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1.
J Parkinsons Dis ; 11(3): 1247-1256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34024780

RESUMO

BACKGROUND: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. OBJECTIVE: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. METHODS: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. RESULTS: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (ß= 1.185, p = 0.013) and Part II (ß= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. CONCLUSION: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.


Assuntos
Encéfalo , Glucose , Atrofia de Múltiplos Sistemas , Fibras Simpáticas Pós-Ganglionares , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/metabolismo , Atrofia de Múltiplos Sistemas/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Fibras Simpáticas Pós-Ganglionares/diagnóstico por imagem , Fibras Simpáticas Pós-Ganglionares/fisiopatologia
2.
Cardiovasc Res ; 117(1): 137-148, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995173

RESUMO

AIMS: Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. METHODS AND RESULTS: Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. CONCLUSIONS: Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Insuficiência Cardíaca/metabolismo , Coração/inervação , Interferência de RNA , Gânglio Estrelado/metabolismo , Fibras Simpáticas Pós-Ganglionares/metabolismo , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/prevenção & controle , Potenciais de Ação , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo N/genética , Sinalização do Cálcio , Células Cultivadas , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Masculino , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Gânglio Estrelado/fisiopatologia , Fibras Simpáticas Pós-Ganglionares/fisiopatologia , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/genética , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia
3.
Mol Cell Neurosci ; 109: 103563, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33039519

RESUMO

Recent work demonstrated that sympathetic neurons innervate the skeletal muscle near the neuromuscular junction (NMJ), and muscle sympathectomy and sympathomimetic agents strongly influence motoneuron synaptic vesicle release ex vivo. Moreover, reports attest that the pontine nucleus locus coeruleus (LC) projects to preganglionic sympathetic neurons and regulates human mobility and skeletal muscle physiology. Thus, we hypothesized that peripheral and central sympathetic neurons projecting directly or indirectly to the skeletal muscle regulate NMJ transmission. The aim of this study was to define the specific neuronal groups in the peripheral and central nervous systems that account for such regulation in adult mice in vivo by using optogenetics and NMJ transmission recordings in 3-5-month-old, male and female ChR2(H134R/EYFP)/TH-Cre mice. After detecting ChR2(H134R)/EYFP fluorescence in the paravertebral ganglia and LC neurons, we tested whether optostimulating the plantar nerve near the lumbricalis muscle or LC neurons effectively modulates motor nerve terminal synaptic vesicle release in living mice. Nerve optostimulation increased motor synaptic vesicle release in vitro and in vivo, while the presynaptic adrenoceptor blockers propranolol (ß1/ß2) and atenolol (ß1) prevented this outcome. The effect is primarily presynaptic since miniature end-plate potential (MEPP) kinetics remained statistically unmodified after stimulation. In contrast, optostimulation of LC neurons did not regulate NMJ transmission. In summary, we conclude that postganglionic sympathetic neurons, but not LC neurons, increased NMJ transmission by acting on presynaptic ß1-adrenergic receptors in vivo.


Assuntos
Locus Cerúleo/fisiologia , Neurônios Motores/fisiologia , Junção Neuromuscular/fisiologia , Optogenética/métodos , Transmissão Sináptica/fisiologia , Nervo Tibial/fisiologia , Animais , Channelrhodopsins/análise , Channelrhodopsins/genética , Dependovirus/fisiologia , Feminino , Gânglios Simpáticos/fisiologia , Genes Reporter , Proteínas de Fluorescência Verde/análise , Lasers , Luz , Masculino , Camundongos , Camundongos Transgênicos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Neurônios Motores/efeitos da radiação , Mutação de Sentido Incorreto , Receptores Adrenérgicos beta 1/fisiologia , Proteínas Recombinantes de Fusão/análise , Fibras Simpáticas Pós-Ganglionares/fisiologia , Transmissão Sináptica/efeitos da radiação , Nervo Tibial/efeitos da radiação
4.
J Mol Cell Cardiol ; 143: 26-37, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277975

RESUMO

RATIONALE: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown. AIM: To investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation. METHODS AND RESULTS: Sympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an "ischemic state" of cultured myocardium, supported by TUNEL and Hif1α expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area. CONCLUSION: Neurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage.


Assuntos
Coração/inervação , Miocárdio/metabolismo , Pericárdio/metabolismo , Fibras Simpáticas Pós-Ganglionares/fisiologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Células Cultivadas , Gânglios Simpáticos/citologia , Gânglios Simpáticos/metabolismo , Humanos , Camundongos , Miocárdio/citologia , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Crescimento Neuronal
5.
Physiol Res ; 69(2): 253-260, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32199013

RESUMO

Beneficial effects of sesame lignans, especially antioxidative effects, have been widely reported; however, its potential effects on autonomic nerves have not yet been investigated. Therefore, the current study aimed to investigate the effect of sesame lignans on the autonomic nervous system. The sympathetic nerve activity in rat skeletal muscle was measured using electrophysiological approaches, with blood flow determined using the laser Doppler method. Sesame lignans were administered intragastrically at 2 and 20 mg/kg, and after 60 min, the sympathetic nerve activity was observed to increase by 45.2% and 66.1%, respectively. A significant increase in blood flow (39.6%) was also observed for the 20-mg/kg dose when measured at 55 min after administration. These sympathomimetic effects were completely prevented by subdiaphragmatic vagotomy, and the increase in blood flow was eliminated in the presence of the beta2-adrenergic receptor inhibitor butoxamine. Thus, it is proposed that sesame lignans can increase the blood flow of skeletal muscle, possibly by exciting sympathetic nerve activity through the afferent vagal nerve.


Assuntos
Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Lignanas/farmacologia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Sesamum , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Animais , Velocidade do Fluxo Sanguíneo/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Lignanas/isolamento & purificação , Masculino , Músculo Esquelético/fisiologia , Ratos , Fibras Simpáticas Pós-Ganglionares/fisiologia
6.
Clin Neurol Neurosurg ; 191: 105690, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31982693

RESUMO

OBJECTIVE: Sympathetic branches to the abducens nerve derived from the internal carotid artery sympathetic plexus, while in the cavernous sinus, have been scantly described in the extant literature. Therefore, the present cadaveric study was performed to better elucidate this anatomy. PATIENTS AND METHODS: Eighteen cadaveric sides underwent dissection. RESULTS: The number of branches derived from the sympathetic plexus traveling with the internal carotid artery in the cavernous sinus was one on 11.1 %, two in 11.1 %, and three in 72.2 %. One side was found to have no branches (5.6 %). The mean diameter of the distance from the posterior border of the internal carotid artery, length, and diameter of the branches was 7.0 ±â€¯4.1 mm, 2.9 ±â€¯1.3 mm, and 0.4 ±â€¯0.1 mm, respectively. Of 44 of 45 sympathetic branches, 97.8 % originated from the lateral wall of the cavernous part of the internal carotid artery with only one from the medial wall. CONCLUSION: Based on our cadaveric findings, sympathetic connections between the internal carotid artery and the abducens nerve are common. Therefore, surgeons who operate in or near the cavernous sinus should be aware of such connections in order not to place unwanted tension on the cavernous part of the internal carotid artery or abducens nerve during dissection.


Assuntos
Nervo Abducente/anatomia & histologia , Artéria Carótida Interna/inervação , Seio Cavernoso/anatomia & histologia , Fibras Simpáticas Pós-Ganglionares/anatomia & histologia , Vias Autônomas/anatomia & histologia , Cadáver , Humanos
7.
Auton Neurosci ; 222: 102589, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31706219

RESUMO

INTRODUCTION: Forearm QSWEAT recordings are occasionally absent in females, likely due to high skin resistance. METHODS: We identified consecutive subjects with no sudomotor abnormalities but absent/markedly reduced QSWEAT forearm volume, and repeated QSWEAT at the same site after gentle abrasion. RESULTS: QSWEAT volumes were absent for 4 subjects and markedly reduced for the other 4 (median 0.01, IQR 0-0.03). After gentle skin abrasion, repeat volumes were significantly higher for all subjects and became normal in 7 of 8 subjects. DISCUSSION: Skin abrasion restores QSWEAT volumes in previously absent/markedly reduced site suggesting that skin preparation using abrasion is more effective.


Assuntos
Axônios/fisiologia , Antebraço/fisiologia , Fenômenos Fisiológicos da Pele , Glândulas Sudoríparas/inervação , Sudorese/fisiologia , Fibras Simpáticas Pós-Ganglionares/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
8.
Clin Auton Res ; 29(6): 587-593, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31673840

RESUMO

BACKGROUND: Autonomic synucleinopathies feature deposition of the protein alpha-synuclein (AS) in neurons [e.g., Lewy body neurogenic orthostatic hypotension (nOH)] or glial cells (multiple system atrophy, MSA). AS in skin biopsies might provide biomarkers of these diseases; however, this approach would be complicated or invalidated if there were substantial loss of AS-containing nerves. We report AS content in arrector pili muscles in skin biopsies after adjustment for local innervation in patients with Lewy body nOH or MSA. Cardiac sympathetic neuroimaging by myocardial 18F-dopamine positron emission tomography (PET) was done to examine pathophysiological correlates of innervation-adjusted AS. METHODS: Thirty-one patients (19 Lewy body nOH, 12 MSA) underwent thoracic 18F-dopamine PET and skin biopsies. AS signal intensity analyzed by immunofluorescence microscopy was adjusted for innervation by the ratio of AS to protein gene product (PGP) 9.5, a pan-axonal marker (Harvard lab site), or the ratio of AS to tyrosine hydroxylase (TH), an indicator of catecholaminergic neurons (NIH lab site). RESULTS: The Lewy body nOH group had higher ratios of AS/PGP 9.5 or log AS/TH than did the MSA group (0.89 ± 0.05 vs. 0.66 ± 0.04, -0.13 ± 0.05 vs. -1.60 ± 0.33; p < 0.00001 each). All 19 Lewy body patients had AS/PGP 9.5 > 0.8 or log AS/TH > 1.2 and had myocardial 18F-dopamine-derived radioactivity < 6000 nCi-kg/cc-mCi, the lower limit of normal. Two MSA patients (17%) had increased AS/PGP or log AS/TH, and two (17%) had low 18F-dopamine-derived radioactivity. CONCLUSIONS: Lewy body forms of nOH are associated with increased innervation-adjusted AS in arrector pili muscles and neuroimaging evidence of myocardial noradrenergic deficiency.


Assuntos
Músculo Liso/inervação , Fibras Simpáticas Pós-Ganglionares/patologia , Sinucleinopatias/diagnóstico , alfa-Sinucleína/análise , Idoso , Biópsia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Atrofia de Múltiplos Sistemas/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Síndrome de Shy-Drager/diagnóstico , Pele/inervação
9.
Am J Physiol Heart Circ Physiol ; 317(6): H1328-H1341, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625779

RESUMO

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after ß-sympathetic blockade.


Assuntos
Arritmias Cardíacas/fisiopatologia , Cardiomiopatias Diabéticas/fisiopatologia , Fibras Simpáticas Pós-Ganglionares/fisiopatologia , Animais , Antiarrítmicos/farmacologia , Arritmias Cardíacas/etiologia , Sinalização do Cálcio , Cardiomiopatias Diabéticas/complicações , Frequência Cardíaca , Ventrículos do Coração/inervação , Ventrículos do Coração/fisiopatologia , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Neurônios/metabolismo , Propranolol/farmacologia , Fibras Simpáticas Pós-Ganglionares/citologia , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Bull Exp Biol Med ; 167(2): 191-193, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236881

RESUMO

We studied the effects of exogenous NO donor (sodium nitroprusside) and NO synthesis blocker (100 µM L-NAME) on baseline electrical activity of postganglionic fibers in the sympathetic superior cervical in rats during postnatal ontogeny. Starting the age of 20 days, sodium nitroprusside increased the mean discharge amplitude and the spectrum power in the respiratory (0.7-1.5 Hz) and cardiac (4-7 Hz) frequency bands. In contrast, application of L-NAME for 1 h decreased the spectrum power in these bands. Both agents produced no significant effect on the rhythmic sympathetic discharges at frequencies >8 Hz.


Assuntos
Gânglios Simpáticos/efeitos dos fármacos , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Envelhecimento , Animais , Feminino , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Ratos , Ratos Wistar
11.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040159

RESUMO

Thoracic paravertebral sympathetic postganglionic neurons (tSPNs) comprise the final integrative output of the distributed sympathetic nervous system controlling vascular and thermoregulatory systems. Considered a non-integrating relay, what little is known of tSPN intrinsic excitability has been determined by sharp microelectrodes with presumed impalement injury. We thus undertook the first electrophysiological characterization of tSPN cellular properties using whole-cell recordings and coupled results with a conductance-based model to explore the principles governing their excitability in adult mice of both sexes. Recorded membrane resistance and time constant values were an order of magnitude greater than values previously obtained, leading to a demonstrable capacity for synaptic integration in driving recruitment. Variation in membrane resistivity was the primary determinant controlling cell excitability with vastly lower currents required for tSPN recruitment. Unlike previous microelectrode recordings in mouse which observed inability to sustain firing, all tSPNs were capable of repetitive firing. Computational modeling demonstrated that observed differences are explained by introduction of a microelectrode impalement injury conductance. Overall, tSPNs largely linearly encoded injected current magnitudes over a broad frequency range with distinct subpopulations differentiable based on repetitive firing signatures. Thus, whole-cell recordings reveal tSPNs have more dramatically amplified excitability than previously thought, with greater intrinsic capacity for synaptic integration and with the ability for maintained firing to support sustained actions on vasomotor tone and thermoregulatory function. Rather than acting as a relay, these studies support a more responsive role and possible intrinsic capacity for tSPNs to drive sympathetic autonomic function.


Assuntos
Potenciais da Membrana/fisiologia , Modelos Neurológicos , Fibras Simpáticas Pós-Ganglionares/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp
12.
Physiol Res ; 68(2): 209-217, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30628826

RESUMO

To determine the influence of IGF-1 deletion on renal sympathetic nerve activity (RSNA), left ventricular dysfunction, and renal function in deoxycorticosterone acetate (DOCA)-salt hypertensive mice. The DOCA-salt hypertensive mice models were constructed and the experiment was classified into WT (Wild-type mice) +sham, LID (Liver-specific IGF-1 deficient mice) + sham, WT + DOCA, and LID+ DOCA groups. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum IGF-1 levels in mice. The plasma norepinephrine (NE), urine protein, urea nitrogen and creatinine, as well as RSNA were measured. Echocardiography was performed to assess left ventricular dysfunction, and HE staining to observe the pathological changes in renal tissue of mice. DOCA-salt induction time-dependently increased the systolic blood pressure (SBP) of mice, especially in DOCA-salt LID mice. Besides, the serum IGF-1 levels in WT mice were decreased after DOCA-salt induction. In addition, the plasma NE concentration and NE spillover, urinary protein, urea nitrogen, creatinine and RSNA were remarkably elevated with severe left ventricular dysfunction, but the creatinine clearance was reduced in DOCA-salt mice, and these similar changes were obvious in DOCA-salt mice with IGF-1 deletion. Moreover, the DOCA-salt mice had tubular ectasia, glomerular fibrosis, interstitial cell infiltration, and increased arterial wall thickness, and the DOCA-salt LID mice were more serious in those aspects. Deletion of IGF-1 may lead to enhanced RSNA in DOCA-salt hypertensive mice, thereby further aggravating left ventricular dysfunction and renal damage.


Assuntos
Acetato de Desoxicorticosterona/toxicidade , Hipertensão/sangue , Fator de Crescimento Insulin-Like I/deficiência , Rim/fisiologia , Fibras Simpáticas Pós-Ganglionares/metabolismo , Disfunção Ventricular Esquerda/sangue , Animais , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Fator de Crescimento Insulin-Like I/genética , Rim/efeitos dos fármacos , Rim/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mineralocorticoides/toxicidade , Norepinefrina/sangue , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/fisiopatologia
13.
Physiol Rep ; 6(18): e13877, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30230240

RESUMO

The astrocytic glutamate transporter (GLT1) plays an important role in the maintenance of extracellular glutamate concentration below neurotoxic levels in brain. However, the functional role of GLT1 within the nucleus of the solitary tract (NTS) in the regulation of cardiovascular function remains unclear. We examined the effect of inhibiting GLT1 in the subpostremal NTS on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA) and heart rate (HR) in anesthetized, artificially ventilated rats. It was found that dihydrokainate (DHK; inhibitor of GLT1, 5 mmol/L, 100 nL) injections into the NTS (n = 6) decreased MAP (50 ± 10 mmHg, mean ± SD), RSNA (89 ± 14%) and HR (37 ± 6 bpm). Pretreatment with kynurenate (KYN; glutamate receptor antagonist, 5 mmol/L, 30 µL) topically applied to the dorsal surface of the brainstem (n = 4) attenuated the responses to NTS injections of DHK (P < 0.01). The effect of DHK on arterial baroreflex function was examined using i.v. infusions of phenylephrine and nitroprusside. DHK reduced baroreflex response range (maximum-minimum) of RSNA by 91 ± 2% and HR by 83 ± 5% (n = 6, P < 0.001). These results indicate that inhibition of GLT1 within the NTS decreases MAP, RSNA, and HR by the activation of ionotropic glutamate receptors. As a result, baroreflex control of RSNA and HR was dramatically attenuated. The astrocytic glutamate transporter in the NTS plays an important role in the maintenance and regulation of cardiovascular function.


Assuntos
Barorreflexo/fisiologia , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Frequência Cardíaca/fisiologia , Núcleo Solitário/metabolismo , Fibras Simpáticas Pós-Ganglionares/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Ácido Caínico/administração & dosagem , Ácido Caínico/análogos & derivados , Masculino , Microinjeções/métodos , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/efeitos dos fármacos , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
14.
Neurosci Lett ; 684: 18-24, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-29966754

RESUMO

The autonomic nervous system innervates various peripheral tissue functions. Various external stimuli affect autonomic nerve activity, however, there is little information about the involvement of sensory receptors in the responses. The TRPA1 is a calcium-permeable non-selective cation channel which plays a crucial role in the susceptibility to various stimuli. ß-Eudesmol, an oxygenated sesquiterpene found in hop essential oil and beer, activates the TRPA1. Intragastric administration of ß-eudesmol decreased efferent adrenal sympathetic nerve activity (ASNA) in rats, whereas subcutaneous administration did not. ASNA suppression by ß-eudesmol was not observed in TRPA1 knockout rats. The ß-eudesmol derived ASNA suppression was partially, but significantly, eliminated by subdiaphragmatic vagotomy in rats, suggesting the afferent vagal nerve from the gastrointestinal tract to the brain is involved in the effect of ß-eudesmol on ASNA. Our results indicate that ß-eudesmol suppresses ASNA, partly through TRPA1 and the afferent vagus nerve. These findings introduce the physiological significance of the TRPA1 in the control of ASNA.


Assuntos
Glândulas Suprarrenais/inervação , Glândulas Suprarrenais/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Fibras Simpáticas Pós-Ganglionares/metabolismo , Sistema Nervoso Simpático/metabolismo , Canal de Cátion TRPA1/deficiência , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Epinefrina/metabolismo , Masculino , Ratos , Ratos Transgênicos , Ratos Wistar , Sesquiterpenos de Eudesmano/química , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos
15.
J Physiol ; 596(18): 4497-4510, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30054928

RESUMO

KEY POINTS: The mechanisms affecting recruitment patterns of postganglionic sympathetic nerves remain unclear. The divergent and convergent preganglionic innervation patterns of postganglionic neurons and the presence of differently sized postganglionic nerves suggest that the ganglia may participate in modifying the discharge patterns of single sympathetic postganglionic neurons innervating the skeletal muscle circulation. Whether the ganglia affect the ordered behaviour of varying sized postganglionic sympathetic neurons in humans has not been studied. Trimethaphan infusion produced an ordered pattern of action potential (AP) de-recruitment whereby the firing of larger, low probability APs present at baseline was abolished first, followed by progressive decreased probability of smaller APs. Although integrated sympathetic bursts were no longer detected after several minutes of trimethaphan, firing of the smallest APs was detected. These data suggest the ganglia affect the distribution of firing probabilities exhibited by differently sized sympathetic neurons. The ganglia may contribute to sympathetic neural emission patterns involved in homeostatic regulation. ABSTRACT: Do the ganglia contribute to the ordered behaviour of postganglionic neuronal discharge within the sympathetic nervous system? To further understand the functional organization of the sympathetic nervous system we employed the microneurographic approach to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to study postganglionic action potential (AP) behaviour during nicotinic blockade at the ganglia (trimethaphan camsylate, 1-7 mg min-1 ) in seven females (37 ± 5 years). Trimethaphan elicited a progressive reduction in sympathetic outflow characterized by fewer integrated bursts with decaying amplitude. Underlying trimethaphan-mediated attenuations in integrated MSNA were reductions in AP incidence (186 ± 101 to 29 ± 31 AP (100 beats)-1 ) and AP content per integrated burst (7 ± 2 to 3 ± 1 APs burst-1 ) (both P < 0.01) in the final minute of detectable bursting activity in the trimethaphan condition, compared to baseline. We observed an ordered de-recruitment of larger to smaller AP clusters active at baseline (14 ± 3 to 8 ± 2 active AP clusters, P < 0.01). Following cessation of integrated bursts in the trimethaphan condition, the smallest 6 ± 2 sympathetic AP clusters persisted to fire in an asynchronous pattern (49 ± 41 AP (100 beats)-1 ) in all participants. Valsalva's manoeuvre did not increase the incidence of these persistent APs (60 ± 42 AP (100 beats)-1 , P = 0.52), or recruit any larger APs in six of seven participants (6 ± 1 total AP clusters, P = 0.30). These data suggest that the ganglia participate in the ordered recruitment of differently sized postganglionic sympathetic nerves.


Assuntos
Potenciais de Ação , Fibras Simpáticas Pós-Ganglionares/fisiologia , Adulto , Feminino , Bloqueadores Ganglionares/farmacologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Recrutamento Neurofisiológico , Fibras Simpáticas Pós-Ganglionares/citologia , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Trimetafano/farmacologia
16.
J Neurophysiol ; 119(3): 944-956, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29142091

RESUMO

It has long been known from microneurographic recordings in human subjects that the activity of postganglionic sympathetic axons occurs as spontaneous bursts, with muscle sympathetic nerve activity (MSNA) exhibiting strong cardiac rhythmicity via the baroreflex and skin sympathetic nerve activity showing much weaker cardiac modulation. Here we review the firing properties of single sympathetic neurons, obtained using highly selective microelectrodes. Individual vasoconstrictor neurons supplying muscle or skin, or sudomotor neurons supplying sweat glands, always discharge with a low firing probability (~30%) and at very low frequencies (~0.5 Hz). Moreover, they usually fire only once per cardiac interval but can fire greater than four times within a burst. Modeling has shown that this pattern can best be explained by individual neurons being driven by, on average, two preganglionic inputs. Unitary recordings of muscle vasoconstrictor neurons have been made in several pathophysiological states, including heart failure, hypertension, obstructive sleep apnea, bronchiectasis, chronic obstructive pulmonary disease, depression, and panic disorder. The augmented MSNA in each of these diseases features an increase in firing probability and discharge frequency of individual muscle vasoconstrictor neurons above that seen in healthy subjects, yet firing rates rarely exceed 1 Hz. However, unlike patients with heart failure, all patients with respiratory disease or panic disorder, and patients with hyperhidrosis, exhibited an increase in multiple within-burst firing, which emphasizes the different modes by which the sympathetic nervous system grades its output in pathophysiological states of high sympathetic nerve activity.


Assuntos
Potenciais de Ação , Neurônios/fisiologia , Fibras Simpáticas Pós-Ganglionares/fisiologia , Humanos , Hipertensão/fisiopatologia , Transtornos Mentais/fisiopatologia , Microeletrodos , Modelos Neurológicos , Músculo Esquelético/inervação , Pele/inervação , Glândulas Sudoríparas/inervação
17.
Int Heart J ; 58(5): 787-793, 2017 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-28966311

RESUMO

A large amount of norepinephrine (NE) released from cardiac sympathetic nerve terminals might accelerate myocardial ischemic injury. Nicorandil (NICO), KATP channel opener, could attenuate cardiac NE release from the sympathetic nerve terminals during ischemia. The present study aimed to investigate the effects of NICO-induced attenuation of cardiac NE release on myocardial ischemia-reperfusion (I/R) injury in rats, by comparison with the effect of cardiac sympathetic denervation on I/R injury.Cardiac interstitial NE (iNE) concentrations were determined using a microdialysis method. Rats were divided into 3 groups; control, NICO, and denervation groups. Cardiac sympathetic denervation was performed by painting 10% phenol on the left ventricular epicardium 7 days before producing ischemia. The left coronary artery was ligated for 30 minutes and then re-perfused for 120 minutes. NICO (50 µg/kg/minute) was infused intravenously starting 20 minutes before the coronary occlusion to the end of the ligation.The infarct size of the left ventricle was smaller in rats treated with NICO than in control rats (20.2 ± 3.0 versus 50.6 ± 14.7%, P < 0.01). Sympathetic denervation also reduced infarct size (28.5 ± 10.4 %, P < 0.01), which was not significantly different from that in the NICO group. At the end of 30-minute ischemia, iNE increased markedly in control rats (0.1 ± 0.1 to 20.6 ± 5.3 × 103 pg/mL), whereas the increase was completely inhibited in denervated rats. NICO markedly attenuated the increase (4.9 ± 3.0 × 103 pg/mL, P < 0.01) during ischemia.NICO-induced attenuation of neural NE release during ischemia might, at least in part, contribute to myocardial protection against I/R injury.


Assuntos
Ventrículos do Coração/inervação , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Nicorandil/farmacologia , Norepinefrina/antagonistas & inibidores , Fibras Simpáticas Pós-Ganglionares/metabolismo , Animais , Modelos Animais de Doenças , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Complexo Vitamínico B/farmacologia
18.
J Neurol Sci ; 380: 191-195, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28870566

RESUMO

BACKGROUND: The detailed pathophysiology of limb coldness in multiple system atrophy (MSA) is unknown. METHODS: We evaluated cutaneous vasomotor neural function in 18 MSA patients with or without limb coldness, and in 20 healthy volunteers as controls. We measured resting skin sympathetic nerve activity (SSNA) and spontaneous changes of the sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex: SVR), as well as SVR and reflex changes of SSNA after electrical stimulation. The parameters investigated were the SSNA frequency at rest, amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and skin blood flow velocity. RESULTS: Both the resting frequency of SSNA and the amplitude of SSNA reflex bursts were significantly lower in the MSA group than the control group (p<0.001 and p<0.05, respectively). There were no significant differences between the two groups with regard to the absolute decrease or percent reduction of SVR volume. The recovery time showed no significant difference between all MSA patients and control groups, but it was significantly prolonged in six MSA patients with limb coldness compared with that in the control group and that in MSA patients without limb coldness (p<0.01). The skin blood flow velocity was significantly slower in the MSA group than in the control group (p<0.001). CONCLUSION: In MSA patients, limb coldness might occur due to impairments of the peripheral circulation based on prolongation of vasoconstriction and a decrease of skin blood flow velocity secondary to combined pre- and postganglionic skin vasomotor dysfunction.


Assuntos
Fibras Autônomas Pós-Ganglionares/fisiologia , Fibras Autônomas Pré-Ganglionares/fisiologia , Atrofia de Múltiplos Sistemas/complicações , Fibras Simpáticas Pós-Ganglionares/fisiopatologia , Doenças Vasculares/etiologia , Vasoconstrição/fisiologia , Idoso , Velocidade do Fluxo Sanguíneo , Estimulação Elétrica , Feminino , Humanos , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Reflexo/fisiologia , Pele/irrigação sanguínea , Pele/inervação
19.
Neurogastroenterol Motil ; 29(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28560787

RESUMO

BACKGROUND: Changes to the structure and function of the innervation of the gut contribute to symptom generation in inflammatory bowel diseases (IBD). However, delineation of the mechanisms of these effects has proven difficult. Previous work on sympathetic neurons identified interleukin (IL)-17A as a novel neurotrophic cytokine. Since IL-17A is involved in IBD pathogenesis, we tested the hypothesis that IL-17A contributes to neuroanatomical remodeling during IBD. METHODS: Immunohistochemistry for tyrosine hydroxylase was used to identify sympathetic axons in mice with dextran sulphate sodium (DSS)-induced colitis and controls. Axon outgrowth from sympathetic neurons in response to incubation in cytokines or endoscopic patient biopsy supernatants was quantified. KEY RESULTS: DSS-induced colitis led to an increase in tyrosine hydroxylase immunoreactivity in the inflamed colon but not the spleen. Colonic supernatants from mice with colitis and biopsy supernatants from Crohn's disease patients increased axon outgrowth from mouse sympathetic neurons compared to supernatants from uninflamed controls. An antibody that neutralized IL-17A blocked the ability of DSS-induced colitis and Crohn's disease supernatants to induce axon extension. CONCLUSIONS AND INFERENCES: These findings identify IL-17A as a potential mediator of neuroanatomical remodeling of the gut innervation during IBD.


Assuntos
Colite/fisiopatologia , Doença de Crohn/fisiopatologia , Doenças Inflamatórias Intestinais/fisiopatologia , Interleucina-17/fisiologia , Plasticidade Neuronal , Sistema Nervoso Simpático/fisiopatologia , Adulto , Idoso , Axônios/fisiologia , Colite/induzido quimicamente , Colite/metabolismo , Colo/inervação , Colo/fisiopatologia , Doença de Crohn/metabolismo , Sulfato de Dextrana/administração & dosagem , Feminino , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-17/administração & dosagem , Masculino , Pessoa de Meia-Idade , Baço/metabolismo , Baço/fisiopatologia , Fibras Simpáticas Pós-Ganglionares/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
20.
Int J Cardiol ; 235: 105-113, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28284503

RESUMO

BACKGROUND: Heart failure (HF) causes atrial remodeling and increases the incidence of atrial fibrillation (AF). Renal denervation (RDN) has been shown to decrease the development of AF. This study aimed to identify the effects of RDN on the atrial arrhythmogenic substrates in HF. METHODS: Rabbits were classified into four groups: control (n=9), RDN (n=10), HF (n=6) and HF-RDN (n=9). Surgical and chemical RDN was approached through bilateral retroperitoneal flank incisions in RDN and HF-RDN. Rapid ventricular pacing of 400bpm for 4weeks was applied in HF and HF-RDN. After 4weeks, the rabbits were sacrificed and atrial myocardium were harvested for Western blot and Trichrome stain. RESULTS: The bi-atrial effective refractory period (ERP) of HF was significantly longer compared with that of control and RDN. In right atrium, the ERP of HF was also significantly longer compared with that of HF-RDN, but there was no significant difference in left atrial ERP. In bi-atrium, ion channel protein expressions of CaV1.2, NaV1.5, Kir2.1 SERCA2 and NCX were similar among 4 groups. However, the degree of atrial fibrosis was extensive in bi-atrium of HF, when compared to that of control, RDN and HF-RDN. CONCLUSION: The ERP of HF-RDN is partially shortened by RDN compared with that of HF. There are no differences ionic channel protein expressions in bi-atrium among all groups. The degree of atrial fibrosis is severe in HF, but not in HF-RDN, suggesting that RDN may regulate the atrial arrhythmogenic substrates in HF mostly through reverse structural remodeling.


Assuntos
Fibrilação Atrial , Átrios do Coração , Insuficiência Cardíaca , Simpatectomia/métodos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial , Modelos Animais de Doenças , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Canais Iônicos/análise , Rim/inervação , Coelhos , Fibras Simpáticas Pós-Ganglionares/cirurgia
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