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Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses.Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts.Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol.These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

Summary Objective Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model. Methods Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and β2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings. Results Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice. Conclusion Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83–0.96, effect size d = 1.9–5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation. NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Objective Blood pressure (BP) management is a vital aspect of stroke prevention and post-stroke care. Different surgical carotid endarterectomy (CEA) techniques may impact on BP control post-operatively. Specifically, the carotid sinus nerve, which innervates the carotid baroreceptors and carotid body, is commonly left intact during conventional CEA but is routinely transected as part of eversion CEA. The aim of this study was to assess long term BP control after eversion and conventional CEA. Methods Patients from the International Carotid Stenting Study (ICSS cohort) and a personal series of patients from the Stroke Clinical Trials Unit at University College London (UCL cohort) were separately analysed and divided into eversion and conventional CEA groups. Mixed effect linear models were fitted and adjusted for baseline demographic data and antihypertensive treatment to test for changes in BP from baseline over a three year follow up period after the respective procedures. Results There were no differences in changes in baseline BP readings and follow up readings between eversion and conventional CEA in the ICSS or UCL cohorts. In the ICSS cohort a mild but significant systolic (–8.6 mmHg; 95% confidence interval [CI] –10.6 – –6.6) and diastolic (–4.9 mmHg; 95% CI –6.0 – –3.8) BP lowering effect was evident at discharge in the conventional group but not in the eversion CEA group. BP monitoring during follow up did not reveal any consistent BP changes with either conventional or eversion CEA vs. baseline levels. Conclusion Neither conventional nor eversion CEA seem to result in clinically significant long term BP changes. Potential concerns related to either short or long term alterations in BP levels with transection of the carotid sinus nerve during eversion CEA could not be substantiated.

Neurons in the organum vasculosum of the lamina terminalis (OVLT) sense extracellular NaCl and angiotensin II concentrations to regulate body fluid homeostasis and arterial blood pressure. Lesion of the anteroventral third ventricular region or OVLT attenuates multiple forms of neurogenic hypertension. However, the extent by which OVLT neurons directly regulate sympathetic nerve activity to produce hypertension is not known. Therefore, the present study tested this hypothesis by using a multi-faceted approach including optogenetics, single-unit and multifiber nerve recordings, and chemogenetics. First, optogenetic activation of OVLT neurons in conscious Sprague-Dawley rats (250–400 g) produced frequency-dependent increases in arterial blood pressure and heart rate. These responses were not altered by the vasopressin receptor antagonist (β-mercapto-β,β-cyclopentamethylenepropionyl1,O-me-Tyr2,Arg8)–vasopressin but eliminated by the ganglionic blocker chlorisondamine. Second, optogenetic activation of OVLT neurons significantly elevated renal, splanchnic, and lumbar sympathetic nerve activity. Third, single-unit recordings revealed optogenetic activation of the OVLT significantly increased the discharge of bulbospinal, sympathetic neurons in the rostral ventrolateral medulla. Lastly, chronic chemogenetic activation of OVLT neurons for 7 days significantly increased 24-hour fluid intake and mean arterial blood pressure. When the 24-hour fluid intake was clamped at baseline intakes, chemogenetic activation of OVLT neurons still produced a similar increase in arterial blood pressure. Neurogenic pressor activity assessed by the ganglionic blocker chlorisondamine was greater at 7 days of OVLT activation versus baseline. Collectively, these findings indicate that acute or chronic activation of OVLT neurons produces a sympathetically mediated hypertension.

Publisher Summary This chapter focuses on the effect of splanchnic circulation on overall circulatory function. The splanchnic circulation powerfully influences systemic arterial pressure via two distinct mechanisms. Widespread contraction of arteries in the splanchnic bed reduces blood flow to the region. Active constriction of veins in the splanchnic organs reduces regional blood volume. This has relatively little effect on total peripheral resistance but raises cardiac output and arterial pressure by increasing central blood volume and thus cardiac preload. Splanchnic sympathetic nerve activity (splSNA) is controlled by arterial and cardiopulmonary baroreceptors, and by inputs from other somatic and visceral afferents. Some stimuli are able to alter splSNA in a selective fashion. Impaired sympathetic splanchnic vasoconstriction is an important cause of orthostatic hypotension and other orthostatic disorders such as postural tachycardia syndrome. In portal hypertension there is a very marked increase in sympathetic nervous system activity, including to the splanchnic organs. During the development of arterial hypertension in humans, increased vascular resistance is observed first in the splanchnic circulation.

To substantially reduce the risk of hospitalization and death among subjects with heart failure (HF) and reduced left ventricular ejection fraction, it is necessary to make a comprehensive approach of the different neurohormonal systems that are implied in its etiopathogenesis, including not only sympathetic nervous system, and renin-angiotensin system, but also vasoactive peptides and sodium-glucose transport protein 2. The DAPA-HF trial demonstrated that the addition of dapagliflozin to the standard treatment in HF with reduced left ventricular ejection fraction, markedly decreases the risk of cardiovascular death, HF hospitalization and overall death. In addition, dapagliflozin improves functional class and quality of life. Importantly, the prognostic benefit starts early after initiating treatment with dapagliflozin, regardless baseline therapy or the presence of diabetes. All these evidences make dapagliflozin as one of the mainstays of treatment for the management of HF with reduced left ventricular ejection fraction.

NEW FINDINGS What is the central question of this study? What is the role of β- and α-adrenergic receptors in the control of the coronary circulation during handgrip exercise and isolated muscle metaboreflex activation in humans? What is the main finding and its importance? β-Adrenergic receptor, but not α-adrenergic receptor, blockade significantly blunted the increases in coronary blood velocity observed during handgrip. Coronary blood velocity was unchanged from baseline during isolated muscle metaboreflex activation. This highlights the important role of β-adrenergic receptors in the coronary circulation during handgrip in humans, and the more limited involvement of the α-adrenergic receptors. ABSTRACT We sought to investigate the role of β- and α-adrenergic receptors in coronary circulation during static handgrip exercise and isolated muscle metaboreflex activation in humans. Seventeen healthy young men underwent two experimental sessions, consisting of 3 min of static handgrip exercise at a target force of 40% maximum voluntary force (not achieved for the full 3 min), and 3 min of metaboreflex activation (post-exercise ischaemia) in two conditions: (1) control and β-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). In both sessions, coronary blood velocity (CBV, echocardiography) was increased during handgrip (Δ8.0 ± 7.4 cm s-1 ) but unchanged with metaboreflex activation (Δ2.5 ± 3.2 cm s-1 ) under control conditions. β-Blockade abolished the increase in CBV during handgrip, while CBV was unchanged from control with α-blockade. Cardiac work, estimated from rate pressure product (RPP; systolic blood pressure multiplied by heart rate), increased during handgrip and metaboreflex in control conditions in both sessions. β-Blockade reduced RPP responses to handgrip and metaboreflex, whereas α-blockade increased RPP, but the responses to handgrip and metaboreflex were unchanged. CBV and RPP were only significantly correlated during handgrip under control (r = 0.71, P

Excessive sympathetic outflow following trauma can lead to cardiac dysfunction, inflammation, coagulopathy, and poor outcomes. We previously reported that buprenorphine analgesia decreased survival after hemorrhagic trauma. Our aim is to examine the underlying mechanisms of mortality in a non-compressible hemorrhage rat model resuscitated with saline or adenosine, lidocaine, magnesium (ALM). Anesthetized adult male Sprague-Dawley rats were randomly assigned to Saline control group or ALM therapy group (both n = 10). Hemorrhage was induced by 50% liver resection. After 15 min, 0.7 mL/kg 3% NaCl ± ALM intravenous bolus was administered, and after 60 min, 0.9% NaCl ± ALM was infused for 4 h (0.5 mL/kg/h) with 72 h monitoring. Animals received 6-12-hourly buprenorphine for analgesia. Hemodynamics, heart rate variability, echocardiography, and adiponectin were measured. Cardiac tissue was analyzed for adrenergic/cholinergic receptor expression, inflammation, and histopathology. Four ALM animals and one Saline control survived to 72 h. Mortality was associated with up to 97% decreases in adrenergic (β-1, α-1A) and cholinergic (M2) receptor expression, cardiac inflammation, myocyte Ca2+ loading, and histopathology, indicating heart ischemia/failure. ALM survivors had higher cardiac output and stroke volume, a 30-fold increase in parasympathetic/sympathetic receptor expression ratio, and higher circulating adiponectin compared to Saline controls. Paradoxically, Saline cardiac adiponectin hormone levels were higher than ALM, with no change in receptor expression, indicating intra-cardiac synthesis. Mortality appears to be a "systems failure" associated with CNS dysregulation of cardiac function. Survival involves an increased parasympathetic dominance to support cardiac pump function with reduced myocardial inflammation. Increased cardiac α-1A adrenergic receptor in ALM survivors may be significant, as this receptor is highly protective during heart dysfunction/failure.

Background: A significant subset of patients with Alzheimer’s disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons—which densely innervate bone and potently modulate bone remodeling—is implicated in this pathological bone reformation. Objective: Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). Methods: Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. Results: PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. Conclusion: Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.

Obstructive sleep apnea is a frequent finding in clinical practice especially with the obesity epidemic and the growing awareness of sleep-disordered breathing as a potential and treatable risk factor for cardiovascular diseases. It frequently coexists undiagnosed activating pathophysiological mechanisms known to participate in development and progression of cardiovascular diseases and resistance to therapeutical strategies. The sympathetic activation and the baroreflex and chemoreflex impairment appear to be the main pathophysiological factors that activating several mechanisms elicit cardiac and vascular damage. Data from cross-sectional population-based studies, prospective studies and meta-analysis have clearly shown the implication of OSA in the development of the hypertensive state and the benefits obtained by continuous positive airway pressure on daytime blood pressure and cardiovascular risk.

Psychological stress predisposes our body to several disorders. Understanding the cellular and molecular mechanisms involved in the physiological responses to psychological stress is essential for the success of therapeutic applications. New studies show, by using in vivo inducible Cre/loxP-mediated approaches in combination with pharmacological blockage, that sympathetic nerves, activated by psychological stress, induce brown adipocytes to produce IL-6. Strikingly, this cytokine promotes gluconeogenesis in hepatocytes, that results in the decline of tolerance to inflammatory organ damage. The comprehension arising from this research will be crucial for the handling of many inflammatory diseases. Here, we review recent advances in our comprehension of the sympathetic nerve-adipocyte axis in the tissue microenvironment.

The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. The Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. Here, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure (EE), decreased respiratory exchange ratio (RER), and prevented high-fat diet (HFD)-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly up-regulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA, and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis; and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.

Supplemental Digital Content is available in the text., Previously, we have shown that male mice exposed to maternal separation and early weaning (MSEW)—a mouse model of early life stress—display increased mean arterial pressure compared with controls when fed a high-fat diet. As the stimulation of sensory nerves from fat has been shown to trigger the adipose afferent reflex, we tested whether MSEW male mice show obesity-associated hypertension via the hyperactivation of this sympathoexcitatory mechanism. After 16 weeks on high-fat diet, MSEW mice displayed increased blood pressure, sympathetic activation, and greater depressor response to an α-adrenergic blocker when compared with controls (P

There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.

Introduction Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder in children and is characterized by recurrent total or partial upper airway collapse episodes during sleep. OSA is associated with cardiovascular, metabolic and neurobehavioural complications related to sympathetic nervous system (SNS) activation. A key role in originating these complications and in underlying pathophysiologic mechanisms can be attributed to altered catecholamines (CAs) metabolism. Methods A systematic review was performed according to the PRISMA Statement guidelines for research studies correlating OSA in children with catecholamines. Results Only 13 studies out of 151 reports were included in the review. Most studies (9 out of 13) showed increased secretion for some catecholamines in patients with a sleep-related breathing disorder or OSA compared to a control group or post treatment control group. Conclusion OSA can activate the sympathetic nervous system (SNS) and increase catecholamines (CAs) production, perhaps contributing to increased morbidity. However, underlying pathophysiologic mechanisms remain still unclear.

Nowadays, there are robust clinical and pathophysiological evidence supporting the beneficial effects of physical activity on cardiovascular (CV) system. Thus, the physical activity is considered a key strategy for CV prevention. In fact, exercise training exerts favourable effects on all risk factors for CV diseases (i.e. essential hypertension, type 2 diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, etc…). In addition, all training modalities such as the aerobic (continuous walking, jogging, cycling, etc.) or resistance exercise (weights), as well as the leisure-time physical activity (recreational walking, gardening, etc) prevent the development of the major CV risk factors, or delay the progression of target organ damage improving cardio-metabolic risk. Exercise training is also the core component of all cardiac rehabilitation programs that have demonstrated to improve the quality of life and to reduce morbidity in patients with CV diseases, mostly in patients with coronary artery diseases. Finally, it is still debated whether or not exercise training can influence the occurrence of atrial and ventricular arrhythmias. In this regard, there is some evidence that exercise training is protective predominantly for atrial arrhythmias, reducing the incidence of atrial fibrillation. In conclusion, the salutary effects evoked by physical acitvity are useful in primary and secondary CV prevention.

Active standing test is clinically used to detect inadequate sympathetic nervous system response to the orthostasis. Peripheral arterial tone (PAT) is a recently developed technology whereby sympathetic activity can be measured through monitoring the digit arterial pulsatile volume. We aimed to determine the response of PAT to the orthostasis. The PAT and short-time frequency domain heart rate variability (HRV) were simultaneously measured during a 5.5-min active standing test in volunteers. The endpoints were changes in the PAT and ratio of low frequency to high frequency (LH/HF) before and after the postural changes: sitting→standing→sitting again. The blood pressure (BP) was constant throughout the test while the heart rate increased during standing in 54 participants. The natural logarithm of the mean LF/HF increased in the standing position (sitting, standing, and sitting again, mean±standard deviation, 1.3±1.04, 1.73±1.15, and 1.51±0.94; p=0.006), and the natural logarithm of its peak value was the highest also while standing (2.58±1.19, 3.08±1.2, and 2.85±1.05; p=0.007). The mean PAT (487.5±277.7, 314.5±180.4, and 458.1±244.3; p

Introduction: Ghrelin is an endogenous peptide with potential protective effects on ischemic heart. Methods: Synthetic ghrelin was administered (100 μg·kg-1 subcutaneous injection, twice daily) for 4 weeks in a rat model of myocardial infarction (MI) with coronary artery occlusion. At the 5th week, electrocardiogram, monophasic action potentials and autonomic nerve function were evaluated. Cardiac tyrosine hydroxylase (TH) was determined by immunofluorescence staining. Results: MI significantly increased sympathetic nerve activity (SNA) and ventricular arrhythmias, and prolonged APD dispersion and APD alternans (p < 0.01). Ghrelin treatment significantly increased ventricular fibrillation threshold (VFT), shortened APD dispersion and APD alternans, inhibited SNA and promoted vagus nerve activities (p < 0.01). Ghrelin also markedly reversed abnormal expression of TH in the peri-infarcted area of the heart (p < 0.01). Discussion/Conclusion: Ghrelin provides a sustained electrophysiological protection by the increase of VFT and improvement of APD dispersion and APD alternans. The mechanism may be related to the regulation of autonomic nerve and sympathetic nerve remodeling. Thus, ghrelin represents a novel drug to prevent ventricular arrhythmia in ischemic heart disease.

Objective: to study the electrophysiological parameters of brain bioelectric activity and features of the autonomous nervous system assessing heart rate variability, sympathetic skin response, clinical and physiological tests depending on the lateralization of migraine pain syndrome in the right or left brain hemisphere in patients with epileptic electroencephalogram (EEG) signs and migraine.Material and methods. Thirty six patients with aura-free episodic migraine at risk of developing epilepsy and 9 age-matched healthy subjects were examined. All participants underwent EEG, clinical and physiological tests, assessment of heart rate variability and sympathetic skin response.Results. Patients with right-hemisphere migraine headache had signs of activated sympathetic nervous system at baseline level and during exercise, lower baseline EEG epileptiform activity and in provocative tests. In contrast to the subjects of this group, patients of other group featured with a more stable migraine pain syndrome in the left hemisphere tended to dominate with functional activity of the parasympathetic system such as increased trophotropic support during exercise, as well as greater magnitude of baseline epileptiform bioelectric activity and during load tests.Conclusion. Values of heart rate variability in combination with objective results of clinical and physiological assessment of the autonomous nervous system and electrophysiological parameters of brain bioelectric activity are reliable prognostic indicators for varying functional conditions in patients with episodic migraine.

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA.

BACKGROUND: Neural circuits allow whole-body yaw rotation to modulate vagal parasympathetic activity, which alters beat-to-beat variation in heart rate. The overall output of spinning direction, as well as vestibular-visual interactions on vagal activity still needs to be investigated. OBJECTIVE: This study investigated direction-dependent effects of visual and natural vestibular stimulation on two autonomic responses: heart rate variability (HRV) and pupil diameter. METHODS: Healthy human male subjects (n = 27) underwent constant whole-body yaw rotation with eyes open and closed in the clockwise (CW) and anticlockwise (ACW) directions, at 90°/s for two minutes. Subjects also viewed the same spinning environments on video in a VR headset. RESULTS: CW spinning significantly decreased parasympathetic vagal activity in all conditions (CW open p = 0.0048, CW closed p = 0.0151, CW VR p = 0.0019,), but not ACW spinning (ACW open p = 0.2068, ACW closed p = 0.7755, ACW VR p = 0.1775,) as indicated by an HRV metric, the root mean square of successive RR interval differences (RMSSD). There were no direction-dependent effects of constant spinning on sympathetic activity inferred through the HRV metrics, stress index (SI), sympathetic nervous system index (SNS index) and pupil diameter. Neuroplasticity in the CW eyes closed and CW VR conditions post stimulation was observed. CONCLUSIONS: Only one direction of yaw spinning, and visual flow caused vagal nerve neuromodulation and neuroplasticity, resulting in an inhibition of parasympathetic activity on the heart, to the same extent in either vestibular or visual stimulation. These results indicate that visual flow in VR can be used as a non-electrical method for vagus nerve inhibition without the need for body motion in the treatment of disorders with vagal overactivity. The findings are also important for VR and spinning chair based autonomic nervous system modulation protocols, and the effects of motion integrated VR.

Summary Objectives Orthodontic tooth movement (OTM) increases sympathetic and sensory neurological markers in periodontal tissue. However, the relationship between the sympathetic and sensory nervous systems during OTM remains unclear. Therefore, the present study investigated the relationship between the sympathetic and sensory nervous systems activated by OTM using pharmacological methods. Materials and Methods We compared the effects of sympathectomy and sensory nerve injury during OTM in C57BL6/J mice. Capsaicin (CAP) was used to induce sensory nerve injury. Sympathectomy was performed using 6-hydroxydopamine. To investigate the effects of a β-agonist on sensory nerve injury, isoproterenol (ISO) was administered to CAP-treated mice. Furthermore, to examine the role of the central nervous system in OTM, the ventromedial hypothalamic nucleus (VMH) was ablated using gold thioglucose. Results Sensory nerve injury and sympathectomy both suppressed OTM and decreased the percent of the alveolar socket covered with osteoclasts (Oc.S/AS) in periodontal tissue. Sensory nerve injury inhibited increases in OTM-induced calcitonin gene-related peptide (CGRP) immunoreactivity (IR), a marker of sensory neurons, and tyrosine hydroxylase (TH) IR, a marker of sympathetic neurons, in periodontal tissue. Although sympathectomy did not decrease the number of CGRP-IR neurons in periodontal tissue, OTM-induced increases in the number of TH-IR neurons were suppressed. The ISO treatment restored sensory nerve injury-inhibited tooth movement and Oc.S/AS. Furthermore, the ablation of VMH, the centre of the sympathetic nervous system, suppressed OTM-induced increases in tooth movement and Oc.S/AS. Conclusions The present results suggest that OTM-activated sensory neurons contribute to enhancements in osteoclast activity and tooth movement through sympathetic nervous signalling.

Objectives Fire departments have employed far-infrared sauna (FIRS) use as part of post-fire call protocols to address concerns related to carcinogens. The inability of the autonomic nervous system (ANS) to fully recover following an emergency call, as demonstrated by heightened sympathetic nervous system activity and delayed parasympathetic nervous system reactivation, has been implicated as a potential factor related to sudden cardiac death. The use of a sauna post-fire call, which has been demonstrated to elevate body temperature, may interfere with the ability of the ANS to fully recover. The purpose of this study was to examine ANS responses to FIRS exposure in firefighters (FFs) with (EX) and without (NONEX) prior maximal exercise. Methods Sixteen career FFs participated in this study. Body temperature (TEMP), heart rate (HR), heart rate variability (HRV), blood pressure (BP), and blood lactate (La─) were measured at the start of each testing session, following a maximal exercise test (EX only), and immediately after a 15-min FIRS exposure for NONEX and EX. Results In NONEX, TEMP increased (P < 0.001); however, there was no change in HR, HRV, BP, or La─. In EX, BP remained unchanged while TEMP, HR, and La─ were significantly (P < 0.001) greater than baseline following FIRS exposure and HRV was significantly (P = 0.018) lower than baseline. Conclusions These findings indicate that FIRS following maximal exercise did support some ANS recovery, but may interfere with restoration of body temperature and parasympathetic nervous system reactivation, potentially influencing post-call cardiovascular risk in FFs.

Introduction. Although its neurophysiological effects have not been fully elucidated, current evidence suggests the clinical effectiveness of spinal manipulation. Different studies suggest that manual therapy induces changes in the autonomic nervous system (ANS). Recent studies showed that mobilization produced a sympatheticexcitatory effect. However, studies using thrust manipulation appeared to be less consistent in their results.Objectives. The main objective of this review was to evaluate whether spinal manipulation induces effects on the ANS. Another objective was to correlate the changes in the measured variables with the activation or inhibition of the sympathetic or parasympathetic nervous system and with the level of spinal manipulation.Materials and methods. We performed a literature search in the following databases: PubMed, PEDro, CINAHL and OVID, using the keywords «Manipulation, spinal» and «Autonomic Nervous System». The PEDro scale was used to assess the methodological quality.Results. Nine studies met the inclusion criteria. Six trials measured cardiovascular function indicators (blood pressure, heart rate, Heart Rate Variability). Three other trials measured the pupil reaction. In most studies, cervical or upper thoracic region was manipulated.Conclusions. Our review does not provide definitive evidence of the effects of spinal manipulation on the ANS. However, most studies observed the existence of autonomic effects by modifying parameters such as blood pressure or Heart Rate Variability after manipulation. Increased parasympathetic activation probably occurs after cervical and lumbar treatment and increased sympathetic activation after dorsal treatment.

Signal-averaged sympathetic transduction of blood pressure (BP) is inversely related to resting muscle sympathetic nerve activity (MSNA) burst frequency in healthy cohorts. Whether this represents a physiological compensatory adaptation or a methodological limitation, remains unclear. The current analysis aimed to determine the contribution of methodological limitations by evaluating the dependency of MSNA transduction at different levels of absolute BP. Thirty-six healthy participants (27 ± 7 yr, 9 females) underwent resting measures of beat-to-beat heart rate, BP, and muscle sympathetic nerve activity (MSNA). Tertiles of mean arterial pressure (MAP) were computed for each participant to identify cardiac cycles occurring below, around, and above the MAP operating pressure (OP). Changes in hemodynamic variables were computed across 15 cardiac cycles within each MAP tertile to quantify sympathetic transduction. MAP increased irrespective of sympathetic activity when initiated below the OP, but with MSNA bursts provoking larger rises (3.0 ± 0.9 vs. 2.1 ± 0.7 mmHg

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during 3rd–6th min ( post A), and 7th–10th min ( post B) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared with baseline, CBRS decreased significantly ( post A: 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), whereas SBRS increased significantly ( post A: 0.8 ± 0.2 to 1.5 ± 0.2 units·beat−1·mmHg−1, P < 0.05) with an upward shift of the operating point. There were no differences in these variables between posts A and B. A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Vagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials-NECTAR-HF and INOVATE-HF-failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose-response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.Für die Vagusnervstimulation (VNS) als einer sinnvollen Therapie bei Herzinsuffizienz bestehen starke pathophysiologische Argumente. Trotz mehrerer vielversprechender präklinischer und Pilotstudien konnten die beiden großen kontrollierten Studien NECTAR-HF und INOVATE-HF den erwarteten klinischen Nutzen jedoch nicht zeigen. Vermutlich wurde hierbei die klinische Anwendung dieser Therapie durchgeführt, bevor die komplexe Pathophysiologie der autonomen elektrischen Modulation ausreichend verstanden worden war, sodass diese Studien nicht in der Lage waren, das Potenzial der VNS zu demonstrieren. Seit diesen Studien wurde mehr Wissen über die klinische Anwendung der VNS erlangt, insbesondere zur Patientenselektion und zur Art der Stimulation („Dosis“, d. h. Amplitude, Impulsfrequenz [Hz], Dauer der Anwendung und Arbeitszyklus der VNS). Eine neue randomisierte Studie mit einem adaptiven Design wird aktuell durchgeführt, um die Fragen nach der optimalen Dosis der VNS zu beantworten.

Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.

Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing N-methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABA(A) receptor (GABA(A)R)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABA(A)R agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABA(A)R inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABA(A)R activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABA(A)R-α1 and K(+)/Cl(−) cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABA(A)R signaling. NEW & NOTEWORTHY We have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABA(A) receptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABA(A) receptor as well as KCC2 transporter immunoreactivity.

Neurogenic stunned myocardium is a form of stress cardiomyopathy. The disorder is sometimes referred to as atypical Takotsubo cardiomyopathy. The pathophysiology of neurogenic stunned myocardium is hypothesized to involve significant overdrive of the sympathetic nervous system after a brain injury. Treatment options for a patient with a brain injury who has progressed to cardiogenic shock remain controversial, with no consistent guidelines. A patient with subarachnoid hemorrhage who progresses to cardiogenic shock with concurrent cerebral vasospasm presents a special treatment challenge. Neurogenic stunned myocardium is reversible; however, it must be recognized immediately to avoid or manage potential complications, such as cardiogenic shock and pulmonary edema. A multifaceted treatment approach is needed for the patient with cardiogenic shock and concurrent vasospasm.

Experiments aimed to evaluate the tissue distribution of Mas-related G protein-coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. To investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40 pmol/100 nL), angiotensin-(1–7), angiotensin II, angiotensin A, and Mas/MrgD antagonist d-Pro7-Ang-1-7 (50 pmol/100 nL), Mas antagonist A779 (100 pmol/100 nL), or vehicle (0.9% NaCl) were made in different rats ( n = 4–6/group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ = 15 ± 2 mmHg), HR (Δ = 36 ± 4 beats/min), and RSNA (Δ = 31 ± 4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1–7) at rIC did not produce any change in MAP, HR, and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist d-Pro7-Ang-(1–7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1–7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1–7) in the brain.

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4–L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem neurodegenerative disorder, comprising autonomic dysfunction. We aimed to assess sudomotor function in ALS by measuring the electrochemical skin conductance (ESC).Thirty-one ALS patients [median age of 62 years (1st-3rd interquartile range - IQR, 56-72), male 71%] were prospectively compared with 29 healthy controls, matched for age and sex. We analysed ESC results from hands and feet, bilaterally.A total of 120 ESC recordings were obtained. Hands and feet ESC measurements were significantly lower in patients compared with controls [64 μS (1st-3rd IQR, 57-58) versus 78 μS (1st-3rd IQR, 70.5-84), p 0.001 and 76 μS (1st-3rd IQR, 68-83) versus 81 μS (1st-3rd IQR, 78-86), p = 0.008, respectively]. In ALS group, no differences were observed between spinal and bulbar-onset forms for hands and feet results (p 0.05). Hands and feet ESC measurements did not correlate also with disease duration, total ALSFRS-R scale, or ALSFRS-R progression rate (all p 0.05).ESC is a non-invasive, fast and quantitative method suitable for assessing sudomotor function. ALS patients revealed a decreased function in upper and lower extremities.Sudomotor dysfunction is part of the ALS manifestations.

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (V̇O2peak) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇O2peak: 78 ± 23 percent age-predicted (%V̇O2peak); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29%V̇O2peak) performed 2 min of mild- (“loadless”) and moderate-intensity (“loaded”) 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher (p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min−1). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of “loadless” and “loaded” cycling, group mean BF fell from baseline values in controls (−5 ± 6 and −7 ± 7 bursts·min−1, respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min−1). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to “loaded” cycling and %V̇O2peak was present in patients (r = −0.43, p < 0.05) but absent in controls (r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in %V̇O2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake (V̇O2peak) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.

Background The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions such as sarcopenia, the age‐dependent decline in muscle mass, force, and power. Devising interventions that can adjust neurotransmitter release to changing physiological demands will require understanding how the sympathetic nervous system affects muscle motor innervation and muscle mass, which will prevent sarcopenia‐associated impaired mobility, falls, institutionalization, co‐morbidity, and premature death. Here, we tested the hypothesis that prolonged heart and neural crest derivative 2 (Hand2) expression in peripheral sympathetic neurons (SNs) ameliorates sympathetic muscle denervation, motor denervation, and sarcopenia in geriatric mice. Methods We delivered either a viral vector encoding the transcription factor Hand2 or an empty vector (EV) driven to SNs by the PRSx8 promoter by injecting the saphenous vein in 16‐month‐old C57BL/6 mice that were sacrificed 10–11 months later. Studies relied on sympathetic and muscle immunohistochemistry analysed by confocal microscopy, nerve and muscle protein expression assessed by immunoblots, nerve‐evoked and muscle‐evoked maximal muscle contraction force, extensor digitorum longus (EDL) muscle RNA sequencing, SN real‐time PCR, and tests of physical performance using an inverted‐cling grip test and in an open‐arena setting. Results Examining the mice 10–11 months later, we found that inducing Hand2 expression in peripheral SNs preserved (i) the number of neurons (EV: 0.32 ± 0.03/μm2, n = 6; Hand2: 0.92 ± 0.08/μm2, n = 7; P

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity. Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.

In this study, we found that the reduction in muscle sympathetic nerve activity at the onset of static handgrip exercise was blunted following GABAA receptor activation with oral administration of diazepam in young, healthy individuals. The present findings provide novel insight into neural circuitry mechanisms controlling muscle sympathetic outflow during exercise in humans.

Background Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. Methods Fifty HTx recipients were assessed at 2.5, 6 and 12 months after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were carried out at supine rest, 0.2 Hz controlled breathing, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 months. Conclusions Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 months after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 months. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.

Introduction The concept of targeting the renal sympathetic nerves therapeutically to lower blood pressure (BP) is based on their crucial role in regulating both renal and cardiovascular control. These effects are mainly mediated via three major mechanisms including alteration of renal blood flow, renin-release, and Na+ retention. Initial surgical approaches applying crude and unselected sympathectomy, while rendering significant BP lowering and cardiovascular event reducing properties, where plagued by side effects. More modern selective catheter-based denervation approaches selectively targeting the renal nerves have been shown to be safe and effective in reducing BP in various forms of hypertension and multiple comorbidities. Areas covered This article covers the background relevant for the concept of renal denervation (RDN), the evidence obtained from relevant randomized controlled trials to substantiate the safety and efficacy of RDN, and recently published clinical recommendations. Expert opinion Catheter-based RDN is safe and has now been shown in sham-controlled randomized clinical trials to result in clinically meaningful BP lowering in both drug naive hypertensive patients and those on concomitant antihypertensive therapy. Real world data from a large global registry further supports the clinical utility of RDN. It now seems time to embed renal denervation into routine clinical care.

Purpose. The PET radiotracers 4-18F-fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis methods. The aim of this study was to evaluate their performance in cardiomyopathy patients.Methods: Eight cardiomyopathy patients selected for surgical placement of an implantable cardioverter defibrillator (ICD) were scanned with 18F-4F-MHPG and 18F-3F-PHPG on different days. In addition, an 13N-ammonia scan was performed to assess regional resting perfusion. The myocardial kinetics of 18F-4F-MHPG and 18F-3F-PHPG were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as quantitative metrics of regional nerve density. Polar maps of the Patlak slopes were generated to map regional nerve density and to estimate the extent of cardiac denervation. For comparison purposes, regional tracer 'retention index' (RI) values (mL blood/min/mL tissue) were also calculated and used to estimate denervation extent metrics. Polar maps of resting perfusion estimates were used to estimate the pattern and extent of hypoperfusion.Results: Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all eight subjects, ranging from 25% to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion.Conclusion: 18F-4F-MHPG and 18F-3F-PHPG provide quantitative metrics of regional sympathetic nerve density and the extent of left ventricular denervation in patients with cardiomyopathy, supporting further clinical development of these agents.Trial registration: Registered at the ClinicalTrials.gov website (NCT02669563).URL: https://clinicaltrials.gov/ct2/show/NCT02669563

Key points Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e., polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. Abstract Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea level inhabitants residing at high altitude. By studying this unique population, which has adapted thru natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity, and characterizing the transport of oxygen thru blood rheology, including haemoglobin mass, blood and plasma volume & blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances thru pharmacological dissected of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity. This article is protected by copyright. All rights reserved.

In ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. This is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. During 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). Quantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone.

Respiratory modulation of sympathetic vasomotor outflow to skeletal muscles (muscle sympathetic nerve activity; MSNA) occurs in resting humans. Specifically, MSNA is highest at end-expiration and lowest at end-inspiration during quiet, resting breathing. We tested the hypothesis that within-breath modulation of MSNA would be amplified during graded leg cycling. Thirteen (n = 3 females) healthy young (age: 25.2 ± 4.7 yr) individuals completed all testing. MSNA (right median nerve) was measured at rest (baseline) and during semirecumbent cycle exercise at 40%, 60%, and 80% of maximal workload (Wmax). MSNA burst frequency (BF) was 20.0 ± 4.0 bursts/min at baseline and was not different during exercise at 40%Wmax (21.3 ± 3.7 bursts/min; P = 0.292). Thereafter, MSNA BF increased significantly compared with baseline (60%Wmax: 31.6 ± 5.8 bursts/min; P < 0.001, 80%Wmax: 44.7 ± 5.3 bursts/min; P < 0.001). At baseline and all exercise intensities, MSNA BF was lowest at end-inspiration and greatest at mid-to-end expiration. The within-breath change in MSNA BF (ΔMSNA BF; end-expiration minus end-inspiration) gradually increased from baseline to 60%Wmax leg cycling, but no further increase appeared at 80%Wmax exercise. Our results indicate that within-breath modulation of MSNA is amplified from baseline to moderate intensity during dynamic exercise in young healthy individuals, and that no further potentiation occurs at higher exercise intensities. Our findings provide an important extension of our understanding of respiratory influences on sympathetic vasomotor control., Published online 13 August 2021

Superior cervical ganglia (SCG) postganglionic neurons receive preganglionic drive via the cervical sympathetic chains (CSC). The SCG projects to structures like the carotid bodies (e.g., vasculature, chemosensitive glomus cells), upper airway (e.g., tongue, nasopharynx), and to the parenchyma and cerebral arteries throughout the brain. We previously reported that a hypoxic gas challenge elicited an array of ventilatory responses in sham-operated (SHAM) freely moving adult male C57BL6 mice and that responses were altered in mice with bilateral transection of the cervical sympathetic chain (CSCX). Since the CSC provides preganglionic innervation to the SCG, we presumed that mice with superior cervical ganglionectomy (SCGX) would respond similarly to hypoxic gas challenge as CSCX mice. However, while SCGX mice had altered responses during hypoxic gas challenge that occurred in CSCX mice (e.g., more rapid occurrence of changes in frequency of breathing and minute ventilation), SCGX mice displayed numerous responses to hypoxic gas challenge that CSCX mice did not, including reduced total increases in frequency of breathing, minute ventilation, inspiratory and expiratory drives, peak inspiratory and expiratory flows, and appearance of noneupneic breaths. In conclusion, hypoxic gas challenge may directly activate subpopulations of SCG cells, including subpopulations of postganglionic neurons and small intensely fluorescent (SIF) cells, independently of CSC drive, and that SCG drive to these structures dampens the initial occurrence of the hypoxic ventilatory response, while promoting the overall magnitude of the response. The multiple effects of SCGX may be due to loss of innervation to peripheral and central structures with differential roles in breathing control. NEW & NOTEWORTHY We present data showing that the ventilatory responses elicited by a hypoxic gas challenge in male C57BL6 mice with bilateral superior cervical ganglionectomy are not equivalent to those reported for mice with bilateral transection of the cervical sympathetic chain. These data suggest that hypoxic gas challenge may directly activate subpopulations of superior cervical ganglia (SCG) cells, including small intensely fluorescent (SIF) cells and/or principal SCG neurons, independently of preganglionic cervical sympathetic chain drive.

The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently affected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guidance on their use. This review discusses the etiology of hypertension, and more specifically the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the effects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline receptor agonists.

Previous studies have demonstrated that sympathetic baroreflex sensitivity (BRS) increases during orthostatic stress in humans. We recently showed that dietary salt intake affects sympathetic neural control in healthy premenopausal women. This study aimed to determine whether salt loading versus salt reduction would impact sympathetic BRS during orthostasis in premenopausal women with a history of normal pregnancy. Nine healthy women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (250 mEq sodium/day) or low-salt (50 mEq sodium/day) diet for 1 wk each (∼2 mo apart with the order randomized), whereas water intake was ad libitum. Laboratory testing was performed following each high- and low-salt period in the midluteal phase of the menstrual cycle. Hemodynamics and muscle sympathetic nerve activity (MSNA) were measured at baseline (supine; 2 min) and during a graded head-up tilt (30° for 5 min and 60° for 20 min). Sympathetic BRS was assessed during baseline and head-up tilt. Hemodynamics were not different between salt conditions during baseline or tilt. Both supine and upright MSNA indices were lower in high salt than low salt (all P < 0.05), however, there was no interaction effect ( P = 0.507–0.996). On moving from supine to upright, sympathetic BRS remained unchanged in high salt but increased in low salt ( P = 0.028 for interaction). Thus, salt loading diminishes the responsiveness of sympathetic BRS during orthostasis compared with salt reduction in healthy premenopausal women with prior normal pregnancy. Whether this is one underlying mechanism for salt-induced development of hypertension during ambulation remains to be determined.

Larger blood pressure (BP) responses to relative-intensity static exercise in men versus women are thought to involve altered muscle metaboreflex activation, but whether this is because of an intrinsic sex difference in metabolite production or differences in muscle strength and absolute load is unknown.Continuous BP and heart rate were recorded in 200 healthy young men and women (women: n = 109) during 2 min of static handgrip exercise at 30% of maximal voluntary contraction (MVC), followed by 2 min of postexercise circulatory occlusion (PECO). Muscle sympathetic nerve activity (MSNA) was recorded in a subset of participants (n = 39; women, n = 21), permitting calculation of signal-averaged resting sympathetic transduction (MSNA-diastolic BP). Sex differences were examined with and without statistical adjustment for MVC. Multivariate regression analyses were performed to identify predictors of BP responses.Men had larger systolic BP responses (interactions, P0.0001) to static handgrip exercise (24 ± 10 vs 17 ± 9 mm Hg [mean ± SD], P0.0001) and PECO (20 ± 11 vs 16 ± 9 mm Hg, P0.0001). Adjustment for MVC abolished these sex differences in BP (interactions, P0.7). In the subset with MSNA, neither burst frequency or incidence responses to static handgrip exercise or PECO differed between men and women (interactions, P0.2). Resting sympathetic transduction was also similar (P = 0.8). Multiple linear regression analysis showed that MVC or the change in MSNA, were predictors of BP responses to static handgrip, but only MVC was associated with BP responses during PECO.Sex differences in absolute contraction load contribute to differences in BP responses during muscle metaboreflex isolation using PECO. These data do not support an intrinsic effect of sex as being responsible for exercise BP differences between men and women.

Adrenergic regulation, acting via the sympathetic nervous system, provides a major mechanism to control cardiac function. It has recently been shown that hypoxia inducible factor-1α (Hif-1α) is necessary for normal development of sympathetic innervation and control of cardiac function in the mouse. To investigate whether this may represent a fundamental trait shared across vertebrates, we assessed adrenergic regulation of the heart in wild-type and Hif-1α knockout (hif-1α −/−) zebrafish (Danio rerio). Wild-type and hif-1α −/− zebrafish larvae (aged 4 and 7 days postfertilisation) exhibited similar routine heart rates within a given age group, and β-adrenergic receptor blockade with propranolol universally reduced heart rate to comparable levels, indicating similar adrenergic tone in both genotypes. In adult fish, in vivo heart rate measured during anaesthesia was identical between genotypes. Treatment of spontaneously beating hearts in vitro with adrenaline revealed a similar positive chronotropic effect and similar maximum heart rates in both genotypes. Tyrosine hydroxylase immunohistochemistry with confocal microscopy demonstrated that the bulbus arteriosus (outflow tract of the teleost heart) of adult fish was particularly well innervated by sympathetic nerves, and nerve density (as a percentage of bulbus arteriosus area) was similar between wild-types and hif-1α −/− mutants. In summary, we did not find any evidence that adrenergic cardiac control was perturbed in larval or adult zebrafish lacking Hif-1α. We conclude that Hif-1α is not essential for the normal development of cardiovascular control or adult sympathetic cardiac innervation in zebrafish, although it is possible that it plays a redundant or auxiliary role.

Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.