Cardiology Research and Practice

Volume 2012 (2012), Article ID 847172, 7 pages

doi:10.1155/2012/847172

Review Article

Central Mechanisms of Abnormal Sympathoexcitation in Chronic Heart Failure

Takuya Kishi¹ and Yoshitaka Hirooka²

¹Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

²Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan

Received 18 May 2012; Accepted 24 June 2012

Academic Editor: Kazuko Masuo

Copyright © 2012 Takuya Kishi and Yoshitaka Hirooka. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

It has been recognized that the sympathetic nervous system is abnormally activated in chronic heart failure, and leads to further worsening chronic heart failure. In the treatment of chronic heart failure many clinical studies have already suggested that the inhibition of the abnormal sympathetic hyperactivity by beta blockers is beneficial. It has been classically considered that abnormal sympathetic hyperactivity in chronic heart failure is caused by the enhancement of excitatory inputs including changes in peripheral baroreceptor and chemoreceptor reflexes and chemical mediators that control sympathetic outflow. Recently, the abnormalities in the central regulation of sympathetic nerve activity mediated by brain renin angiotensin system-oxidative stress axis and/or proinflammatory cytokines have been focused. Central renin angiotensin system, proinflammatory cytokines, and the interaction between them have been determined as the target of the sympathoinhibitory treatment in experimental animal models with chronic heart failure. In conclusion, we must recognize that chronic heart failure is a syndrome with an abnormal sympathoexcitation, which is caused by the abnormalities in the central regulation of sympathetic nerve activity.

1. Introduction

Sympathetic nervous system has a wide variety of cardiovascular actions, including heart rate acceleration, increase in cardiac contractility, reduction of venous capacitance, and constriction of resistance vessels [1, 2]. It has already been known that abnormal autonomic nervous system regulation is involved in the pathogenesis of chronic heart failure [1–4]. Among the abnormal autonomic nervous regulation, this paper focuses on the central mechanisms of abnormal sympathoexcitation in chronic heart failure.

2. Sympathetic Nerve Activity Is Abnormally Activated in Chronic Heart Failure

Activation of sympathetic nervous system, reduction of the vagal activity, and the secretion of renin angiotensin-aldosterone axis are occurred in chronic heart failure with left ventricular systolic dysfunction [1, 2, 5] and diastolic dysfunction [6, 7]. A previous study demonstrated that the spillover of norepinephrine and epinephrine in internal jugular venous is increased in chronic heart failure [2]. Chronic heart failure is characterized by rapidly responsive arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation of MSNA, a cardiac sympathoexcitatory reflex related to increased cardiopulmonary filling pressure, and by individual variation in non-baroreflex-mediated sympathoexcitatory mechanisms, including coexisting sleep apnea, myocardial ischemia, obesity, and reflexes from exercising muscle [2]. In several animal models with chronic heart failure, the sensitivity of various sympathoinhibitory reflexes is reduced [8, 9]. Furthermore, experimental abnormal function of cardiovascular reflex contributes to the sympathetic activation in animal models with chronic heart failure [10]. These previous reports suggest that the reduction of sympathoinhibitory reflex is a main cause of abnormal sympathoexcitation in chronic heart failure.

There are several animal models with chronic heart failure, and those animal models may mimic the human condition with chronic heart failure closely [11]. In spite of various methodologies, all animal models with chronic heart failure have sympathoexcitation [11], which strongly suggest that abnormal sympathoexcitation is commonly occurred in chronic heart failure, independent of its pathophysiology. In the aspect of abnormal sympathetic activation in chronic heart failure, it should be considered that abnormal central mechanisms of sympathetic nervous system regulation is occurred in chronic heart failure [3], because sympathetic nervous system activation is determined by brain [12]. Interestingly, in the patients with heart failure, significant increases in internal jugular venous spillover of metabolites of norepinephrine and epinephrine, with a positive correlation between brain norepinephrine turnover and cardiac norepinephrine spillover [2]. Moreover, central mechanisms of abnormal sympathoexcitation would be a target of the treatments for chronic heart failure.

3. Central Mechanisms of Abnormal Sympathoexcitation in Chronic Heart Failure: Brain Renin Angiotensin System

In the brain, renin angiotensin system is considered to be a main system of regulating sympathetic nervous system [12]. In the brain of experimental heart failure, it has been demonstrated that angiotensin II and aldosterone produced locally in the brain are related to sympathetic activation and progression of heart failure with left ventricular systolic dysfunction [9, 13]. The brain renin angiotensin system is activated in experimental chronic heart failure with enhanced central sympathetic outflow [8, 14–18]. Angiotensin II type 1 (AT₁) receptors are found in the central nervous system and are expressed to a high degree in areas of the hypothalamus and medulla, which regulate sympathetic outflow [9, 19]. Aldosterone increases angiotensin-converting enzyme and AT₁ receptor in the paraventricular nucleus (PVN) of the hypothalamus in chronic heart failure with postmyocardial infarction [20]. These previous reports have suggested that the activation of renin angiotensin system in the brain is associated with sympathoexcitation in chronic heart failure.

As the mechanisms in which brain renin angiotensin system causes sympathoexcitation, brain oxidative stress has been focused. Brain renin angiotensin system is involved in the production of oxidative stress in the brain [8, 21–23]. It has been determined that mitochondria-derived oxidative stress mediates sympathoexcitation induced by angiotensin II in the brain [24, 25]. Particularly, in the brain, rostral ventrolateral medulla (RVLM) is well known as a vasomotor center [26], and oxidative stress in the RVLM causes sympathoexcitation [27]. It is well established that the AT₁ receptor-induced oxidative stress in the RVLM causes sympathoexcitation in the animal models with chronic heart failure [8, 21, 22, 28]. Microinjection of angiotensin II into the RVLM causes sympathoexcitation, and microinjection of AT₁ receptor blocker into the RVLM causes sympathoinhibition in experimental chronic heart failure [8, 14–18]. AT₁ receptor protein, AT₁ receptor mRNA, and angiotensin II levels are increased in the RVLM and nucleus tractus solitarii (NTS) in rabbits and rats with chronic heart failure [8, 21, 22]. These previous results strongly indicate that the upregulation of central AT₁ receptor and oxidative stress plays a critical role in the abnormal sympathoexcitation in chronic heart failure. Furthermore, the balance between angiotensin-converting enzyme (ACE) and its homolog ACE2 or between AT₁ and angiotensin II type 2 receptor in the brain may be an important determinant of sympathoexcitation in chronic heart failure [8, 25, 29, 30]. Combined these previous studies, it should be considered that the AT₁ receptor-induced oxidative stress in the brain, especially in the RVLM, might be a novel target of the therapy for chronic heart failure through the sympathoinhibition.

4. Central Mechanisms of Sympathoexcitation in Chronic Heart Failure: Brain Inflammation

Brain inflammatory mediators and the brain renin angiotensin system are both implicated in sympathoexcitation in experimental chronic heart failure [31, 32]. Recently, the further central mechanisms of sympathoexcitation associated with oxidative stress are focused, such as upregulating brain proinflammatory cytokines with renin angiotensin system [33–37], perivascular macrophages in the brain [38, 39], neuronastrocyte uncoupling [40, 41], transcription factor nuclear factor kappa B (NF-κB) [42], or microglial cytokines [43] in the brain. Proinflammatory cytokines, such as tumor-necrosis factor alpha, increase the number of brain perivascular macrophages, thereby activating cyclooxygenase 2 and generating prostaglandin E2, which leads to sympathoexcitation in rats with chronic heart failure after myocardia infarction [38]. There may be some interactions between proinflammatory cytokines and autonomic nervous system [44]. In addition, microglial activation with inflammation also plays an important role in sympathoexcitation [45]. Moreover, NF-κB-mediates cross talk between proinflammatory cytokines and brain renin angiotensin system in rats with chronic heart failure [31, 37]. Interestingly, peroxisome proliferator-activated receptor gamma in rats with ischemia-induced heart failure is involved in the expression of inflammatory mediators and a key component of the brain renin angiotensin system in PVN, reduced sympathetic nerve activity [46]. Combined with these previous reports, brain inflammatory pathway, probably associated with renin angiotensin system, could be considered to be the important mechanisms of abnormal sympathoexcitation in chronic heart failure. Further basic and clinical experiments are necessary to determine whether the brain inflammation could be a novel target of the treatment for chronic heart failure or not.

5. Central Mechanisms of Abnormal Sympathoexcitation in Chronic Heart Failure: Other Possible Mechanisms

We have also demonstrated other several mechanisms of abnormal sympathoexcitation in chronic heart failure. In the brain, nitric oxide (NO) causes sympathoinhibition [47, 48], and the dysfunction of NO production in the brain occurs in the rats with chronic heart failure [49]. Overexpression of NO synthase in the brain attenuates the abnormal sympathoexcitation in mice with heart failure [50]. In the brain, NO could counteract against oxidative stress [51]. These results indicate that the dysfunction of NO pathway in the brain would cause sympathoexcitation in chronic heart failure. Moreover, it has been demonstrated that each of small G protein Rho/Rho kinase pathway, mineral corticoid receptors and/or Na sensitivity, or toll-like receptor 4 in the brain causes sympathoexcitation in rats with chronic heart failure [52–55]. It would be necessary to clarify whether these various mechanisms have interaction with brain renin angiotensin system and/or inflammation in chronic heart failure with sympathoexcitation.

6. Sympathoinhibitory Therapy for Chronic Heart Failure

Many clinical studies have already and strongly suggested that chronic beta blocker therapy improves left ventricular performance and reverses left ventricular remodeling, reduces risk of hospitalization for heart failure, and improves survival of chronic heart failure [56–61]. Among all beta blockers, bisoprolol (except in the USA), carvedilol, and metoprolol succinate (except in Canada) are almost universally approved for the treatment of chronic heart failure [56–61]. However, previous studies could not demonstrate the benefits of alpha1-blocker in chronic heart failure [62–64].

Central alpha2 receptor has been considered to be possible targets of treatment for chronic heart failure, because the excitation of the central alpha2 receptor causes sympathoinhibition [9, 65]. In modest doses of clonidine, it significantly attenuates cardiac and renal sympathetic tone in the patients with chronic heart failure [66]. The other centrally acting sympathoinhibitory agent, moxonidine, acts through both alpha2- and imidazoline receptors [9, 67]. However, in clinical trials, moxonidine led to increased mortality [9, 68].

Angiotensin II and aldosterone production enhances the release and inhibits the uptake of norepinephrine at nerve endings [69]. ACE inhibitors have a predictable effect in increasing plasma renin and decreasing angiotensin II and aldosterone levels, whereas norepinephrine and vasopressin reduction is attributed to the hemodynamic improvement [70]. Previous large clinical trial has already shown the benefit with aldosterone antagonists in patients with chronic heart failure and may be partially related to their effect on norepinephrine [71]. The high density of AT₁ receptors is present in brain regions outside of the blood-brain barrier where peripherally administered AT₁ receptor blockers are able to access without considering the existence of the blood-brain barrier as well as inside of the blood-brain barrier [72]. Recent studies suggest that the systemic administered AT₁ receptor blockers also act on the AT₁ receptors within the brain, thereby reducing blood pressure in hypertensive rats [51, 73–77]. It should be determined in future studies whether ACE inhibitors or AT₁ receptor blockers could cause beneficial sympathoinhibition via blockade of brain renin angiotensin system.

Several studies in rabbits with pacing-induced heart failure have demonstrated that statins normalize abnormal sympathetic hyperactivity in experimental chronic heart failure [78–80]. Previous studies have suggested that simvastatin could inhibit AT₁ receptor and production of superoxide with upregulating NO synthase in the RVLM of the animal models with chronic heart failure [78, 80]. We also demonstrated that orally administered atorvastatin causes sympathoinhibition and improves baroreflex dysfunction via reduction of oxidative stress and upregulation of NO synthase in the brain of hypertensive rats [81–83]. Although there is no clinical study suggesting the benefits of statins on chronic heart failure, these experimental results suggest that stains could attenuate sympathoexcitation in chronic heart failure, independent of cholesterol-lowering effect. Further clinical trials are necessary to clarify whether statins in clinical dose would have the sympathoinhibitory benefit in chronic heart failure or not.

As the nonpharmacological therapy for chronic heart failure, exercise training is considered to have sympathoinhibitory benefit on chronic heart failure. Exercise intolerance is a characteristic of patients with chronic heart failure, and skeletal myopathy contributes to the limitation of functional capacity in chronic heart failure [1, 2, 9]. Abnormal sympathetic hyperactivity contributes to the skeletal myopathy in chronic heart failure [84]. Interestingly, current evidences have suggested that exercise training improves central hemodynamics, peripheral muscle function, and symptoms and causes sympathoinhibition even in patients treated with beta blockers [85–88]. Recent experimental evidence suggests that the exercise training-induced beneficial effects on autonomic activity in heart failure may be due to an upregulation in central antioxidative mechanisms and suppressed central pro-oxidant mechanisms [29].

Recent novel topic in the therapy with sympathoinhibition is renal sympathetic denervation. Renal afferent nerves may also contribute to the blood pressure elevation according to the recent findings of the renal nerve ablation in patients with resistant hypertension [89–91]. Renal afferent nerves project directly into many areas in the central nervous system controlling the sympathetic nervous system activity [92–94]. We consider that the renal nerve ablation could be a novel therapy for chronic heart failure, and further clinical trials and basic researches are expected.

7. Summary and Future Prospects

In chronic heart failure, it has been recognized that the abnormal sympathoexcitation occurs. In the treatment of chronic heart failure, the therapy with sympathoinhibition, such as beta blockers and/or exercise training, has already been considered to be important. We must recognize that chronic heart failure is a complex syndrome with sympathoexcitation and that the abnormal sympathoexcitation should be the target of the treatments for chronic heart failure. In this aspect, conservative pharmacological therapy is not sufficient, and the additive new and novel device therapy and/or nonpharmacological therapy are necessary.

The mechanisms in which the abnormal sympathoexcitation occurred in chronic heart failure have not been fully determined. Particularly, the central abnormalities need further examinations in clinical and basic research. It is interesting and important to consider that AT₁ receptors, oxidative stress, and inflammatory pathway in the brain are novel sympathoinhibitory therapeutic targets for chronic heart failure (Figure 1).

Figure 1: A schema of the concept in the central abnormalities of regulation for sympathetic nerve activity in chronic heart failure.

Conflict of Interests

There is no conflict of interests.

References

F. Triposkiadis, G. Karayannis, G. Giamouzis, J. Skoularigis, G. Louridas, and J. Butler, “The sympathetic nervous system in heart failure. physiology, pathophysiology, and clinical implications,” Journal of the American College of Cardiology, vol. 54, no. 19, pp. 1747–1762, 2009.

J. S. Floras, “Sympathetic nervous system activation in human heart failure. clinical implications of an updated model,” Journal of the American College of Cardiology, vol. 54, no. 5, pp. 375–385, 2009.

T. Kishi, “Heart failure as an autonomic nervous system dysfunction,” Journal of Cardiology, vol. 59, pp. 117–122, 2012.

A. M. D. Watson, S. G. Hood, and C. N. May, “Mechanisms of sympathetic activation in heart failure,” Clinical and Experimental Pharmacology and Physiology, vol. 33, no. 12, pp. 1269–1274, 2006.

V. J. Dzau, W. S. Colucci, N. K. Hollenberg, and G. H. Williams, “Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure,” Circulation, vol. 63, no. 3, pp. 645–651, 1981.

K. Hogg and J. McMurray, “Neurohumoral pathways in heart failure with preserved systolic function,” Progress in Cardiovascular Diseases, vol. 47, no. 6, pp. 357–366, 2005.

G. Grassi, G. Seravalle, F. Quarti-Trevano et al., “Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction,” Hypertension, vol. 53, no. 2, pp. 205–209, 2009.

I. H. Zucker, H. D. Schultz, K. P. Patel, W. Wang, and L. Gao, “Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure,” American Journal of Physiology, vol. 297, no. 5, pp. H1557–H1566, 2009.

J. P. Fisher, C. N. Young, and P. J. Fadel, “Central sympathetic overactivity: maladies and mechanisms,” Autonomic Neuroscience, vol. 148, no. 1-2, pp. 5–15, 2009.

I. H. Zucker, J. F. Hackley, K. G. Cornish et al., “Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure,” Hypertension, vol. 50, no. 5, pp. 904–910, 2007.

S. R. Houser, K. B. Margulies, A. M. Murphy, et al., “Animal models of heart failure: a scientific statement from the American Heart Association,” Circulation Research, vol. 111, no. 1, pp. 131–150, 2012.

P. G. Guyenet, “The sympathetic control of blood pressure,” Nature Reviews Neuroscience, vol. 7, no. 5, pp. 335–346, 2006.

H. Wang, B. S. Huang, D. Ganten, and F. H. H. Leenen, “Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen,” Circulation Research, vol. 94, no. 6, pp. 843–849, 2004.

L. Hu, D. N. Zhu, Z. Yu, J. Q. Wang, Z. J. Sun, and T. Yao, “Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats,” Journal of Applied Physiology, vol. 92, no. 5, pp. 2153–2161, 2002.

B. S. Huang and F. H. H. Leenen, “The brain renin-angiotensin-aldosterone system: a major mechanism for sympathetic hyperactivity and left ventricular remodeling and dysfunction after myocardial infarction,” Current Heart Failure Reports, vol. 6, no. 2, pp. 81–88, 2009.

F. H. H. Leenen, “Brain mechanisms contributing to sympathetic hyperactivity and heart failure,” Circulation Research, vol. 101, no. 3, pp. 221–223, 2007.

A. G. Dupont and S. Brouwers, “Brain angiotensin peptides regulate sympathetic tone and blood pressure,” Journal of Hypertension, vol. 28, no. 8, pp. 1599–1610, 2010.

V. Reja, A. K. Goodchild, J. K. Phillips, and P. M. Pilowsky, “Upregulation of angiotensin AT1 receptor and intracellular kinase gene expression in hypertensive rats,” Clinical and Experimental Pharmacology and Physiology, vol. 33, no. 8, pp. 690–695, 2006.

A. M. Allen, I. Moeller, T. A. Jenkins et al., “Angiotensin receptors in the nervous system,” Brain Research Bulletin, vol. 47, no. 1, pp. 17–28, 1998.

B. S. Huang, H. Zheng, J. Tan, et al., “Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone,” Experimental Physiology, vol. 96, pp. 1028–1038, 2011.

L. Gao, W. Wang, Y. L. Li et al., “Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM,” American Journal of Physiology, vol. 288, no. 5, pp. H2271–H2279, 2005.

D. Liu, L. Gao, S. K. Roy, K. G. Cornish, and I. H. Zucker, “Neuronal angiotensin II type 1 receptor upregulation in heart failure: activation of activator protein 1 and Jun N-terminal kinase,” Circulation Research, vol. 99, no. 9, pp. 1004–1011, 2006.

Y. F. Li, W. Wang, W. G. Mayhan, and K. P. Patel, “Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide,” American Journal of Physiology, vol. 290, no. 4, pp. R1035–R1043, 2006.

M. Nozoe, Y. Hirooka, Y. Koga et al., “Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart rate in stroke-prone spontaneously hypertensive rats,” Hypertension, vol. 50, no. 1, pp. 62–68, 2007.

M. C. Zimmerman and I. H. Zucker, “Mitochondrial dysfunction and mitochondrial-produced reactive oxygen species new targets for neurogenic hypertension?” Hypertension, vol. 53, no. 2, pp. 112–114, 2009.

R. A. L. Dampney, “Functional organization of central pathways regulating the cardiovascular system,” Physiological Reviews, vol. 74, no. 2, pp. 323–364, 1994.

T. Kishi, Y. Hirooka, Y. Kimura, K. Ito, H. Shimokawa, and A. Takeshita, “Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats,” Circulation, vol. 109, no. 19, pp. 2357–2362, 2004.

R. Ramchandra, S. G. Hood, A. M. D. Watson, et al., “Central angiotensin type 1receptor blockade decreases cardiac but not renal sympathetic nerve activity in heart failure,” Hypertension, vol. 59, pp. 634–641, 2012.

L. Gao, W. Wang, D. Liu, and I. H. Zucker, “Exercise training normalizes sympathetic outflow by central antioxidant mechanisms in rabbits with pacing-induced chronic heart failure,” Circulation, vol. 115, no. 24, pp. 3095–3102, 2007.

L. Gao, W. Z. Wang, W. Wang, and I. H. Zucker, “Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla potential mechanism for sympathetic overactivity in heart failure,” Hypertension, vol. 52, no. 4, pp. 708–714, 2008.

R. B. Felder, Y. Yu, Z. H. Zhang, and S. G. Wei, “Pharmacological treatment for heart failure: a view from the brain,” Clinical Pharmacology and Therapeutics, vol. 86, no. 2, pp. 216–220, 2009.

R. B. Felder, J. Francis, Z. H. Zhang, S. G. Wei, R. M. Weiss, and A. K. Johnson, “Heart failure and the brain: new perspectives,” American Journal of Physiology, vol. 284, no. 2, pp. R259–R276, 2003.

Y. Yu, Z. H. Zhang, S. G. Wei et al., “Central gene transfer of interleukin-10 reduces hypothalamic inflammation and evidence of heart failure in rats after myocardial infarction,” Circulation Research, vol. 101, no. 3, pp. 304–312, 2007.

Y. Yu, S. G. Wei, Z. H. Zhang, E. Gomez-Sanchez, R. M. Weiss, and R. B. Felder, “Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure?” Hypertension, vol. 51, no. 3, pp. 727–733, 2008.

S. G. Wei, Y. Yu, Z. H. Zhang, R. M. Weiss, and R. B. Felder, “Angiotensin II-triggered p44/42 mitogen-activated protein kinase mediates sympathetic excitation in heart failure rats,” Hypertension, vol. 52, no. 2, pp. 342–350, 2008.

B. S. Huang, M. Ahmad, J. Tan, and F. H. H. Leenen, “Chronic central versus systemic blockade of AT1 receptors and cardiac dysfunction in rats post-myocardial infarction,” American Journal of Physiology, vol. 297, no. 3, pp. H968–H975, 2009.

Y. M. Kang, Y. Ma, C. Elks, J. P. Zheng, Z. M. Yang, and J. Francis, “Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-κB,” Cardiovascular Research, vol. 79, no. 4, pp. 671–678, 2008.

Y. Yu, Z. H. Zhang, S. G. Wei, J. Serrats, R. M. Weiss, and R. B. Felder, “Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial infarction,” Hypertension, vol. 55, no. 3, pp. 652–659, 2010.

Y. Hirooka, “Brain perivascular macrophages and central sympathetic activation after myocardial infarction: heart and brain interaction,” Hypertension, vol. 55, no. 3, pp. 610–611, 2010.

T. Kishi, Y. Hirooka, and K. Sunagawa, “Autoimplantation of astrocytes into cardiovascular center of brainstem causes sympathoinhibition and decreases the mortality rate in hypertensive rats,” Circulation, vol. 122, Article ID A13856, 2010.

T. Kishi, Y. Hirooka, and K. Sunagawa, “Autoimplantation of astrocytes into the cardiovascular center of brainstem causes sympathoinhibition and decreases the mortality rate in myocardial infarction-induced heart failure,” Circulation, vol. 124, Article ID A11489, 2011.

J. P. Cardinale, S. Sriramula, N. Mariappan, et al., “Angiotensin II-induced hypertension is modulated by nuclear factor-kB in the paraventricular nucleus,” Hypertension, vol. 59, pp. 113–121, 2011.

P. Shi, C. Diez-Freire, J. Y. Jun et al., “Brain microglial cytokines in neurogenic hypertension,” Hypertension, vol. 56, no. 2, pp. 297–303, 2010.

J. C. Schiltz and P. E. Sawchenko, “Specificity and generality of the involvement of catecholaminergic afferents in hypothalamic responses to immune insults,” Journal of Comparative Neurology, vol. 502, no. 3, pp. 455–467, 2007.

M. L. Block, L. Zecca, and J. S. Hong, “Microglia-mediated neurotoxicity: uncovering the molecular mechanisms,” Nature Reviews Neuroscience, vol. 8, no. 1, pp. 57–69, 2007.

Y. Yu, Z. H. Zhang, S. G. Wei, et al., “Peroxisome proliferator-activated receptor-g regulates inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorates peripheral manifestations of heart failure,” Hypertension, vol. 59, pp. 477–484, 2012.

T. Kishi, Y. Hirooka, K. Sakai, H. Shigematsu, H. Shimokawa, and A. Takeshita, “Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release,” Hypertension, vol. 38, no. 4, pp. 896–901, 2001.

Y. Hirooka, T. Kishi, K. Sakai, H. Shimokawa, and A. Takeshita, “Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats,” Journal of Cardiovascular Pharmacology, vol. 41, no. 1, pp. S119–S126, 2003.

Y. Hirooka, H. Shigematsu, T. Kishi, Y. Kimura, Y. Ueta, and A. Takeshita, “Reduced nitric oxide synthase in the brainstem contributes to enhanced sympathetic drive in rats with heart failure,” Journal of Cardiovascular Pharmacology, vol. 42, no. 1, pp. S111–S115, 2003.

K. Sakai, Y. Hirooka, H. Shigematsu et al., “Overexpression of eNOS in brain stem reduces enhanced sympathetic drive in mice with myocardial infarction,” American Journal of Physiology, vol. 289, no. 5, pp. H2159–H2166, 2005.

Y. Hirooka, Y. Sagara, T. Kishi, and K. Sunagawa, “Oxidative stress and central cardiovascular regulation—pathogenesis of hypertension and therapeutic aspects,” Circulation Journal, vol. 74, no. 5, pp. 827–835, 2010.

K. Ito, Y. Kimura, Y. Hirooka, Y. Sagara, and K. Sunagawa, “Activation of Rho-kinase in the brainstem enhances sympathetic drive in mice with heart failure,” Autonomic Neuroscience, vol. 142, no. 1-2, pp. 77–81, 2008.

K. Ito, Y. Hirooka, and K. Sunagawa, “Blockade of mineralocorticoid receptors improves salt-induced left-ventricular systolic dysfunction through attenuation of enhanced sympathetic drive in mice with pressure overload,” Journal of Hypertension, vol. 28, no. 7, pp. 1449–1458, 2010.

K. Ito, Y. Hirooka, and K. Sunagawa, “Acquisition of brain na sensitivity contributes to salt-induced sympathoexcitation and cardiac dysfunction in mice with pressure overload,” Circulation Research, vol. 104, no. 8, pp. 1004–1011, 2009.

K. Ogawa, Y. Hirooka, T. Kishi, and K. Sunagawa, “Brain AT1 receptor activates the sympathetic nervous system through toll-like receptor 4 in mice with heart failure,” Journal of Cardiovascular Pharmacology, vol. 58, no. 5, pp. 543–549, 2011.

S. A. Hunt, W. T. Abraham, M. H. Chin, et al., “ACC/AHA, 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society,” Circulation, vol. 112, pp. e154–e235, 2005.

H. F. MERIT- Investigators, “Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF),” The Lancet, vol. 353, pp. 2001–2007, 1999.

H. J. Dargie, “Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial,” The Lancet, vol. 357, no. 9266, pp. 1385–1390, 2001.

M. Packer, M. B. Fowler, E. B. Roecker et al., “Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study,” Circulation, vol. 106, no. 17, pp. 2194–2199, 2002.

P. A. Poole-Wilson, K. Swedberg, J. G. F. Cleland et al., “Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial,” The Lancet, vol. 362, no. 9377, pp. 7–13, 2003.

R. Willenheimer, D. J. van Veldhuisen, B. Silke et al., “Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III,” Circulation, vol. 112, no. 16, pp. 2426–2435, 2005.

J. N. Cohn, D. G. Archibald, and S. Ziesche, “Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study,” The New England Journal of Medicine, vol. 314, no. 24, pp. 1547–1552, 1986.

W. S. Colucci, G. H. Williams, and E. Braunwald, “Increased plasma norepinephrine levels during prazosin therapy for severe congestive heart failure,” Annals of Internal Medicine, vol. 93, no. 3, pp. 452–453, 1980.

ALLHAT Collaborative Research Group, “Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT),” Journal of the American Medical Association, vol. 283, no. 15, pp. 1967–1975, 2000.

K. Starke, M. Gothert, and H. Kilbinger, “Modulation of neurotransmitter release by presynaptic autoreceptors,” Physiological Reviews, vol. 69, no. 3, pp. 864–989, 1989.

T. D. Giles, M. G. Thomas, A. C. Quiroz, et al., “Acute and short-term effects of clonidine in heart failure,” Angiology, vol. 38, no. 7, pp. 537–548, 1987.

P. Ernsberger, M. P. Meeley, and D. J. Reis, “An endogenous substance with clonidine-like properties: selective binding to imidazole sites in the ventrolateral medulla,” Brain Research, vol. 441, no. 1-2, pp. 309–318, 1988.

J. N. Cohn, M. A. Pfeffer, J. Rouleau et al., “Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON),” European Journal of Heart Failure, vol. 5, no. 5, pp. 659–667, 2003.

C. Sumners and M. K. Raizada, “Angiotensin II stimulates norepinephrine uptake in hypothalamus-brain stem neuronal cultures,” American Journal of Physiology, vol. 250, no. 2, pp. C236–C244, 1986.

C. R. Benedict, G. S. Francis, B. Shelton et al., “Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction,” American Journal of Cardiology, vol. 75, no. 16, pp. 1151–1157, 1995.

B. Pitt, W. Remme, F. Zannad et al., “Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction,” The New England Journal of Medicine, vol. 348, no. 14, pp. 1309–1321, 2003.

M. J. McKinley, A. L. Albiston, A. M. Allen et al., “The brain renin-angiotensin system: location and physiological roles,” International Journal of Biochemistry and Cell Biology, vol. 35, no. 6, pp. 901–918, 2003.

T. Tsuchihashi, S. Kagiyama, K. Matsumura, I. Abe, and M. Fujishima, “Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR,” Journal of Hypertension, vol. 17, no. 7, pp. 917–922, 1999.

F. H. H. Leenen and B. Yuan, “Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade,” Hypertension, vol. 37, no. 3, pp. 981–984, 2001.

Y. Lin, K. Matsumura, S. Kagiyama, M. Fukuhara, K. Fujii, and M. Iida, “Chronic administration of olmesartan attenuates the exaggerated pressor response to glutamate in the rostral ventrolateral medulla of SHR,” Brain Research, vol. 1058, no. 1-2, pp. 161–166, 2005.

S. Araki, Y. Hirooka, T. Kishi, K. Yasukawa, H. Utsumi, and K. Sunagawa, “Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method,” Hypertension Research, vol. 32, no. 12, pp. 1091–1096, 2009.

T. Kishi, Y. Hirooka, and K. Sunagawa, “Sympathoinhibition caused by orally administered telmisartan through inhibition of AT(1) receptor in the rostral ventrolateral medulla,” Hypertension Research. In press

L. Gao, W. Wang, Y. L. Li et al., “Simvastatin therapy normalizes sympathetic neural control in experimental heart failure: roles of angiotensin II type 1 receptors and NAD(P)H oxidase,” Circulation, vol. 112, no. 12, pp. 1763–1770, 2005.

R. U. Pliquett, K. G. Cornish, J. D. Peuler, and I. H. Zucker, “Simvastatin normalizes autonomic neural control in experimental heart failure,” Circulation, vol. 107, no. 19, pp. 2493–2498, 2003.

L. Gao, W. Wang, and I. H. Zucker, “Simvastatin inhibits central sympathetic outflow in heart failure by a nitric-oxide synthase mechanism,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 1, pp. 278–285, 2008.

T. Kishi, Y. Hirooka, Y. Mukai, H. Shimokawa, and A. Takeshita, “Atorvastatin causes depressor and sympatho-inhibitory effects with upregulation of nitric oxide synthases in stroke-prone spontaneously hypertensive rats,” Journal of Hypertension, vol. 21, no. 2, pp. 379–386, 2003.

T. Kishi, Y. Hirooka, H. Shimokawa, A. Takeshita, and K. Sunagawa, “Atorvastatin reduces oxidative stress in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats,” Clinical and Experimental Hypertension, vol. 30, no. 1, pp. 3–11, 2008.

T. Kishi, Y. Hirooka, S. Konno, et al., “Atorvastatin improves the impaired baroreflex control of stroke-prone spontaneously hypertensive rats through the anti-oxidant effect in the RVLM,” Clinical and Experimental Hypertension, vol. 31, pp. 698–704, 2009.

T. Kishi and Y. Hirooka, “Sympathoinhibitory effects of atorvastatin in hypertension,” Circulation Journal, vol. 74, no. 12, pp. 2552–2553, 2010.

C. E. Negrao and H. R. Middlekauff, “Adaptations in autonomic function during exercise training in heart failure,” Heart Failure Reviews, vol. 13, no. 1, pp. 51–60, 2008.

R. Fraga, F. G. Franco, F. Roveda et al., “Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol,” European Journal of Heart Failure, vol. 9, no. 6-7, pp. 630–636, 2007.

C. M. O'Connor, D. J. Whellan, K. L. Lee et al., “Efficacy and safety of exercise training in patients with chronic heart failure HF-ACTION randomized controlled trial,” Journal of the American Medical Association, vol. 301, no. 14, pp. 1439–1450, 2009.

V. Adams, C. Doring, and G. Schuler, “Impact of physical exercise on alterations in the skeletal muscle in patients with chronic heart failure,” Frontiers in Bioscience, vol. 13, no. 1, pp. 302–311, 2008.

H. Krum, M. Schlaich, R. Whitbourn et al., “Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study,” The Lancet, vol. 373, no. 9671, pp. 1275–1281, 2009.

G. F. DiBona and M. Esler, “Translational medicine: the antihypertensive effect of renal denervation,” American Journal of Physiology, vol. 298, no. 2, pp. R245–R253, 2010.

Simplicity HTN-2 Investigators, “Renal sympathetic denervation in patients with treatment-resistant hypertension (The Simplicity HTN-2 Trail): a randomized controlled trial,” The Lancet, vol. 376, pp. 1903–1909, 2010.

F. R. Calaresu and J. Ciriello, “Renal afferent nerves affect discharge rate of medullary and hypothalamic single units in the cat,” Journal of the Autonomic Nervous System, vol. 3, no. 2–4, pp. 311–320, 1981.

J. Ciriello and F. R. Calaresu, “Central projections of afferent renal fibers in the rat: an anterograde transport study of horseradish peroxidase,” Journal of the Autonomic Nervous System, vol. 8, no. 3, pp. 273–285, 1983.

A. Stella, R. Golin, S. Genovesi, and A. Zanchetti, “Renal reflexes in the regulation of blood pressure and sodium excretion,” Canadian Journal of Physiology and Pharmacology, vol. 65, no. 8, pp. 1536–1539, 1987.