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We review our recent data obtained on the cortical and subcortical components of the human sympathetic connectome - the network of regions involved in the sympathetic control of blood pressure. Specifically, we functionally identified the human homologue of the rostral ventrolateral medulla (RVLM), the primary premotor sympathetic nucleus in the medulla responsible for generating sympathetic vasoconstrictor drive. By performing functional magnetic resonance imaging (fMRI) of the brain at the same time as recording muscle sympathetic nerve activity (MSNA), via a microlectrode inserted into the common peroneal nerve, we are able to identify areas of the brain involved in the generation of sympathetic outflow to the muscle vascular bed, a major contributor to blood pressure regulation. Together with functional connectivity analysis of areas identified through MSNA-coupled fMRI, we have established key components of the human sympathetic connectome and their roles in the control of blood pressure. Whilst our studies confirm the role of lower brainstem regions such as the NTS, CVLM and RVLM in baroreflex control of MSNA, our findings indicate that the insula – hypothalamus – PAG – RVLM circuitry is tightly coupled to MSNA at rest. This fits with data obtained from experimental animals, but also emphasizes the role of areas above the brainstem in the regulation of blood pressure. •We review our recent data obtained on the cortical and subcortical components of the human sympathetic connectome.•We performed fMRI of the brain at the same time as recording muscle sympathetic nerve activity (MSNA) via a microlectrode inserted into a peripheral nerve.•This allows us to identify areas of the brain involved in the generation of sympathetic outflow to the muscle vascular bed.•Our studies emphasize the contributions of areas above the brainstem in the regulation of blood pressure.

Appropriate cardiovascular adjustment is necessary to meet the metabolic demands of working skeletal muscle during exercise. The sympathetic nervous system plays a crucial role in the regulation of arterial blood pressure and blood flow during exercise, and several important neural mechanisms are responsible for changes in sympathetic vasomotor outflow. Changes in sympathetic vasomotor outflow (i.e., muscle sympathetic nerve activity: MSNA) in inactive muscles during exercise differ depending on the exercise mode (static or dynamic), intensity, duration, and various environmental conditions (e.g., hot and cold environments or hypoxic). In 1991, Seals and Victor [6] reviewed MSNA responses to static and dynamic exercise with small muscle mass. This review provides an updated comprehensive overview on the MSNA response to exercise including large-muscle, dynamic leg exercise, e.g., two-legged cycling, and its regulatory mechanisms in healthy humans.

Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals’ eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC–SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues.

The progression from conception through to the postpartum period represents an extraordinary period of physiological adaptation in the mother to support the growth and development of the fetus. Healthy, normotensive human pregnancies are associated with striking increases in both plasma volume and sympathetic nerve activity, yet normal or reduced blood pressure; it represents a unique period of apparent healthy sympathetic hyperactivity. However, how this normal blood pressure is achieved in the face of sympathoexcitation, and the mechanisms responsible for this increased activity are unclear. Importantly, sympathetic activation has been implicated in hypertensive pregnancy disorders – the leading causes of maternal–fetal morbidity and mortality in the developed world. An understudied link between pregnancy and the development of maternal hypertension may lie in the sympathetic nervous system regulation of blood pressure. This brief review presents the latest data on sympathoexcitation in both healthy and hypertensive pregnancies, and concurrent adaptations along the neurovascular cascade. What is the topic of this review? Sympathoexcitation in both healthy and hypertensive pregnancies, and concurrent adaptations along the neurovascular cascade. What advances does it highlight? Known and plausible adaptations along the neurovascular cascade which may offset elevated MSNA in normotensive pregnancy while also highlighting knowledge gaps regarding understudied pathways.

Sympathetic neural remodeling, which involves the inflammatory response, plays an important role in ventricular arrhythmias (VAs) after myocardial infarction (MI). Adrenergic receptors on macrophages potentially modulate the inflammatory response. We hypothesized that the increased level of catecholamines activates macrophages and regulates sympathetic neural remodeling after MI. We treated MI mice with either clodronate or metoprolol for 5 days following coronary artery ligation. Mice without treatment after MI and sham-operation mice served as the positive control and negative control, respectively. The norepinephrine levels in plasma and the peri-infarct myocardium increased by almost two-fold in the MI mice compared with the sham-operation mice. Both in vivo and ex vivo electrophysiology examinations showed that the vulnerability to VAs induced by MI was alleviated by macrophage depletion with clodronate and β1-adrenergic blockade with metoprolol, which was in line with circulating and peri-infarct norepinephrine levels, sympathetic reinnervation, and the expression of nerve growth factor (NGF) 7 days after surgery. To further verify the interaction between catecholamines and macrophages, we preconditioned lipopolysaccharide-stimulated RAW 264.7 cells using epinephrine or epinephrine with selective adrenergic antagonists. The expression and release of inflammatory factors including NGF were enhanced by epinephrine. This effect was inhibited by metoprolol but not by other subtype antagonists. Our data suggested that the increased level of catecholamines, traditionally known as positive inotropes secreted from sympathetic nerve endings, might regulate cardiac sympathetic neural remodeling through β1-adrenergic receptors on macrophages, subsequently inducing VAs after MI.

Carotid body (CB) hyperactivity promotes hypertension in response to chronic intermittent hypoxia (CIH). The plasma concentration of adrenaline is reported to be elevated in CIH and our previous work suggests that adrenaline directly activates the CB. However, a role for chronic adrenergic stimulation in mediating CB hyperactivity is currently unknown. This study evaluated whether beta-blocker treatment with propranolol (Prop) prevented the development of CB hyperactivity, vascular sympathetic nerve growth and hypertension caused by CIH. Adult male Wistar rats were assigned into 1 of 4 groups: Control (N), N + Prop, CIH and CIH + Prop. The CIH paradigm consisted of 8 cycles h−1, 8 h day−1, for 3 weeks. Propranolol was administered via drinking water to achieve a dose of 40 mg kg−1 day−1. Immunohistochemistry revealed the presence of both β1 and β2-adrenoceptor subtypes on the CB type I cell. CIH caused a 2–3-fold elevation in basal CB single-fibre chemoafferent activity and this was prevented by chronic propranolol treatment. Chemoafferent responses to hypoxia and mitochondrial inhibitors were attenuated by propranolol, an effect that was greater in CIH animals. Propranolol decreased respiratory frequency in normoxia and hypoxia in N and CIH. Propranolol also abolished the CIH mediated increase in vascular sympathetic nerve density. Arterial blood pressure was reduced in propranolol groups during hypoxia. Propranolol exaggerated the fall in blood pressure in most (6/7) CIH animals during hypoxia, suggestive of reduced sympathetic tone. These findings therefore identify new roles for β-adrenergic stimulation in evoking CB hyperactivity, sympathetic vascular hyperinnervation and altered blood pressure control in response to CIH.

Aims/hypothesisWe determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits.MethodsDiabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits.ResultsFour weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (−43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05).Conclusions/interpretationAs empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion.

Early in the twentieth century, Walter B. Cannon (1871–1945) introduced his overarching hypothesis of “homeostasis” (Cannon 1932)—the ability to sustain physiological values within a narrow range necessary for life during periods of stress. Physical exercise represents a stress in which motor, respiratory and cardiovascular systems must be integrated across a range of metabolic stress to match oxygen delivery to oxygen need at the cellular level, together with appropriate thermoregulatory control, blood pressure adjustments and energy provision. Of these, blood pressure regulation is a complex but controlled variable, being the function of cardiac output and vascular resistance (or conductance). Key in understanding blood pressure control during exercise is the coordinating role of the autonomic nervous system. A long history outlines the development of these concepts and how they are integrated within the exercise context. This review focuses on the renaissance observations and thinking generated in the first three decades of the twentieth century that opened the doorway to new concepts of inquiry in cardiovascular regulation during exercise. The concepts addressed here include the following: (1) exercise and blood pressure, (2) central command, (3) neurovascular transduction with emphasis on the sympathetic nerve activity and the vascular end organ response, and (4) tonic neurovascular integration.

Sinusoidal galvanic vestibular stimulation (sGVS) induces robust modulation of muscle sympathetic nerve activity (MSNA) alongside perceptions of side-to-side movement, sometimes with an accompanying feeling of nausea. We recently showed that transcranial alternating current stimulation (tACS) of the dorsolateral prefrontal cortex (dlPFC) also modulates MSNA, but does not generate any perceptions. Here, we tested the hypothesis that when the two stimuli are given concurrently, the modulation of MSNA would be additive. MSNA was recorded from 11 awake participants via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve at the fibular head. Sinusoidal stimuli (± 2 mA, 0.08 Hz, 100 cycles) were applied in randomised order as follows: (i) tACS of the dlPFC at electroencephalogram (EEG) site F4 and referenced to the nasion; (ii) bilateral sGVS applied to the vestibular apparatuses via the mastoid processes; and (iii) tACS and sGVS together. Previously obtained data from 12 participants supplemented the data for stimulation protocols (i) and (ii). Cross-correlation analysis revealed that each stimulation protocol caused significant modulation of MSNA (modulation index (paired data): 35.2 ± 19.4% for sGVS; 27.8 ± 15.2% for tACS), but there were no additive effects when tACS and sGVS were delivered concurrently (32.1 ± 18.5%). This implies that the vestibulosympathetic reflexes are attenuated with concurrent dlPFC stimulation. These results suggest that the dlPFC is capable of blocking the processing of vestibular inputs through the brainstem and, hence, the generation of vestibulosympathetic reflexes.

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.