Nina Eikelis

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 …

Sympathetic activation in chronic renal failure.

The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.

Renal denervation: a potential new treatment modality for polycystic ovary syndrome?

Objective Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension. Methods Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation. Results Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5–3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced. Conclusion These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.

Sympathetic Nervous System Activity Is Associated With Obesity-Induced Subclinical Organ Damage in Young Adults

Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young individuals. To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index <25 kg/m2) and 25 overweight or obese (body mass index >25 kg/m2) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function; (2) left ventricular structure and systolic and diastolic function; and (3) endothelial function. Muscle sympathetic nervous activity was assessed by microneurography. Participants with excess weight had decreased endothelial function (P<0.01), elevated creatinine clearance (P<0.05), increased left ventricular mass index (P<0.05), increased left ventricular wall thickness (P<0.01), lower systolic and diastolic function (P<0.01), and elevated muscle sympathetic nervous activity (P<0.001) compared with lean individuals. In multiple regression analysis, endothelial function was inversely related to muscle sympathetic nervous activity (R2=0.244; P<0.05), whereas creatinine clearance and left ventricular mass index were positively related to muscle sympathetic nervous activity, after adjustment for body mass index, sex, and blood pressure (R2=0.318, P<0.01 and R2=0.312, P<0.05, respectively). Excess weight in young individuals is associated with subclinical alterations in renal and endothelial function, as well as in the structure of the heart, even in the absence of hypertension. Sympathetic activity is closely associated with cardiovascular and renal alterations observed in these subjects.

Exposure to a High-Fat Diet Alters Leptin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 &mgr;g) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: −54%, paraventricular: −69%, and dorsomedial hypothalamus: −65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked “selective leptin resistance” in these animals.

Chronic mental stress is a cause of essential hypertension: Presence of biological markers of stress

1 In searching for biological evidence that essential hypertension is caused by chronic mental stress, a disputed proposition, parallels are noted with panic disorder, which provides an explicit clinical model of recurring stress responses. 2 There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. Plasma cortisol is elevated in both. 3 In panic disorder and essential hypertension, but not in health, single sympathetic nerve fibres commonly fire repeatedly within an individual cardiac cycle; this appears to be a signature of stress exposure. For both conditions, adrenaline cotransmission is present in sympathetic nerves. 4 Tissue nerve growth factor is increased in both (nerve growth factor is a stress reactant). There is induction of the adrenaline synthesizing enzyme, phenylethanolamine‐N‐methyltransferase, in sympathetic nerves, an explicit indicator of mental stress exposure. 5 The question of whether chronic mental stress causes high blood pressure, still hotly debated, has been reviewed by an Australian Government body, the Specialist Medical Review Council. Despite the challenging medicolegal implications, the Council determined that stress is one proven cause of hypertension, this ruling being published in the 27 March 2002 Australian Government Gazette. This judgement was reached after consideration of the epidemiological evidence, but in particular after review of the specific elements of the neural pathophysiology of essential hypertension, described above.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.

BACKGROUND AND OBJECTIVES Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. RESULTS Average office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. CONCLUSIONS RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Gender differences in sympathetic nervous activity: influence of body mass and blood pressure.

Background Obesity and high blood pressure (BP) commonly coexist in patients, and both conditions are associated with elevated sympathetic nervous activity. We tested whether the sympathetic nervous system was differently affected in men and women by the body mass index (BMI), BP, leptin and weight loss. Methods We measured muscle sympathetic nerve activity (MSNA, microneurography), BP and plasma leptin concentrations in 167 age-matched normotensive and hypertensive men and women divided into three subgroups: lean, BMI < 25 kg/m2; overweight, BMI ≥ 25 and < 30 kg/m2; and obese, BMI ≥ 30 kg/m2. These measurements were repeated in a subgroup of 19 obese subjects who underwent a 12-week diet. Results Women with hypertension had increased MSNA compared with their normotensive counterparts (37 ± 2 versus 25 ± 2 bursts/min, analysis of variance, P < 0.001) and MSNA was significantly related to BP (P < 0.05, r2 = 0.236) but not to BMI. MSNA in men with hypertension was no different from that in normotensive subjects (33 ± 2 versus 30 ± 2 bursts/min), but MSNA was significantly related to BMI (P < 0.05, r2 = 0.249). Diet resulted in the same degree of weight loss in men and women, but induced a decrease in MSNA only in men (43 ± 3 to 34 ± 3 bursts/min, P < 0.01). The plasma leptin concentration was higher in women than in men, and for both groups it was related to BMI not BP (r2 = 0.497, P < 0.001 in women and r2 = 0.483, P < 0.001 in men). Conclusion These data demonstrate a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to BP in women and to BMI in men.

Estrogen increases prepulse inhibition of acoustic startle in rats

Epidemiological studies have shown gender differences in the age of onset and symptoms of schizophrenia. Because sensorimotor gating mechanisms are deficient in schizophrenia, we studied the effect of administration of estrogen on prepulse inhibition of startle in rats, an animal model of sensorimotor gating. Rats were tested in an automated startle apparatus for their responses to random combinations of 115-dB sound pulses and prepulses of various intensity. Startle responses were reduced by increasing intensities of prepulses, indicating prepulse inhibition. Repeated administration of startle pulses caused gradual habituation of startle responses. Ovariectomy did not induce significant changes in either habituation of the startle response or prepulse inhibition of startle. Treatment with 17beta-estradiol caused an increase in percentage prepulse inhibition at all prepulse intensities at 18 h, but only at higher prepulse intensities at 30 min after injection. Habituation of startle responses was not affected. The enhancing effect of estradiol on prepulse inhibition was mimicked by testosterone, but not by dihydrotestosterone. Estradiol treatment increased prepulse inhibition similarly in controls or after disruption of prepulse inhibition induced by treatment with apomorphine or dizocilpine (MK-801). Our results may help to explain gender differences in schizophrenia and some of the beneficial clinical effects of estrogen treatment in this disease.

Rapid Onset of Renal Sympathetic Nerve Activation in Rabbits Fed a High-Fat Diet

Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus.