Higher Norepinephrine Research Articles

Abstract # 2041 Biobehavioral effects on epithelial mesenchymal transition in ovarian cancer

Epithelial mesenchymal transition (EMT) is a process by which transformed epithelial cells undergo changes to a more mesenchymal phenotype, thereby enhancing metastasis. We examined effects of beta-adrenergic signaling and/or biobehavioral exposures on EMT polarization in primary ovarian tumor cells and in exosomes, cell-derived vesicles involved in intercellular signaling. Exosomal profiles from 40 ovarian cancer patients with low vs. high social support were examined for EMT polarization. We recently reported a significant up-regulation of 67 mesenchymal-characteristic gene transcripts and down-regulation of 63 epithelial-characteristic transcripts in exosomes of patients with low levels of social support, demonstrating increased EMT polarization (p = 0.0002). Here, genome-wide transcriptome profiling of advanced stage ovarian tumors from 98 patients was performed, and EMT profiles of those above vs. below a median split on tumor norepinephrine (NE) were compared, adjusting for clinical covariates. In vitro stimulation of ovarian cancer cells with NE assessed effects of NE exposure on EMT mediators. High NE tumors showed significant polarization to a more mesenchymal phenotype, as well as decreased expression of a variety of anti-metastatic genes. In two ovarian cancer cell lines, exposure to stress-concentrations of NE significantly increased transcription of EMT mediators SNAI1, SNAI2, and IL6. Induction of EMT gene expression programs by biobehavioral factors and beta-adrenergic signaling provide a plausible pathway through which biobehavioral risk factors may promote ovarian cancer progression.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 inhibits noradrenaline-induced acute increase of blood pressure in rats.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) inhibits protein translation through the phosphorylation of its specific substrate, eEF2. We previously demonstrated that eEF2K expression increases in superior mesenteric artery from spontaneously hypertensive rats (SHR) and that eEF2K mediates development of hypertension in SHR. In addition, we recently revealed that A484954, a selective eEF2K inhibitor induced relaxation via opening smooth muscle inward rectifier K+ (Kir) channel in rat isolated superior mesenteric artery. Here, we further examined the effects of A484954 on contractility and blood pressure (BP) in rats. Isometric contraction of rat isolated superior mesenteric artery was measured. BP was measured by a carotid cannulation method. A484954 (10 µM) inhibited noradrenaline (NA)-induced contraction in a biphasic manner (magnitude of inhibition higher at high dose NA). A484954 also inhibited an α1-receptor agonist, phenylephrine-induced contraction, while it was not biphasic. Specifically, a β-receptor antagonist, propranolol (1 µM) prevented the A484954-mediated inhibition of NA (high-dose)-induced contraction. A484954 (10 µM) potentiated a β-receptor agonist, isoproterenol-induced relaxation, which was completely prevented by BaCl2 (1 mM), a Kir channel blocker. In vivo, A484954 (122 µg/kg) inhibited NA-induced increase of BP in rats. Another eEF2K inhibitor, NH125 (22 µg/kg) also inhibited the NA-induced BP increase in rats. In summary, it was concluded that A484954 lowers NA-induced BP rise perhaps through activation of β2-receptor-Kir channel and subsequent vasorelaxation via inhibiting eEF2K activity.

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome

BackgroundChronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. MethodsWe analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). ResultsA group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. ConclusionWe identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets.

Intrauterine growth restriction (IUGR) increases the risk of developing diabetes in later life, which indicates developmental programming of islets. IUGR fetuses with placental insufficiency develop hypoxemia, elevating epinephrine and norepinephrine (NE) concentrations throughout late gestation. To isolate the programming effects of chronically elevated catecholamines, NE was continuously infused into normally grown sheep fetuses for 7 days. High plasma NE concentrations suppress insulin, but after the NE infusion was terminated, persistent hypersecretion of insulin occurred. Our objective was to identify differential gene expression with RNA sequencing (RNAseq) in fetal islets after chronic adrenergic stimulation. After determining the NE-regulated genes, we identified the subset of differentially expressed genes that were common to both islets from NE fetuses and fetuses with IUGR to delineate the adrenergic-induced transcriptional responses. A portion of these genes were investigated in mouse insulinoma (Min6) cells chronically treated with epinephrine to better approximate the β-cell response. In islets from NE fetuses, RNAseq identified 321 differentially expressed genes that were overenriched for metabolic and hormone processes, and the subset of 96 differentially expressed genes common to IUGR islets were overenriched for protein digestion, vitamin metabolism, and cell replication pathways. Thirty-eight of the 96 NE-regulated IUGR genes changed similarly between models with functional enrichment for proliferation. In Min6 cells, chronic epinephrine stimulation slowed proliferation and augmented insulin secretion after treatment. These data establish molecular mechanisms underlying persistent adrenergic stimulation in hyperfunctional fetal islets and identify a subset of genes dysregulated by catecholamines in IUGR islets that may represent programming of β-cell proliferation capacity.

Can patients with a large sporadic pheochromocytoma and very high norepinephrine secretion be normotensive? Yes, they can!

Can patients with a large sporadic pheochromocytoma and very high norepinephrine secretion be normotensive? Yes, they can!

Transient Increase in Sympathetic Constriction of Mesenteric Arteries from High Fat Diet‐Fed Dahl Salt‐sensitive Female Rats

Obesity (BMI ≥ 30) is a risk factor for hypertension. Obesity‐associated hypertension is a risk factor for cardiovascular disease, stroke, type 2 diabetes and kidney failure. Hypertension is less common in premenopausal women compared to age‐matched men. This disparity fades away after the onset of menopause. Increased sympathoexcitation in the neuroeffector junction leads to increase in constriction of blood vessels. Differences in the mechanism/s neurogenic arterial constriction in male and female are not well understood. We hypothesized that sympathetic nerve activity in high fat diet‐induced hypertension is greater in male than female rat mesenteric arteries (MA). Rats were fed either control (C) or high fat (HF) diet beginning at 3 weeks of age, and used at 10, 17 and 24 weeks on diet. Body weight and systolic blood pressure (SBP) were measured weekly. HF males gained more weight than HF females at all time points. SBP was higher in HF rats compared to C rats in both sexes and across all time points. The estrus cycle stage was determined cytologically by vaginal lavage prior to euthanasia. Mesenteric arteries (Inner diameter; male=275–350 μm, female=245–315 μm) were harvested and mounted in a pressure (60 mmHg) myograph and inner diameter was measured continuously. MA contractile responses to electrical field stimulation (30 stimuli at 0.2–30 Hz) and drug applications were measured. Neurogenic constriction of MA from HF females was greater than HF males at 5 and 10 Hz at 10 wks, and at 5–30 Hz at 17 wks. At 24 wks the difference disappears. Constrictions caused by norepinephrine (NE) and ATP were similar in MA from HF male and female rats. Immunostaining for tyrosine hydroxylase (sympathetic nerve marker) and vesicular nucleotide transporter (ATP marker) revealed greater sympathetic nerve intensity in HF male than female rats at 10 and 24 wks. There was also greater intensity in MA from HF males than HF females at 10 and 17 wks. Moreover, HF males have higher NE and ATP nerve density than HF females at 10 and 17 but not for ATP at 24 wks. MA NE levels were similar in male and female rats. Prejunctional α2‐AR and NE transporter functions were not impaired in MA from HF Dahl salt‐sensitive rats. Taken together, despite sex differences in sympathetic nerve density in MA, we detected only transient sex differences in sympathetic neurogenic arterial constrictions. Contrary to our hypothesis, we found that HF females transiently have an upregulation of neurogenic sympathetic activity and this warrants further investigation into the mechanism.Support or Funding InformationResearch supported by PPG NIH Grant P01HL070687This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β‐adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β‐adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β‐blockade (AUCP ropranolol–AUCS aline, β‐REE) and as a percent (%) of control (AUCP ropranolol÷AUCS aline × 100). β‐REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β‐REE R = −0.58, P = 0.03; %REE R = −0.56, P = 0.04; NE: β‐REE R = −0.55, P = 0.0535; %REE R = −0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.

Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples

Cloninger's biosocial personality theory postulates a biological basis for the basic temperaments. With respect to reward dependence (RD) characterized by a tendency to sustain rewarding behaviors and to prefer behaviors previously associated with reward, he hypothesized low noradrenaline (NA) levels. Previous endocrine and genetic association studies have supported this hypothesis. The aim of the present study was to test for an association between the functional single nucleotide polymorphism rs1611115 (C-970T) on the dopamine-β-hydroxylase (DBH) gene and RD. DBH is an enzyme crucial for the synthesis of NA by catalyzing the oxidative hydroxylation of dopamine to NA.In two independent samples (N=1144 and N=826) of healthy participants we found significant genotype effects (p≤0.0001 and p≤0.05). Carriers of the C allele had significant higher RD scores than carriers homozygous for the T allele.Although the general RD–NA hypothesis was corroborated, the directionality of the observed effect was antithetical. Based on previous functionality studies reporting low enzymatic activity related to the TT genotype, present results indicate high NA levels in subjects scoring high on RD (in contrast to Cloninger's thesis). Future studies have to analyze how DBH activity and NA levels are dependent on the availability of dopamine.

Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice.

Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise.

Comparison Between 2 Strategies of Fluid Management on Blood Loss and Transfusion Requirements During Liver Transplantation

To compare the effects of low central venous pressure (LCVP) and transesophageal Doppler (TED)-guided fluid management on blood loss and blood transfusion during liver transplantation (LTx). Retrospective study. Single institution, university hospital. Adult recipients of LTx. Two groups: control (LCVP G), n=45 with CVP maintained 40% lower than the preoperative value during the preanhepatic phase. The mean arterial pressure was kept >60 mmHg. This group was matched with the second group (TED G); n = 45, in which a TED protocol was followed maintaining the systemic vascular resistance (SVR) more than 750 dynes•s•cm-5. Coagulation defects were corrected following thromboelastometry. Intraoperative blood loss, blood products, perioperative creatinine, lactate, and postoperative patients' stratification according to the Acute Kidney Injury Network classification were compared. Prior to the anhepatic phase, CVP was significantly lower in LCVP G (p < 0.001). TED G tended to have less but nonsignificant, blood loss, packed red blood cells, fresh frozen plasma, and platelets and received significantly less colloid and higher norepinephrine. Lactate was significantly higher in LCVP G at the end of the anhepatic phase and end of surgery while urine output in the preanhepatic phase was significantly lower. Creatinine was significantly lower on postoperative days 1 and 3, and Acute Kidney Injury Network stages were better on postoperative day 1 in TED G. During LTx, TED-guided fluid management, with norepinephrine used to maintain SVR, was similar to LCVP regarding blood loss and transfusion requirements and had better impacts on kidney function and lactate.

Islet adaptations in fetal sheep persist following chronic exposure to high norepinephrine.

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. After an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129 ± 1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were performed again on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P < 0.01) fetal plasma NE concentrations and lowered (P < 0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P < 0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P < 0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P < 0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P < 0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity.

Comparative Analysis of the Potentiating Action of Noradrenaline on Neurogenic Vasoconstriction Diminished by Various Factors

The effect of 0.03-1.0 μM noradrenaline on the neurogenic response to electrical field stimulation of the juvenile rat tail artery segment in control conditions, after cooling from 36 to 25 degrees C, and after solution pH decrease from 7.4 to 6.6 was studied. Noradrenaline was shown to potentiate neurogenic vasoconstriction diminished by low temperature or low pH. Decrease in neurogenic vasoconstriction being equal, low dose noradrenaline was most effective at low temperature and high dose noradrenaline was most effective at low pH. 1.0 μM noradrenaline was equally effective in both cases. Increase in the neurogenic tone of the rat tail artery evoked by noradrenaline at low temperature and acidosis may contribute to decrease in heat emission at low ambient temperature in vivo.

Asiatic acid attenuates renin-angiotensin system activation and improves vascular function in high-carbohydrate, high-fat diet fed rats.

BackgroundIn the rat model of high carbohydrate, high fat (HCHF) diet-induced metabolic syndrome (MS), previous studies have found that asiatic acid has an antihypertensive effect. In this study, we investigated effects of asiatic acid on vascular structure, vascular function and renin-angiotensin system (RAS) in HCHF diet-induced MS rats.MethodsMale Sprague–Dawley rats were divided into three treatment groups for the 15 week study: a control group fed a normal diet, a MS group fed HCHF diet plus 15 % fructose in their drinking water for 15 weeks, and an asiatic acid treated group that received a HCHF diet plus fructose for 15 weeks and also received orally administered asiatic acid (20 mg/kg BW/day) for the final 3 weeks. Vascular structure and function were investigated. AT1 receptor expression in aortic tissues and eNOS protein expression in the mesenteric arteries were detected. The levels of serum angiotensin (Ang) II, angiotensin converting enzyme (ACE) and plasma norepinephrine (NE) were measured. The differences among treatment groups were analyzed by one-way analysis of variance (ANOVA) followed by post-hoc Bonferroni tests.ResultsAt the end of the study, all rats fed a HCHF diet exhibited signs of MS including, hypertension, dyslipidemia and insulin resistance. Vascular remodeling in large and small arteries, overexpression of AT1 receptor, and high levels of serum Ang II and ACE were also observed in MS group (p < 0.05). Contractile responses to sympathetic nerve stimulation were enhanced relating to high plasma NE level in MS rats (p < 0.05). The response to exogenous NE was not changed in the mesenteric bed. Vasorelaxation responses to acetylcholine were blunted in thoracic aorta and mesenteric beds, which is consistent with downregulation of eNOS expression in MS rats (p < 0.05). Restoration of metabolic alterations, hemodynamic changes, RAS and sympathetic overactivity, increased plasma NE, endothelium dysfunction, and downregulation of eNOS expression was observed in the asiatic acid treated group (p < 0.05). However, asiatic acid failed to alleviate vascular remodeling in MS rats.ConclusionOur findings suggest that the observed antihypertensive effect of asiatic acid in MS rats might be related to its ability to alleviate RAS overactivity and improve vascular function with restoration of sympathetic overactivity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1100-6) contains supplementary material, which is available to authorized users.

Increased Energy Expenditure, White Adipose Tissue Browning, And Resistance to Central Obesity And Type 2 Diabetes in Mice Lacking Alpha2‐Adrenoceptors

The three subtypes of α2‐adrenoceptors (ARs) (α2A, α2B and α2C) are Gi‐coupled receptors of which the α2A and α2C subtypes function as autoreceptors to inhibit the release of norepinephrine (NE) and epinephrine (Epi). α2A‐ARs also have important postjunctional functions in regulation of insulin secretion and lipolysis. We have earlier shown that mice lacking α2A‐ARs, and mice lacking receptor subtypes A and C (α2A−/− and α2AC−/− mice, respectively) display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. The purpose of this study was to (1) reveal the roles and mechanisms of sympathoneural vs. adrenomedullary activity on susceptibility to obesity in a longitudinal study setting in mice, and (2) study the efficacy of α2‐AR blockade as a possible target for drug discovery in obesity and type 2 diabetes (T2D). α2A−/−, α2AC−/− and wildtype (WT) C57BL/6J male mice were exposed to 45% high fat diet (HFD) for 9 weeks to study the development of obesity and T2D. In further cohorts of mice, HFD was fed for 3 weeks in order to study the mechanisms just before the weights began to differ. As results, we found that WT and α2A−/− mice gained weight at a similar rate, whereas α2AC−/− mice were more resistant to obesity. However, α2A−/− mice accumulated less visceral fat than WT mice. Food intake did not differ between the groups. WT mice developed T2D, but both knock‐outs remained glucose tolerant. α2A−/−And α2AC−/− mice were physically less active, yet showed higher basal metabolic rate. HFD increased energy expenditure in all groups, but more profoundly in the knock‐outs. Baseline NE and Epi levels were significantly higher in α2A−/− and α2AC−/− mice. However, HFD had strong effects on urine NE and Epi levels in all mice, suggesting that increased weight gain associates with high NE and low Epi, and resistance to obesity with high NE and high Epi. Consequently, adrenalectomy abolished the diet‐resistant phenotype of the α2AC−/− mouse. Furthermore, the knock‐out mice displayed enhanced lipolytic response to β‐AR agonists, and increased amounts of lipids in their feces suggesting altered fat mobilization and absorption. Expression levels of UCP‐1 were higher in knock‐out inguinal white fat (iWAT), whereas HFD suppressed BAT UCP‐1 in all study groups. Leptin‐hypothalamus axis showed normal function, but NE‐induced suppression of hypothalamic neuropeptide Y was not evident in α2A−/− and α2AC−/− mice suggesting it may be under α2A‐AR regulation. In conclusion, obesity is linked with chronic activation of the sympathoneural and suppression of adrenomedullary tones in obesity‐prone C57BL/6J WT mice providing evidence that inducing only NE release may not be a sufficient mechanism for weight loss. We have also shown that depletion of α2A‐AR signalling was effective in preventing obesity‐induced diabetes, and reducing central adiposity by increasing energy expenditure, visceral lipolytic activity and stimulating iWAT browning without affecting food intake; a phenotype resembling the use of direct β‐AR agonists.Support or Funding InformationThis study was supported by the Academy of Finland (grant 252441), Finnish Cultural Foundation and Turku University Foundation.

The Role of Beta-Blockers in the Treatment of Hypertension.

Two major guide-line committees (JNC-8 and NICE UK) have dropped beta-blockers as first-line therapy in the treatment of hypertension. Also, recent meta-analyses (that do not take age into account) have concluded that beta-blockers are inappropriate first-line agents in the treatment of hypertension. This review seeks to shed some light on the "rights and wrongs" of such actions and conclusions. Because the pathophysiology of primary/essential hypertension differs in elderly and younger subjects, the latter being closely linked to obesity and increased sympathetic nerve activity, the author sought to clarify the efficacy of beta-blockers in the younger/middle-aged group in reducing the risk of death, and cardiovascular end-points. Four searches were undertaken, utilising PubMed up to 31st Dec 2015. One search was under the terms "hypertension AND obesity AND sympathetic nerve activity". A second was "hypertension AND plasma noradrenaline/norepinephrine AND survival". A third was "beta-blockers or adrenergic beta-antagonists AND hypertension AND age AND stroke or myocardial infarction or death". A fourth was "meta-analysis of beta-blockers AND hypertension AND age AND death, stroke, myocardial infarction" RESULTS: Diastolic (with or without systolic) hypertension, in contrast to isolated systolic hypertension, occurs primarily in younger subjects, and is linked to overweight/obesity and increased sympathetic nerve activity. In younger/middle-aged hypertensive subjects, high plasma norepinephrine levels are linked (independent of blood pressure) to an increased risk of future cardiovascular events and death. High resting heart rates (a surrogate for high sympathetic nerve activity) likewise predict premature all-cause death, coronary heart disease and cardiovascular events in younger hypertensive subjects. In this younger/middle-aged hypertensive group, antihypertensive agents that increase sympathetic nerve activity (diuretics, dihydropyridine calcium blockers, and angiotensin receptor blockers (ARBs)) do not decrease (and may increase) the risk of myocardial infarction, and are therefore inappropriate first-line agents in this age-group. By contrast, in younger/middle-aged hypertensive subjects (less than 60years old), meta-analysis has shown that beta-blockers are significantly superior to randomised placebo, and at least as effective as randomised comparator agents, in reducing death/stroke/myocardial infarction. In this younger/middle-aged hypertensive group beta-blockers have been shown (vs randomised placebo or diuretics) to reduce the risk of myocardial infarction by 35-50 %, and stroke by 50-55 % (vs placebo), in non-smoker men. Atenolol was at least as effective as ACE-inhibition (captopril) in reducing all 7 cardiovascular endpoints (including stroke which was reduced by 50 %), vs less tight control of blood pressure, in obese hypertensive subjects with type-2 diabetes (UKPDS study); and after 20 years follow-up, atenolol was significantly (23 %) superior to the ACE-inhibitor in reducing the risk of all-cause death (beta-blockers have anti-cancer properties, which maybe relevant). Primary/essential hypertension in younger/middle-age is underpinned by high sympathetic nerve activity. In this age-group high resting heart rates and high plasma norepinephrine levels (independent of blood pressure) are linked to premature cardiovascular events and death. Thus, anti-hypertensive agents that increase sympathetic nerve activity ie diuretics, dihydropyridine calcium blockers, and ARBs, are inappropriate first-line choices in this younger age-group. Beta-blockers perform well vs randomised placebo and other antihypertensive agents regarding reduced risk of death/stroke/myocardial infarction in younger (<60years) hypertensive subjects, and are a reasonable first-line choice of therapy (certainly in men). These facts should be reflected in the recommendations of guideline committees around the world.

Discriminating Depression, Physical and Social Anhedonia by Neurotransmitter Related Challenge Tests

The aim of this study was to investigate, if anhedonia, a salient component of depression, shows similar response patterns to neurotransmitter challenge tests as depression, and if the two questionnaire based components Physical (PA) and Social (SA) Anhedonia can be discriminated by differences in drug related size and time of cortisol responses elicited by the specific serotonin (5- HT) and noradrenaline (NA) reuptake inhibitors citalopram and reboxetine and prolactin responses to the dopamine (DA) agonist bromocriptine orally applied to 36 male volunteers in a double blind balanced cross-over design. Analyses of variance applied to placebo corrected hormone responses revealed that low and late DA responses were characteristics of global Depression and of Physical Anhedonia, and that low DA responses were associated with high NA responses in PA, and with low 5-HT responses in SA. These patterns were explained by differences in transmitter production and receptor sensitivities and proved to be suitable to discriminate PA from SA and from global depression by analysing neurochemical response patterns rather than single means of variables.

P3-19: Treatment with candesartan unmasks higher urinary norepinephrine excretion in white coat hypertensive patients compared to healthy normotensive participants

Objectifs L'hypertension de la blouse blanche est un etat pre-hypertensif relativement frequent, dans lequel le systeme sympathique semble etre implique. L'objectif de cette etude etait de comparer la reponse du systeme nerveux sympathique a un stress orthostatique chez des patients avec une hypertension de la blouse blanche (HBB) et chez des volontaires sains normotendus (NT). Methodes Il s'agissait d'une etude randomisee, croisee, en double aveugle, Candesartan versus placebo. Les patients HBB ont ete inclus si leur pression arterielle (PA) mesuree au cabinet etait ≥ 140/90 mmHg et la PA ambulatoire e jour de traitement, l'hemodynamique systemique et renale, ainsi que la norepinephrine plasmatique (NEp) et l'excretion urinaire de Normetanephrine etaient mesurees a l'etat basal, apres une heure de pression negative au niveau des membres inferieurs a -30 mBar ( lower body negative pressure LBNP), puis apres une heure de recuperation. L'excretion totale de NMNu a ete calculee par la somme cumulee de NMNu excretee durant ces 3 heures. Des t-tests apparies ou non apparies ont ete utilises pour la comparaison. Resultats 25 patients NT et 12 patients HBB ont ete inclus dans l'etude. L'âge moyen et l'IMC etaient respectivement de 31 ± 10,5 ans et de 22 ± 2,2 Kg/m 2 chez les NT tandis que chez les HBB, ils etaient de 40.7 ± 17,8 ans et de 26.7 ± 6,3 Kg/m 2 . Abstract P3-19 – Tableau . PAM de base, norepinephrine plasmatique basale et NMNu cumulee sous placebo et sous candesartan. Placebo Candesartan 16 mg PAM (mmHg) HBB 96,8 ± 11,5 91,8 ± 10,3 NT 79,5 ± 7,6 77,0 ± 6,9 NEp (nM) HBB 1,71 ± 1,31 1,94 ± 0,91 NT 1,30 ± 0,69 1,54 ± 0,73 CumNMNu HBB 178 ± 34 246 ± 32 * NT 135 ± 9 170 ± 12 * ¶ P * P , La PAM etait plus elevee sous placebo et sous candesartan chez les patients HBB compares aux NT. Le traitement par candesartan augmentait l'excretion cumulee de NMNu dans les deux groupes. Comparee au groupe NT, l'excretion cumulee de NMNu etait plus importante chez le groupe HBB apres traitement par candesartan. Conclusion L'excretion urinaire de normetanephrine est plus elevee chez les patients HBB par rapports aux sujets NT apres un traitement par candesartan. Cette surexcretion urinaire de normetanephrine lors du blocage du Systeme Renine Angiotensine Aldosterone pourrait refleter une sensibilite accrue du systeme nerveux sympathique chez les patients avec HBB lors de conditions de stress telles que l'orthostatisme.

The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications

Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.

Abstract P633: Low Serum Vitamin D is Associated with Greater Impairment in Autonomic Function upon Head Up Tilt in Children with Orthostatic Intolerance

In previous work we identified a group of children (n = 48) between the ages of 10-18 years whose diagnostic workup for chronic nausea unexplained by conventional diagnostic tests revealed that 60% had underlying cardiovascular instability (n = 30) presenting as orthostatic intolerance (OI). The OI could be sub-classified based on head up tilt (HUT) testing into three groups: Postural Orthostatic Tachycardia Syndrome (POTS), orthostatic hypotension (OH) and syncope. Children with OI in all three groups had a greater reduction in autonomic control upon HUT manifested as greater loss of baroreflex sensitivity (BRS) and heart rate variability (HRV) and higher norepinephrine levels compared to those in the non OI group. Vitamin D deficiency is associated with impaired vascular responses to vasoconstrictors and alterations in autonomic control mechanisms in adults. In this study we sought to determine if vitamin D level is lower in these pediatric OI subjects and if it correlates with the hemodynamic responses to tilt. Serum 25(OH)D tended to be lower in OI vs non OI (18.6 ± 0.7 ng/ml, n = 25, vs 22.2 ± 2.4 ng/ml, n = 15; p = 0.16). Most importantly 25(OH)D showed a high positive correlation with supine measures of BRS (seq ALL, R = 0.51, p = 0.05), HRV (rMSSD, R = 0.44, p = 0.02) only in the OI group and there was a trend for a negative correlation with sympathovagal balance ( LF/HF ratio: R =-0.35, p = 0.08). Low 25(OH)D correlated with greater loss of both BRS (R = 0.51, p = 0.01) and HRV (R = 0.44, p = 0.05) upon HUT. These findings support the concept that low vitamin D may contribute to impaired responses to tilt in OI subjects. Further work is needed to evaluate if vitamin D supplementation will improve the vascular and hemodynamic responses to tilt and help improve the OI symptoms. Our goal is to provide a safer therapeutic alternative for the treatment of OI in children.

The Association Between Air Pollution And Stress Hormones: Evidence From The Multi-Ethnic Study Of Atherosclerosis

Introduction: Autonomic nervous system effects have been hypothesized as a mechanism of air pollutant health effects, though scant prior epidemiologic research has examined the association between air pollutants and catecholamines. Methods: We examined the association between air pollutants and urinary catecholamines in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study with participants from six US areas. Data from two ancillary studies, the MESA Air Study and the MESA Stress Study, provide exposure and outcome data. Dopamine (DA), epinephrine (EPI), norepinephrine (NE) data were collected from 2004 – 2006 from 1002 white, black and Hispanic participants from the New York and Los Angeles study sites. Urinary analyte concentrations were adjusted for creatinine and log-transformed for analysis. Spatio-temporal models incorporated cohort-specific monitoring and modeled estimated annual average pollutant concentrations (PM2.5 and NOx) at participant's homes the year prior to urine collection. Several covariates were considered confounders: age, race, sex, site, socioeconomic status, cardiovascular disease risk factors (smoking, second hand smoke, BMI, alcohol use and hypertension) and psychosocial stressors (depression, social support, anxiety, anger and chronic stress) and linear regression models were employed. Results: Preliminary models show a 40 ppb higher NOx concentration was associated with 10% higher NE (95% confidence interval (CI): 4%, 20%) and 17% higher EPI level (95% CI: 3%, 33%). A 5 µg/m3 higher PM2.5 concentration was associated with 23% higher EPI (95% CI: 8%, 41%) and 14% higher DA level (95% CI: 5%, 23%). Conclusions: We found a cross-sectional association between several urinary catecholamines and long-term residential concentrations of PM2.5 and NOx. These novel finding support the hypothesis that air pollutant exposures are related to sympathetic nervous system activation; however, additional investigation is warranted.