Harold D. Schultz

Superoxide Mediates Sympathoexcitation in Heart Failure: Roles of Angiotensin II and NAD(P)H Oxidase

Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase–derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5±13.3% of control) and CHF (193.6±11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (P<0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPH-dependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT1) receptor and subunits of NAD(P)H oxidase (p40phox, p47phox, and gp91phox) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF.

Neural regulation of sympathetic nerve activity in heart failure

One of the hallmarks of chronic congestive heart failure is an increase in sympathetic tone to the peripheral circulation and to the heart. A correlation between plasma norepinephrine and the severity of the heart failure state has been demonstrated. One mechanism that has been proposed to account for this sympathoexcitation is a depression in the baroreflex and, perhaps, cardiac reflex control of sympathetic nerve activity. This review summarizes work from several laboratories, including our own, that documents a depressed baroreflex control of heart rate and sympathetic nerve activity in both animals and humans with heart failure. The mechanism of the depressed baroreflex most likely is caused by reduced baroreceptor sensitivity as well as enhanced input to the central nervous system from cardiac receptors that are chemosensitive. Although sympathetic tone and arterial baroreflex sensitivity are altered in heart failure, there have been no studies showing a cause-and-effect relationship. Increases in plasma norepinephrine are similar in baroreceptor-denervated and intact dogs paced into heart failure. This latter observation cells into question the traditional concept of baroreceptor-mediated increases in sympathetic tone in heart failure.

Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure Roles of Angiotensin II Type 1 Receptors and NAD(P)H Oxidase

Background—In a previous study, we showed that simvastatin (SIM) therapy normalized sympathetic outflow and cardiovascular reflex regulation in chronic heart failure (CHF). However, the precise neural and cellular pathways for these effects are unknown. We hypothesized that SIM exerts its beneficial effect on autonomic function in CHF by downregulating central angiotensin II (Ang II) and superoxide mechanisms. Methods and Results—Experiments were carried out on 36 male New Zealand White rabbits, 13 normal and 23 CHF. All rabbits were identically instrumented to record mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA). Echocardiography was used to monitor cardiac function. Reverse transcription–polymerase chain reaction, Western blotting, and lucigenin-enhanced chemiluminescence were used to measure gene expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and NAD(P)H oxidase activity in the rostral ventrolateral medulla. Compared with the CHF control group, SIM significantly reduced the central Ang II–induced pressor and sympathoexcitatory responses, decreased baseline RSNA (57.3±3.2% to 22.4±2.1% of maximum, P<0.05), increased baroreflex control of heart rate (gainmax, 1.6±0.3 to 4.5±0.2 bpm/mm Hg, P<0.05), and increased RSNA (gainmax, 1.7±0.2% to 4.9±0.6% of maximum/mm Hg, P<0.01). Importantly, SIM improved left ventricular function (EF, 32.4±4.1% to 51.7±3.2%, P<0.05). SIM also downregulated mRNA and protein expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and inhibited NAD(P)H oxidase activity in the rostral ventrolateral medulla of CHF rabbits. Chronic intracerebroventricular infusion of Ang II completely abolished the aforementioned effects of SIM in CHF rabbits. Conclusions—These data strongly suggest that SIM normalizes autonomic function in CHF by inhibiting central Ang II mechanisms and therefore the superoxide pathway. These data also demonstrate that SIM improves left ventricular function in pacing-induced CHF rabbits.

Arterial Chemoreceptors and Sympathetic Nerve Activity. Implications for Hypertension and Heart Failure

Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: role of the angiotensin II type 1 receptor.

Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-s apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91(phox) subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin-angiotensin system.

Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure

A strong correlation between disordered breathing patterns, elevated sympathetic nerve activity and enhanced chemoreflex sensitivity exists in patients with heart failure. Evidence indicates that disordered breathing patterns and increased sympathetic nerve activity increases arrhythmia incidence in patients with heart failure. Enhanced coupling between sympathetic and respiratory neural drive underlies elevated sympathetic nerve activity in an animal model of sleep apnoea. We investigated the impact of carotid body chemoreceptor denervation on sympathetic nerve activity, disordered breathing and sympatho‐respiratory coupling in an animal model of heart failure. Renal sympathetic nerve activity, apnoea/hypopnoea incidence, variability measures of tidal volume and respiratory rate and arrhythmia incidence were quantified during resting breathing in heart failure animals with and without carotid body ablation. Our results indicate that carotid body chemoreceptor denervation reduces sympathetic nerve activity, disordered breathing patterns, arrhythmia incidence and sympatho‐respiratory coupling in experimental heart failure. These findings suggest that device‐oriented ablation of carotid body chemoreceptors is a viable treatment option for reduction of sympathetic nerve activity, disordered breathing patterns and arrhythmia incidence in heart failure.

Carotid chemoreceptor ablation improves survival in heart failure: Rescuing autonomic control of cardiorespiratory function

OBJECTIVES This study sought to investigate whether selective ablation of the carotid body (CB) chemoreceptors improves cardiorespiratory control and survival during heart failure. BACKGROUND Chronic heart failure (CHF) is a recognized health problem worldwide, and novel treatments are needed to better improve life quality and decrease mortality. Enhanced carotid chemoreflex drive from the CB is thought to contribute significantly to autonomic dysfunction, abnormal breathing patterns, and increased mortality in heart failure. METHODS Chronic heart failure was induced by coronary ligation in rats. Selective CB denervation was performed to remove carotid chemoreflex drive in the CHF state (16 weeks post-myocardial infarction). Indexes of autonomic and respiratory function were assessed in CB intact and CB denervated animals. CB denervation at 2 weeks post-myocardial infarction was performed to evaluate whether early targeted CB ablation decreases the progression of left ventricular dysfunction, cardiac remodeling, and arrhythmic episodes and improves survival. RESULTS The CHF rats developed increased CB chemoreflex drive and chronic central pre-sympathetic neuronal activation, increased indexes of elevated sympathetic outflow, increased breathing variability and apnea incidence, and desensitization of the baroreflex. Selective CB ablation reduced the central pre-sympathetic neuronal activation by 40%, normalized indexes of sympathetic outflow and baroreflex sensitivity, and reduced the incidence of apneas in CHF animals from 16.8 ± 1.8 events/h to 8.0 ± 1.4 events/h. Remarkably, when CB ablation was performed early, cardiac remodeling, deterioration of left ventricle ejection fraction, and cardiac arrhythmias were reduced. Most importantly, the rats that underwent early CB ablation exhibited an 85% survival rate compared with 45% survival in CHF rats without the intervention. CONCLUSIONS Carotid chemoreceptors play a seminal role in the pathogenesis of heart failure, and their targeted ablation might be of therapeutic value to reduce cardiorespiratory dysfunction and improve survival during CHF.

CAROTID BODY FUNCTION IN HEART FAILURE

In this review, we summarize the present state of knowledge of the functional characteristics of the carotid body (CB) chemoreflex with respect to control of sympathetic nerve activity (SNA) in chronic heart failure (CHF). Evidence from both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in SNA. This adaptive change derives from altered function at the level of both the afferent and central nervous system (CNS) pathways of the reflex arc. At the level of the CB, an elevation in basal afferent discharge occurs under normoxic conditions in CHF rabbits, and the discharge responsiveness to hypoxia is enhanced. Outward voltage-gated K(+) currents (I(K)) are suppressed in CB glomus cells from CHF rabbits, and their sensitivity to hypoxic inhibition is enhanced. These changes in I(K) derive partly from downregulation of nitric oxide synthase (NOS)/NO signaling and upregulation of angiotensin II (Ang II)/Ang II receptor (AT(1)R) signaling in glomus cells. At the level of the CNS, interactions of the enhanced input from CB chemoreceptors with altered input from baroreceptor and cardiac afferent pathways and from central Ang II further enhance sympathetic drive. In addition, impaired function of NO in the paraventricular nucleus of the hypothalamus participates in the increased SNA response to CB chemoreceptor activation. These results underscore the principle that multiple mechanisms involving Ang II and NO at the level of both the CB and CNS represent complementary and perhaps redundant adaptive mechanisms to enhance CB chemoreflex function in CHF.

Role of blood flow in carotid body chemoreflex function in heart failure.

Activation of the sympathetic nervous system hastens the rate of progression and severity of chronic heart failure (CHF). Chemically sensitive nerves in the carotid body (CB) that stimulate sympathetic nerve activity become overly active in CHF and contribute to this phenomenon. The stimulus for activation of these CB chemoreceptors is not known. Blood supply to tissues is impaired due to the failing heart. In this study we tested whether a chronic reduction in blood flow to the CB may contribute to altered CB chemoreceptor function. The results show that changes that occur in CB chemoreceptor function during CHF are identical to those that occur if blood flow is simply reduced to the CB for several weeks. The results suggest that chronic impairment of blood flow may be the key step in the pathophysiological events that cause sympathetic nervous system activation in heart failure.

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.