Sympathetic Outflow In Heart Failure Research Articles

Exercise training upregulates Nrf2 protein in the rostral ventrolateral medulla of mice with heart failure.

Chronic heart failure (CHF) is associated with global oxidative stress, which contributes to sympathoexcitation. Increased reactive oxygen species in the brain accumulate within neurons and lead to enhanced neuronal excitability. Exercise training (ExT) is associated with a reduction of oxidative stress by upregulation of antioxidant enzymes. The link between ExT and antioxidant enzyme expression in the brain of animals with CHF is not clear. We hypothesized that ExT enhances transcription and translation of the nuclear factor erythroid 2-related factor 2 (Nrf2) gene, a master transcription factor that modulates antioxidant enzyme gene expression, in the rostral ventrolateral medulla (RVLM) of mice with CHF. Mice were divided into the following groups: Sham sedentary (Sham-Sed), Sham-ExT, CHF-Sed, and CHF-ExT. After 8 wk of ExT, we measured Nrf2 and NAD(P)H dehydrogenase [quinone] 1 (NQO-1) message and protein expression along with maximal exercise tolerance and urinary norepinephrine (NE) excretion. We found that Nrf2 and NQO-1 mRNA and protein expression in the RVLM were lower in CHF-Sed mice compared with Sham-Sed. ExT attenuated the CHF-induced reduction of Nrf2 and NQO-1 mRNA and protein expression in the RVLM. NE excretion was higher in CHF-Sed mice compared with Sham-Sed (666.8 ± 79.3 ng/24 h, n = 6 vs. 397.8 ± 43.7 ng/24 h, P = 0.04). CHF-ExT mice exhibited reduced urinary NE excretion compared with CHF-Sed (360.7 ± 41.7 ng, n = 4 vs. 666.8 ± 79.3 ng, n = 6; P = 0.03). We conclude that ExT-induced upregulation of Nrf2 in the RVLM contributes to the beneficial effects of ExT on sympathetic function in the heart failure state.NEW & NOTEWORTHY This study provide evidence for an important role for exercise training in the modulation of antioxidant enzyme production in the rostral ventrolateral medulla (RVLM) in the heart failure state. We show here a correlation between exercise training and the expression of the antioxidant transcription factor Nrf2 in the RVLM. Exercise training reduced sympathetic function (norepinephrine excretion) and upregulated both Nrf2 and the antioxidant enzyme NQO-1. We conclude that Nrf2 in the RVLM may be an important target for controlling sympathetic outflow in heart failure.

Pharmacological cardiac sympathetic afferent denervation in pacing‐induced heart failure

Chronic sympathoexcitation is a hallmark of congestive heart failure. Enhanced input from the cardiac sympathetic afferent reflex (CSAR) appears to be a major contributor to augmented central sympathetic outflow in heart failure (HF) in rats (Myocardial ischemia model. Wang et al., Hypertension, 2014) and dogs (Rapid ventricular pacing model. Wang and Zucker, Am. J. Physiol., 1996). Transient receptor potential vanilloid 1 (TRPV1) expressing cardiac afferent fibers are responsible for CSAR activation, since systemic (Zahner et al., J. Physiol., 2003) and epicardial (Wang et al., Hypertension, 2014) administration of resiniferatoxin (RTX), an ultra‐potent analog of capsaicin that degenerates TRPV1‐expressing neurons, can almost completely abolish CSAR activation in rats. We tested whether epicardial application of RTX degenerates cardiac sympathetic TRPV1‐expressing neurons therefore reducing CSAR reactivity, in canines with pacing‐induced HF. In control studies, stimulation of left ventricular afferents containing TRPV1 via topical application of capsaicin (2 mg/ml) caused a pressor response and tachycardia (Δ=+15 mmHg, +44bpm). These responses were abolished by acute topical application of RTX (50 μg/mL). Experiments were repeated 9 weeks following RTX treatment and the subsequent induction of HF via rapid ventricular pacing. RTX pretreatment abolished the responses to capsaicin, whereas CSAR was preserved in HF if no RTX pretreatment was performed. TRPV1 expressing neuronal degeneration was evaluated through immunofluorescence histology (IFH) in left ventricle tissue samples, with triple labeling for DAPI (nuclei marker), PGP9.5 (nerve terminal marker,) and TRPV1 receptors. RTX treated tissue samples showed considerably lower TRPV1 positive staining when compared to non‐treated samples. The present study validates RTX as a potential therapeutic method to block excessive CSAR activation in pacing‐induced heart failure dogs, therefore expanding pharmacotherapy options for heart failureSupport or Funding InformationNIH HL55473 and HL126706

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT₁R) in the brain stem leads to sympathoexcitation due to neuronal AT₁R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT₁R are only weakly expressed in astrocytes. We hypothesized that AT₁R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT₁R, we investigated whether AT₁R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT₁R knockout (GFAP/AT₁RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/AT₁RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT₁RKO mice than in control mice. Prognosis was significantly improved in GFAP/AT₁RKO-MI mice compared with control-MI mice. Our findings indicated that AT₁R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT₁R, AT₁R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.

Sympathetic Nervous System Moves Toward Center Stage in Cardiovascular Medicine

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN

Exercise training (ExT) normalizes the increased sympathetic outflow in chronic heart failure (HF). The underlying mechanisms are not clearly understood. We hypothesized that ExT normalized the blunted central component of the baroreflex control of renal sympathetic nerve activity (RSNA) in HF. Four groups of rats [sham operated (sham)-sedentary (Sed), sham-ExT, HF-Sed, and HF-ExT] were used. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In anesthetized rats, the decrease in RSNA in response to aortic depressor nerve stimulation (5-40 Hz) in the HF-Sed group was significantly lower than that in the sham-Sed group (-37 ± 7% vs. -63 ± 8% at 40 Hz, P < 0.05). In the HF-ExT group, responses in RSNA, mean arterial pressure (MAP), and heart rate (HR) were not significantly different from those in the sham-Sed or sham-ExT groups. ExT normalized blunted RSNA, MAP, and HR responses to bicuculline microinjections into the paraventricular nucleus (PVN) in rats with HF. Activation of the PVN by blockade of GABA receptors with bicuculline in normal control rats blunted the centrally component of the baroreflex arc. GABAA-α1 and -β1 receptor protein expression were significantly lower (by 48% and 30%) in the HF-Sed group, but ExT normalized this difference between the HF and sham groups. These data suggest that one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of central integrative mechanisms, perhaps via improving the inhibitory GABAergic mechanism within the PVN, on the baroreflex arc.

Changes in GABAergic inputs in the paraventricular nucleus maintain sympathetic vasomotor tone in chronic heart failure

The paraventricular nucleus (PVN) of the hypothalamus is an important region of the brain involved in the regulation of sympathetic vasomotor tone. Accumulating evidence supports the idea that a change in hypothalamic γ-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory inputs contribute to the exacerbated sympathetic drive in chronic heart failure (HF). The purpose of this study was to determine whether a possible imbalance between glutamatergic and GABAergic inputs to the PVN contributes to increased sympathetic outflow in HF in two different sympathetic territories. Renal (RSNA) and splanchnic sympathetic nerve activity (SSNA), mean arterial blood pressure (MAP) and heart rate were recorded from urethane-anesthetized HF or sham rats. The NMDA-glutamate and GABA-A receptor densities within the PVN were quantified in HF and sham rats by autoradiography. Bilateral microinjection of kynurenic acid (4nmol) into the PVN decreased MAP and RSNA and SSNA in HF but not in sham rats. Furthermore, in response to GABA-A blockade in the PVN by bicuculline (400 pmol), hypertension and SSNA were reduced in HF compared to sham. The quantification of ionotropic NMDA receptors and GABA-A receptors in the PVN showed a significant reduction of GABA-A in HF rats; however, the NMDA density in the PVN did not differ between groups. Thus, this study provides evidence that the sympathoexcitation is maintained by an imbalance between GABAergic and glutamatergic inputs in the PVN in HF. The reduced GABAergic input results in relatively augmented glutamatergic actions in the PVN of HF rats.

Exercise training normalizes enhanced sympathetic activation from the paraventricular nucleus in chronic heart failure: role of angiotensin II

Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the underlying mechanisms are not known. We hypothesized ExT would normalize the augmented activation of the paraventricular nucleus (PVN) via an angiotensinergic mechanism during HF. Four groups of rats used were the following: 1) sham-sedentary (Sed); 2) sham-ExT; 3) HF-Sed, and 4) HF-ExT. HF was induced by left coronary artery ligation. Four weeks after surgery, 3 wk of treadmill running was performed in ExT groups. The number of FosB-positive cells in the PVN was significantly increased in HF-Sed group compared with the sham-Sed group. ExT normalized (negated) this increase in the rats with HF. In anesthetized condition, the increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in response to microinjection of angiotensin (ANG) II (50∼200 pmol) in the PVN of HF-Sed group were significantly greater than of the sham-Sed group. In the HF-ExT group the responses to microinjection of ANG II were not different from sham-Sed or sham-ExT groups. Blockade of ANG II type 1 (AT(1)) receptors with losartan in the PVN produced a significantly greater decrease in RSNA, MAP, and HR in HF-Sed group compared with sham-Sed group. ExT prevented the difference between HF and sham groups. AT(1) receptor protein expression was increased 50% in HF-Sed group compared with sham-Sed group. In the HF-ExT group, AT(1) receptor protein expression was not significantly different from sham-Sed or sham-ExT groups. In conclusion, one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of angiotensinergic mechanisms within the PVN.

Central neural control of sympathetic nerve activity in heart failure following exercise training

Typical characteristics of chronic congestive heart failure (HF) are increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation. These abnormalities lead to an increased risk of mortality, particularly in the late stage of chronic HF. Recent evidence suggests that central nervous system (CNS) mechanisms may be important in these abnormalities during HF. Exercise training (ExT) has emerged as a nonpharmacological therapeutic strategy substitute with significant benefit to patients with HF. Regular ExT improves functional capacity as well as quality of life and perhaps prognosis in chronic HF patients. The mechanism(s) by which ExT improves the clinical status of HF patients is not fully known. Recent studies have provided convincing evidence that ExT significantly alleviates the increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation in HF. This review describes and highlights the studies that examine various central pathways involved in autonomic outflow that are altered in HF and are improved following ExT. The increased sympathoexcitation is due to an imbalance between inhibitory and excitatory mechanisms within specific areas in the CNS such as the paraventricular nucleus (PVN) of the hypothalamus. Studies summarized here have revealed that ExT improves the altered inhibitory pathway utilizing nitric oxide and GABA mechanisms within the PVN in HF. ExT alleviates elevated sympathetic outflow in HF through normalization of excitatory glutamatergic and angiotensinergic mechanisms within the PVN. ExT also improves volume reflex function and thus fluid balance in HF. Preliminary observations also suggest that ExT induces structural neuroplasticity in the brain of rats with HF. We conclude that improvement of the enhanced CNS-mediated increase in sympathetic outflow, specifically to the kidneys related to fluid balance, contributes to the beneficial effects of ExT in HF.

Inflammation and Neurogenic Hypertension

See related article, pages 263–270 The brain renin–angiotensin system (RAS) plays a critical role in maintaining blood pressure regulation and volume homeostasis. Components of the RAS, including angiotensinogen, renin, angiotensin (Ang)-converting enzymes, and Ang receptors, are expressed in various nuclei located between the anteroventral region of the third ventricle (AV3V) and the brain stem.1,2 Accordingly, formation of the various Ang peptides, notably Ang II and Ang(1-7) can take place in the brain, independently of the endocrine RAS, and participate in the regulation of water intake, salt appetite, cardiac baroreflex and autonomic functions. Upregulation of Ang II type 1 (AT1) receptors in these nuclei has been shown to reduce baroreflex sensitivity and increase sympathetic tone, thus contributing to the development and maintenance of hypertension and heart failure, ultimately leading to end-organ damage.3 On the other hand, treatment with ACE inhibitors and Ang receptor blockers can prevent RAS overactivity and restore a normal cardiovascular function. In addition to Ang II generated in the brain, blood-borne Ang peptides can also enter the central nervous system via the circumventricular organs (CVOs) and contribute to the regulation of blood pressure and volume homeostasis.4 The CVOs are represented by the OVLT (organum vasculosum of the lamina terminalis), the subfornical organ (SFO), the median eminence and the neurohypophysis, …

Brain Perivascular Macrophages and Central Sympathetic Activation After Myocardial Infarction

Heart failure (HF) is characterized by an enhanced neurohumoral drive, which is currently the major therapeutic target.1,2 Recent studies to explore the mechanisms involved in central sympathetic outflow in HF have revealed several candidate mechanisms, such as reduced NO activity, increased oxidative stress, and activation of the brain angiotensin-aldosterone system.1–3 Interactions between these complex factors may also induce transcription factor alterations and increase sympathetic nervous system activity. The article in the present issue of Hypertension by Yu et al4 describes a very interesting concept that peripheral macrophages mediate central sympathetic activation after myocardial infarction (MI). Kang et al5 suggested previously that cyclooxygenase-2 (COX-2) and the subsequently generated prostaglandin E2 (PGE2), which crosses the blood-brain barrier, increase sympathetic activity. In this study, Yu et al4 injected clodronate liposomes intracerebroventricularly into rats 24 hours after inducing acute MI to selectively eliminate MI-induced brain perivascular macrophages. Because the effects of the clodronate liposomes peak ≈1 week after injection, COX-2 immunoreactivity in perivascular macrophages and COX-2 mRNA and protein levels were evaluated 1 week later. Perivascular macrophages in the blood-brain barrier were successfully eliminated in rats treated with clodronate liposomes; as a result, COX-2 immunoreactivity was not observed, and …

Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure.

Angiotensin type 1 receptors (AT(1)Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which AT(1)Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of AT(1)R regulation in the setting of chronic heart failure (CHF). There is now good evidence that AT(1)R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in AT(1)R expression and transcription factor activation can be blocked by the AT(1)R antagonist losartan, a positive feedback mechanism of AT(1)R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of AT(1)R expression by altering the balance between the octapeptide ANG II and ANG- (1-7). Finally, exercise training reduces both central oxidative stress and AT(1)R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter AT(1)R expression in CHF.

Simvastatin Inhibits Central Sympathetic Outflow in Heart Failure by a Nitric-Oxide Synthase Mechanism

Our previous study demonstrated that oral treatment with simvastatin (SIM) suppressed renal sympathetic nerve activity (RSNA) in the rabbits with chronic heart failure (CHF). The purpose of this experiment was to determine the effects of direct application of SIM to the central nervous system on RSNA and its relevant mechanisms. Experiments were carried out on 21 male New Zealand White rabbits with pacing-induced CHF. The CHF rabbits received infusion of vehicle, SIM, or SIM + N(omega)-nitro-L-arginine methyl ester into the lateral cerebral ventricle via osmotic minipump for 7 days. We found that 1) in CHF rabbits, intracerebroventricular infusion of SIM significantly suppressed basal RSNA (1st day 69.5 +/- 8.9% maximum; 7th day 26.0 +/- 6.0% maximum; P < 0.05, n = 7) and enhanced arterial baroreflex function starting from the 2nd day and lasting through the following 5 days; 2) statin treatment significantly up-regulated neuronal nitric-oxide synthase (nNOS) protein expression in the rostral ventrolateral medulla (RVLM) (control, n = 6, 0.12 +/- 0.04; SIM-treated, n = 7, 0.31 +/- 0.05. P < 0.05); 3) in CATH.a neurons, incubation with SIM significantly up-regulated the nNOS mRNA expression, which was blocked by coincubation with mevalonate, farnesyl-pyrophosphate, or geranylgeranyl-pyrophosphate; and 4) incubation with Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] significantly up-regulated nNOS mRNA expression in these neurons. These results suggest that central treatment with SIM decreased sympathetic outflow in CHF rabbits via up-regulation of nNOS expression in RVLM, which may be due to the inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and a decrease in Rho kinase by SIM.

Exercise training normalizes enhanced glutamate-mediated sympathetic activation from the PVN in heart failure

Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the mechanisms are not known. We hypothesized that ExT would normalize the augmented glutamatergic mechanisms mediated by N-methyl-d-aspartic acid (NMDA) receptors within the paraventricular nucleus (PVN) that occur with HF. Four groups of rats were used: 1) sham-operated (Sham) sedentary (Sed), 2) Sham ExT, 3) HF Sed, and 4) HF ExT. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In alpha-chloralose-urethane-anesthetized rats, the increase in renal sympathetic nerve activity in response to the highest dose of NMDA (200 pmol) injected into the PVN in the HF Sed group was approximately twice that of the Sham Sed group. In the HF ExT group the response was not different from the Sham Sed and Sham ExT groups. Relative NMDA NR1 receptor subunit mRNA expression was 63% higher in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not different from the Sham Sed and Sham ExT groups. NR1 receptor subunit protein expression was increased 87% in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not significantly different from the Sham Sed and Sham ExT groups. Thus one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of glutamatergic mechanisms within the PVN.

A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Exercise Training Reduces Angiotensin II Receptor Expression and Sympathetic Outflow in Heart Failure

Exercise Training Reduces Angiotensin II Receptor Expression and Sympathetic Outflow in Heart Failure

The Regulation of Sympathetic Outflow in Heart Failure

Sympatho-excitation is a hallmark of the chronic heart failure (CHF) state. It has long been assumed that this sympatho-excitation is mediated by a reduction in sensory input from cardiopulmonary and arterial baroreceptors. However, recent data suggest that these reflexes may only be important in the initiation of the sympatho-excitatory state and may not be necessary for the sustained increase in sympathetic nerve activity (SNA) in CHF. Two humoral factors that can influence SNA are nitric oxide (NO) and angiotensin II (AngII). Animals with CHF exhibit a downregulation in central gene expression for the neuronal isoform of nitric oxide synthase (nNOS). In addition, blockade of AngII receptors in combination with NO donation reduces SNA in animals with CHF, while NO donation alone has no effect on SNA. Chronic exercise training (EX) reduces both plasma AngII and SNA in rabbits with CHF while improving baroreflex function. Blockade of AT1 receptors enhances baroreflex function in non-EX CHF rabbits, but has little effect in EX CHF rabbits. These data suggest that the sympatho-excitatory state that is typical of CHF is, in part, due to changes in AngII and NO. Depressed baroreflex function and the elevated SNA can be improved by EX in animals with CHF.

Angiotensin II--nitric oxide interactions in the control of sympathetic outflow in heart failure.

Activation of the sympathetic nervous system is a compensatory mechanism which initially provides support for the circulation in the face of a falling cardiac output. It has been recognized for some time that chronic elevation of sympathetic outflow with the consequent increase in plasma norepinephrine, is counterproductive to improving cardiac function. Indeed, therapeutic targeting to block excessive sympathetic activation in heart failure is becoming a more accepted modality. The mechanism(s) by which sympathetic excitation occurs in the heart failure state are not completely understood. Components of abnormal cardiovascular reflex regulation most likely contribute to this sympatho-excitation. However, central mechanisms which relate to the elaboration of angiotensin II (Ang II) and nitric oxide (NO) may also play an important role. Ang II has been shown to be a sympatho-excitatory peptide in the central nervous system while NO is sympatho-inhibitory. Recent studies have demonstrated that blockade of Ang II receptors of the AT(1) subtype augments arterial baroreflex control of sympathetic nerve activity in the heart failure state, thereby predisposing to a reduction in sympathetic tone. Ang II and NO interact to regulate sympathetic outflow. Blockade of NO production in normal conscious rabbits was only capable of increasing sympathetic outflow when accompanied by a background infusion of Ang II. Conversely, providing a source of NO to rabbits with heart failure reduced sympathetic nerve activity when accompanied by blockade of AT(1) receptors. Chronic heart failure is also associated with a decrease in NO synthesis in the brain as indicated by a reduction in the mRNA for the neuronal isoform (nNOS). Chronic blockade of Ang II receptors can up regulate nNOS expression. In addition, exercise training of rabbits with developing heart failure has been shown to reduce sympathetic tone, decrease plasma Ang II, improve arterial baroreflex function and increase nNOS expression in the central nervous system. This review summarizes a large number of studies which have concentrated on the mechanisms of sympatho-excitation in heart failure. It now seems clear that one mechanism which is important in regulating sympathetic outflow in this disease state depends upon a central interaction between Ang II and NO at the cellular and nuclear levels.

Cardiac sympathetic afferent reflexes in heart failure.

Heart failure is characterized by an elevation in sympathetic tone. The mechanisms responsible for this sympatho-excitation of heart failure are not completely understood. Several studies from this laboratory have compared differences in the cardiac "sympathetic afferent" reflex between sham dogs and dogs with pacing-induced heart failure. We found 1) that the cardiac sympathetic afferent reflex is augmented in heart failure, 2) tonic cardiac sympathetic afferent inputs play an important role in the elevated sympathetic tone in heart failure, 3) cardiac sympathetic afferents are sensitized in heart failure and 4) the central gain of the cardiac sympathetic afferent reflex in heart failure is sensitized and that this sensitization may be related to augmented central Ang II and blunted NO mechanisms. These studies integrate into the regulation of sympathetic outflow in heart failure which is likely to be mediated by a variety of peripheral inputs modulated by central substances. If the cardiac sympathetic afferent reflex is one of the excitatory reflexes which contribute to sympathetic activation in heart failure, a comprehensive understanding of neuro-humoral regulation of this reflex may result in more definitives and rational therapy targeted to the sympathetic nervous system in this disease state.

Role of paraventricular nucleus in mediating sympathetic outflow in heart failure.

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of norepinephrine. Few studies have been performed to examine the role of the central nervous system in the activation of sympathetic outflow during heart failure (HF). In this paper I review these limited studies, with particular emphasis on examining the role of the paraventricular nucleus (PVN) in the exaggerated sympathetic outflow commonly observed in heart failure. The conclusion is that heart failure is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the PVN are likely related to abnormalities in vasopressin production, blood volume regulation, and sympathoexcitation observed in the heart failure state. Furthermore, neuronal nitric oxide within the PVN that is involved in mediating sympathetic outflow via a GABA mechanism from the PVN may be deficient in inhibiting overall sympathetic outflow leading to the exaggerated sympathetic outflow commonly observed in heart failure.

Increased sympathetic nervous system activity and its therapeutic reduction in arterial hypertension, portal hypertension and heart failure

Although the underlying mechanisms no doubt differ, activation of the sympathetic nervous system is an important pathophysiological feature in primary arterial hypertension, in portal hypertension accompanying hepatic cirrhosis, and in heart failure, and is a logical therapeutic target for centrally acting sympathetic nervous system suppressant drugs. Portal hypertension: The sympathetic outflows to skeletal muscle vasculature, the heart, the kidneys and to the hepatomesenteric circulation are stimulated in patients with alcoholic cirrhosis of the liver, perhaps as a reflex response to the vasodilatation and vascular shunting present. Acute dosing with clonidine produces dose dependent reduction in noradrenaline spillover from visceral organs and reduction in hepatic vein wedge pressure, with preservation of hepatic blood flow and negligible fall in arterial pressure. These findings indicate the clinical potential of drugs such as clonidine, moxonidine and rilmenidine for chronically lowering portal venous pressure in cirrhosis. Arterial hypertension: Activation of the sympathetic outflow to the heart, kidneys and skeletal muscle vasculature is commonly present in younger (<45 years) patients with essential hypertension. The sympathetic stimulation appears to have adverse consequences in hypertensive patients beyond blood pressure elevation. Neural vasoconstriction in skeletal muscle has metabolic effects by impairing glucose delivery, which is a basis for insulin resistance and hyperinsulinemia. Within the heart a trophic effect of sympathetic activation on cardiac growth, contributing to the development of left ventricular hypertrophy, and an arrhythmogenic effect are also likely. Cardiac failure: The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest being increased as much as 50-fold, similar to the level seen in healthy people during near maximum exercise. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmogenesis and possibly to progression of the heart failure, and has been directly linked to mortality; a high rate of spillover of noradrenaline from the heart is a strong, independent predictor of poor prognosis in severe cardiac failure. The mechanisms underlying sympathetic nervous stimulation are not entirely clear. Increased intracardiac diastolic pressure seems to be one peripheral signal, and increased forebrain norepinephrine turnover an important central mechanism. Following the demonstration of the beneficial effect of the beta-adrenergic blocker, carvedilol, and with second generation centrally acting sympathetic suppressants now under clinical investigation, elucidation of the abnormalities in central nervous control of sympathetic outflow in heart failure has become clinically relevant.