Central Sympathetic Nervous System Research Articles

Central and peripheral nervous system activity and muscle oxygenation in athletes during repeated-sprint exercise in normoxia and normobaric hypoxia.

To investigate central and peripheral nervous system activity and muscle oxygenation in athletes during repeated-sprint exercise in normoxia and normobaric hypoxia. The effects on vastus lateralis muscle strength in a cross-over study were examined in 18 athletes (13 males, 5 females) completing 10 × 6-s cycle sprints. Immediately after and again 5 minutes post-exercise, electromyography (EMG), heart rate variability, maximal voluntary contraction (MVC), muscle oxygenation, peak power output, and arterial oxygen saturation were compared to 2 baseline sets named ("Baseline" and "Pre"). Post-exercise MVC was significantly lower (6.7 ± 10.0%) than Baseline, but root-mean-square amplitude during hypoxia (all-times) was significantly lower than normoxia (0.38 ± 0.19 vs 0.41 ± 0.17 mV). Comparative frequency analysis of the percentage change in pre- to post-exercise EMG area, at low 1-29 hz (type-1 fibre) and high 75-100 hz (type-2 fibre) areas, revealed a significant reduction in type-1 fibre activity relative to type-2, by 20-30% across time and by 10% in type-1 activity between conditions. Exercise in hypoxia appeared to cause a temporary increase in central sympathetic nervous system activity and greater recruitment of type-2 muscle fibres, with accompanying reduction in type-1. Acute hypoxia may stimulate type-2 fibre conditioning.

Assessing the Sympatholytic Effects of SGLT2 Inhibitors in Anuric Haemodialysis Patients Using Microneurography: Study Protocol for a Mechanistic Proof-of-Concept Trial

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug’s ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. Methods: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. Discussion: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673).

Impact of sympathetic hyperactivity induced by brain microglial activation on organ damage in sepsis with chronic kidney disease

BackgroundSympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD.Methods and resultsIn protocol 1, male Sprague–Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group.ConclusionsIn septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN.

Management of intensive care unit withdrawal syndrome

Intensive care unit (ICU) patients frequently develop physical and psychological dependence on analgesic and sedative medications, which can lead to Iatrogenic withdrawal syndrome (IWS) upon discontinuation or tapering. The incidence of IWS in adult ICU patients varies significantly, with reported rates ranging from 12% to 100%. Identified risk factors for IWS include advanced age, obesity, medication dosage, and duration of exposure. The clinical manifestations of IWS are varied and include increased excitability of the central nervous system, gastrointestinal disturbances, and sympathetic nervous system hyperactivity. Preventive and therapeutic strategies for IWS encompass individualized medication regimens, structured withdrawal protocols, and a combination of pharmacological and non-pharmacological interventions. This review emphasizes the critical need for heightened awareness and improved management strategies to mitigate the incidence of IWS in ICU patients.

An atlas of brain-bone sympathetic neural circuits in mice.

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow-these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta-hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to the bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei, and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to the bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

Mutual Information between EDA and EEG in Multiple Cognitive Tasks and Sleep Deprivation Conditions.

Sleep deprivation, a widespread phenomenon that affects one-third of normal American adults, induces adverse changes in physical and cognitive performance, which in turn increases the occurrence of accidents. Sleep deprivation is known to increase resting blood pressure and decrease muscle sympathetic nerve activity. Monitoring changes in the interplay between the central and autonomic sympathetic nervous system can be a potential indicator of human's readiness to perform tasks that involve a certain level of cognitive load (e.g., driving). The electroencephalogram (EEG) is the standard to assess the brain's activity. The electrodermal activity (EDA) is a reflection of the general state of arousal regulated by the activation of the sympathetic nervous system through sweat gland stimulation. In this work, we calculated the mutual information between EDA and EEG recordings in order to consider linear and non-linear interactions and provide an insight of the relationship between brain activity and peripheral autonomic sympathetic activity. We analyzed EEG and EDA data from ten participants performing four cognitive tasks every two hours during 24 h (12 trials). We decomposed EEG data into delta, theta, alpha, beta, and gamma spectral components, and EDA into tonic and phasic components. The results demonstrate high values of mutual information between the EDA and delta component of EEG, mainly in working memory tasks. Additionally, we found an increase in the theta component of EEG in the presence of fatigue caused by sleep deprivation, the alpha component in tasks demanding inhibition and attention, and the delta component in working memory tasks. In terms of the location of brain activity, most of the tasks report high mutual information in frontal regions in the initial trials, with a trend to decrease and become uniform for all the nine analyzed EEG channels as a consequence of the sleep deprivation effect. Our results evidence the interplay between central and sympathetic nervous activity and can be used to mitigate the consequences of sleep deprivation.

Influence of catheter-based renal denervation on carbohydrate metabolism in patients with diabetes and hypertension

Aim. To study the effect of catheter-based sympathetic renal denervation (RDN) by radiofrequency ablation on glucose metabolism in patients with type 2 diabetes and uncontrolled hypertension.Material and methods. Sixty patients were randomly assigned in a 1:1 ratio to the RDN group and the control group. Radiofrequency ablation was performed through the femoral access using a Symplicity Spyral™ renal denervation system (Medtronic, USA).Results. The technical success was 100%. There were no any complications. During the follow-up period, patients in the RDN group showed a significant decrease in the average level of glycated hemoglobin — from 7,9 (6,83-8,35) to 6,85 (6,12-7,10)% (p<0,001) and basal glycemia — from 9,5 (7,17-10,28) to 7,55 (6,43-8,95) mmol/l (p<0,001) with no significant changes in the control group. Changes in glucose levels and the degree of insulin resistance correlated with a decrease in office systolic blood pressure (r=0,36, p=0,005). After 6-month follow-up period in the RDN group, along with a significant decrease in the HOMA-IR by 1,92 (p<0,001), the average high-density lipoprotein cholesterol level also significantly increased by 0,17 mmol/l (p<0,001), and mean triglyceride level decreased by -0,55 mmol/l (p<0,001).Conclusion. The study results confirm the hypothesis of pleiotropic effects of RDN in patients with comorbid pathology associated with central sympathetic nervous system hyperactivity (diabetes, hypertension, dyslipidemia).

Food odor perception promotes systemic lipid utilization.

Food cues during fasting elicit Pavlovian conditioning to adapt for anticipated food intake. However, whether the olfactory system is involved in metabolic adaptations remains elusive. Here we show that food-odor perception promotes lipid metabolism in male mice. During fasting, food-odor stimulation is sufficient to increase serum free fatty acids via adipose tissue lipolysis in an olfactory-memory-dependent manner, which is mediated by the central melanocortin and sympathetic nervous systems. Additionally, stimulation with a food odor prior to refeeding leads to enhanced whole-body lipid utilization, which is associated with increased sensitivity of the central agouti-related peptide system, reduced sympathetic activity and peripheral tissue-specific metabolic alterations, such as an increase in gastrointestinal lipid absorption and hepatic cholesterol turnover. Finally, we show that intermittent fasting coupled with food-odor stimulation improves glycemic control and prevents insulin resistance in diet-induced obese mice. Thus, olfactory regulation is required for maintaining metabolic homeostasis in environments with either an energy deficit or energy surplus, which could be considered as part of dietary interventions against metabolic disorders.

Comparison of TWA and PEP as indices of α2- and ß-adrenergic activation.

Pre-ejection period (PEP) and T-wave amplitude (TWA) have been used to assess sympathetic nervous system (SNS) activity. Here we report two single-blinded, placebo-controlled intravenous (IV) drug application studies in which we pharmacologically modified SNS activity with epinephrine (study 1) as well as dexmedetomidine (alpha2-agonist) and yohimbine (alpha2-antagonist) (study 2). Restricted heart rate (HR) intervals were analyzed to avoid confounding effects of HR changes. Study 1 served to replicate previous findings and to validate our approach, whereas study 2 aimed to investigate how modulation of central SNS activity affects PEP and TWA. Forty healthy volunteers (58% females) participated in study 1 (between-subject design). Twelve healthy men participated in study 2 (within-subject design). TWA and PEP were derived from ECG and impedance cardiography, respectively. Epinephrine shortened PEP and induced statistically significant biphasic TWA changes. However, although the two alpha2-drugs significantly affected PEP as expected, no effects on TWA could be detected. PEP is better suited to reflect SNS activity changes than TWA.

Fetal Undernutrition Programming, Sympathetic Nerve Activity, and Arterial Hypertension Development.

A wealth of evidence showed that low birth weight is associated with environmental disruption during gestation, triggering embryotic or fetal adaptations and increasing the susceptibility of progeny to non-communicable diseases, including metabolic and cardiovascular diseases, obesity, and arterial hypertension. In addition, dietary disturbance during pregnancy in animal models has highlighted mechanisms that involve the genesis of arterial hypertension, particularly severe maternal low-protein intake (LP). Functional studies demonstrated that maternal low-protein intake leads to the renal decrease of sodium excretion and the dysfunction of the renin-angiotensin-aldosterone system signaling of LP offspring. The antinatriuretic effect is accentuated by a reduced number of nephron units and glomerulosclerosis, which are critical in establishing arterial hypertension phenotype. Also, in this way, studies have shown that the overactivity of the central and peripheral sympathetic nervous system occurs due to reduced sensory (afferent) renal nerve activity. As a result of this reciprocal and abnormal renorenal reflex, there is an enhanced tubule sodium proximal sodium reabsorption, which, at least in part, contributes directly to arterial hypertension development in some of the programmed models. A recent study has observed that significant changes in adrenal medulla secretion could be involved in the pathophysiological process of increasing blood pressure. Thus, this review aims to compile studies that link the central and peripheral sympathetic system activity mechanisms on water and salt handle and blood pressure control in the maternal protein-restricted offspring. Besides, these pathophysiological mechanisms mainly may involve the modulation of neurokinins and catecholamines pathways.

An Observational Study of Intravenous Dexmedetomidine and Clonidine for Attenuating Haemodynamic Response to Laryngoscopy and Intubation in Patients Undergoing General Anaesthesia

Background: Laryngoscopy and endotracheal intubation alters cardiovascular physiology causinghypertension and tachycardia. Dexmedetomidine, an alpha 2 adrenergic receptor produces analgesiaby direct activation of descending inhibitory pain pathway and inhibiting the release of substance P.Clonidine a centrally acting alpha 2 adrenergic agonist decreases central sympathetic nervous system in allhyperadrenergic situations. Hence we compare haemodynamic effects between dexmedetomidine 0.5 mcg/kg and clonidine 1mcg/kg during after laryngoscopy and tracheal intubation for patients undergoing generalanaesthesia.Method: Patients were allocated randomly into 2 groups of 30 each. Group D received dexmedetomidine0.5mcg/kg diluted in 10ml NS and group C- clonidine 1 mcg/kg diluted in 10ml NS intravenously andhemodynamic parameters were observed. Dexmedetomidine/ Clonidine according to groups is givenintravenously with premedication. After 5 minutes patients were induced with 2.5% thiopentone 5-7 mg/kgand succinyl choline 2mg/kg and intubated with appropriate sized cuffed ETT. Anaesthesia was maintainedwith O2, N2O, isoflurane and vecuronium bromide 0.08mg/kg.Results: Haemodynamic changes after laryngoscopy and intubation were recorded at baseline, premedication,induction, intubation, 1, 3, 5,10 and 15 minutes. The initial fall in HR is more in Group C compared to GroupD but the difference was insignificant, but since intubation till 10min post intubation HR was significantly(p<0.05) supressed more in Group D. Similarly fall in SBP and DBP is significantly (p<0.05) more in GroupD compared to Group C.Conclusion: Dexmedetomedine 0.5 mcg/kg intravenously 15 minutes prior to laryngoscopy and intubationattenuates the sympathetic response better as compared to clonidine without major side effects.

Renin‐Angiotensin System Blockade is Associated with Exercise Capacity, Sympathetic Activity and Endothelial Function in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) patients have exercise intolerance that is associated with cardiovascular mortality. CKD patients have exaggerated increases in blood pressure (BP) reactivity and impaired ability to maintain skeletal muscle perfusion during exercise mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. Activation of the renin-angiotensin system (RAS) increases central SNS activation and reduces NO synthesis, and prior studies have suggested that RAS blockade may modulate physical function declines. The aim of this study was to investigate whether use of RAS inhibitors (RASi) is associated with greater exercise capacity in CKD, and whether greater exercise capacity with RASi is linked to lower SNS activity and increased NO-dependent endothelial function. 35 hypertensive CKD patients (56.7 ± 7.0 yr) and 20 age-matched controls without CKD (CON, 52.5 ± 8.2 yr) were recruited. Exercise capacity was measured via VO2 peak from a maximal treadmill test, muscle sympathetic nervous activity (MSNA) was measured via microneurography, and vascular endothelial function was measured by flow-mediated dilation (FMD). Participants with CKD were further grouped by current usage of RASi including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) for group difference analyses. There were no baseline differences in demographics or hemodynamics between CKD patients with and without RASi. VO2 peak was greater in CKD patients with RASi compared to CKD patients not on RASi and lower compared to CON (23.3 ± 5.8 vs.16.4 ± 2.9, p=0.007; vs.30.0 ± 7.7, p=0.005 ml/min/kg respectively). MSNA in CKD patients with RASi was lower compared to CKD patients not on RASi but similar with CON (43.9 ± 7.1 vs. 53.8 ± 8.2; p=0.009, vs.38.0 ± 20.3; p=0.103 bursts/min respectively). FMD in CKD patients with RASi was greater compared to CKD patients not on RASi and lower compared to CON (3.2 ± 2.6 vs. 1.3 ± 1.6; p=0.007, vs. 5.0 ± 3.0; p=0.045 % respectively). VO2 peak was positively associated with FMD (r=0.417, p=0.038) and was predicted by the combination of FMD and RASi status (r2 =0.344, p=0.01) and MSNA and RASi status (r2 =0.575, p=0.040) in CKD patients. In summary, hypertensive CKD patients on RASi have better exercise capacity compared to those not on RASi. Furthermore, greater exercise capacity in RASi-treated group was associated with lower resting SNS activity and better NO-dependent vascular endothelial function. Long-term randomized trials examining the effects of RASi on physical function and underlying autonomic and vascular mechanisms are needed to determine its causal effect and its responsible mechanisms in CKD.

Zamicastat is a noncompetitive Dopamine‐β‐hydroxylase inhibitor that modulates sympathetic nervous system activity

Dopamine‐β‐hydroxylase (DβH; EC 1.14.17.1) is an enzyme responsible for the conversion of dopamine (DA) into norepinephrine (NE). It is present in the chromaffin cells of adrenal medulla and in noradrenergic nerve terminals of the central and peripheral sympathetic nervous system. DβH inhibition has been proposed as an alternative mechanism for the treatment of hypertension and chronic heart failure. Zamicastat ((R)‐5‐(2‐(benzylamino)ethyl)‐1‐(6,8‐difluorochroman‐3‐yl)‐1H‐imidazole‐2(3H)‐thione) is a novel DβH inhibitor. The aim of this study was to characterize the pharmacodynamics of Zamicastat in vivo, both in Wistar Han and in spontaneously hypertensive rats (SHR), and on DβH in human cells. DβH activity was measured by a modification of the Nagatsu and Udenfriend (1) spectrophotometric method, based on the conversion of tyramine into octopamine either in adrenal tissues of rats administered orally with Zamicastat (30 mg/Kg) or vehicle, or in human neuroblastoma (SK‐N‐SH) cells. Zamicastat pharmacodynamic characterization in vivo was performed in Wistar rats by evaluating NE and DA levels in tissues using HPLC with electrochemical detection at 9h post‐administration. Additionally, systolic and diastolic blood pressure, heart rate and activity were measured continually by telemetry in SHR rats (a model of essential hypertension) and their controls, Wistar Kyoto (WKY). Zamicastat was found to be a reversible noncompetitive inhibitor of DβH towards tyramine, with a Ki value of 43 (21; 66) nM and either noncompetitive or uncompetitive towards ascorbic acid. Zamicastat (30 mg/Kg, p.o.) fully inhibits adrenal DβH activity from 2 to 8h recovering to baseline values after 24h. This is accompanied with a decrease in NE and an increase in DA in peripheral tissues, namely left ventricle and kidney but not significantly in the central nervous system (brain stem or prefrontal‐cortex). Zamicastat at 3, 30 and 100 mg/Kg displayed a dose‐dependent decrease on systolic and diastolic blood pressure with no effect in heart rate or overall activity when evaluated in SHR rats by telemetry. In conclusion, Zamicastat is a DβH inhibitor displaying binding affinity for both the free enzyme and the complex enzyme‐substrate, that when orally administered at 30 mg/Kg to rats acts peripherally and significantly reduces sympathetic activity by decreasing NE levels and consequently systolic and diastolic blood pressure in an animal model of essential hypertension.

Central Sympathetic Nervous System Effects on Cognitive-Motor Performance.

The intriguing interplay between acute stress physiology and cognitive processes has long been noted. However, while stress-induced release of glucocorticoids has repeatedly been shown to impact brain mechanisms underlying cognition and memory, less experimental research addressed the effects of stress-induced central sympathetic nervous system (SNS) activation on cognitive performance. Moreover, despite the long-standing notion that the way performance is modulated by arousal may crucially depend on task complexity, mechanistic research demonstrating a direct, causal influence of altered SNS activity is scarce. Twelve healthy men participated in a placebo-controlled, pharmacologic dose-response study involving three within-subject assessments (1-week intervals). Subjective and objective indices of SNS activity as well as reaction time (RT) in three different tasks varying in cognitive demand (simple RT, choice RT, and verbal RT in complex mental arithmetic) were assessed during modulation of central SNS tone by intravenous infusions of dexmedetomidine (alpha2-agonist), yohimbine (alpha2-antagonist), and placebo. Cognitive performance was negatively affected by alpha2-agonism in all task conditions. By contrast, administration of yohimbine improved simple RT, while diminishing complex RT, supporting the assumption of a nonlinear way of action depending on task characteristics. Our results highlight the consequences of central (noradrenergic) SNS activation for cognitive-motor performance in RT tasks of varying complexity.

Tyrosine hydroxylase and β2-adrenergic receptor expression in leukocytes of spontaneously hypertensive rats: putative peripheral markers of central sympathetic activity.

The sympathetic nervous system (SNS) plays a fundamental role in the pathophysiology of cardiovascular diseases, including primary arterial hypertension. In this study, we aimed to investigate whether the expression of the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and the β2-adrenergic receptor (β2-AR) in immune cells from peripheral blood, reflect central SNS activity in spontaneously hypertensive rats (SHR). TH expression in the lower brainstem and adrenal glands and β2-AR expression in the lower brainstem were analyzed by western blot analyses. In the leukocytes, TH and β2-AR expression was evaluated by flow cytometry before and after chronic treatment with the centrally-acting sympathoinhibitory drug clonidine. Western blot analyses showed increased TH and β2-AR expression in the lower brainstem and increased TH in adrenal glands from SHR compared to normotensive Wistar Kyoto rats (WKY). Lower brainstem from SHR treated with clonidine presented reduced TH and β2-AR levels, and adrenal glands had decreased TH expression compared to SHR treated with vehicle. Flow cytometry showed that the percentage of leukocytes that express β2-AR is higher in SHR than in WKY. However, the percentage of leukocytes that expressed TH was higher in WKY than in SHR. Moreover, chronic treatment with clonidine normalized the levels of TH and β2-AR in leukocytes from SHR to similar levels of those of WKY. Our study demonstrated that the percentage of leukocytes expressing TH and β2-AR was altered in arterial hypertension and can be modulated by central sympathetic inhibition with clonidine treatment.

Role of the brain-gut axis in gastrointestinal cancer.

Several studies have largely focused on the significant role of the nervous and immune systems in the process of tumorigenesis, including tumor growth, proliferation, apoptosis, and metastasis. The brain-gut-axis is a new paradigm in neuroscience, which describes the biochemical signaling between the gastrointestinal (GI) tract and the central nervous system. This axis may play a critical role in the tumorigenesis and development of GI cancers. Mechanistically, the bidirectional signal transmission of the brain-gut-axis is complex and remains to be elucidated. In this article, we review the current findings concerning the relationship between the brain-gut axis and GI cancer cells, focusing on the significant role of the brain-gut axis in the processes of tumor proliferation, invasion, apoptosis, autophagy, and metastasis. It appears that the brain might modulate GI cancer by two pathways: the anatomical nerve pathway and the neuroendocrine route. The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers. In addition, neurotransmitters and neurotrophic factors can produce stimulatory or inhibitory effects in the progression of GI cancers. Insights into these mechanisms may lead to the discovery of potential prognostic and therapeutic targets.

Prenatal cold exposure causes hypertension in offspring by hyperactivity of the sympathetic nervous system.

Environmental temperature plays a role in the variation of blood pressure. Maternal cold stress could affect the physiological phenotype of the offspring, including blood pressure elevation. In the present study, we found that adult offspring of dams exposed to cold have increased systolic and diastolic blood pressure, and decreased urine volume and sodium excretion, accompanied by increased heart rate and heart rate variability, secondary to increased activity of the sympathetic nervous system. Renal denervation or adrenergic receptor blockade decreased blood pressure and increased sodium excretion. The increase in peripheral sympathetic nerve activity can be ascribed to the central nervous system because administration of clonidine, a centrally acting α2 adrenergic receptor agonist, lowered blood pressure to a greater degree in the prenatal cold-exposed than control offspring. Moreover, these prenatal cold-exposed offspring had hypothalamic paraventricular nucleus (PVN) disorder because magnetic resonance spectroscopy showed decreased N-acetylaspartate and increased choline and creatine ratios in the PVN. Additional studies found that prenatal cold exposure impaired the balance between inhibitory and excitatory neurons. This led to PVN overactivation that was related to enhanced PVN-angiotensin II type 1 (AT1) receptor expression and function. Microinjection of the AT1 receptor antagonist losartan in the PVN lowered blood pressure to a greater extent in prenatal cold-exposed that control offspring. The present study provides evidence for overactive peripheral and central sympathetic nervous systems in the pathogenesis of prenatal cold-induced hypertension. Central AT1 receptor blockade in the PVN may be a key step for treatment of this type hypertension.

BP.02.05] FEASIBILITY AND EFFICACY OF RENAL DENERVATION THERAPY IN HEMODIALYSIS PATIENTS WITH RESISTANT HYPERTENSION.

Objective: Nephrectomy has been considered for patients with malignant hypertension on dialysis to remove the pressor effects reflexly induced by afferent fibers originating in the renal structure and still active in nonfunctioning kidneys. Because the morbidity and mortality associated with the surgical procedures has limited its adoption, endovascular procedures that might denervate the native nonfunctioning kidney much less invasively has been proposed as an alternative therapeutic strategy. Design and method: we enrolled 5 consecutive dialised patients affected by resistant hypertension (RH,4 men, 1 women, mean age 50 years). The average duration of dialysis was of 5,4 years and the average number of antihypertensive drugs for each patient was 3.5. The renal arteries average diameter was 3.96 mm. The cohort underwent bilateral percutaneous trans-catheter renal denervation (RDT) with the EnligHTN System (St. Jude Medical, St Paul, MN, USA). Measurements included intra-arterial Systolic blood pressure (SBP), diastolic (D) BP, mean (M) BP and heart rate (HR). Results: The small basket device of the EnligHTN was used in all patients. RDT was performed without complications, with an average number of ablations of 33,8. SBP was reduced by the procedure from 162,7 to 130,4 mmHg (p-value 0.02) with also a reduction of DBP (from 97,6 to 83,6 mmHg,p-value 0.04) and MBP (from 119,3 to 99,2 mmHg, p-value 0.03) and no significant HR changes (from 78 to 72 bpm, p-value 0.74). Conclusions: the bilateral RDT procedure in dialised patients with RH was feasible without complications and produced an acute statistically significant decrease in BP.. Diseased kidneys might be the source of a persistently elevated activity of afferent signals to the central sympathetic nervous system, the interruption of which may favour BP reduction. This may be obtain by renal denervation with no need of surgical kidney removal.

Does aging alter the molecular substrate of ionotropic neurotransmitter receptors in the rostral ventral lateral medulla? - A short communication

Aging alters sympathetic nervous system (SNS) regulation, although central mechanisms are not well understood. In young rats the rostral ventral lateral medulla (RVLM) is critically involved in central SNS regulation and RVLM neuronal activity is mediated by a balance of excitatory and inhibitory ionotropic neurotransmitters and receptors, providing the foundation for hypothesizing that with advanced age the molecular substrate of RVLM ionotropic receptors is characterized by upregulated excitatory and downregulated inhibitory receptor subunits. This hypothesis was tested by comparing the relative mRNA expression and protein concentration of RVLM excitatory (NMDA and AMPA) and inhibitory (GABA and glycinergic) ionotropic neurotransmitter receptor subunits in young and aged Fischer (F344) rats. Brains were removed from anesthetized rats and the RVLM-containing area was micropunched and extracted RNA and protein were subsequently used for TaqMan qRT-PCR gene expression and quantitative ELISA analyses. Bilateral chemical inactivation of RVLM neurons and peripheral ganglionic blockade on visceral sympathetic nerve discharge (SND) was determined in additional experiments. The relative gene expression of RVLM NMDA and AMPA glutamate-gated receptor subunits and protein concentration of select receptor subunits did not differ between young and aged rats, and there were no age-related differences in the expression of RVLM ionotropic GABAA and Gly receptors, or of protein concentration of select GABAA subunits. RVLM muscimol microinjections significantly reduced visceral SND by 70±2% in aged F344 rats. Collectively these findings from this short communication support a functional role for the RVLM in regulation of sympathetic nerve outflow in aged rats, but provide no evidence for an ionotropic RVLM receptor-centric framework explaining age-associated changes in SNS regulation.

Separate and shared sympathetic outflow to white and brown fat coordinately regulates thermoregulation and beige adipocyte recruitment.

White adipose tissue (WAT) and brown adipose tissue (BAT) are innervated and regulated by the sympathetic nervous system (SNS). It is not clear, however, whether there are shared or separate central SNS outflows to WAT and BAT that regulate their function. We injected two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer, with unique fluorescent reporters into interscapular BAT (IBAT) and inguinal WAT (IWAT) of the same Siberian hamsters to define SNS pathways to both. To test the functional importance of SNS coordinated control of BAT and WAT, we exposed hamsters with denervated SNS nerves to IBAT to 4°C for 16-24 h and measured core and fat temperatures and norepinephrine turnover (NETO) and uncoupling protein 1 (UCP1) expression in fat tissues. Overall, there were more SNS neurons innervating IBAT than IWAT across the neuroaxis. However, there was a greater percentage of singly labeled IWAT neurons in midbrain reticular nuclei than singly labeled IBAT neurons. The hindbrain had ~30-40% of doubly labeled neurons while the forebrain had ~25% suggesting shared SNS circuitry to BAT and WAT across the brain. The raphe nucleus, a key region in thermoregulation, had ~40% doubly labeled neurons. Hamsters with IBAT SNS denervation maintained core body temperature during acute cold challenge and had increased beige adipocyte formation in IWAT. They also had increased IWAT NETO, temperature, and UCP1 expression compared with intact hamsters. These data provide strong neuroanatomical and functional evidence of WAT and BAT SNS cross talk for thermoregulation and beige adipocyte formation.