RESUMEN
Vitiligo is an acquired autoimmune skin disease characterized by patchy depigmentation of the skin, often accompanied by white hair. The aetiology of vitiligo is complex and difficult to cure, and its disfiguring appearance significantly impacts patients' mental and physical health. Psychological stress is a major factor in inducing and exacerbating vitiligo, as well as affecting its treatment efficacy, though the specific mechanisms remain unclear. Increasing research on the brain-skin axis in skin immunity suggests that psychological stress can influence local skin immunity through this axis, which may play a crucial role in the pathogenesis of vitiligo. This review focuses on the role of brain-skin axis in the pathogenesis of vitiligo, and explores the possible mechanism of brain-skin axis mediating the pathogenesis of vitiligo from the aspects of sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis and hormones and neuropeptides, aiming to provide the necessary theoretical basis for psychological intervention in the prevention and treatment of vitiligo.
Asunto(s)
Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Piel , Estrés Psicológico , Vitíligo , Vitíligo/psicología , Vitíligo/terapia , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Estrés Psicológico/inmunología , Estrés Psicológico/psicología , Piel/patología , Piel/inmunología , Sistema Hipófiso-Suprarrenal/metabolismo , Encéfalo , Sistema Nervioso Simpático/fisiopatología , Neuropéptidos/metabolismoRESUMEN
BACKGROUND: A detailed understanding of the sympathetic innervation of coronary arteries is relevant to facilitate the development of novel treatment approaches. AIMS: This study aimed to quantitatively examine periarterial innervation in human epicardial coronary arteries. METHODS: Coronary arteries with adjacent epicardial adipose tissue were excised along the left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) from 28 body donors and examined histologically. Immunofluorescence staining was performed to characterise sympathetic nerve fibres. RESULTS: A total of 42,573 nerve fibres surrounding 100 coronary arteries (LMCA: n=21, LAD: n=27, LCx: n=26, RCA: n=26) were analysed. The nerve fibre diameter decreased along the vessel course (median [interquartile range]): (proximal 46 µm [31-73], middle 38 µm [26-58], distal 31 µm [22-46]; p<0.001), with the largest nerve fibre diameter along the LMCA (50 µm [31-81]), followed by the LAD (42 µm [27-72]; p<0.001). The total nerve fibre density was highest along the RCA (123 nerves/cm² [82-194]). Circumferentially, nerve density was higher in the myocardial tissue area of the coronary arteries (132 nerves/cm² [76-225]) than in the epicardial tissue area (101 nerves/cm² [61-173]; p<0.001). The median lumen-nerve distance was smallest around the LMCA (2.2 mm [1.2-4.1]), followed by the LAD (2.5 mm [1.1-4.5]; p=0.005). CONCLUSIONS: Human coronary arteries are highly innervated with sympathetic nerve fibres, with significant variation in the distribution and density. Understanding these patterns informs pathophysiological understanding and, potentially, the development of catheter-based approaches for cardiac autonomic modulation.
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Vasos Coronarios , Humanos , Vasos Coronarios/inervación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Sistema Nervioso Simpático , Tejido Adiposo/inervación , Pericardio/inervación , Anciano de 80 o más Años , Fibras NerviosasRESUMEN
The adrenal gland is a player in the Ominous Octet of obesity, which lists eight endocrine contributors to the development of obesity. Baro-adrenal axis describes the bidirectional, multifaceted link between weight homoeostasis and adrenal function, in health and disease. This communication lists the various ways in which adrenal function influences, and is impacted by, obesity.
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Glándulas Suprarrenales , Obesidad , Humanos , Obesidad/fisiopatología , Glándulas Suprarrenales/fisiología , Glándulas Suprarrenales/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/fisiologíaRESUMEN
Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC.
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Calcio , Ratones Endogámicos C57BL , Sistema Nervioso Simpático , Animales , Ratones , Sistema Nervioso Simpático/efectos de la radiación , Sistema Nervioso Simpático/metabolismo , Femenino , Calcio/metabolismo , Rayos X , Corazón/efectos de la radiación , Corazón/fisiopatología , Remodelación Atrial/efectos de la radiaciónRESUMEN
This study aimed to investigate effects of epigallocatechin gallate (EGCG) on blood pressure (BP) and autonomic nervous system, indicated by 5-min heart rate variability (HRV) measurement in obese subjects, and determine correlations of BP with metabolic factors. In a double-blind, randomized controlled trial, obese subjects (n = 30) were randomly allocated to receive 150 mg EGCG (n = 15) or placebo (n = 15) twice a day without dietary restrictions. After 8-week EGCG treatment, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) significantly decreased, while the low-frequency (LF) to high-frequency power (HF) ratio (LF/HF ratio) significantly increased (P < 0.05 all), indicating a shift toward sympathetic dominance, either directly or indirectly after BP lowering. SBP had positive correlations with obesity parameters, leptin, insulin, and insulin resistance but had a negative correlation with insulin sensitivity. DBP was positively correlated with age and HF in normalized unit, but negatively correlated with height and LF in ms2. High-density lipoprotein cholesterol (HDL-C) was negatively correlated with SBP, DBP, and MAP reflecting its protective effect against elevated BP. In conclusion, the 8-week EGCG treatment decreased BP and increased the LF/HF ratio, reflecting increased sympathetic activity, either a direct EGCG effect or an indirect compensatory response following BP reduction.
Asunto(s)
Presión Sanguínea , Catequina , Frecuencia Cardíaca , Obesidad , Humanos , Catequina/análogos & derivados , Catequina/farmacología , Catequina/administración & dosificación , Obesidad/fisiopatología , Obesidad/tratamiento farmacológico , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Femenino , Presión Sanguínea/efectos de los fármacos , Adulto , Persona de Mediana Edad , Método Doble Ciego , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Obesity has been associated with a chronic increase in sympathetic nerve activity, which can lead to hypertension and other cardiovascular diseases. Preliminary studies from our lab found that oxidative stress and neuroinflammation in the brainstem contribute to sympathetic overactivity in high-fat-diet-induced obese mice. However, with glial cells emerging as significant contributors to various physiological processes, their role in causing these changes in obesity remains unknown. In this study, we wanted to determine the role of palmitic acid, a major form of saturated fatty acid in the high-fat diet, in regulating sympathetic outflow. Human brainstem astrocytes (HBAs) were used as a cell culture model since astrocytes are the most abundant glial cells and are more closely associated with the regulation of neurons and, hence, sympathetic nerve activity. In the current study, we hypothesized that palmitic acid-mediated oxidative stress induces senescence and downregulates glutamate reuptake transporters in HBAs. HBAs were treated with palmitic acid (25 µM for 24 h) in three separate experiments. After the treatment period, the cells were collected for gene expression and protein analysis. Our results showed that palmitic acid treatment led to a significant increase in the mRNA expression of oxidative stress markers (NQO1, SOD2, and CAT), cellular senescence markers (p21 and p53), SASP factors (TNFα, IL-6, MCP-1, and CXCL10), and a downregulation in the expression of glutamate reuptake transporters (EAAT1 and EAAT2) in the HBAs. Protein levels of Gamma H2AX, p16, and p21 were also significantly upregulated in the treatment group compared to the control. Our results showed that palmitic acid increased oxidative stress, DNA damage, cellular senescence, and SASP factors, and downregulated the expression of glutamate reuptake transporters in HBAs. These findings suggest the possibility of excitotoxicity in the neurons of the brainstem, sympathoexcitation, and increased risk for cardiovascular diseases in obesity.
Asunto(s)
Astrocitos , Tronco Encefálico , Senescencia Celular , Regulación hacia Abajo , Obesidad , Estrés Oxidativo , Ácido Palmítico , Ácido Palmítico/farmacología , Estrés Oxidativo/efectos de los fármacos , Humanos , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Obesidad/metabolismo , Senescencia Celular/efectos de los fármacos , Tronco Encefálico/metabolismo , Tronco Encefálico/efectos de los fármacos , Sistema de Transporte de Aminoácidos X-AG/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Células CultivadasRESUMEN
Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults.NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.
Asunto(s)
Amilorida , Barorreflejo , Presión Sanguínea , Frecuencia Cardíaca , Humanos , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Amilorida/farmacología , Amilorida/administración & dosificación , Masculino , Femenino , Adulto , Frecuencia Cardíaca/efectos de los fármacos , Adulto Joven , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Administración Oral , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Bloqueadores del Canal de Sodio Epitelial/farmacología , Bloqueadores del Canal de Sodio Epitelial/administración & dosificaciónRESUMEN
An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life condition of balance loss. We asked: do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and-if so-does it habituate after a series of perturbations? Thirty-four young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using electrodermal activity and compared before and immediately after each unannounced perturbation. All perturbations elicited a significant increase of electrodermal activity (P < 0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of electrodermal activity caused by the first perturbation was significantly higher than the last perturbation (P < 0.05). Three different types of electrodermal activity behavior were observed: steady-level tonic SNS activity, increased SNS activity, and decreased SNS activity. Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.NEW & NOTEWORTHY Up to date, the literature typically provides information about sympathetic nervous system activity and relatively static balance. We believe that exposing participants to a balance loss during walking, i.e., unexpected perturbation, provides a more ecologically valid situation to measure sympathetic nervous system response; this provides new and vital knowledge that can have a significant impact and understanding of how the SNS responds to a loss of balance in a real-life situation.
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Respuesta Galvánica de la Piel , Equilibrio Postural , Sistema Nervioso Simpático , Caminata , Humanos , Masculino , Sistema Nervioso Simpático/fisiología , Caminata/fisiología , Femenino , Equilibrio Postural/fisiología , Adulto Joven , Adulto , Respuesta Galvánica de la Piel/fisiologíaRESUMEN
The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the "fight-or-flight response". Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis.
Asunto(s)
Ganglios Simpáticos , Neuronas Motoras , Cresta Neural , Células de Schwann , Sistema Nervioso Simpático , Animales , Sistema Nervioso Simpático/embriología , Ratones , Neuronas Motoras/fisiología , Células de Schwann/metabolismo , Cresta Neural/citología , Cresta Neural/metabolismo , Ganglios Simpáticos/citología , Ganglios Espinales , Semaforinas/metabolismo , Semaforinas/genética , Ratones Transgénicos , Neuroglía/metabolismo , FemeninoRESUMEN
Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.
Asunto(s)
Azetidinas , Fibroblastos , Fibrosis , Ratones Endogámicos C57BL , Purinas , Pirazoles , Sulfonamidas , Animales , Fibrosis/tratamiento farmacológico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Masculino , Fibroblastos/efectos de los fármacos , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Miocardio/patología , Isoproterenol , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.
Asunto(s)
Tejido Adiposo Pardo , Hipotálamo , Luz , Animales , Hipotálamo/metabolismo , Hipotálamo/efectos de la radiación , Humanos , Tejido Adiposo Pardo/metabolismo , Masculino , Ratones , Obesidad/metabolismo , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Opsinas de Bastones/metabolismo , Sistema Nervioso Simpático/metabolismo , Tejido Adiposo/metabolismo , Neuronas/metabolismo , Neuronas/efectos de la radiación , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de la radiación , Adipocitos Blancos/metabolismo , Adipocitos Blancos/efectos de la radiaciónRESUMEN
ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.
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Trastornos de Ansiedad , Fibrilación Atrial , Modelos Animales de Enfermedad , Atrios Cardíacos , Ratas Sprague-Dawley , Receptores AMPA , Animales , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Masculino , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Receptores AMPA/metabolismo , Remodelación Atrial/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Potenciales de Acción/efectos de los fármacos , Fosforilación , Transducción de Señal , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Factor de Transcripción ReIA/metabolismo , Ratas , Antiinflamatorios/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismoRESUMEN
BACKGROUND: Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. METHODS AND RESULTS: In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). CONCLUSIONS: We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.
Asunto(s)
Estudios Cruzados , Antebrazo , Insulina , Microcirculación , Obesidad , Fentolamina , Flujo Sanguíneo Regional , Sistema Nervioso Simpático , Vasodilatación , Humanos , Antebrazo/irrigación sanguínea , Masculino , Fentolamina/farmacología , Femenino , Obesidad/fisiopatología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Adulto , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Microcirculación/efectos de los fármacos , Velocidad del Flujo Sanguíneo , Persona de Mediana Edad , Técnica de Clampeo de la Glucosa , Resistencia a la Insulina , Bloqueo Nervioso Autónomo/métodosRESUMEN
BACKGROUND: Adipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting. METHODS: We sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression. RESULTS: Tumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group. CONCLUSION: The SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.
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Caquexia , Progresión de la Enfermedad , Ratones Endogámicos BALB C , Sistema Nervioso Simpático , Animales , Caquexia/metabolismo , Caquexia/patología , Caquexia/etiología , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Masculino , Ratones , Proteína Desacopladora 1/metabolismo , Línea Celular Tumoral , Canales Iónicos/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Oxidopamina , Simpatectomía Química , Interleucina-6/metabolismo , Índice de Masa Corporal , Neoplasias/complicaciones , Neoplasias/patología , Neoplasias/metabolismoRESUMEN
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
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Hemodinámica , Hipertensión , Microglía , Núcleo Hipotalámico Paraventricular , Sistema Nervioso Simpático , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Microglía/metabolismo , Hipertensión/fisiopatología , Ratones , Sistema Nervioso Simpático/fisiopatología , Masculino , Ratones Endogámicos C57BL , Adenosina Trifosfato/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Inflamación/inmunología , Presión Sanguínea , Neuronas/metabolismoRESUMEN
Catheter based renal denervation has recently been FDA approved for the treatment of hypertension. Traditionally, the anti-hypertensive effects of renal denervation have been attributed to the ablation of the efferent sympathetic renal nerves. In recent years the role of the afferent sensory renal nerves in the regulation of blood pressure has received increased attention. In addition, afferent renal denervation is associated with reductions in sympathetic nervous system activity. This suggests that reductions in sympathetic drive to organs other than the kidney may contribute to the non-renal beneficial effects observed in clinical trials of catheter based renal denervation. In this review we will provide an overview of the role of the afferent renal nerves in the regulation of renal function and the development of pathophysiologies, both renal and non-renal. We will also describe the central projections of the afferent renal nerves, to give context to the responses seen following their ablation and activation. Finally, we will discuss the emerging role of the kidney as an interoceptive organ. We will describe the potential role of the kidney in the regulation of interoceptive sensitivity and in this context, speculate on the possible pathological consequences of altered renal function.
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Interocepción , Riñón , Humanos , Riñón/inervación , Riñón/fisiopatología , Interocepción/fisiología , Animales , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/fisiología , Presión Sanguínea/fisiología , Vías Aferentes/fisiología , Hipertensión/fisiopatología , Enfermedades Renales/fisiopatologíaRESUMEN
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
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Tejido Adiposo Pardo , Adiposidad , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Obesidad , Oxitocina , Sistema Nervioso Simpático , Animales , Oxitocina/farmacología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/inervación , Masculino , Ratones , Obesidad/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Adiposidad/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Ratones Obesos , Metabolismo Energético/efectos de los fármacos , Norepinefrina/metabolismoRESUMEN
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.
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Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Secreción de Insulina , Ratones Endogámicos C57BL , Bulbo Olfatorio , Núcleo Hipotalámico Paraventricular , Animales , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Secreción de Insulina/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Insulina/metabolismo , Obesidad/metabolismo , Sistema Nervioso Simpático/metabolismo , Neuronas/metabolismo , Transducción de Señal , Norepinefrina/metabolismo , Glucosa/metabolismoRESUMEN
PURPOSE: Early differentiation between Parkinson's disease (PD) and Multiple system atrophy (MSA), particularly the parkinsonian subtypes (MSA-P), is challenging due to similar clinical symptoms. We aimed to evaluate Sympathetic skin response (SSR) and Cutaneous silent period (CSP) parameters in patients with MSA-P and PD to identify possible biomarkers that could distinguish the two groups of patients in early stage. METHODS: 22 individuals with early-stage MSA-P, 29 with early-stage PD, and 28 healthy controls were recruited from Guangdong Provincial People's Hospital. Demographic data was collected for all participants. Their SSR and CSP were evaluated using clinical electromyography equipment. Data were compared between different groups. The diagnostic accuracy of SSR and CSP parameters was calculated using the ROC curve. Logistic regression was used to produce an integration model to enhance diagnostic utility. RESULTS: Foot amplitude, CSP end latency and duration distinguished MSA-P from PD with the area under the curve (AUC) 0.770, 0.806, and 0.776, respectively. Foot and hand SSR amplitude distinguished PD from HC with the AUC 0.871 and 0.768, respectively. Foot SSR amplitude, hand SSR amplitude, and CSP end latency distinguished MSA-P from HC with the AUC 0.964, 0.872, and 0.812, respectively. The combination of SSR and CSP parameters differentiation between MSA-P and PD, PD and HC with the AUC 0.829 and 0.879, respectively. CONCLUSIONS: Analysis of SSR and CSP parameters showed excellent diagnostic accuracy in discriminating patients with early-stage MSA-P from HC and good diagnostic accuracy in discriminating patients with MSA-P from PD with early stages.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , Atrofia de Múltiples Sistemas/fisiopatología , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Diagnóstico Diferencial , Respuesta Galvánica de la Piel/fisiología , Electromiografía , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Acupuncture can reduce blood pressure, heart rate (HR), and ameliorate cardiac damage by modulating the excitability of the sympathetic nervous system, but the exact mechanism of this effect remains unclear. This study investigated the potential mechanisms of acupuncture in the treatment of cardiac damage in hypertension. Spontaneously hypertensive rats (SHR) were used as the hypertension model with Wistar-Kyoto rats as the control. Manual acupuncture, electroacupuncture, and metoprolol were used as interventions. Systolic and diastolic blood pressure (SBP, DBP) plus HR were monitored with cardiac structure determined using Masson staining. Angiotensin II (Ang II) and norepinephrine in myocardium were detected with ELISA as was Ang(1-7) and gamma aminobutyric acid (GABA) in the rostral ventrolateral medulla (RVLM). Expression of mRNA for collagen type I (Col-I), Col-III, actin α1 (ACTA1), and thrombospondin 4 (THBS4) in myocardium was detected using real-time PCR. Expression of angiotensin converting enzyme (ACE), Ang II, angiotensin II type 1 receptor (AT1R), ACE2, and Mas receptor (MasR) proteins in RVLM was monitored using western blot. After manual acupuncture and electroacupuncture treatment, SHRs showed decreased SBP, DBP and HR, reduced myocardial damage. There was decreased expression of the ACE/Ang II/AT1R axis, and increased expression of the ACE2/Ang(1-7)/MasR axis within the RVLM. GABA levels were increased within the RVLM and norepinephrine levels were decreased in myocardial tissue. Metoprolol was more effective than either manual acupuncture or electroacupuncture. Acupuncture directed against hypertensive cardiac damage may be associated with regulation of ACE/Ang II/AT1R and the ACE2/Ang(1-7)/MasR pathway within the RLVM to reduce cardiac sympathetic excitability.