A role for benzamil-sensitive proteins of the central nervous system in the pathogenesis of salt-dependent hypertension

1. Although increasing evidence suggests that salt-sensitive hypertension is a disorder of the central nervous system (CNS), little is known about the critical proteins (e.g. ion channels or exchangers) that play a role in the pathogenesis of the disease. 2. Central pathways involved in the regulation of arterial pressure have been investigated. In addition, systems such as the renin-angiotensin-aldosterone axis, initially characterized in the periphery, are present in the CNS and seem to play a role in the regulation of arterial pressure. 3. Central administration of amiloride, or its analogue benzamil hydrochloride, has been shown to attenuate several forms of salt-sensitive hypertension. In addition, intracerebroventricular (i.c.v.) benzamil effectively blocks pressor responses to acute osmotic stimuli, such as i.c.v. hypertonic saline. Amiloride or its analogues have been shown to interact with the brain renin-angiotensin-aldosterone system (RAAS) and to effect the expression of endogenous ouabain-like compounds. Alterations of brain RAAS function and/or endobain expression could play a role in the interaction between amiloride compounds and arterial pressure. Peripheral treatments with benzamil, even at higher doses than those given centrally, have little or no effect on arterial pressure. These data provide strong evidence that benzamil-sensitive proteins (BSPs) of the CNS play a role in cardiovascular responsiveness to sodium. 4. Mineralocorticoids have been linked to human hypertension; many patients with essential hypertension respond well to pharmacological agents antagonizing the mineralocorticoid receptor and certain genetic forms of hypertension are caused by chronically elevated levels of aldosterone. The deoxycorticosterone acetate (DOCA)-salt model of hypertension is a benzamil-sensitive model that incorporates several factors implicated in the aetiology of human disease, including mineralocorticoid action and increased dietary sodium. The DOCA-salt model is ideal for investigating the role of BSPs in the pathogenesis of hypertension, because mineralocorticoid action has been shown to modulate the activity of at least one benzamil-sensitive protein, namely the epithelial sodium channel. 5. Characterizing the BSPs involved in the pathogenesis of hypertension may provide a novel clinical target. Further studies are necessary to determine which BSPs are involved and where, in the nervous system, they are located.     

Pathogenesis of hypertension in renal failure: role of the sympathetic nervous system and renal afferents

1. The kidney receives a dense innervation of sympathetic and sensory fibres and can be both a target of sympathetic activity and a source of signals that drive sympathetic tone. In the normal state, interactions between the kidney and sympathetic nervous system (SNS) serve to maintain blood pressure and glomerular filtration rate within tightly controlled levels. In renal failure, a defect in renal sodium excretory function leads to an abnormal pressure natriuresis relationship and activation of the renin-angiotensin-aldosterone system, contributing to the development of hypertension and progression of kidney disease. 2. Evidence now strongly indicates a role for the SNS in the pathogenesis of hypertension in renal failure. Hypertension occurs commonly and early in renal disease and is paralleled by increases in SNS activity, as indicated by increased muscle sympathetic nerve activity and circulating catecholamines. This appears to be driven by the diseased kidneys, because nephrectomy or denervation has been shown to correct blood pressure and SNS activity in human and animal studies. 3. Afferent signals from the kidney, detected by chemoreceptors and mechanoreceptors, feed directly into central nuclei of the SNS, including the hypothalamus and circumventricular organs, in addition to the stimulus provided by circulating and brain-derived angiotensin II. Therefore, the pathogenesis of hypertension in renal failure is complex and arises from the interaction of haemodynamic and neuroendocrine factors. 4. Increased SNS activity has significant implications with regard to increased risk of cardiovascular disease and is an important consideration in the treatment of renal failure.     

Sodium sensitivity and sympathetic nervous system in hypertension induced by long-term nitric oxide blockade in rats

1. Pharmacological inhibition of nitric oxide (NO) synthesis is known to produce acute and chronic hypertension in many animal species, but the underlying mechanisms mediating the hypertension are not completely understood. In particular, the pathogenetic roles of sodium sensitivity and the sympathetic nervous system in this model of hypertension are controversial. The present study was designed to test the hypothesis that long-term administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to male Sprague-Dawley rats would produce a sodium-sensitive hypertension and that the enhanced activity of the sympathetic nervous system in this type of hypertension contributes to the sodium sensitivity. 2. NG-Nitro-L-arginine methyl ester was added to drinking fluid for 8 weeks at a concentration of 16 mg/dL. Rats received tap water for the first 4 weeks of the study and were then divided into two groups and placed on either a normal or high sodium intake (ingestion of either tap water or 0.9% NaCl, respectively). Awake systolic blood pressure was measured by the tail-cuff method every week. Urinary excretion rates of the stable NO metabolites and catecholamines during NO synthesis inhibition were examined. 3. Long-term administration of L-NAME produced a marked and sustained elevation in arterial pressure without altering urine flow, or sodium excretion rate. NG-Nitro-L-arginine methyl ester-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites NO2- and NO3- and was aggravated when rats drank 0.9% NaCl in place of tap water. Urinary excretion of adrenaline and noradrenaline, but not dopamine, in L-NAME-treated rats increased significantly within the first week of the study compared with control rats. L-Arginine (2 g/dL in drinking fluid) completely reversed the elevation of arterial pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment by 3 weeks of concomitant administration. 4. These results suggest that long-term inhibition of NO synthesis produces a sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.     

Neural control of the renal vasculature in angiotensin II-induced hypertension

1. Chronic administration of angiotensin (Ang) II causes an increase in blood pressure via a multitude of actions, including direct vasoconstriction, hypertrophy and increased sympathetic nerve activity. In the present study, we assessed whether the hypertension resulting from chronic Ang II alters the ability of the renal vasculature to respond to sympathetic activity. 2. Angiotensin II was administered for 7 weeks via an osmotic minipump at a dose of 50 ng/kg per min, i.v., to a group of six rabbits. Blood pressure, measured at 0, 1, 2 and 6 weeks after insertion of the pump, increased from 76 +/- 2 to 104 +/- 6 mmHg at the end of 6 weeks, without any significant change in heart rate. The blood pressure in the control group remained constant at 76 +/- 2 mmHg. 3. After 7 weeks, rabbits were anaesthetized and the renal nerves were stimulated at 0.5, 1, 1.5, 2, 3, 5 or 8 Hz for 3 min at their supramaximal voltage (5.5 +/- 1.0 V in the normotensive group and 6.5 +/- 1.5 V in the hypertensive group) while the renal blood flow (RBF) response was recorded. Under anaesthesia, there was no difference in mean arterial pressure between the normotensive and hypertensive animals (77 +/- 2 and 80 +/- 7 mmHg, respectively). The resting RBF under these conditions was not significantly different in the hypertensive group (30 +/- 4 vs 26 +/- 5 mL/min in the normotensive vs hypertensive group, respectively). 4. Stimulation at increasing frequencies was associated with increasing reductions in RBF (e.g. 36 +/- 8% at 2 Hz in normotensive rabbits and 48 +/- 7% at 2 Hz in hypertensive rabbits). However, there were no significant differences between RBF responses in normotensive and hypertensive rabbits. 5. We conclude that hypertension associated with chronic Ang II administration does not alter the response in RBF to electrical stimulation of the nerves.     

Role of the epithelial sodium channel in salt-sensitive hypertension

The epithelial sodium channel (ENaC) is a heteromeric channel composed of three similar but distinct subunits, α, β and γ. This channel is an end-effector in the rennin-angiotensin-aldosterone system and resides in the apical plasma membrane of the renal cortical collecting ducts, where reabsorption of Na(+) through ENaC is the final renal adjustment step for Na(+) balance. Because of its regulation and function, the ENaC plays a critical role in modulating the homeostasis of Na(+) and thus chronic blood pressure. The development of most forms of hypertension requires an increase in Na(+) and water retention. The role of ENaC in developing high blood pressure is exemplified in the gain-of-function mutations in ENaC that cause Liddle's syndrome, a severe but rare form of inheritable hypertension. The evidence obtained from studies using animal models and in human patients indicates that improper Na(+) retention by the kidney elevates blood pressure and induces salt-sensitive hypertension.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Effects of the dopaminergic agonist cianergoline on blood pressure,the renin-angiotensin-aldosterone axis and the sympathetic nervous system in patients with essential hypertension

Summary Cianergoline is a new dopaminergic agonist with a predominant cardiovascular action. Its effects on blood pressure, the renin-angiotensin-aldosterone axis, the sympathetic nervous system and lipid metabolism were assessed in 20 patients with benign essential hypertension. Cianergoline given in increasing doses for 4 weeks (maximum daily dose 12±2 mg (SD)) and placebo both caused a slight decrease in arterial pressure, (from 159/104 to 152/98 mm Hg and from 154/104 to 149/103 mm, respectively; difference not significant). Supine and upright plasma renin activity, plasma aldosterone, norepinephrine, epinephrine and dopamine levels, urinary catecholamine excretion rates as well as serum prolactin, low and high density cholesterol and triglyceride concentrations were not changed after cianergoline or placebo. Total serum cholesterol and triglyceride levels decreased significantly after placebo, but were unchanged after cianergoline. 3 out of 10 patients in the cianergoline group complained of nausea. The findings indicate that the new dopaminergic agonist cianergoline exerts only a mild blood pressure lowering effect in patients with essential hypertension and does not modify the release of prolactin, lipid metabolism or the basal activity or postural responsiveness of the renin-angiotensin-aldosterone axis and of the sympathetic nervous system.     

INTERACTIONS BETWEEN ANGIOTENSIN II AND THE SYMPATHETIC NERVOUS SYSTEM IN THE THE LONG-TERM CONTROL OF ARTERIAL PRESSURE

1. The role of the renin-angiotensin system in long-term control of sympathetic activity and arterial pressure is reviewed. 2. There is evidence that favours a necessary role for the sympathetic nervous system in long-term arterial pressure regulation. First, appropriate changes in sympathetic activity appear to be produced in response to chronic changes in blood volume or blood pressure. Second, prevention of the normal homeostatic decrease in sympathetic activity in response to an increase in sodium intake produces hypertension. 3. Long-term changes in sympathetic activity cannot be mediated by the baroreceptor reflex, because it adapts to sustained changes in pressure. Therefore, an hypothesis is presented that evokes a key role for angiotensin II (AngII) in determining the chronic level of sympathetic activity. The key feature of this model is that the role of AngII is non-adaptive: chronic changes in extracellular fluid volume produce sustained reciprocal changes in AngII, and long-term increases in AngII produce sustained increases in sympathetic activity. 4. Evidence is reviewed that suggests that a lack of the normal suppression in AngII and/or sympathetic activity in response to an increase in sodium intake produces salt-sensitive hypertension.     

Gender differences in sympathetic nervous system regulation

1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho-adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented. 2. The central control of sympatho-adrenal function is different in females and responses vary during the oestral and menstrual cycles. Pathways regulating the SNS appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli in females compared with males. 3. Gender differences in arterial baroreflex sensitivity suggest that females may have a greater baroreflex sensitivity, such that alterations in blood pressure are more efficiently controlled than in males. Cardiopulmonary reflex inhibition of sympathetic nerve activity is greater in females, possibly resulting in a greater renal excretory function. 4. An attenuated sensitivity to adrenergic nerve stimulation, but not to noradrenaline (NA), suggests that gender differences in noradrenergic neurotransmission may protect females against sympathetic hyperactivity. Gender differences in the regulation of NA release via presynaptic alpha 2-adrenoceptors, the vasoconstrictor response to the cotransmitter neuropeptide Y and the clearance of catecholamines are consistent with this hypothesis. 5. Similarly, attenuated stress-induced increases in plasma catecholamines in women suggest that females are less sensitive and/or less responsive to adrenal medullary activation. This is supported by findings of gender differences in adrenal medullary catecholamine content, release and degradation. 6. We conclude that there is strong evidence that supports the hypothesis that, in females, the regulation of the SNS is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented.     

Reactive oxygen species and the central nervous system in salt-sensitive hypertension: possible relationship with obesity-induced hypertension

1. There are multiple and complex mechanisms of salt-induced hypertension; however, central sympathoexcitation plays an important role. In addition, the production of reactive oxygen species (ROS) is increased in salt-sensitive hypertensive humans and animals. Thus, we hypothesized that brain ROS overproduction may increase blood pressure (BP) by central sympathostimulation. 2. Recently, we demonstrated that ROS levels were elevated in the hypothalamus of salt-sensitive hypertensive animals. Moreover, intracerebroventricular anti-oxidants suppressed BP and renal sympathetic nerve activity more in salt-sensitive than non-salt-sensitive hypertensive rats. Thus, brain ROS overproduction increased BP through central sympathoexcitation in salt-sensitive hypertension. 3. Salt sensitivity of BP is enhanced in obesity and metabolic syndrome. Interestingly, it is also suggested that, in obesity-induced hypertension models, increases in BP are caused by brain ROS-induced central sympathoexcitation. 4. Recent studies suggest that increased ROS production in the brain and central sympathoexcitation may share a common pathway that increases BP in both salt- and obesity-induced hypertension.     

Role of the medial amygdala in mediating responses to aversive stimuli leading to hypertension

1. The amygdala is a part of the limbic system that is associated with mediating the emotional and hormonal response to stress and although studies have focused on the central amygdala, there is increasing evidence that the medial amygdala is a major region activated by stressful stimuli. 2. Neuroanatomical studies in rats have shown greater activation in the medial amygdala following aversive stresses compared with other brain regions, including the central amygdala. Inhibition of the medial, but not the central, amygdala attenuates the development of hypertension in spontaneously hypertensive rats. 3. Schlager (BPH/2J) mice have a neurogenic form of hypertension that is most evident during the night when the mice are most active and is closely correlated with the level of activation of neurons in the medial, but not the central, amygdala. Pressor responses to aversive stimuli, such as restraint and cage‐switch stress, are much greater in BPH/2J hypertensive than BPN/3J normotensive mice, but appetitive arousal produces normal increases in blood pressure. The degree of activation in the medial amygdala in BPH/2J hypertensive mice during aversive stress closely correlates with the increased blood pressure. 4. Thus, the inappropriate activation of the medial amygdala evoked by specific fear or aversive stimuli may be key to the neurogenic hypertension.     

Angiotensin II receptor blockers for the treatment of hypertension

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.     

The role of the sympathetic nervous system in controlling bone metabolism

Experimental studies have generally shown that increased sympathetic nervous activity causes bone loss via an increase in bone resorption and a decrease in bone formation. Increased bone resorption is based on the stimulation of both osteoclast formation and osteoclast activity. These effects are associated with β2-adrenergic activity towards both osteoblastic and osteoclastic cells. Decreased bone formation is based on the inhibition of osteoblastic activity through β2-adrenergic receptors on osteoblasts. Such findings indicate that β-blockers may be effective against osteoporosis, in which case there is increased sympathetic activity. In fact, in a population-based, case-control study, the current use of β-blockers has been demonstrated to be associated with a reduced risk of fractures. These clinical studies suggest that pharmacological blockade of the β-adrenergic system is beneficial to the human skeleton. In another prospective study, however, no association between β-blocker use and fracture risk was shown in perimenopausal and older women. To confirm this important new therapeutic avenue to prevent bone loss, the relationship between the pharmacological effectiveness of β-blockers and the pathogenesis of osteoporosis must be explored in detail.     

Role of mineralocorticoid action in the brain in salt-sensitive hypertension

1. The mechanisms by which excessive salt causes hypertension involve more than retention of sodium and water by the kidneys and are far from clear. Mineralocorticoids act centrally to increase salt appetite, sympathetic drive and vasopressin release, resulting in hypertension that is prevented by the central infusion of mineralocorticoid receptor (MR) antagonists. The MR has similar affinity for aldosterone and the glucocorticoids corticosterone or cortisol. Specificity is conferred in transport epithelia by the colocalization of the MR with 11β-hydroxysteroid dehydrogenase Type 2. Coexpression also occurs in some neurons, notably those of the nucleus tractus solitarius that are activated by sodium depletion and aldosterone and mediate salt-seeking behaviour. 2. The salt-induced hypertension of the Dahl salt-sensitive rat is mitigated by the central infusion of a mineralocorticoid antagonist even though circulating aldosterone is normal or reduced in salt-sensitive (SS). Contrary to reports that salt appetite in the Dahl salt-sensitive rat is depressed, we found that it is increased compared with that in Spraque-Dawley rats. 3. Extra-adrenal aldosterone synthesis in the brain occurs in minute amounts that could only be relevant locally. Expression of aldosterone synthase mRNA and aldosterone concentrations in the brain of Dahl salt-sensitive rats are increased compared with Spraque-Dawley rats. The central infusion of inhibitors of aldosterone synthesis lowers salt-induced hypertension in the Dahl salt-sensitive rat, suggesting a role for excessive Dahl salt-sensitive synthesis in the brain. Brain MR, particularly those in the paraventricular nuclei, regulate inflammatory processes that are exacerbated by sodium and lead to cardiovascular dysfunction.     

Eprosartan modulates the reflex activation of the sympathetic nervous system in sodium restricted healthy humans

AIMS

To test the hypothesis that eprosartan inhibits both nonbaroreflex and arterial baroreflex mediated activation of the sympathetic nervous system, assessed by renal tubular function, systemic haemodynamics and vasoactive hormones, in sodium restricted healthy humans.

METHODS

The effect of eprosartan on urinary sodium, lithium and water excretion, heart rate (HR), blood pressure and vasoactive hormones was measured before, during and after a cold pressor test (CPT) and sodium nitroprusside (SNP) infusion in a randomized, placebo controlled, double-blind, crossover study in 17 healthy subjects. Glomerular filtration rate and renal tubular function were determined by a continuous infusion clearance technique and vasoactive hormones by radioimmunoassays.

RESULTS

Eprosartan attenuated the impact of the CPT on HR (mean difference from placebo (95% confidence interval) (3.9 (0.7, 7.0) min⁻¹) and mean arterial pressure (MAP) (4.7 (0.3, 9.2) mmHg), but no effect of eprosartan was observed on the impact of the CPT on renal tubular function. During a SNP induced reduction in MAP of 10 mmHg eprosartan decreased fractional excretions of sodium (0.46 (0.14, 0.76)%) and lithium (5.1 (2.5, 7.6)%) and tended to increase HR (4.1 (−0.26, 8.4) min⁻¹) and plasma concentrations of norepinephrine (33.8 (−5.8, 72.1) pg ml⁻¹).

CONCLUSIONS

These findings suggest that during mild sodium restriction eprosartan has a small inhibitory effect on nonbaroreflex mediated activation of the sympathetic nervous system. During arterial baroreflex mediated activation of the sympathetic nervous system this effect is, however, completely overruled by an increased sensitivity of the arterial baroreflex.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• A sympatho-inhibitory effect of ACE-inhibitors and AT₁ receptor antagonists has been widely demonstrated in animal models, but in humans this effect tends only to be present during chronic treatment in conditions with pre-existing high levels of sympathetic activity.
• Sodium restriction increases renal sympathetic nerve activity and the activity of the renin-angiotensin system and may be a favourable condition to demonstrate sympatho-inhibition as a short-term effect of the AT₁ receptor antagonist eprosartan in healthy humans.

WHAT THIS STUDY ADDS

• Results from our study indicate that during sodium restriction eprosartan has a small inhibitory effect on nonbaroreflex mediated activation of the sympathetic nervous system.
• During arterial baroreflex mediated activation of the sympathetic nervous system this effect is, however, completely overruled by an increased sensitivity of the arterial baroreflex.

     

Area postrema and sympathetic nervous system effects of vasopressin and angiotensin II

1. Precise control over the cardiovascular system requires the integration of both neural and humoral signals related to blood volume and blood pressure. Humoral signals interact with neural systems, modulating their control over the efferent mechanisms that ultimately determine the level of pressure and volume. 2. Peptide hormones such as angiotensin (Ang)II and arginine vasopressin (AVP) act through circumventricular organs (CVO) to influence cardiovascular regulation. 3. The area postrema (AP), a CVO in the brainstem, mediates at least some of the central actions of these peptides. Vasopressin appears to act in the AP to cause sympathoinhibition and a shift in baroreflex control of the sympathetic nervous system (SNS) to lower pressures. These effects of AVP and the AP appear to be mediated by alpha2-adrenoceptor and glutamatergic mechanisms in the nucleus tractus solitarius. 4. In contrast to AVP AngII has effects in the AP to blunt baroreflex control of heart rate and cause sympathoexcitation. The effects of chronic AngII to increase activity of the SNS may be due to AP-dependent activation of neurons in the rostral ventrolateral medulla.     

Exercise training and sympathetic nervous system activity: evidence for physical activity dependent neural plasticity

1. It has been generally accepted that regular physical activity is associated with beneficial effects on the cardiovascular system. In fact, the idea that exercise maintains cardiovascular health is evident by the direct links between a sedentary lifestyle and the risk of cardiovascular and other disease states. 2. Cardiovascular diseases, such as hypertension and heart failure, are often associated with sympathetic nervous system (SNS) overactivity. Conversely, exercise has been shown to reduce hypertension and decrease elevated SNS activity. In addition, there is evidence that exercise may reduce resting blood pressure and sympathetic outflow in normal individuals. 3. Although somewhat controversial in humans, evidence from animal studies also indicates that exercise training reduces baroreflex-mediated and other forms of sympathoexcitation in normal individuals. Collectively, these data are consistent with the hypothesis that physical activity may decrease, and physical inactivity may increase, the incidence of cardiovascular disease via alterations in SNS activity. Despite the important clinical implications of this possibility, the mechanisms by which exercise alters control of SNS activity remain to be fully elucidated. 4. Recent evidence suggests that central nervous system (CNS) plasticity occurs under a variety of conditions, including varying levels of physical activity. The purpose of the present brief review is to provide evidence that changes within the CNS contribute importantly to altered regulation of the SNS observed following exercise training. The primary hypothesis is that physical activity versus inactivity produces plasticity within neural networks that regulate SNS activity. This hypothesis is supported by published and preliminary data that suggest that exercise training may reduce sympathoexcitation by reducing activation of neurons within cardiovascular regions of the brain. These mechanisms are likely to be important in disease states of sympathetic overactivity and in normal healthy individuals whose risk of cardiovascular disease is reduced by leading an active versus sedentary lifestyle.     

Mechanisms of sympathetic activation in heart failure

1. Heart Failure (HF) is a serious, debilitating condition with poor survival rates and an increasing level of prevalence. A characteristic of HF is a compensatory neurohumoral activation that increases with the severity of the condition. 2. The increase in sympathetic activity may be beneficial initially, providing inotropic support to the heart and peripheral vasoconstriction, but in the longer term it promotes disease progression and worsens prognosis. This is particularly true for the increase in cardiac sympathetic nerve activity, as shown by the strong inverse correlation between cardiac noradrenaline spillover and prognosis and by the beneficial effect of beta-adrenoceptor antagonists. 3. Possible causes for the raised level of sympathetic activity in HF include altered neural reflexes, such as those from baroreceptors and chemoreceptors, raised levels of hormones, such as angiotensin II, acting on circumventricular organs, and changes in central mechanisms that may amplify the responses to these inputs. 4. The control of sympathetic activity to different organs is regionally heterogeneous, as demonstrated by a lack of concordance in burst patterns, different responses to reflexes, opposite responses of cardiac and renal sympathetic nerves to central angiotensin and organ-specific increases in sympathetic activity in HF. These observations indicate that, in HF, it is essential to study the factors causing sympathetic activation in individual outflows, in particular those that powerfully, and perhaps preferentially, increase cardiac sympathetic nerve activity.