness, but DβH activity in the adrenals appears to be an appropriate marker. However, the effect size upon DA/NE tissue ratios (an indirect measure of DβH activity) as induced by nepicastat was very similar in sympathetically innervated tissues, left ventricle and kidney, and the adrenal medulla.

A novel GTPCH deficiency mouse model exhibiting tetrahydrobiopterin-related metabolic disturbance and infancy-onset motor impairments

BackgroundGTP cyclohydrolase I (GTPCH) deficiency could impair the synthesis of tetrahydrobiopterin and causes metabolic diseases involving phenylalanine catabolism, neurotransmitter synthesis, nitric oxide production and so on. Though improvements could be achieved by tetrahydrobiopterin and neurotransmitter precursor levodopa supplementation, residual motor and mental deficits remain in some patients. An appropriate GTPCH deficiency animal model with clinical symptoms, especially the motor impairments, is still not available for mechanism and therapy studies yet. Objectives and methodsTo investigate whether the heterozygous GTPCH missense mutation p.Leu117Arg identified from a patient with severe infancy-onset dopa-responsive motor impairments is causative and establish a clinical relevant GTPCH deficiency mouse model, we generated a mouse mutant mimicking this missense mutation using the CRISPR/Cas9 technology. Series of characterization experiments on the heterozygous and homozygous mutants were conducted. ResultsThe expressions of GTPCH were not significantly changed in the mutants, but the enzyme activities were impaired in the homozygous mutants. BH4 reduction and phenylalanine accumulation were observed both in the liver and brain of the homozygous mutants. Severer metabolic disturbance occurred in the brain than in the liver. Significant reduction of neurotransmitter dopamine, norepinephrine and serotonin was observed in the brains of homozygous mutants. Live-born homozygous mutants exhibited infancy-onset motor and vocalization deficits similar to the disease symptoms observed in the patient, while no obvious symptoms were observed in the young heterozygous mutant mice. With benserazide-levodopa treatment, survival of the homozygous mutants was improved but not completely rescued. ConclusionsThe GTPCH p.Leu117Arg missense mutation is deleterious and could cause tetrahydrobiopterin, phenylalanine and neurotransmitter metabolic disturbances and infancy-onset motor dysfunctions recessively. This is the first GTPCH deficiency mouse model which could be live-born and exhibits significant motor impairments. The different extents of BH4 reduction and phenylalanine accumulation observed between liver and brain in response to GTPCH deficiency gives potential new insights into the vulnerability of brain to GTPCH deficiency.

Antidepressant and anxiolytic effects of the proprietary Chinese medicine Shexiang Baoxin pill in mice with chronic unpredictable mild stress

Depression and anxiety often co-occur with cardiac diseases. The Shexiang Baoxin pill (SBP) is a proprietary Chinese medicine initially used to treat cardiac conditions. This study explored whether SBP has antidepressant and anxiolytic effects in addition to hormonal and psychotropic mechanisms. Mice underwent 6 weeks of chronic unpredictable mild stress (CUMS) to induce depression- and anxiety-like behavior. During the 6-week experiment, mice received SBP at intragastric doses of 20.25 mg/kg or 40.5 mg/kg daily. Animals were then tested for depression in sucrose preference, forced-swimming, and tail suspension paradigms, and for anxiety in open field and elevated plus maze tests. Both SBP doses significantly reduced anhedonic behavior in the sucrose preference test; the high SBP dose also increased the number of entries into the central zone of the open field. SBP-treated mice had markedly lower blood levels of corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) than stressed mice treated with vehicle. Either low- or high-dose SBP reversed stress-induced reductions of norepinephrine (NE) and dopamine (DA) metabolites and the expression levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) in related brain regions. These results suggest that SBP could prevent and alleviate prolonged stress-induced anhedonia and anxiety in association with its suppression of the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, modulation of brain monoamine neurotransmitter metabolism and neurotrophins. SBP may be particularly suitable for the management of depressive and anxiety disorders in patients with cardiac conditions.

CON: Persistent Central Sleep Apnea/Hunter-Cheyne-Stokes Breathing, Despite Best Guideline-Based Therapy of Heart Failure With Reduced Ejection Fraction, Is Not a Compensatory Mechanism and Should Be Suppressed.

CON: Persistent Central Sleep Apnea/Hunter-Cheyne-Stokes Breathing, Despite Best Guideline-Based Therapy of Heart Failure With Reduced Ejection Fraction, Is Not a Compensatory Mechanism and Should Be Suppressed.

A single-center experience with resin adsorption hemoperfusion combined with continuous veno-venous hemofiltration for septic shock patients

Our primary goal was to investigate whether treatment of CVVH-HP in patients with septic shock caused decreased vasoconstrictor and inotropic drug requirements. As a secondary objective, to determine whether CVVH-HP had an effect on inflammatory biomarkers and mortality. 11 septic shock patients who received CVVH-HP treatment within 12 months were included in the study. The following parameters were taken from patientsÂ’ medical records; hemodynamic parameters, infection markers, inotropes and vasopressors use. Also, Intensive care mortality and duration of ICU stay were assessed. The survival rate after the 24 hours from the start of treatment was 63.6% and 28 days survival rate was 36.4%. Four of the remaining seven survivors at the 24 hours were discharged home. CVVH- HP treatment was associated with an increase of mean arterial pressure, reduction of vasoconstrictor/ionotropic requirement, reduction of C-reactive protein and procalcitonin levels. In our retrospective study, we found that patients treated with CVVH-HP treatment had approximately 40% reduction in norepinephrine and dopamine requirement in the first 24 hours and patients had higher mean arterial pressures.

Xenon as an Adjuvant to Propofol Anesthesia in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery: A Pragmatic Randomized Controlled Clinical Trial.

Xenon was shown to cause less hemodynamic instability and reduce vasopressor needs during off-pump coronary artery bypass (OPCAB) surgery when compared with conventionally used anesthetics. As xenon exerts its organ protective properties even in subanesthetic concentrations, we hypothesized that in patients undergoing OPCAB surgery, 30% xenon added to general anesthesia with propofol results in superior hemodynamic stability when compared to anesthesia with propofol alone. Fifty patients undergoing elective OPCAB surgery were randomized to receive general anesthesia with 30% xenon adjuvant to a target-controlled infusion of propofol or with propofol alone. The primary end point was the total intraoperative dose of norepinephrine required to maintain an intraoperative mean arterial pressure >70 mm Hg. Secondary outcomes included the perioperative cardiorespiratory profile and the incidence of adverse and serious adverse events. Adding xenon to propofol anesthesia resulted in a significant reduction of norepinephrine required to attain the predefined hemodynamic goals (cumulative intraoperative dose: median [interquartile range]: 370 [116-570] vs 840 [335-1710] µg, P = .001). In the xenon-propofol group, significantly less propofol was required to obtain a similar depth of anesthesia as judged by clinical signs and the bispectral index (propofol effect site concentration [mean ± SD]: 1.8 ± 0.5 vs 2.8 ± 0.3 mg, P≤ .0001). Moreover, the xenon-propofol group required significantly less norepinephrine during the first 24 hours on the intensive care unit (median [interquartile range]: 1.5 [0.1-7] vs 5 [2-8] mg, P = .048). Other outcomes and safety parameters were similar in both groups. Thirty percent xenon added to propofol anesthesia improves hemodynamic stability by decreasing norepinephrine requirements in patients undergoing OPCAB surgery.

Neuropsychological effects of occupational exposure to polychlorinated biphenyls

In the context of a health surveillance program for former PCB-exposed workers of a transformer and capacitor recycling company in Germany, their family members, employees of surrounding companies and area residents a broad range of cognitive functions covering attention, executive processing, reasoning, memory and motor performance was examined. The study aimed at identifying potential adverse effects of PCB load on cognitive functions. Detailed analysis of PCB burden of the participants revealed rather high correlations of lower and higher chlorinated as well as dioxin-like PCBs. Nearly one half of the participants exhibited increased burden in all three PCB classes whereas only 33 out of 237 participants did not show any increased PCB burden. Thus, data analysis followed a two-fold strategy: (1) Based on studies providing data on PCB exposure of the German general population the PCB burden of every participant was classified as normal (percentile rank PR <95) or increased (PR ≥95). Increased burden with respect to lower (LPCBs) and higher chlorinated (HPCBs) as well as dioxin-like (dlPCBs) PCBs was assumed if a participant showed at least one congener surpassing the PR95 criterion for the respective congener class and (2) Overall plasma PCB level per congener class was used as measure of PCB load. In a multivariate approach using structural equation modelling and multiple regression analysis we found a significant impact of PCBs on word fluency and sensorimotor processing irrespective of the measure of PCB burden (PR95 criterion or overall plasma level). However, no effect of PCB burden on memory, attention, and cognitive flexibility could be demonstrated. Particularly, an increase of LPCBs was associated with an overall reduction of verbal fluency of letter and semantic word generation as well as word production based on a single or two alternating criteria. In addition, participants with increased burden of LPCBs exhibited a time-on-task effect in terms of a stronger decline of performance with increasing duration of the verbal fluency task. Moreover, we found adverse effects of HPCBs on Aiming and of dlPCBs on Line Tracking. Results are discussed in terms of (1) a decrease of cerebral dopamine (DA) with non-coplanar PCBs resulting in an impact on fronto-striatal cerebral structures subserving verbal fluency and motor processing, (2) a PCB-induced reduction of norepinephrine leading to the time-on-task effect with verbal fluency, and (3) adverse effects of PCBs on dopaminergic receptors in the cerebellum resulting in impaired fine motor function.

Radiosurgical Ablation of the Renal Nerve in a Porcine Model: A Minimally Invasive Therapeutic Approach to Treat Refractory Hypertension.

BackgroundHypertension is strongly associated with cardiovascular diseases such as heart failure, stroke, kidney disease, and has been correlated with an increased risk for heart attack. Current treatment regimens for hypertension are highly inadequate, with reports indicating that only 50.1% of the clinical population with the disease has their blood pressure under control.ObjectiveTo study the feasibility of using minimally invasive radiosurgery to ablate the renal nerves as a novel treatment for refractory hypertension, and to assess the safety and efficacy of such an approach.MethodsA Hanford porcine (miniswine) model (N = 6) was used to investigate the feasibility of using the CyberHeart radiosurgical platform (CyberHeart Inc., Mountain View, CA, USA) to create safe renal nerve ablations. Norepinephrine (NE) levels were measured pre and post treatment. Additionally, renal nerve and arterial histology were studied to examine effect.ResultsPlasma norepinephrine levels showed a decrease over the six-month time point. Urea, nitrogen, and creatinine levels showed no changes post procedure. Histology documented no significant arterial injury in targeted areas. Renal nerves documented histologic change consistent with nerve ablation.ConclusionCyberHeart radiosurgery of the renal nerve is feasible and resulted in norepinephrine reduction and renal nerve injury consistent with radiosurgical targeted ablation.

Renal Artery Vasodilation May Be An Indicator of Successful Sympathetic Nerve Damage During Renal Denervation Procedure.

Autonomic nervous system plays a crucial role in maintaining and regulating vessel tension. Renal denervation (RDN) may induce renal artery vasodilation by damaging renal sympathetic fibers. We conducted this animal study to evaluate whether renal artery vasodilation could be a direct indicator of successful RDN. Twenty-eight Chinese Kunming dogs were randomly assigned into three groups and underwent RDN utilizing temperature-controlled catheter (group A, n = 11) or saline-irrigated catheter (group B, n = 11) or sham procedure (group C, n = 6). Renal angiography, blood pressure (BP) and renal artery vasodilation measurements were performed at baseline, 30-minute, 1-month, and 3-month after interventions. Plasma norepinephrine concentrations were tested at baseline and 3-month after intervention. Results showed that, in addition to significant BP reduction, RDN induced significant renal artery vasodilation. Correlation analyses showed that the induced renal artery vasodilation positively correlated with SBP reduction and plasma norepinephrine reduction over 3 months after ablation. Post hoc analyses showed that saline-irrigated catheter was superior to TC catheter in renal artery vasodilation, especially for the acute dilatation of renal artery at 30-minute after RDN. In conclusion, renal artery vasodilation, induced by RDN, may be a possible indicator of successful renal nerve damage and a predictor of blood pressure response to RDN.

Common functional pain syndromes

### Key points When a patient presents with pain of no obvious organic origin, they are often labelled as having ‘functional’ pain. The exact diagnosis is derived from the organ system displaying the predominant symptoms e.g. musculoskeletal pain in fibromyalgia (FM) or visceral pain in irritable bowel syndrome (IBS). The worldwide prevalence of all functional pain syndromes (FPS) is 15–20%. World Health Organization (WHO) surveys reveal that ∼10% of primary care patients develop a chronic pain condition within 12 months of initial registration. Of these, at least 50% continue to have symptoms beyond 1 yr. FPS cause enormous economic burden on society with concurrent ramifications for the individual's family in particular and society in general. FM alone has been estimated to cost around £4000 per patient per year. There has been a paradigm shift in the understanding of FPS. The old model of multiple discrete chronic pain conditions is being replaced by a more overarching, although no less complex, state of central sensitivity syndrome (CSS). Evidence is being accrued that FPS represent the phenotypic output of a complex interplay between genetic susceptibility, gene–environment interactions, and environmental triggers. Four common FPS will be reviewed in this article: FM, IBS, temporomandibular dysfunction (TMD), and chronic cardiac chest pain (CCCP). The pathophysiology and management of each will be examined and the case presented for a shared underlying mechanism called CSS. Once this new mechanism is adopted more widely, it will allow for future novel management options to be …

Effects of vagus nerve stimulation on cognitive functioning in rats with cerebral ischemia reperfusion.

BackgroundVagus nerve stimulation (VNS) has become the most common non-pharmacological treatment for intractable drug-resistant epilepsy. However, the contribution of VNS to neurological rehabilitation following stroke has not been thoroughly examined. Therefore, we investigated the specific role of acute VNS in the recovery of cognitive functioning and the possible mechanisms involved using a cerebral ischemia/reperfusion (I/R) injury model in rats.MethodsThe I/R-related injury was modeled using occlusion and reperfusion of the middle cerebral artery (MCAO/R) in Sprague–Dawley rats. VNS was concurrently applied to the vagus nerve using a stimulation intensity of 1 mA at a fixed frequency of 20 Hz with a 0.4-ms bipolar pulse width. The stimulation duration and inter-train interval were both 3 s. Next, Morris water maze and shuttle-box behavioral experiments were conducted to assess the effects of VNS on the recovery of learning, memory, and inhibitory avoidance following I/R injury. Intracerebroventricular injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective neurotoxin for noradrenergic neurons, was used to evaluate the role of norepinephrine (NE) as a mediator of therapeutic effects of VNS on cognitive recovery.ResultsCompared with the MCAO/R group, the VNS+MCAO/R group had improved spatial memory as indicated by swimming path lengths and escape latencies in the Morris water maze, and fear memory, as indicated by the avoidance conditioned response rate, mean shock duration, and avoidance time in shuttle-box behavior experiments. Compared with the VNS+MCAO/R group, the DSP-4+VNS+MCAO/R group, which had reduced NE levels in cortical and hippocampal brain regions, showed a reversal of the VNS-induced benefits on spatial and fear memory performance.ConclusionsVNS improves spatial and fear memory in a rat model of MCAO/R injury. However, a reduction in NE from the administration of DSP-4 blocks these protective effects, suggesting that NE may contribute to the influence exhibited by VNS on memory performance in rats with cerebral I/R-related injury.

6-Hydroxydopamine-Induced Dopamine Reductions in the Nucleus Accumbens, but not the Medial Prefrontal Cortex, Impair Cincinnati Water Maze Egocentric and Morris Water Maze Allocentric Navigation in Male Sprague-Dawley Rats.

The nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) receive dopaminergic innervation from the ventral tegmental area and are involved in learning. Male rats with 6-hydroxydopamine (6-OHDA)-induced dopaminergic and noradrenergic reductions in the Nacc or mPFC were tested for allocentric and egocentric learning to determine their role in these forms of neuroplasticity. mPFC dopaminergic and noradrenergic reductions did not result in changes to either type of learning or memory. Nacc dopaminergic and noradrenergic reductions resulted in allocentric learning and memory deficits in the Morris water maze (MWM) on acquisition, reversal, and probe trials. MWM cued performance was also affected, but straight-channel swim times and swim speed during hidden platform trials in the MWM were not affected. Nacc dopaminergic and noradrenergic reductions also impaired egocentric learning in the Cincinnati water maze (CWM). Nacc-lesioned animals tested in the CWM in an alternate path through the maze were not significantly affected. 6-OHDA injections in the Nacc resulted in 63% dopamine and 62% norepinephrine reductions in the Nacc and 23% reductions in adjacent dorsal striatum. 6-OHDA injections in the mPFC resulted in 88% reductions in dopamine and 59% reductions in norepinephrine. Hence, Nacc dopamine and/or norepinephrine play a role in egocentric and allocentric learning and memory, while mPFC dopamine and norepinephrine do not.

Renal sympathetic denervation using MR-guided high-intensity focused ultrasound in a porcine model.

BackgroundInitial catheter-based renal sympathetic denervation (RSD) studies demonstrated promising results in showing a significant reduction of blood pressure, while recent data were less successful. As an alternative approach, the objective of this study was to evaluate the feasibility of using magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) to perform RSD in a porcine model.MethodsAn intravascular fiber optic temperature probe was used to confirm energy delivery during MRgHIFU. This technique was evaluated both in a vascular phantom and in a normotensive pig model. Five animals underwent unilateral RSD using MRgHIFU, and both safety and efficacy were assessed. MRI was used to evaluate the acoustic window, target sonications, monitor the near-field treatment region using MR thermometry imaging, and assess the status of tissues post-procedure. An intravascular fiber optic temperature probe verified energy delivery. Animals were sacrificed 6 to 9 days post-treatment, and pathological analysis was performed. The norepinephrine present in the kidney medulla was assessed post-mortem.ResultsAll animals tolerated the procedure well with no observed complications. The fiber optic temperature probe placed in the target renal artery confirmed energy delivery during MRgHIFU, measuring larger temperature rises when the MRgHIFU beam location was focused closer to the tip of the probe. Following ablation, a significant reduction (p = 0.04) of cross-sectional area of nerve bundles between the treated and untreated renal arteries was observed in all of the animals with treated nerves presenting increased cellular infiltrate and fibrosis. A reduction of norepinephrine (p = 0.14) in the kidney medulla tissue was also observed. There was no indication of tissue damage in arterial walls.ConclusionsPerforming renal denervation non-invasively with MRgHIFU was shown to be both safe and effective as determined by norepinephrine levels in a porcine model. This approach may be a promising alternative to catheter-based strategies.