The Effects of Drugs Used to Treat Obesity on the Autonomic Nervous System

Objective: Body fatness is partly under hypothalamic control with effector limbs, which include the endocrine system and the autonomic nervous system (ANS). In previous studies we have shown, in both obese and never‐obese subjects, that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the involvement of such ANS mechanisms in the action of anti‐obesity drugs, independent of change in weight. Research Methods and Procedures: Normal weight males (ages 22 to 38 years) were fed a solid food diet, carefully measured to maintain body weight, for at least 2 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single‐blind, placebo/drug/placebo design, eight subjects received dexfenfluramine, seven phentermine (PHE), and seven sibutramine (SIB). ANS measures of parasympathetic and sympathetic activity included: determination of amount of parasympathetic control (PC) and sympathetic control (SC) of heart period (interbeat interval), using sequential pharmacological blockade by intravenous administration of atropine and esmolol. These autonomic controls of heart period are used to estimate the overall level of parasympathetic and sympathetic activities. Norepinephrine, dopamine, and epinephrine levels in 24‐hour urine collections were measured and also resting metabolic rate (RMR). Results: Sufficient food intake maintained constant body weight in all groups. PHE and SIB produced significant increases in SC but no change in PC or in RMR. In contrast, dexfenfluramine produced marked decreases in SC, PC, and RMR. For all three drugs, the effects on urine catecholamines directly paralleled changes in cardiac measures of SC. Discussion: ANS responses to PHE and SIB were anticipated. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.     

Autonomic Nervous System Activity During Actual and Mentally Simulated Preparation for Movement

The aim of this study was to compare actual versus mentally simulated preparation for a complex motor skill. Two behavioral periods are observed during weightlifting: (i) an initial phase in which the subject standing behind the bar is thought to focus his attention on forthcoming execution and (ii) a second phase between hands/bar contact and execution during which the subject is thought to increase activation. Such mental processes accompanying behavioral sequences are correlated with autonomic nervous system activity, phasic responses corresponding to allocation of attentional resources, and tonic variations related to increasing general activation. To study mental processes during preparation for action, 12 subjects performed actual and imagined preparation phases of execution. Six autonomic variables were measured continuously. Skin potential (² = 0.16), skin temperature amplitude (Z = –0.66) and duration (Z = –1.78), skin blood flow amplitude (Z = –0.56) and duration (Z = –1.51), respiratory frequency amplitude (Z = –0.14) and duration (Z = –0.13), and duration of heart rate response (Z = –1.25) were shown to be comparable (p >.05), whatever the modality of preparation. However, during mentally simulated preparation, skin resistance response was shorter than in actual preparation (Z = –2.12, p <.05), thus attesting to a weaker load, whereas lower decrease in heart rate was elicited (Z = –1.96, p <.05). This may be explained by this particular experimental condition because mental preparation would not lead to actual action. Such autonomic variables could be used as feedback to improve performance.     

Cardiac Autonomic Nervous System Activity in Obese and Never-Obese Young Men

ARONNE, LOUIS J, RONALD MACKINTOSH, MICHAEL ROSENBAUM, RUDOLPH L LEIBEL, JULES HIRSCH. Cardiac autonomic nervous system activity in obese and never-obese young men. Autonomic nervous system (ANS) activity in age-matched, weight-stable, free-living, ad libitumfed, obese (OB) and never-obese (NO) young men (body mass index means [SD], 38.5 [3.9] and 22.0 [1.7], respectively) was evaluated by sequential blockade of cardiac autonomic innervation with weight-adjusted doses of parasympathetic (atropine) and sympathetic (esmolol) blockers so as to produce maximal effects on heart rate. Change in heart period (interbeat interval) from baseline, induced by atropine, defined parasympathetic control (PC), and the subsequent change, after esmolol administration, defined sympathetic control (SC). The heart period, after PC and SC blockade, defined intrinsic heart period (I). In the OB group, baseline heart period and PC were lower, and SC and I were higher, than in the NO group. The results in the OB, relative to the NO subjects, are similar to those reported in a previous study of NO subjects who had undergone a 10% weight gain by overfeeding. These findings suggest that the ANS of individuals with obesity is chronically altered in a way that would tend to oppose their excessive adiposity, and that these autonomic changes are more likely to be responses to other forces that induce obesity, rather than being primary agents in the production of the disease.     

Autonomic denervation for the treatment of atrial fibrillation

The influence of the autonomic nervous system (ANS) on triggering and perpetuation of atrial fibrillation (AF) is well established. Ganglionated plexi (GP) ablation achieves autonomic denervation by affecting both the parasympathetic and sympathetic components of the ANS. An anatomic approach for GP ablation at relevant atrial sites appears to be safe, and improves the results of PV isolation in patients with paroxysmal and persistent AF. GP ablation can be accomplished endocardially or epicardially, ie, during the maze procedure or thoracoscopic approaches. Further experience is needed to assess the clinical value of this promising technique.     

Autonomic Nervous System Activity and the State and Development of Obesity in Japanese School Children

Objective: The autonomic nervous system (ANS) plays an important role in regulating energy expenditure and body fat content; however, the extent to which the ANS contributes to pediatric obesity remains inconclusive. The aim of this study was to evaluate whether sympathetic and/or the parasympathetic nerve activities were altered in an obese pediatric population. We further examined a physiological association between the duration of obesity and the sympatho‐vagal activities to scrutinize the nature of ANS alteration as a possible etiologic factor of childhood obesity. Research Methods and Procedures: Forty‐two obese and 42 non‐obese healthy sedentary school children were carefully selected from 1080 participants initially recruited to this study. The two groups were matched in age, gender, and height. The clinical records of physical characteristics and development of the obese children were retrospectively reviewed to investigate the onset and progression of obesity. The ANS activities were assessed during a resting condition by means of heart rate variability power spectral analysis, which enables us to identify separate frequency components, i.e., total power (TP), low‐frequency (LF) power, and high‐frequency (HF) power. The spectral powers were then logarithmically transformed for statistical testing. Results: The obese children demonstrated a significantly lower TP (6.77 ± 0.12 vs. 7.11 ± 0.04 ln ms², p < 0.05), LF power (6.16 ± 0.12 vs. 6.42 ± 0.05 ln ms², p < 0.05), and HF power (5.84 ± 0.15 vs. 6.34 ± 0.07 ln ms², p < 0.01) compared with the non‐obese children. A partial correlation analysis revealed that the LF and HF powers among 42 obese children were negatively associated with the duration of obesity independent of age (LF: partial r = ?0.55, p < 0.001; HF: partial r = ?0.40, p < 0.01). The obese children were further subdivided into two groups based on the length of their obesity. All three spectral powers were significantly reduced in the obese group with obesity of >3 years (n = 18) compared to the group with obesity of <3 years. Discussion: Our data indicate that obese children possess reduced sympathetic as well as parasympathetic nerve activities. Such autonomic depression, which is associated with the duration of obesity, could be a physiological factor promoting the state and development of obesity. These findings further imply that preventing and treating obesity beginning in the childhood years could be an urgent and crucial pediatric public health issue.     

Autonomic Nervous System Regulation of Epicardial Adipose Tissue: Potential Roles for Regulator of G Protein Signaling-4

The epicardial adipose tissue (EAT) or epicardial fat is a visceral fat depot in the heart that contains intrinsic adrenergic and cholinergic nerves, through which it interacts with the cardiac sympathetic (adrenergic) and parasympathetic (cholinergic) nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine, epinephrine, and free fatty acids. The production of these molecules is biologically relevant for the heart, since abnormalities in EAT secretion are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction, leading to a variety of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc.; therefore, several studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In addition, Regulator of G protein Signaling (RGS)-4 is a protein with significant regulatory roles in both adrenergic and muscarinic receptor signaling in the heart. In this review, we provide an overview of the autonomic regulation of EAT, with a specific focus on cardiac RGS4 and the potential roles this protein plays in this regulation.     

Effect of Post-Weaning Individual Housing on Autonomic Responses in Male Rats to Sexually Receptive Female Rats

Post-weaning individual housing induces significant alterations in the reward system of adult male rats presented with sexually receptive female rats. In this study, we examined the effects of post-weaning individual housing on autonomic nervous activity in adult male rats during encounters with sexually receptive female rats to assess whether different affective states depending on post-weaning housing conditions are produced. Changes in heart rate and spectral parameters of heart rate variability indicated that in post-weaning individually housed male rats, both sympathetic and parasympathetic activity increased with no change in the sympathovagal balance, while in post-weaning socially housed male rats, both sympathetic and parasympathetic activity decreased with a predominance of parasympathetic activity. These two patterns of shifts in sympathovagal balances closely resembled changes in autonomic nervous activity with regard to classical appetitive conditioning in male rats. The autonomic changes in male rats housed individually after weaning corresponded to changes associated with the reward-expecting state evoked by the conditioned stimulus, and the autonomic changes observed in male rats housed socially after weaning corresponded to changes associated with the reward-receiving state evoked by the unconditioned stimulus. These results suggest that different affective states were induced in adult male rats during sexual encounters depending on male–male social interactions after weaning. The remarkable change caused by post-weaning individual housing may be ascribed to alteration of the reward system during sexual encounters induced by deficiency of intermale social communication after weaning.     

A Deletion in the α2B‐Adrenergic Receptor Gene and Autonomic Nervous Function in Central Obesity

Objective: We investigated the impact of a three‐amino acid deletion (12Glu9) polymorphism in the α_2B‐adrenergic receptor gene on autonomic nervous function. The short form (Glu⁹/Glu⁹) of the polymorphism has previously been associated with a reduced basal metabolic rate in obese subjects. Because autonomic nervous function participates in the regulation of energy metabolism, there could be a link between this polymorphism and autonomic nervous function. Research Methods and Procedures: Data of a 10‐year follow‐up study with 126 nondiabetic control subjects and 84 type 2 diabetic patients were used to determine the effects of the 12Glu9 polymorphism on autonomic nervous function. A deep breathing test and an orthostatic test were used to investigate parasympathetic and sympathetic autonomic nervous function. In addition, cardiovascular autonomic function was studied using power spectral analysis of heart rate variability. Results: No significant differences were found in the frequency of the 12Glu9 deletion polymorphism between nondiabetic and diabetic subjects. The nondiabetic men with the Glu⁹/Glu⁹ genotype, especially those with abdominal obesity, had significantly lower total and low‐frequency power values in the power spectral analysis when compared with other men. Furthermore, in a longitudinal analysis of 10 years, the decrease in parasympathetic function was greater in nondiabetic men with the Glu⁹/Glu⁹ genotype than in the men with the Glu⁹/Glu¹² or Glu¹²/Glu¹² genotypes. Discussion: The results of the present study suggest that the 12Glu9 polymorphism of the α_2B‐adrenergic receptor gene modulates autonomic nervous function in Finnish nondiabetic men. In the nondiabetic men with the Glu⁹/Glu⁹ genotype, the general autonomic tone is depressed, and vagal activity especially becomes impaired with time. Furthermore, this association is accentuated by central obesity.     

Autonomic control of heart rate in the neonatal rhesus monkey

Autonomic control of resting heart rate was assessed using atropine and propranolol in 20 neonatal (2 to 3 weeks old) male Rhesus monkeys. After release from restraint for placement of a venous catheter, the average heart rate significantly decreased from 220 +/- 7 beats/min to 181 +/- 6 beats/min within 15 minutes and remained stable for the 2 hours. Autonomic control of resting heart rate is mediated through both divisions of the autonomic nervous system with the sympathetic system having a dominant influence. This is in contrast to the adult Rhesus, where the parasympathetic nervous system controls resting heart rate.     

Disorders of Autonomic Control of Microcirculation in Explosion-Induced Coal-Mine Trauma: Experimental Modeling,Pathogenetic Analysis,and Pharmacological Correction

We modeled the consequences of explosion-induced coal-mine trauma, ECMT, i.e., contusion, intoxication by explosion products, burns, emotional stress, etc., in rats using a specially developed device. ECMT was produced by a dosed explosion of a methane-air mixture. In addition, the device allowed us to model effects of coal-mine occupational factors, CMOF (high air pressure, temperature, and humidity, high contents of dust and alien gases in the air, and intensive physical loading). We examined modifications of microcirculation in the vessels of the abdominal cavity (mesenterial vessels) after ECMT and after such a trauma aggravated by the premorbid action of CMOF (for 1 h daily over 14 days). The long-lasting influence of CMOF evoked noticeable vasoconstriction and a drop in the volume velocity of blood flow through the mesenteric vessels. Both complicated and noncomplicated ECMT resulted in significant dilatation of the mesenteric vessels (their mean diameter increased in 1 h by about 40% as compared with the norm) and an increase in the volume blood flow velocity (by 71 and 41% as compared with the norm, respectively). Injections of 3 mg/kg diazepam (i.p., immediately after ECMT) considerably corrected the shifts of the pressure in and linear velocity of blood flow through the microvessels under study, whereas their diameter and the volume flow velocity remained increased (the former, somewhat, and the latter, significantly). The mechanisms of disorders of regional circulation evoked by the actions of ECMT and CMOF in the visceral microvessels (with special attention to metabolic factors, which evoke vasodilation), the importance of the phenomenon of blood sequestration in these vessels to the clinical course of ECMT, and approaches for pharmacological correction of the above disorders by drugs of the benzodiazepine family are discussed.     

外周神经损伤引起的神经病理性痛：对神经损伤 的一种适应不良反应

外周神经损伤可引起对神经系统的一种适应不良反应,其产生神经病理性痛的主要特点为痛觉增敏和异常疼痛。目前文献报道多种机制涉及此反应,包括离子通道改变引起的异常放电、突触易化、多种轴突水平抑制作用缺失导致的中枢敏化、神经元细胞的凋亡以及异常的突触连接等结构的改变,另外神经损伤引起的神经免疫之间的相互作用在神经病理性痛的持续性发展中发挥着不可替代的作用。了解外周神经损伤引起的神经病理性的发病机制将对我们寻找治疗靶点和治疗策略提供坚实的理论基础。     

Evidence that endogenous thyrotropin-releasing hormone (TRH) may control vagal efferents to thyroid gland: neural inhibition by central administration of TRH antiserum

The intracerebroventricular (i.c.v.) injection of rabbit antiserum to thyrotropin-releasing hormone (TRH) to the urethane anesthetized rat inhibited the spontaneous electrical discharge of the superior laryngeal nerve (n.sl). On the other hand, the i.c.v. injection of rabbit antiserum to somatostatin (SRIF) failed to influence the nerve activity whereas SRIF itself is capable of inhibiting the n.sl activity. These findings suggest that TRH in the brain takes a role continuously in regulating the neural activity while SRIF is involved in the neuronal circuits as an agent for the down regulation of the autonomic nervous system.     

Toll信号通路在中枢神经系统损伤中的作用

Toll样受体(Toll-like receptors,TLR)是先天性免疫反应识别病原体的一个重要分子,在免疫系统中发挥关键作用.其家族各种成员的主要功能是识别入侵病原体表面的各种不同分子模式,随后启动免疫反应,达到保护机体作用.在大脑中,小胶质细胞可以作为抗原提呈细胞,参与脑内免疫反应,也可以通过分泌各种促炎症因子启动或促进免疫反应,而TLR家族在中枢神经免疫系统的作用仍存在争议,它既可以通过促进神经免疫反应枢纽因子的表达来增强免疫,也可因免疫过度而损伤神经细胞.总之,Toll信号通路对中枢神经系统疾病有一定的调控作用.     

Studies on the Aroma Constituents of Fuiien Ti Kuan Yin Tea,Se Chung Tea,Wu-I Shui Hsien Tea and Wu-I Chi Chung Tea in China

This paper reports, for the first time, the aroma constituents of the famous Fujian Oolong tea—Ti kuan Yin Tea, Se Chung Tea, Wu-I Shut Hsien Tea and Wu-I Chi Chung Tea. 70 aroma concentrates of tea samples were identified by the use of (IC-MS, SCOT capillary coumn GC standard sample addition method and IR. Among which benzyl alcohol, translinalooloxide (furanoid), cis-linalooloxide (fuconoid), 3,7-dimeihy-l,5, 7-octatrien-3-ol, β-phenylethanol, translinalooloxide (pyranoid), geraniol, indole, eisjasmone, pasmine laetone, nerolidol and mthyl jasmonate are the typical character the aroma constituents. Consequently the aroma is varied by different varieties of the tea, different regions of their growth and different processing.     

The placebo effect and the autonomic nervous system: evidence for an intimate relationship

For many subjectively experienced outcomes, such as pain and depression, rather large placebo effects have been reported. However, there is increasing evidence that placebo interventions also affect end-organ functions regulated by the autonomic nervous system (ANS). After discussing three psychological models for autonomic placebo effects, this article provides an anatomical framework of the autonomic system and then critically reviews the relevant placebo studies in the field, thereby focusing on gastrointestinal, cardiovascular and pulmonary functions. The findings indicate that several autonomic organ functions can indeed be altered by verbal suggestions delivered during placebo and nocebo interventions. In addition, three experimental studies provide evidence for organ-specific effects, in agreement with the current knowledge on the central control of the ANS. It is suggested that the placebo effects on autonomic organ functions are best explained by the model of 'implicit affordance', which assumes that placebo effects are dependent on 'lived experience' rather than on the conscious representation of expected outcomes. Nevertheless, more studies will be needed to further elucidate psychological and neurobiological pathways involved in autonomic placebo effects.     

Golgi Method without Osmium Tetroxide for the Study of the Central Nervous System

A variant Golgi technique was developed that consisted of substituting osmium tetroxide with formaldehyde as the initial fixative in intracardiac perfusion, along with the addition of glacial acetic acid to the chromating fluid. This procedure avoids disposal of dangerous waste substances into the environment. Other advantages include 1) reduction of cost, danger to lab workers, and risk of disruption of the tissue slices during their handling by eliminating the osmium tetroxide, 2) clear tissue background, 3) greater quantity of impregnated neurons than in the classical procedure, with distinct morphological details easily identified even in gross sections and 4) reduction in processing time.     

In Situ Ca2+ Imaging of the Enteric Nervous System

Reflex behaviors of the intestine are controlled by the enteric nervous system (ENS). The ENS is an integrative network of neurons and glia in two ganglionated plexuses housed in the gut wall. Enteric neurons and enteric glia are the only cell types within the enteric ganglia. The activity of enteric neurons and glia is responsible for coordinating intestinal functions. This protocol describes methods for observing the activity of neurons and glia within the intact ENS by imaging intracellular calcium (Ca²⁺) transients with fluorescent indicator dyes. Our technical discussion focuses on methods for Ca²⁺ imaging in whole-mount preparations of the myenteric plexus from the rodent bowel. Bulk loading of ENS whole-mounts with a high-affinity Ca²⁺ indicator such as Fluo-4 permits measurements of Ca²⁺ responses in individual neurons or glial cells. These responses can be evoked repeatedly and reliably, which permits quantitative studies using pharmacological tools. Ca²⁺ responses in cells of the ENS are recorded using a fluorescence microscope equipped with a cooled charge-coupled device (CCD) camera. Fluorescence measurements obtained using Ca²⁺ imaging in whole-mount preparations offer a straightforward means of characterizing the mechanisms and potential functional consequences of Ca²⁺ responses in enteric neurons and glial cells.     

Golgi Method without Osmium Tetroxide for the Study of the Central Nervous System

A variant Golgi technique was developed that consisted of substituting osmium tetroxide with formaldehyde as the initial fixative in intracardiac perfusion, along with the addition of glacial acetic acid to the chromating fluid. This procedure avoids disposal of dangerous waste substances into the environment. Other advantages include 1) reduction of cost, danger to lab workers, and risk of disruption of the tissue slices during their handling by eliminating the osmium tetroxide, 2) clear tissue background, 3) greater quantity of impregnated neurons than in the classical procedure, with distinct morphological details easily identified even in gross sections and 4) reduction in processing time.