Norepinephrine Spillover Rate Research Articles

Evaluation of elevated heart rate as a sympathetic nervous system biomarker in essential hypertension.

There is a need for an easily accessible biomarker of sympathetic nervous activation in essential hypertension, but none exists. Heart rate (HR) has been suggested, but requires validation, now doubly important as an elevated HR in hypertension has emerged as an independent cardiovascular risk factor. Isotope dilution methodology was used to measure total and regional noradrenaline spillover and adrenaline secretion rates in 30 patients with unmedicated essential hypertension and in a comparator group of 48 healthy participants with normal blood pressure. The particular interest was in the relationship of measured HR to cardiac noradrenaline spillover, the measure of cardiac sympathetic activity. Sympathetic activation was present in the patients with essential hypertension, evident in significantly increased mean cardiac, renal and total noradrenaline spillover rates. Adrenaline secretion was normal. HR in hypertension correlated directly with cardiac noradrenaline spillover (r = 0.82, P = 9.3 × 10), but not with renal noradrenaline spillover or adrenaline secretion. 67% of the variance in HR was attributable to differences in cardiac sympathetic activity. Among hypertensive patients there was no internal correlation between cardiac noradrenaline spillover, renal noradrenaline spillover and adrenaline secretion; the sympathetic activation commonly was not 'global'. In healthy participants HR did not correlate with measures of sympathetic activity or adrenaline secretion. When sympathetic activation exists in essential hypertension it is differentiated, not necessarily involving all sympathetic outflows. An elevated HR proved to be a biomarker of cardiac sympathetic activation but not activation of the renal sympathetic outflow. Identifying activation of the cardiac sympathetic outflow as the prime mechanism of hypertension tachycardia is relevant to therapies which should now be considered to minimize cardiovascular risk in this clinical setting. Is an elevated HR a valid biomarker of sympathetic activation in essential hypertension? Yes, but only for the cardiac sympathetic outflow. The unavoidable principle is that regional differentiation of sympathetic responses in essential hypertension means that no simple test can ever represent each and every sympathetic outflow.

Liver sympathetic nerve activity and steatosis.

Liver sympathetic nerve activity and steatosis.

Effects of weight changes in the autonomic nervous system: A systematic review and meta-analysis

Obesity has been linked to autonomic dysfunction, which is thought to be one of the main contributors for hypertension, cardiac remodelling and death. Exercise and diet-based weight loss are the mainstay therapy for obesity, but there is a paucity of data regarding the effect of weight changes in autonomic nervous system (ANS) activity. To describe the impact of weight changes in autonomic nervous system. A systematic literature search of four biomedical databases was performed evaluating effects of weight changes, thorough diet and/or exercise-based interventions, in the following ANS outcomes: heart rate variability, namely low frequency (LF)/high frequency (HF) ratio (LF/HF ratio), normalized units of LF (LFnu) and HF (HFnu), muscle sympathetic nerve activity (MSNA), noradrenaline spillover rate (NA-SR), standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), baroreflex sensitivity and pupillometry. Quality appraisal was performed using the GRADE methodology and, where fitting, studies with comparable outcomes were pooled for meta-analysis. Twenty-seven studies - 7 controlled clinical trials and 20 observational studies - were included. Weight gain was reported in 4 studies and weight loss in all the other studies. Interventions inducing weight changes included: hypocaloric or hypercaloric diets, exercise (strength, endurance or aerobic training) and hypocaloric diet coupled with exercise programs. Most studies which resulted in weight loss reported decreases in LF/HF ratio, LFnu, MSNA burst frequency and incidence, NA-SR, and an increase of baroreflex sensitivity, HF, HFnu and RMSSD, pointing to a parasympathetic nervous system activation. Meta-analysis regarding weight loss interventions showed a significant pooled effect size (95% CI) with a decreased of MSNA burst frequency-5.09 (-8.42,-1.75), MSNA incidence-6.66 (-12.40,-0.62), however this was not significant for SDNN 14.32 (-4.31, 32.96). Weight gain was associated with an increase in LF/HF, LFnu, MSNA burst frequency and incidence. The weight loss effects were potentiated by the association of hypocaloric diet with exercise. Nevertheless, weight changes effects in these outcomes were based in low or very low quality of evidence. Diet and exercise based weight loss appears to increase parasympathetic and decrease sympathetic activity, the opposing effects being observed with weight gain. These findings are not uniformly reported in the literature, possibly due to differences in study design, methodology, characteristics of the participants and techniques used to estimate autonomic nervous activity.

Comparable Attenuation of Sympathetic Nervous System Activity in Obese Subjects with Normal Glucose Tolerance, Impaired Glucose Tolerance, and Treatment Naïve Type 2 Diabetes following Equivalent Weight Loss.

Background and Purpose: Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss.Methods: Un-medicated obese individuals categorized as normal glucose tolerant (NGT, n = 15), impaired glucose tolerant (IGT, n = 24), and newly-diagnosed T2D (n = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m2), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test.Results: Weight loss averaged −7.5 ± 0.8, −8.1 ± 0.5, and −8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC0−120) compared to NGT and IGT (group effect, P <0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group × time, P = 0.04). The magnitude of reduction in MSNA (−7 ± 3, −8 ± 4, −15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (−28 ± 8, −18 ± 6, and −25 ± 7%, respectively), time effect both P <0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC0−120 was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA.Conclusions: Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention.

Clinical experimental stress studies: methods and assessment

Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Stress induction methods are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these methods are also important for the development of novel pharmacological agents for stress management. The well-described methods to induce stress in humans include the cold pressor test, Trier Social Stress Test, Montreal Imaging Stress Task, Maastricht Acute Stress Test, CO2 challenge test, Stroop test, Paced Auditory Serial Addition Task, noise stress, and Mannheim Multicomponent Stress Test. Stress assessment in humans is done by measuring biochemical markers such as cortisol, cortisol awakening response, dexamethasone suppression test, salivary α-amylase, plasma/urinary norepinephrine, norepinephrine spillover rate, and interleukins. Physiological and behavioral changes such as galvanic skin response, heart rate variability, pupil size, and muscle and/or skin sympathetic nerve activity (microneurography) and cardiovascular parameters such as heart rate, blood pressure, and self-reported anxiety are also monitored to assess stress response. This present review describes these commonly employed methods to induce stress in humans along with stress assessment methods.

Renal denervation using catheter-based radiofrequency ablation with temperature control: renovascular safety profile and underlying mechanisms in a hypertensive canine model

Objective: Renal denervation is a novel method for hypertension treatment. In this study, we aimed to investigate the safety and efficacy of radiofrequency ablation (RFA) at ablation temperatures of 45 °C or 50 °C and its possible mechanisms. Methods: A hypertensive canine model was established by abdominal aortic constriction in 20 healthy hybrid dogs. These dogs were then randomly assigned to the treatment and the control groups, with dogs in the treatment group further randomly assigned to receive RFA at ablation temperatures of 45 °C or 50 °C. In the treatment group, RFA was performed at 1 month after modeling; renal angiography was performed at 2 months after ablation. The arterial vessels of the dogs were examined histologically with hematoxylin and eosin staining. Changes in blood pressure in the foreleg and whole-body norepinephrine spillover rate were also assessed. Results: No arterial stenosis, dissection, thrombosis or other abnormalities were detected in the treated vessels by renal angiography, yet histology results showed minimal to mild renal arterial injury. Renal denervation resulted in a marked decrease in the whole-body norepinephrine spillover rate (p < 0.05) in addition to significantly reducing blood pressure (p < 0.05), with no significant differences detected between the 45 °C and 50 °C subgroups for both (p > 0.05). Conclusion: Renal denervation can be performed without acute major adverse events, using catheter-based RFA with temperature control. The procedure was feasible in reducing blood pressure by at least partially inhibiting sympathetic drive and systemic sympathetic outflow.

A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.

Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

Sympathetic Nervous System Moves Toward Center Stage in Cardiovascular Medicine

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

The effects of dietary weight loss on indices of norepinephrine turnover: Modulatory influence of hyperinsulinemia

This study was conducted to examine (1) the effects of dietary weight loss on indices of norepinephrine (NE) turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations. Obese individuals aged 56 ± 1 year, BMI 32.5 ± 0.4 kg/m(2) , with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylglycol (DHPG), and NE concentrations, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates. Body weight decreased by -7.4 ± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE, and DHPG averaging -14 ± 5% (P = 0.001), -23 ± 4% (P <0.001), and -5 ± 4% (P = 0.03), respectively. NE spillover rate decreased by -88 ± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE and NE spillover rate, compared to normoinsulinemic subjects (group by time interaction P < 0.05). Weight loss is associated with down-regulation of sympathetic nervous activity but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.

Effects of intermittent standing bouts during the workday on energy expenditure in desk-bound office workers

Background: Chronic sympathetic nervous system overactivity is a characteristic of the metabolic syndrome that contributes to insulin resistance, target organ damage and a worse clinical prognosis. Plasma noradrenaline (NE) levels reflect the dynamic interplay of synthesis, release and disposition. Objectives: This study was conducted to examine (1) the effects of dietary weight loss on indices of noradrenaline turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations. Subjects and methods: Obese individuals aged 56± 1 yr, body mass index 32.5± 0.4 kg/m2, with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylglycol (DHPG) concentrations, intraneuronal precursor and metabolite respectively of NE, arterial NE, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates. Hyperinsulinemia was defined as an insulin AUC0—120 during oral glucose tolerance test > 10,000mU/Lmin. Results: Body weight decreased by −7.4± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE and DHPG averaging −14± 5% (P = 0.001), −23± 4% (P < 0.001) and −5± 4% (P = 0.03), respectively. NE spillover rate decreased by −88± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE, NE spillover rate and diastolic blood pressure, compared to normoinsulinemic subjects (group by time interaction P < 0.05). Change in insulin AUC0—120 during weight loss, independently predicted the reduction in NE level. Conclusions: Weight loss is associated with down regulation of NE production and reduced spillover rate into plasma, but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.

The Relation of Glucose Metabolism to Left Ventricular Mass and Function and Sympathetic Nervous System Activity in Obese Subjects With Metabolic Syndrome

Altered cardiac structure and function have been reported in prediabetic and diabetic populations; however, the contribution of the sympathetic nervous system (SNS) to these changes has yet to be delineated. Our objective was to examine interrelationships between glucose metabolism, left ventricular mass and function, and SNS activity in obese metabolic syndrome subjects. Unmedicated impaired glucose tolerant (IGT) (n = 31) or treatment-naive type 2 diabetic (T2D) (n = 25) subjects, matched for age (mean 58 ± 1 years), gender, body mass index (32.2 ± 0.5 kg/m(2)), and blood pressure, participated. They underwent echocardiography and assessments of whole-body norepinephrine kinetics, muscle sympathetic nerve activity, and insulin sensitivity by euglycemic clamp (M value). T2D subjects had higher left ventricular mass index (LVMI) (93.6 ± 3.5 vs 77.2 ± 3.4 g/m(2), P = .002) and Doppler-derived isovolumetric relaxation and deceleration times (both P < .05) and lower early/late transmitral inflow velocities (E/A) (P = .02) compared with IGT. Total muscle sympathetic nerve activity and arterial norepinephrine concentration were higher in the T2D group (by 18% and 32%, respectively, both P ≤ .05), whereas plasma norepinephrine clearance was reduced (1.94 ± 0.11 vs 2.26 ± 0.10 L/min, P = .02). M value correlated inversely with left ventricular septal thickness (r = -0.46, P = .007). Whole-body noradrenaline spillover rate correlated with LVMI in the T2D subgroup (r = 0.47, P = .03). In the pooled cohort, LVMI was independently predicted by pulse pressure (r = 0.38, P = .004) and E/A ratio by 2-hour glucose (r = -0.38, P = .005). Transition from IGT to T2D is associated with cardiac enlargement and diastolic dysfunction, which relate to metabolic, hemodynamic, and SNS alterations.

Response to Comment on: Straznicky et al. neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects. Diabetes 2012;61:2506-2516.

We wish to thank Dr. Frontoni (1) for her insightful comments regarding the disparate relationship of glucose utilization to two indices of sympathetic nervous system activity—whole-body norepinephrine spillover rate and muscle sympathetic nerve activity (MSNA), within our cohort of obese metabolic syndrome subjects (2). Both arterial norepinephrine concentration and norepinephrine spillover rate showed a strong inverse relationship with clamp-derived glucose utilization (M/I value, r = −0.47, P = 0.008), whereas MSNA was not significantly associated with glucose utilization. Rather, total MSNA was influenced by the prevailing insulin concentration as indicated by positive associations with fasting C-peptide levels ( r = 0.37, P = 0.04) and insulin area under the curve …

Renal nerve ablation reduces blood pressure in a patient with renovascular hypertension resistant to drug and revascularisation therapies

Amongst specific causes of secondary hypertension renovascular hypertension remains the second most common form which frequently presents with resistance to pharmacologic treatment. Activation of both the renin–angiotensin system and the sympathetic nervous system are well recognized mechanisms involved in renovascular hypertension as evidenced by increased plasma renin activity and angiotensin II levels, as well as increased rates of efferent sympathetic-nerve firing and total body noradrenaline spillover [1,2].

The Effects of Weight LossVersusWeight Loss Maintenance on Sympathetic Nervous System Activity and Metabolic Syndrome Components

Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity. We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components. Untreated subjects (14 males, four females; mean age, 53 ± 1 yr; body mass index, 30.9 ± 0.9 kg/m(2)) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n = 8) or together with aerobic exercise training (n = 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed. Body weight decreased by 9.3 ± 0.8% at wk 12 (P < 0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23 ± 16% (P = 0.004), MSNA by 25 ± 3 bursts per 100 heartbeats (P < 0.001), and PRA by 0.25 ± 0.09 ng/ml · h (P = 0.007), whereas baroreflex sensitivity increased by 5.2 ± 2.2 msec/mm Hg (P = 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24 ± 0.11 ng/ml · h, P = 0.02; and 20 ± 5 bursts/100 heartbeats, P = 0.0003), and baroreflex sensitivity was attenuated. Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance.

Neuroadrenergic dysfunction in obesity: an overview of the effects of weight loss

The prevalence of obesity is rising to epidemic proportions worldwide, and in tandem so is that of type 2 diabetes. Neuroadrenergic abnormalities, comprising increased resting sympathetic nervous system activity and blunted sympathetic neural responsiveness are recognized features of metabolic syndrome obesity, which contribute importantly to both the pathophysiology and adverse clinical prognosis of this high-risk population. Weight loss is recommended as first-line treatment for obesity. This review examines the effects of nonpharmacological weight loss on sympathetic nervous system function under basal and stimulated conditions. Human weight loss trials show that even moderate weight reduction is accompanied by significant attenuation in resting whole-body norepinephrine spillover rate and muscle sympathetic nerve activity, an improvement in cardiac autonomic modulation, and a reversal of blunted sympathetic responsiveness at both peripheral and central nervous system levels. Recent findings underscore the relevance of insulin resistance in mediating blunted sympathetic responsiveness to endogenous hyperinsulinemia induced by glucose ingestion. Impaired insulin transport across the blood-brain barrier may be one mechanism mediating these effects. Weight loss reverses blunted sympathetic responsiveness to glucose, which has implications for postprandial energy expenditure and body weight homeostasis. The autonomic dysfunction of obesity is reversible with weight loss, highlighting the importance of lifestyle intervention as a key therapeutic modality.

Renal Sympathetic-Nerve Ablation for Uncontrolled Hypertension

To the Editor: The renal sympathetic nerves have been identified as a major contributor to the complex pathophysiology of hypertension in both experimental models and in humans.1 Patients with essential hypertension generally have increased efferent sympathetic drive to the kidneys, as evidenced by elevated rates of renal norepinephrine spillover, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus “spills over” into the circulation. Hypertension is also characterized by an increased rate of sympathetic-nerve firing, possibly modulated by afferent signaling from renal sensory nerves.2–4 A 59-year-old male patient with long-standing essential hypertension that was . . .

Weight Loss May Reverse Blunted Sympathetic Neural Responsiveness to Glucose Ingestion in Obese Subjects With Metabolic Syndrome

OBJECTIVEThe purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted.RESEARCH DESIGN AND METHODSThirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 ± 1 years (mean ± SE) with BMI 31.6 ± 0.6 kg/m2, who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program.RESULTSBody weight decreased by 8.1 ± 0.9 and 8.4 ± 1.1 kg and resting norepinephrine spillover by 94 ± 31 and 166 ± 58 ng/min (all P ≤ 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged −3 ± 25 versus 73 ± 24 ng/min at 30 min (P = 0.039), 36 ± 21 versus 115 ± 28 ng/min at 60 min (P = 0.045), 9 ± 21 versus 179 ± 50 ng/min at 90 min (P < 0.001), and 40 ± 48 versus 106 ± 39 ng/min at 120 min (P = 0.24).CONCLUSIONSWeight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.

Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome

BackgroundGlucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. ObjectiveThe objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. DesignNineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. ResultsIR subjects had a higher insulin area under the curve from 0 to 120 min (AUC0–120: 13,468 ± 677 compared with 6399 ± 612 mU/L · min; P < 0.001), glucose AUC0–120 (P < 0.05), and resting MSNA (41 ± 3 compared with 31 ± 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 ± 7% and 40 ± 13%, respectively; P ≤ 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC0–120 were independent (inverse) predictors of the SNS response. ConclusionsIR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

Sympathetic activation and inflammatory response in patients with subarachnoid haemorrhage

The aim of this study was to evaluate the correlation between sympathetic nervous activation and the immune response in patients following subarachnoid haemorrhage (SAH). Clinical study in a neurosurgical intensive care unit. Fourteen patients with acute non-traumatic SAH were included. Fifteen healthy, age-matched volunteers served as controls for measurement of catecholamine spillover. Blood sampling for C3a, C5b-9, IL-6, IL-8 and norepinephrine kinetic determination was made within 48 h, at 72 h and on the 7th-10th day after the SAH. SAH patients exhibited a profound increase in the rate of norepinephrine spillover to plasma at 48 h, 72 h and 7-10 days after the insult, 3-4 times that in healthy individuals. The plasma levels of C3a, IL-6 and C5b-9 were significantly elevated at 48 h, at 72 h and 7-10 days after the SAH, but the plasma level of IL-6 decreased significantly 7-10 days after the SAH. There was no relationship between the magnitude of sympathetic activation and the levels of inflammatory markers. Following SAH a pronounced activation of the sympathetic nervous system and the inflammatory system occurs. The lack of significant association between the rate of spillover of norepinephrine to plasma and the plasma levels of inflammatory markers indicates that the two processes, sympathetic activation and the immune response, following SAH are not quantitatively linked. In spite of a persistent high level of sympathetic activation the plasma level of IL-6 decreased significantly one week after SAH.

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …