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The sympathetic nervous system and blood pressure in humans: implications for hypertension


A neurogenic component to primary hypertension (hypertension) is now well established. Along with raised vasomotor tone and increased cardiac output, the chronic activation of the sympathetic nervous system in hypertension has a diverse range of pathophysiological consequences independent of any increase in blood pressure. This review provides a perspective on the actions and interactions of angiotensin II, inflammation and vascular dysfunction/brain hypoperfusion in the pathogenesis and progression of neurogenic hypertension. The optimisation of current treatment strategies and the exciting recent developments in the therapeutic targeting of the sympathetic nervous system to control hypertension (for example, catheter-based renal denervation and carotid baroreceptor stimulation) will be outlined.

The sympathetic renaissance

Primary (or essential) hypertension (termed hypertension from here on) accounts for the vast majority of hypertensive cases (95%).1 Although the aetiology of this condition is incompletely understood, it appears that along with genetic factors, several environmental and behavioural ‘hypertensiogenic’ factors have been identified, such as obesity, insulin resistance, high-salt intake, low physical activity levels and stress.1 Given the elevated risk of stroke, renal failure, myocardial infarction and coronary heart disease in those afflicted with high blood pressure, the elucidation of the key pathogenic features and optimisation of effective therapeutic strategies are critical.

The most common form of hypertension is neurogenic hypertension, defined as high blood pressure with sympathetic overdrive, loss of parasympathetically mediated cardiac variability and excessive angiotensin II (Ang II) activity.2 The importance of the sympathetic nervous system in the short-term regulation of blood pressure via the modulation of peripheral vascular tone and cardiac output is well established, while the role of the sympathetic nerve activity (SNA) in long-term blood pressure control is more controversial.3, 4, 5 Although the concept of a potential neurogenic component to hypertension is not new,4 it has perhaps received less attention than the renin–angiotensin system (RAS), which has been a prominent therapeutic and research target in hypertension over the past few decades. Nevertheless, the activation of the sympathetic nervous system and the RAS in hypertension appears inextricably, and reciprocally, linked. Evidence from studies in both patients and animal models of hypertension strongly implicate the chronic sympathetic neural activation in the aetiology and progression of hypertension (Figure 1).2, 6, 7, 8, 9

Figure 1

Triangulation of neurogenic hypertension. The establishment of positive feedback loops between Ang II, inflammation and vascular dysfunction/brain hypoperfusion may form the basis of refractory hypertension.

The use of regional surgical sympathectomy to treat hypertension over 50 years ago before the availability of antihypertensive medications that lower sympathetic activity provides an early indication of the clinical appreciation for a significant neurogenic component to hypertension.10 Recent clinical interventions showing impressive blood pressure lowering effects by targeting reductions in SNA11, 12, 13, 14 and progress in the elucidation of the central sympathetic regulatory pathways altered in hypertension15, 16, 17 are part of a renaissance of interest in the control of the sympathetic nervous system and its utility as a clinical target. The purpose of the present review is to provide a perspective on the evidence for a neurogenic component to hypertension. We will address the issue of a causal role of heightened SNA in the onset of hypertension, highlight some novel putative causal mechanisms and recent developments in the targeting of the sympathetic nervous system as a therapeutic strategy to control hypertension.

‘Neuro-adrenergic’ overdrive in hypertension

With the advent of sensitive assays for the quantification of plasma noradrenaline concentrations, direct evidence for an elevated activation of the sympathetic nervous system in hypertensive patients was provided.18 However, this was not a universal finding, perhaps partly owing to the assessment of plasma noradrenaline providing a limited measure of sympathetic nervous activation.18 Although being a convenient ‘global’ index of whole-body SNA,18, 19 it is not known whether high levels of circulating noradrenaline result from increased central sympathetic outflow, or can be explained by facilitated release of noradrenaline from peripheral adrenergic stores, or from altered synthesis and metabolism of noradrenaline (for example, altered local reuptake mechanisms).20 Furthermore, plasma catecholamine measurements neglect the fact that the sympathetic nervous system has distinct organ-specific differential control.21

These limitations can be circumvented by more technically advanced, albeit more invasive methods whereby noradrenaline spillover from individual organs can be quantified (for example, brain, heart and kidneys).19, 20 Additionally, direct intraneural recordings of sympathetic vasoconstrictor traffic directed to the cutaneous and skeletal muscle blood vessels can be made using the microneurography technique.22 Using such approaches, it has been estimated that a neurogenic component is observed in 40–65% of hypertension patients,2 with studies typically reporting an 100–200% greater SNA targeting the brain, heart, kidneys and skeletal muscle vasculature in human hypertension.21, 23, 24, 25, 26, 27 Furthermore, SNA is elevated in white coat and borderline hypertensives6, 9 and the magnitude of the elevation in SNA is related to the magnitude of hypertension.28, 29 Indeed, Grassi et al.29 reported that the increase in blood pressure from control subjects (135±4/83±3 mm Hg), to mildly hypertensive (140±4/97±4 mm Hg), to more severely hypertensive patients (150±5/107±4 mm Hg) was accompanied by a parallel increase in muscle SNA (40±3, 56±4 and 68±4 bursts per 100 heart beats, respectively). Although, it is acknowledged that reports of an elevation in muscle SNA in hypertension have not been universal.30 Reductions in cardiac parasympathetic nerve activity, estimated with heart rate variability analyses, are also an established feature of hypertension and have been associated with increased mortality.31, 32

As in hypertensive patients, studies of the adult spontaneously hypertensive rat (SHR) have also identified a reduced cardiac parasympathetic nerve activity,33 elevated SNA and increased noradrenaline release.34, 35 Notably, neonatal sympathectomy prevents the SHR from developing hypertension,36 while our group,7 and others,37 have shown that SNA is elevated in young SHR prior to the development of hypertension. An amplified burst pattern of SNA that is respiratory related and contributes to the elevations in vascular resistance and blood pressure has also been identified in rat models of hypertension7, 38 while our preliminary investigations suggest alterations in respiratory–sympathetic coupling in human hypertension.39, 40 The functional implications of this remain to be verified.

Clinical implications of elevated SNA

Chronic activation of the sympathetic nervous system is not only associated with raised vasomotor tone and increased cardiac output, but also with a plethora of pathophysiological consequences independent of any increase in blood pressure (Figure 2).15 Indeed, the infusion of subpressor doses of noradrenaline increases myocardial mass and left ventricle wall thickness in animals,41 while in patients with hypertension left ventricular hypertrophy is related to elevations in sympathetic outflow determined with microneurography.42 Furthermore, both left ventricular hypertrophy and high cardiac SNA promote cardiac arrhythmias, and precipitate sudden cardiac death, particularly when parasympathetic tone is low, when it is in neurogenic hypertension.43, 44 Experimental infusion of noradrenaline can elicit vascular remodelling and increase aortic medial thickening33 without marked changes in mean blood pressure,45 while vertebral and basilar artery stenosis have been reported in the pre-hypertensive SHR,16, 46 which may be reversed with angiotensin-converting enzyme (ACE) inhibition.47, 48 Such pathophysiological alterations in the vasculature may be expected to modify the functional properties of the blood vessels. Notably, increases in large artery stiffness have been reported in hypertensives and prehypertensives, and have been identified as a powerful predictor of cardiovascular risk in hypertensive humans.49, 50 Notably, increases in muscle SNA are associated with increased carotid–femoral pulse wave velocity, an index of arterial stiffness.51 Furthermore, Grassi et al.52 demonstrated that local pharmacological blockade of the high tonic sympathetic activity noted in chronic heart failure patients improved the distensibility of the radial artery. Taken together, these findings indicate that sympathetic neural activity can influence the mechanical properties of the arteries. Elevated SNA in pro-atherosclerotic53 and flow-mediated endothelium-dependent dilatation can be reduced by acute sympathetic activation,54 while reductions in nitric oxide bioavailability associated with elevations in oxidative stress can augment sympathetic vasoconstriction in the SHR55 and humans with hypertension.56 This is significant as endothelial dysfunction is associated with poor survival rates in hypertension.57 Aside from deleterious alterations in cardiovascular health, sympathetic hyperactivity has also been shown to contribute to metabolic,58 renal59 and immune60 dysfunction, and is an independent risk factor of mortality in several clinical populations.61, 62, 63

Figure 2

Deleterious consequences of heightened sympathetic neural outflow in hypertension. VSM, vascular smooth muscle cell.

Therapeutic targeting to reduce SNA

Current recommendations for the treatment of hypertension are broadly governed by the severity of the elevation in blood pressure and the coexistence of cardiovascular risk factors, complications and/or target organ damage.64, 65 Standard treatment options include lifestyle modifications (for example, weight loss, physical activity, smoking cessation, alcohol and dietary alterations) and pharmacological treatment (for example, ACE inhibitor, Ang II type 1 receptor (AT1-R) blocker, β-adrenoceptor blocker, calcium channel antagonist, diuretic and α-adrenoceptor blocker). A thorough discussion of this topic is beyond the scope of the present review, but as might be expected the implementation of a specific lifestyle modification should be specific to the needs of the patient (for example, weight loss in the overweight individual), while the choice of pharmacological treatment should be determined by several factors including the presence of co-morbidities (for example, diabetes and coronary artery disease), whether the patient has high cardiac output or peripheral vascular resistance, and the extent to which the patient is responsive to treatment.64, 65

The potential for SNA lowering in primary hypertension, with conventional pharmacological agents prescribed as a monotherapy or in combination, remains incompletely understood. The activity of both the systemic and tissue RAS in hypertension is upregulated in many patients with primary hypertension.66 Ang II can directly modulate blood pressure via activation of AT1-R in vascular smooth muscle cells and the kidney, thus causing vasoconstriction and sodium and water retention. AT1-R has also been identified in several other tissues (for example, heart and central nervous system) and may also indirectly modulate blood pressure. Hypertension evoked by chronic infusion of Ang II in experimental normotensive animals is believed to be mediated, at least in part, by amplification of SNA.67 Yet, in hypertensive animals raised sympathetic nervous system enhances the activity of RAS (Figure 1).16 The temporal coupling between elevated activation of the sympathetic nervous system and RAS requires clearer elucidation in human hypertension. Irrespectively, it may be argued that successful blood pressure lowering strategies must break into the positive reciprocating feedback relationship between the sympathetic nervous system and RAS. Inhibition of ACE with imidapril (5–10 mg per day) in hypertensive humans for 12 weeks significantly decreases muscle SNA and blood pressure.68 ACE inhibition also prevents development of hypertension in newborn SHR.48 However, reductions in blood pressure with shorter duration ACE inhibitor treatment are not associated with reductions in SNA69 (2 months, lispinopril, 10 mg per day). This contrasting effect may be related to differing pharmokinetic properties of the drugs, interactions with the blood–brain barrier and methods of SNA assessment. Nevertheless, the observation that SNA remains elevated whereas Ang II and blood pressure are lowered with ACE inhibition69 suggests that changes in SNA and RAS do not always occur in parallel and may be independently regulated in hypertension. Krum et al.70 reported no alteration in muscle SNA or whole-body norepinephrine spillover following 4 weeks administration of AT1-R antagonism with eprosartan (600 mg per day) or losartan (50 mg per day) in patients with uncomplicated hypertension. β-adrenergic blockade also appears to have a negligible effect on muscle SNA in human hypertension (6–29 weeks, metoprolol, 200 mg per day).71 However, the actions of metoprolol within the central nervous system appear to exert favourable effects on the failing rat heart, likely due to reductions in cardiac sympathetic outflow.72 Whether these previously unrecognised pleiotropic effects of β-adrenergic blockade are manifested in human hypertension remains to be determined. Of note, despite lowering blood pressure certain diuretics (for example, chlorthalidone73), dihydropridine calcium channel blockers74 and combination therapies (for example, AT1-R antagonism plus diuretic75) may actually raise SNA due to baroreceptor unloading. Said differently, assuming the baroreceptors are not desensitised by these drugs, a fall in arterial pressure may trigger a baroreflexly mediated increase in sympathetic activity and arterial pressure.

Ganglionic blockade (for example, hexamethonium), reserpine and guanethidine were early pharmacological approaches (replacing sympathectomy) to directly interrupt SNA in hypertensives.76 Although blood pressure lowering could be successfully achieved, these strategies suffered from side effects, for example the vagolytic effects of ganglionic blockade can elicit constipation, mydriasis and impotence.76 Alternatively, central pharmacological inhibition of SNA may be achieved by administration of sympatholytic agents, which act on α2-adrenoceptors or imidazoline receptors within the brain.27 Based on animal experiments, central activity generated by catecholamine-containing neurons (for example, C1 and A2) may contribute to high levels of sympathetic activity as has been described in the SHR.77 Both α-methyldopa and clonidine have been recognised as antihypertensive agents for many years, although side effects such as orthostatic intolerance have limited their widespread use.78 Newer central sympatholytics such as moxonidine and rilmenidine appear to be better tolerated, and shown to reduce SNA and blood pressure in humans.79, 80 The time course of the relationship between reductions in SNA and blood pressure during treatment with such central sympatholytic agents is presently unknown, although examining this may provide a mechanistic insight into the temporal coupling between sympathetic and vasomotor tone in hypertension, especially if the effect is reversible.

Non-pharmacological, lifestyle interventions have been associated with reductions in SNA and blood pressure in hypertension. Anecdotal reports indicating a hypotensive effect of acute aerobic exercise (for example, running) first arose in the 19th century,81 and since then a substantial number of studies have highlighted the blood pressure lowering effects of aerobic endurance exercise training in patients with hypertension.82 Indeed, regular (3–5 days per week), moderate intensity (50–80% of maximal oxygen consumption) exercise using a large muscle mass (for example, jogging, cycling and swimming) appears to achieve a 10 mm Hg average fall in systolic and diastolic blood pressure in hypertensive patients.82 To the authors’ knowledge, only one study in humans has examined the potential sympatho-inhibitory effects of exercise training in hypertensive patients. Laterza et al.83 reported that a 4-month programme of aerobic exercise training reduced muscle SNA (by 37%) and blood pressure (145/94 to 130/84 mm Hg) in never-treated hypertensives. Exercise training consisted of three 60 min exercise sessions per week, comprising stretching exercise (10 min), leg cycling (40 min at 70% of maximal oxygen consumption) and resistance exercise (10 min). Although the mechanism underlying the impressive reduction in sympathetic neural activity remains unclear, the ability of exercise to upregulate central antioxidant concentrations, reduce pro-oxidant levels and increase central nitric oxide synthase activity (endothelial function) have been shown.84 Weight loss following exercise training and/or caloric intake can also reduce SNA,85, 86 which is significant given that a neurogenic component to obesity-related hypertension has been implied.87 Chronic psychosocial stress has been associated with heighted sympathetic activation and high blood pressure,88 thus stress reduction measures may reduce SNA and blood pressure in hypertension. In a recent meta-analysis, transcendental meditation was reported to effectively lower blood pressure in patients with hypertension, whereas psychological approaches to stress management were deemed ineffective.89 Intriguingly, the results of several studies indicate that device-guided, home-based training with slow, deep breathing can effectively reduce blood pressure in patients with hypertension,90, 91, 92 although this has not been a universal finding.93 These findings are particularly intriguing given the recent identification of an amplified bursting of SNA related to the respiratory cycle that appears to contribute to the progression and maintenance of hypertension in rats,7 and the alterations in respiratory–sympathetic coupling recently reported in human hypertension.39, 40 Further studies are required to determine whether central sympathetic outflow is decreased by stress reduction programs, which effectively reduce blood pressure.

Drug-resistant hypertension—how to treat?

The success of a treatment paradigm in lowering blood pressure via targeting the sympathetic nervous system may depend upon the timing of an intervention. Indeed, the pathophysiological progression of the disease state may be important in terms of guiding treatment regimes (or preventative treatment). In fact, certain drugs may fail to reduce SNA because other drivers of SNA have emerged or become predominant in elevating SNA, and these are independent of the standard armoury of antihypertensive strategies and better-described ‘early’ mechanisms. Notably, of the one-billion individuals worldwide with hypertension,94 it is estimated that 20% have resistant hypertension, defined as elevated blood pressure despite treatment with three or more antihypertensive medications of different classes.95 The scale of this problem highlights the need to better understand the underlying causal mechanisms, optimise existing treatment strategies and develop new approaches.

Surgical methods have shown recent promise in tackling refractory or drug-resistant hypertension. Such approaches include ablation of afferent and efferent renal artery nerves, carotid baroreflex stimulation and deep brain stimulation. As these have been the subject of recent detailed reviews,96, 97 they will only be mentioned briefly here. It has been known for some time that renal denervation reduces blood pressure in several experimental animal models of hypertension.59 Subsequent to ground breaking human work by Krum et al.13 in a recent multicentre, prospective, randomised trial, catheter-based renal sympathetic denervation in patients with resistant hypertension was shown to elicit marked and sustained blood pressure lowering.12 Indeed, the Simplicity HTN-2 trial reported reductions in office-based blood pressure from 178/96 to 146/84 mm Hg 6 months after the catheter-based renal denervation procedure in treatment-resistant hypertensives (n=52).12 Notably, all patients remained on hypertensive medication, although crucially no deleterious effect on renal function was observed and no serious complications relating to the device or surgical procedure were noted over this period. However, the efficacy of this approach in longer-term blood pressure lowering and the potential benefit to patients with less marked hypertension remains to be determined as do the mechanisms through which this treatment works. Physiological increases in renal SNA have multiple pro-hypertensive effects including increased renin secretion, sodium retention and renal vasoconstriction,59 thus ablation of efferent renal SNA is likely to be a major contributor to the consequent blood pressure lowering. However, renal denervation has also been shown to elicit marked reductions in muscle SNA (by 66%) at 1 and 12 months after the procedure, suggesting that removal of sensory afferent activity from the kidney and a consequent general suppression of sympathetic vasoconstrictor drive may also make an important contribution to the antihypertensive effects of this treatment.98

Following animal studies first conducted over 50 years ago99, 100 and extensive technical development work,101, 102 surgical implantation of a device eliciting chronic carotid baroreflex stimulation (Rheo, CVRx, Minneapolis, MN, USA) has recently been demonstrated to effectively lower blood pressure and muscle SNA in humans.14, 71, 72, 103, 104 This has been based on the recently resurrected idea that arterial baroreceptors control arterial pressure in the long term.105 In his original study, Thrasher (2002) showed that unloading of baroreceptors at one carotid sinus (with all other arterial baroreceptors denervated) caused a sustained pressor response lasting up to 3 weeks in conscious dogs.105 Lohmeier et al.106 electrically stimulated the carotid sinus directly and also showed reductions in arterial pressure for up to 3 weeks. Subsequently, carotid sinus stimulation has been performed in humans with hypertension. This requires placement of a battery-powered impulse generator at the infraclavicular space and surgical exposure of the carotid sinus for bilateral placement of electrodes around the carotid sinus adventitia. This avoids activation of the carotid sinus nerve containing the peripheral chemoreceptor afferents that are sympathoexcitatory in function. It also bypasses the baroreceptor transducer (mechanoreceptor), which is prone to adaptation when exposed to persistently high blood pressure.107, 108 Potential caveats to this approach include its relative invasive nature compared with the renal nerve ablation technique, the potential for peri-operative complications and that significant blood pressure lowering is not always evident.14

Intriguingly, deep brain stimulation of the ventrolateral periaqueductal grey matter area has also been shown to effectively reduce blood pressure in refractory hypertension.109, 110 Animal studies have identified the ventrolateral periaqueductal grey as a depressor area and shown that its stimulation elicits hypotension with peripheral vasodilatation, indicative of sympathetic withdrawal.111 Owing to its analgesic effects, this region is clinically targeted with chronic electrical stimulation in patients with chronic pain, however long-term blood pressure lowering can be independent of pain.110 Notably, in one particular patient, the normalisation of blood pressure with deep brain stimulation meant that all prescribed antihypertensive medications could be withdrawn and when the stimulator was turned off after 3 years, blood pressure remained low, suggesting that a central resetting of blood pressure control had occurred.110

New horizons in central regulation of SNA in hypertension

Recent progress in the elucidation of the central pathways contributing to the genesis of neurogenic hypertension may precipitate the next generation of therapeutic strategies for hypertensive patients. In this rapidly developing field, a multitude of putative mechanisms and potentially interconnected working hypotheses are emerging, which implicate functional alterations in several autonomic nuclei, neurotransmitters, neuromodulators, circulating factors and peripheral afferent inputs in neurogenic hypertension. A perspective on the potential actions and interactions of Ang II, inflammation and vascular dysfunction follows.

The brainstem is the principal regulatory site of central sympathetic outflow (Figure 3).112 Sympathetic pre-ganglionic neurones located in the intermediolateral cell column of the spinal cord receive strong excitatory drive from ‘pre-sympathetic’ motoneurones of the rostral ventrolateral medulla (RVLM)—a ‘vasomotor centre’ located within the medulla oblongata. This intrinsic excitatory drive from the RVLM may be modulated by neural inputs from supramedullary sites (for example, pontine and hypothalamic regions) and local chemical mediators. Oxidative stress in the brain (for example, at the RVLM and paraventricular nucleus) contributes to neurogenic hypertension in the SHR and stroke-prone SHR17, 113, 114 and renovascular hypertension115 (Figure 4). Increased reactive oxygen species (for example, superoxide) may directly activate or sensitise sympathetic neurones and also scavenge nitric oxide, which ordinarily acts to tonically restrain central sympathetic outflow.17 A major source of central reactive oxygen species generation in the hypertensive brain is the enzyme NADPH oxidase, which can be upregulated via activation of AT1-Rs.17, 79, 116 Notably, renal SNA is increased following upregulation of NADPH oxidase in the RVLM.117 While elevated local brain RAS has been implicated in the upregulation of NADPH,118 the observation that experimental renovascular hypertension (2-kidney 1-clip rat model) elicits increased oxidative stress at the RVLM and neurogenic hypertension suggests that elevated circulating Ang II may also be able to promote central pro-oxidant and hypertensive effects.114, 115 The central actions of circulating Ang II may occur by its actions at the circumventricular organs, which lack a blood–brain barrier and are rich in AT1-Rs.119

Figure 3

Central neural sites involved in the regulation of sympathetic outflow. CVLM, caudal ventrolateral medulla; CVO, circumventricular organs; IML, intermediolateral cell column; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla.

Figure 4

Putative contribution of angiotensin II (Ang II), inflammation and vascular dysfunction to elevated sympathetic neural outflow in hypertension. Elevated circulating Ang II activates AT1 receptors (AT1-R) at the circumventricular organs (CVO) and/or paraventricular nucleus (PVN) directly. The resultant signals cause microglial activation, increased reactive oxygen species (ROS) and cytokine generation in the PVN. Nicotinamide adenine dinucleotide phosphate-mediated increase in oxidative stress in autonomic nuclei within the medulla oblongata (for example, RVLM) also results as a consequence of Ang II activity. Increased oxidative stress and cytokine concentration at the PVN and RVLM augment sympathetic neuronal activity. Sympathetic neural outflow will also be facilitated by the upregulation of AT1-R on cerebral blood vessels due to elevated circulating Ang II levels. The associated local oxidative stress, inflammation and upregulation of junctional adhesion molecules (for example, junctional adhesion molecule-1) promote leukocyte adhesion within the brain microvasculature. The subsequently increased cerebral vascular tone could impair perfusion, cause local tissue hypoxia and evoke reflex sympathoexcitation (that is, Cushing response).

The interaction between the sympathetic nervous system and RAS is well established. It has been known since 1961 that increased circulating angiotensin stimulates the sympathetic nervous system,120 while renal sympathetic activation facilitates renin release from the juxtaglomerular apparatus. The sympathetic nervous system and RAS share a number of common pro-hypertensive actions (for example, increased vascular resistance and endothelial dysfunction) and both have been implicated in activating the immune system.60, 121, 122 Primary hypertension is associated with increased circulating concentration of several inflammatory molecules such as tumour necrosis factor alpha (TNFα), interleukin-6, C-reactive protein and adhesion molecules (for example, P-selectin and intercellular adhesion molecule-1), and vascular inflammation may contribute to the pathophysiology of hypertension.88, 123, 124 T-lymphocytes appear particularly critical for Ang II and deoxycorticosterone acetate-salt-induced hypertension and the concomitant vascular and kidney dysfunction.121, 122, 125 T-cell activation is increased by Ang II and leads to the production of pro-inflammatory cytokines.121 Intriguingly, anti-TNFα therapy (etanercept) has been shown to prevent Ang II-induced hypertension and vascular oxidative stress.121

The importance of peripheral vascular inflammation in hypertension is clear;123 however, the significance of inflammation within the microvasculature of the brainstem is also gaining increased recognition. Waki et al. (2007) demonstrated that inducing inflammation in the brainstem triggered hypertension in a normotensive rat.126 Specifically, increased expression of junctional adhesion molecule-1 in normotensive rats led to leukocyte adhesion in the microvasculature of the nucleus of the solitary tract (NTS) and hypertension. Importantly, junctional adhesion molecule-1 expression is significantly increased in the NTS of the SHR,126 and it is possible that the resulting leukocyte accumulation can cause platelet aggregation, cellular migration and infiltration and cytokine release. As indicated below, the latter could then directly or indirectly influence central autonomic control and raise blood pressure.126 Intriguingly, single-nucleotide polymorphisms in the junctional adhesion molecule-1 gene have recently been associated with blood pressure on a population-wide basis.127

Experimental elevations in Ang II have been shown to concomitantly raise blood pressure and cause central inflammation and oxidative stress.114 Specifically, Ang II-mediated hypertension is associated with increased brain levels of TNFα, nuclear factor κB and reactive oxygen species.128, 129 Studies by Raizada and colleagues130 suggest that Ang II infusion increases microglial cell and pro-inflammatory cytokine activation at the paraventricular nucleus, a region which receives descending neural inputs from the circumventricular organs. Notably, intracerebroventricular administration of the anti-inflammatory antibiotic minocycline inhibits the Ang II-mediated hypertension and the activation of microglia and cytokines. The effects of administering antibiotics anti-inflammatory properties, such as minocycline, on SNA in human hypertension remain to be determined. In fact, most studies to date that have examined the relationship between the sympathetic nervous system and immune system have focused on one arm of this interaction, that is, sympathetic modulation of immune cells in various lymphoid organs.60 However, accumulating evidence from animal investigations suggests that pro-inflammatory cytokines are powerful modulators of central neural circuits responsible for regulating sympathetic nerve discharge.131, 132, 133 Intracerebroventricular administration of interleukin-6 increases splenic SNA,134 while central administration of IL-1β increases adrenal, splenic and renal SNA.135 Furthermore, microinjection of interleukin-6 into the NTS decreases baroreflex sensitivity,131 while abnormal gene expression of specific inflammatory molecules have been identified in the NTS in the SHR (for example, chemokine CcI5), which may contribute to the hypertensive phenotype.136 Injection of TNFα into central sympathetic nuclei, such as the paraventricular nucleus and RVLM, increases SNA, blood pressure and heart rate in rats.137 Intravenous administration of TNFα elicits similar sympathetic and cardiovascular effects.137 This suggests that although blood-borne cytokines do not readily cross the blood–brain barrier, they still may trigger the central neurocircuitry-mediating alterations in sympathetic function possibly by acting via the circumventricular organ or a soluble mediator (for example, prostaglandins).137 In addition, the disruption of blood–brain barrier integrity in hypertension may permit infiltration of inflammatory cells into the brain parachyma, thus precipitating microglial cell activation and elevating pro-inflammatory cytokine levels at central sites, such as the paraventricular nucleus, consequently augmenting central sympathetic outflow.130

Aside from elevating central cytokine concentration, leukocyte accumulation within the brain microvasculature may precipitate neurogenic hypertension by raising cerebral vascular resistance, impairing perfusion and causing local tissue hypoxia (that is, Cushing response).16, 138 Neurons within the RVLM and spinal cord are known to be sensitive to hypoxia and can produce sympathoexcitation.139, 140 In humans, arterial compression at the ventrolateral medulla elevates muscle SNA141 and causes hypertension, which can be reversed by surgical decompression.142 Intriguingly, narrower lumens and thicker vessel walls are observed in the vertebral and basilar arteries of the pre-hypertensive SHR compared with normotensive rats.16, 143 Similarly, in humans with hypertension, the vertebral arteries also appear to be narrowed and thickened and their vascular resistance is highly correlated with arterial pressure levels.138 It has been proposed that triggering of SNA and systemic hypertension in response to inadequate cerebral blood flow is a protective mechanism to maintain perfusion.16, 46, 143, 144 This warrants further exploration as a potential mediator of human hypertension.


Accumulating evidence suggests that neurogenic hypertension is associated with a triangulation of raised Ang II, inflammation and vascular dysfunction/brain hypoperfusion, where each intercommunicates positively and reciprocally setting up a cascade of interrelated cardiovascular pathology, which becomes increasingly more difficult to treat with time (Figure 1). The resultant increase in central oxidative stress drives up central sympathetic outflow to the periphery, but in a vicious cycle this itself can potentiate increases in Ang II and consequently drive inflammation and vascular dysfunction.16, 17, 116, 121 Breaking into this vicious cycle could be the key to successful treatment of neurogenic hypertension. However, the success of a therapeutic strategy may vary as the pathophysiology of this dynamic condition changes. As more positive feedback loops between Ang II, inflammation and vascular dysfunction/brain hypoperfusion are established over time, the hypertension may become more resistant to treatment, and ultimately refractory. Tremendous advances have been made in the development of blood pressure lowering strategies, but the staggering prevalence of the condition, particularly resistant hypertension (20% of hypertension),95 highlights that we do not fully understand the aetiology of the disease, particularly in the later stages. Given the costs associated with the development of completely new strategies for targeting hypertension, the optimisation of present strategies is desirable.95 We propose that the overactivity of the sympathetic nervous system is both a major early prognostic indicator for hypertension and conspirator affecting the heart, vasculature, RAS and immune system. As sympathetic overactivity appears to be present before the hypertensive phenotype,7, 9, 28 its early antagonism should be considered a potential preventative measure before end organ damage becomes irreversible and hypertension becomes drug resistant. This implies that SNA should be measured in patients first presenting hypertensive trends and targeted to arrest the inevitable pathological cascade and ultimate disease progression. It is tempting to speculate that early targeting of an overactive sympathetic nervous system would reduce the likelihood of future progression to drug-resistant hypertension.


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The authors acknowledge the support of the British Heart Foundation and the National Institutes of Health (HL033610). JFR Paton is a recipient of a Royal Society Wolfson Research Merit Award.

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Correspondence to J P Fisher or J F R Paton.

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Fisher, J., Paton, J. The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens 26, 463–475 (2012).

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  • sympathetic nerve activity
  • neurogenic hypertension
  • immune-to-brain signalling

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