Human Sympathetic Nervous System Research Articles

OR01-5 Leptin Acts through Altering Energy Intake and Lipolysis to Reduce Body Weight but Has No Effect on Energy Expenditure, Physical Activity, and Sympathetic Nervous System in Humans

It remains unknown whether leptin regulates body weight in humans and whether this occurs through actions centrally and/or peripherally i.e. by altering hormone and sympathetic nervous system (SNS) activity in humans as it has been suggested by experiments in rodents. We explored body weight and body composition changes in response to short and long term leptin administration to lean humans and explored potential underlying mechanisms by studying changes in energy intake, energy expenditure, lipolysis and hormonal and SNS changes in response to leptin administered in physiological and supraphysiological doses in lean subjects. We utilized the following study designs: a) open-label long-term leptin replacement study aiming at keeping circulating leptin levels within the physiological range and b) randomized, placebo-controlled, long-term leptin replacement study aiming at keeping total body weight stable by adjusting leptin doses in females with acquired hypoleptinemia. To further explore underlying mechanisms we also performed a) short-term placebo vs. leptin physiological replacement study during a three day long fasting-induced hypoleptinemia in lean subjects; and b) short-term leptin dose escalation study to supraphysiological levels in the fed i.e. normoleptinemic vs. in fasting-induced hypoleptinemic state for three days in both lean and overweight individuals. Long-term leptin replacement decreased body weight (p-value<0.001) through decreasing fat mass (p-value<0.001) and without affecting lean mass. Underlying mechanisms included decreased energy intake with leptin (caloric intake - leptin association r=-0.644, p-value<0.001), but not energy expenditure. Leptin also increased lipolysis demonstrated by elevated free fatty acids which were increased in response to leptin at time points that corresponded to fat mass loss (p-value=0.01). Long- but not short-term leptin replacement downregulated the renin-angiotensin-aldosterone axis at time points corresponding to maximum lipolytic effects (p-value=0.024 renin; p-value=0.001 aldosterone). Importantly, no changes in heart rate, blood pressure and body temperature were demonstrated with leptin. Thus, leptin administration decreases body weight in lean subjects, without changes to lean mass, by acting through decreasing body fat primarily through lipolysis and decreased caloric intake.

Acute Hypoxia Induces Enkephalin Production and Release in an Adrenergic Cell Line Model of Neonatal Chromaffin Cell Responses to Hypoxic Stress.

Prior to maturation of the human sympathetic nervous system, the neonatal adrenal medulla senses and responds to hypoxia. In addition to catecholamine release, the adrenal medulla synthesizes and stores opioid peptides, notably enkephalin (ENK). However, it is not known whether acute hypoxia evokes adrenal ENK production and release, as seen in the central nervous system (CNS). We hypothesize that acute hypoxia stimulates synthesis and release of ENK in chromaffin cells. Cultures of adrenergic mouse pheochromocytoma cells (MPC) 10/9/96CR were incubated in 10% oxygen (O2) at intervals of up to 60 minutes. ENK content and release were measured by Met-ENK enzyme-linked immunosorbent assay (ELISA). ENK messenger ribonucleic acid (mRNA) was analyzed by quantitative reverse-transcriptase polymerase chain reaction (PCR). Incubation of MPC 10/9 cells in 10% O2 evoked rapid release of epinephrine and of Met-ENK which increased approximately twofold in 15 minutes. Reduced [O2] also induced an overall increase (14%) in cellular ENK peptide content within 60 minutes. Acute hypoxia-stimulated release of Met-ENK was accompanied by increased mRNAENK expression in MPC 10/9s, a cell culture model of adrenergic chromaffin cells. We speculate that the ability of reduced [O2] to evoke ENK release from chromaffin cells may influence blood pressure regulation and heart contractility, thereby providing an adaptive survival advantage during neonatal asphyxia.

Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans.

As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96-108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans.

Recording sympathetic nerve activity in conscious humans and other mammals: guidelines and the road to standardization.

Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.

In our series profiling the world's leading and most influential cardiologists, EHJ CardioPulse meets Professor Murray D Esler.

Professor Murray Esler MBBS PhD is Senior Director of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and is renowned for his work on the development of a valid method for testing the human sympathetic nervous system. The application in turn provided a rationale for testing beta-adrenergic blockers in heart failure, and a rationale for developing the renal denervation treatment of hypertension. Born in the Australian provincial city of Geelong, 80 km south of Melbourne, I received local state education to university entry. The fourth of five children, tertiary education was not on the horizon until I came along. My father was an ambulance officer, who in a less regulated era took me in the ambulance to calls. I am sure this influenced my interest in medicine. As a young person I was an enthusiastic sportsman, playing cricket and Australian Rules football. My wife Rosemary is a psychiatrist and we have three daughters (Danielle, doctor; Nicky, lawyer; Simone, engineer), but my youngest, a son Ben, broke the mould to become an actor and more recently was in the cast of the US TV series Hell on Wheels. ![Graphic][1] My interest in medicine came before my interest in science. As a 7 year-old I had whooping cough over the 6-week summer vacation, during which I was confined to bed (standard care for the times). I felt cheated, but saw a lot of my family doctor, a caring man with stately demeanour who I admired and decided to emulate. My trips in the ambulance with my father clinched the case that I would become a doctor. My first exposure to science was in childhood encyclopaedias, which I enjoyed, then in high school chemistry and physics classes. For the Melbourne University medical course, science was an obligatory preamble in … [1]: /embed/inline-graphic-1.gif

Blood Pressure: Return of the Sympathetics?

This brief review highlights new ideas about the role of the sympathetic nervous system in human blood pressure regulation. We emphasize how this role varies with age and sex and use our findings to raise questions about the sympathetic nervous system and hypertension in humans. We also focus on three additional areas, including (1) novel ideas about the carotid body and sympathoexcitation as it relates to hypertension, (2) clinical trials of renal denervation that attempted to treat hypertension by reducing ongoing sympathoexcitation, and (3) new ideas about resistant hypertension and cerebral blood flow. We further highlight that success of device-based therapy to modulate the sympathetic nervous system relies heavily on patient selection. Furthermore, data suggest that the majority of patients respond to anti-hypertensive therapy and the major cause of "resistant" hypertension is poor patient adherence. While the enthusiasm for device therapy or perhaps even "precision medicine" is high, it is likely that by far the most benefit to the most patients will occur via better screening, more aggressive therapy, and the development of strategies that improve patient adherence to medication regimens and lifestyle changes.

The sympathetic nervous system alterations in human hypertension.

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

Potential future denervation targets

The human sympathetic nervous system has an important regulatory role. In its dysfunctional hyperexcitatory state, it can lead to multiple pathologies. The renal sympathetic nerves play a significant role in these pathological states. Percutaneous renal sympathetic denervation (RSDN) allows for safe minimally invasive selective denervation of the renal sympathetic nerves. RSDN has been shown to be safe and efficacious in blood pressure reduction in earlier nonblinded SYMPLICITY HTN-1 and -2 trials. In Europe, it is approved for a select group of truly resistant severe essential hypertension. However, its real efficacy is now in doubt with the blinded SYMPLICITY HTN-3 trial that showed no significant difference in change in office and mean 24-h ambulatory systolic blood pressure between RSDN and sham-procedure arms. This review will look at the potential targets for percutaneous RSDN-heart failure, cardiac arrhythmias and kidney disease, sleep-disordered breathing and insulin resistance.

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 …

Pneumatic antishock garment inflation activates the human sympathetic nervous system by abdominal compression

Pneumatic antishock garments (PASG) have been proposed to exert their blood pressure-raising effect mechanically, i.e. by increasing venous return and vascular resistance of the lower body. We tested whether, alternatively, PASG inflation activates the sympathetic nervous system. Five men and four women wore PASG while mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), heart rate and stroke volume were measured. One leg bladder (LEG) and the abdominal bladder (ABD) of the trousers were inflated individually and in combination (ABD+LEG), at 60 or 90 mmHg for 3 min. By the end of 3 min of inflation, conditions that included the ABD region caused significant increases in MAP in a dose-dependent fashion (7 ± 2, 8 ± 3, 14 ± 4 and 13 ± 5 mmHg for ABD60, ABD+LEG60, ABD90 and ABD+LEG90, respectively, P < 0.05). Likewise, inflation that included ABD caused significant increases in total MSNA compared with control values [306 ± 70, 426 ± 98 and 247 ± 79 units for ABD60, ABD90 and ABD+LEG90, respectively, P < 0.05 (units = burst frequency × burst amplitude]. There were no changes in MAP or MSNA in the LEG-alone conditions. The ABD inflation also caused a significant decrease in stroke volume (-11 ± 3 and -10 ± 3 ml per beat in ABD90 and ABD+LEG90, respectively, P < 0.05) with no change in cardiac output. Neither cardiopulmonary receptor deactivation nor mechanical effects can account for a slowly developing rise in both sympathetic activity and blood pressure during ABD inflation. Rather, these data provide direct evidence that PASG inflation activates the sympathetic nervous system secondarily to abdominal, but not leg, compression.

Prenatal development of the fetal thoracic sympathetic trunk in sheep (Ovis aries)

This study aims at clarifying the detailed morphological and topographical changes of the thoracic part of the sympathetic trunk of sheep during fetal development. Bilateral micro-dissection of the thoracic sympathetic trunk was performed on 40 sheep fetuses aged 6-20 weeks (18 males and 22 females) under a stereomicroscope. The cervicothoracic ganglion (CTG) was observed on 75/80 sides (93.7%) and was composed of the caudal cervical and the first thoracic ganglia on 45/80 sides (56.2%), and of the caudal cervical and the first two thoracic ganglia on 30/80 sides (37.5%). The presence of the two last (12th-13th) thoracic ganglia was not constant. The influence of the sex, the side of the body, and the ages of the fetus on the morphology and topography of the thoracic sympathetic trunk in sheep were identified. In spite of the differences in the morphology and topography of the thoracic sympathetic trunk between early and late fetal developments, the morphology and topography of the older fetal thoracic sympathetic trunk tended to be similar to that of the adult sheep. To comprehend the comparative morphology of the fetal thoracic sympathetic trunk more completely, our results were compared with previous studies. Consequently, differences and similarities in the composition and position of the CTG, presence of single caudal cervical ganglion without fusion to the thoracic ganglia, and absence of the thoracic ganglia, and presence of splitting of the interganglionic branch were found among sheep, pig, and human fetuses. Therefore, sheep might be the appropriate animal model to be applied in human sympathetic nervous system.

The human sympathetic nervous system: its relevance in hypertension and heart failure

Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is at different stages of development with regard to the two disorders. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to the introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on the demonstration of activation of the renal sympathetic outflow. Additional evidence in this regard is provided by the results of pilot studies exploring the possibility to reduce blood pressure in resistant hypertensives through electrical stimulation of the area of carotid baroreceptors. Despite the general importance of the sympathetic nervous system in blood pressure regulation, and the specific demonstration that the blood pressure elevation in essential hypertension is commonly initiated and sustained by sympathetic nervous activation, drugs antagonizing this system are currently underutilized in the care of patients with hypertension. Use of beta-adrenergic blocking drugs is waning, given the propensity of this drug class to have adverse metabolic effects, including predisposition to diabetes development. The blood pressure lowering achieved with carotid baroreceptor stimulation and with the renal denervation device affirms the importance of the sympathetic nervous system in hypertension pathogenesis, and perhaps suggests a wider role for anti-adrenergic antihypertensives, such as the imidazoline drug class (moxonidine, rilmenidine) which act within the CNS to inhibit central sympathetic outflow, although the lack of large-scale outcome trials with this drug class remains a very material deficiency.

The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management

Sympathetic nervous system responses typically are regionally differentiated, with activation in one outflow sometimes accompanying no change or sympathetic inhibition in another. Regional sympathetic activity is best studied in humans by recording from postganglionic sympathetic efferents (multiunit or single fiber recording) and by isotope dilution-derived measurement of organ-specific norepinephrine release to plasma (regional "norepinephrine spillover"). Evidence assembled in this review indicates that sympathetic nervous system abnormalities are crucial in the development of cardiovascular disorders, notably heart failure, essential hypertension, disorders of postural circulatory control causing syncope, and "psychogenic heart disease," heart disease attributable to mental stress and psychiatric illness. These abnormalities involve persistent, adverse activation of sympathetic outflows to the heart and kidneys in heart failure and hypertension, episodic or ongoing cardiac sympathetic activation in psychogenic heart disease, and defective sympathetic circulatory reflexes in disorders of postural circulatory control. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this "mechanisms-to-management" transition is at differing stages of development with the different conditions. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension, perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on demonstration of activation of the renal sympathetic outflow. With psychogenic heart disease and postural syncope syndromes, knowledge of the neural pathophysiology is emerging, but clinical translation remains for the future.

Physiological Changes in Human Cardiac Sympathetic Innervation and Activity Assessed by 123I-Metaiodobenzylguanidine (MIBG) Imaging

Physiologic changes in the human sympathetic nervous system (SNS) may be associated with cardiovascular diseases, so the present study assessed the age and gender differences in global cardiac SNS in normal subjects. The 163 subjects (74 men, 89 women; age range 40-89 years) whose coronary arteriogram was normal, and who had no other cardiac or neurohormonal diseases, and no medication affecting the autonomic nervous system were included. All study subjects underwent metaiodobenzylguanidine imaging. Both initial and delayed heart-to-mediastinum (H/M) ratios had a significant gender difference and showed a progressive decrease with aging. In addition, the initial H/M ratio had a significant positive correlation with the delayed H/M ratio (r=0.89, P<0.0001). Females (50-59 years) demonstrated significantly higher delayed H/M ratio than males of the same age. After the age of 60, the delayed H/M ratio in females progressively decreased with aging, similar to males. As for the washout rate, both genders had a significantly progressive increase with aging. In addition, there was a significant decrease in the delayed H/M ratio in 10 females with surgical menopause compared with 15 age-matched females without surgical menopause. Cardiac SNS appears to be regulated by various physiological factors.

Drs. Otte and Whooley Reply

Back to table of contents Previous article Next article Letters to the EditorFull AccessDrs. Otte and Whooley ReplyCHRISTIAN OTTE M.D.MARY A. WHOOLEY M.D.,CHRISTIAN OTTE M.D.Search for more papers by this authorMARY A. WHOOLEY M.D.Search for more papers by this author,Published Online:1 Jan 2008https://doi.org/10.1176/appi.ajp.2007.07091377rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: We appreciate the thoughtful comments by Mr. Bayles et al. on our recent article. We agree that sympathetic nervous activation may contribute to the development of left ventricular hypertrophy and that this could be a potential mechanism by which s allele carriers of the 5-HTTLPR might be at increased risk for worse cardiovascular outcome. However, in our cohort there were no differences between s allele carriers and l/l homozygote subjects with regard to left ventricular hypertrophy, defined as a left ventricular mass index >90 g/m 2 by echocardiography (202/383 [54%] of s allele carriers vs. 99/174 [59%] of l/l homozygote subjects). Further, both groups did not differ in functionally relevant variables, such as left ventricular ejection fraction (s allele carriers: mean=62% [SD=10] vs. l/l homozygote subjects: mean=61% [SD=10]) and wall motion score (s allele carriers: mean=1.2 [SD=36] vs. l/l homozygote subjects: mean=1.2 [SD=33]), an index of ischemia. This suggests that greater 24-hour urinary norepinephrine in s allele carriers did not contribute to left ventricular hypertrophy in this study. However, as Dr. Bayles et al. correctly point out, human sympathetic nervous system activity is regionalized, with the outflow to some organs, such as the heart, sometimes being preferentially activated. Indeed, 24-hour urinary norepinephrine as a broad measure of overall sympathetic nervous system activity might lack the sensitivity to detect associations between sympathetic nervous activity and regional processes, such as the development of left ventricular hypertrophy. Given the large number of participants in our epidemiological cohort study, we were unable to use more localized measures of norepinephrine, such as cardiac catheterization techniques coupled with norepinephrine isotope dilution methodology. However, we agree that it would be an interesting next step to examine the association between HTTLPR and bimodal sympathetic activation in depressed patients (1). Certainly, much more work has to be done to elucidate the mechanisms by which 5-HTTLPR, depression, stress, and catecholamine secretion are linked and how they might affect outcome in cardiovascular disease. Hamburg, GermanyThe authors’ disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2007.07091377r) was accepted for publication in September 2007. FiguresReferencesCited byDetailsCited ByNone Volume 165Issue 1 January, 2008Pages 137-138THE AMERICAN JOURNAL OF PSYCHIATRY January 2008 Volume 165 Number 1 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Is obstructive sleep apnea the cause of sympathetic nervous activation in human obesity?

based on findings in experimental models of obesity, the sympathetic nervous system has commonly been assumed to have a determining role in obesity development through its influence on the regulation of energy expenditure. An earlier hypothesis was that sympathetic nervous activity was low in

Coexpression of cholinergic and noradrenergic phenotypes in human and nonhuman autonomic nervous system

It has long been known that the sympathetic innervation of the sweat glands is cholinergic in most mammalian species and that, during development, rodent sympathetic cholinergic sweat gland innervation transiently expresses noradrenergic traits. We show here that some noradrenergic traits persist in cholinergic sympathetic innervation of the sweat glands in rodents but that lack of expression of the vesicular monoamine transporter renders these cells functionally nonnoradrenergic. Adult human sweat gland innervation, however, is not only cholinergic but coexpresses all of the proteins required for full noradrenergic function as well, including tyrosine hydroxylase, aromatic amino acid decarboxylase, dopamine beta-hydroxylase, and the vesicular monoamine transporter VMAT2. Thus, cholinergic/noradrenergic cotransmission is apparently a unique feature of the primate autonomic sympathetic nervous system. Furthermore, sympathetic neurons innervating specifically the cutaneous arteriovenous anastomoses (Hoyer-Grosser organs) in humans also possess a full cholinergic/noradrenergic cophenotype. Cholinergic/noradrenergic coexpression is absent from other portions of the human sympathetic nervous system but is extended in the parasympathetic nervous system to intrinsic neurons innervating the heart. These observations suggest a mode of autonomic regulation, based on corelease of norepinephrine and acetylcholine at parasympathocardiac, sudomotor, and selected vasomotor neuroeffector junctions, that is unique to the primate peripheral nervous system.

The neurobiology of human obesity

Earlier ideas that sympathetic nervous system activity is low in human obesity, contributing to weight gain through absence of sympathetically mediated thermogenesis, can now be discounted. The application of sympathetic nerve recording techniques and isotope dilution methodology quantifying neurotransmitter release from sympathetic nerves has established that the sympathetic outflows to the kidneys and skeletal muscle vasculature are activated in obese humans. The cause remains unclear. The adipocyte hormone, leptin, stimulates the sympathetic nervous system in rodents, but whether this applies in humans is uncertain. Cross-sectional studies suggest a quantitative link exists between regional sympathetic nervous tone (most notably in the kidneys) and rates of leptin release, but definitive studies documenting that leptin administration activates the human sympathetic nervous system have not been done. What might be the clinical implications of these new findings? The demonstration that the suppressed sympathetic tone characterizing many experimental models of obesity does not exist in human obesity weakens the case for the use of beta3-adrenergic agonists as thermogenic agents to facilitate weight loss. Although the neurogenic character of obesity-related hypertension is now established, whether antiadrenergic antihypertensive drugs are the preferred agents for blood pressure reduction has not been adequately tested. Multiple site central venous sampling, disclosing release of leptin into the internal jugular veins, led to the demonstration that the leptin gene is also expressed in the brain, in addition to adipocytes. Brain resistance to leptin has been inferred in human obesity, given that overweight is accompanied by high plasma leptin levels. The fact that the genes for leptin and its receptors are normally expressed in the brain in human obesity, and that release of leptin from the brain is actually increased, argues against this. Brain leptin release has the potential to override the peripheral, adipocyte leptin system.

The sympathetic nervous system and hypertension: recent developments.

A major hypothesisfor the development of hypertension is that abnormal renal excretory function is critical for the initiation, development, and maintenance of primary hypertension.1 The renal body fluid feedback mechanism couples the long-term regulation of arterial pressure to extracellular volume (sodium and water) homeostasis via pressure natriuresis, whereby the kidneys respond to changes in arterial pressure by altering urinary sodium and water excretion. The obligatory requirement for maintenance of sodium and water balance by the kidneys is believed to be primary in the long-term control of arterial pressure. An increase in arterial pressure (via increases in total peripheral resistance or cardiac output or both) leads to an increased urinary sodium and water excretion via the pressure natriuresis mechanism, with consequent reduction in blood volume until arterial pressure is returned to normal. Thus, factors that decrease renal excretory function and disrupt the maintenance of sodium and water balance by the kidneys lead to an increase in arterial pressure, which is required to reestablish and maintain sodium and water balance. Based on computer modeling studies, a long-term increase in arterial pressure can only occur if there is a chronic and sustained decrease in renal excretory function. Increased renal sympathetic nerve activity (RSNA) is known to be a factor capable of decreasing renal excretory function.2,3 The renal effects of increased RSNA include increased renal tubular sodium reabsorption leading to renal sodium retention; decreased renal blood flow and glomerular filtration rate with renal vasoconstriction and increased renal vascular resistance; and increased renin release leading to angiotensin II production. Each of these renal functional alterations can decrease renal excretory function. The role of increased RSNA as being a critically important factor contributing to this renal excretory dysfunction in hypertension is strengthened by the fact that increased RSNA has been identified in hypertensive human …

Elevation of sympathetic activity by eprosartan in young male subjects

Background Selective blockade of the type 1 angiotensin II receptors (AT1 receptors) reduced blood pressure (BP) elevation caused by sympathetic stimulation in the pithed rat model. This has been attributed to blockade of AT1 receptors located presynaptically on sympathetic nerve endings normally facilitating norepinephrine release. We examined the effects of AT1 receptor blockade on the sympathetic nervous system in humans. Methods Twenty-nine young white men with normal to mildly hypertensive BP values participated in a double-blind, placebo-controlled, randomized cross-over protocol receiving 600 mg/d of eprosartan or placebo for 1 week. At the last day of intake we measured hemodynamic parameters, muscle sympathetic nerve activity by microneurography, and plasma levels of norepinephrine, epinephrine, and angiotensin II during rest and cardiovascular stress. Results Eprosartan lowered resting mean arterial pressure (73.6 ± 11.0 v 78.0 ± 10.3 mm Hg, P < .05; Finapres, Ohmeda, Englewood, CO), and elevated heart rate (64.4 ± 7.6 v 61.1 ± 6.8 beats/min, P = .01), muscle sympathetic nerve activity (14.1 ± 10.4 v 9.8 ± 6.3 bursts/min, P < .05) and plasma angiotensin II (37.0 ± 33.7 v 6.9 ± 2.8 ng/L, P < .01), as well as norepinephrine levels (234.2 ± 87.6 v 187.8 ± 59.3 ng/L, P < .01). Eprosartan did not blunt sympathetic activation caused by lower body negative pressure or mental stress. Conclusions These results contrast with animal data showing antiadrenergic properties of this drug. If any, it appeared, that eprosartan causes augmented central neural vasoconstrictor outflow paralleled by increased plasma levels of norepinephrine, which casts doubt on its ability to dampen norepinephrine release from peripheral sympathetic nerve endings in humans. We hypothesize that eprosartan leads to a resetting of the baroreflex, presumably by the markedly elevated circulating angiotensin II.