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Aim. To identify the role of the autonomic nervous system in stress cardiomyopathy in an experimental model of Takotsubo syndrome.Materials and methods. The study was carried out on 120 female Wistar rats. Stress modeling was performed by immobilizing animals on the back for 24 hours. Intact rats were used as controls. The rats were decapitated after termination of immobilization under general anesthesia with ether. Stress cardiomyopathy (SCM) was quantified by accumulation of 99mTc pyrophosphate radiopharmaceutical (99mTc PP) in the myocardium. The pharmacological agents used included the ganglionic blocker hexamethonium, administered five times at a dose of 20 mg / kg; guanethidine (50 mg / kg) administered subcutaneously once a day for three days, the last injection was performed 24 hours before immobilization; the muscarinic receptor antagonist atropine methyl nitrate (1 mg / kg); the α1-AR (adrenergic receptor) antagonist prazosin (2 mg / kg); the α2-AR antagonist yohimbine, administered at a dose of 2 mg / kg; the β1-AR antagonist nebivolol (1.2 mg / kg); the β2-AR antagonist ICI 118,551 (0.3 mg / kg); and the β3-AR antagonist L-748337 (0.1 mg / kg).Results. Three-day administration of guanethidine caused a decrease in the degree of 99mTc-PP accumulation in the heart by 35.9%. Hexamethonium did not affect the degree of SCM. The blockade of the muscarinic receptor caused an increase in accumulation of 99mTc-PP by 26.5%. Inhibition of α1-AR did not affect SCM. The blockade of α2-AR caused a 2.2-fold increase in the accumulation compared with stress control. The blockade of β1-AR reduced 99mTc-PP accumulation by 2.5 times. The blockade of β2-AR by ICI 118,551 increased the degree of 99mTcPP accumulation by 34.6%. Inhibition of β3-AR had no effect on SCM.Conclusion. The adrenergic system and β1-adrenergic receptor play an important role in the development of SCM. The parasympathetic nervous system ensures resistance of the heart to stress.

The present study aimed to investigate the effects of the combination of Marukome Nenrin miso, which has natriuretic effects, and Marukome MK-34-1 miso, which has potent angiotensin converting enzyme inhibitory effects, on blood pressure (BP) in humans. A total of 40 subjects aged 40–69 years with high-normal BP or stage I hypertension were randomly assigned to two groups: 1) the miso group (32 g 2:1 w/w Nenrin and MK-34-1 with 3.8 g salt/day) or 2) the control soy food group (14.4 g soy food with 0.2 g salt/day). The levels of major nutrients were equal in the miso and control food servings, except for the fiber and Na levels, which were higher in the miso food serving. Daytime and nighttime BP were measured with an automated BP monitor. Compared with the soy food intake, miso intake for 8 weeks did not affect daytime clinical BP but significantly decreased nighttime BP without affecting pulse rate (PR). Moreover, miso shifted the nighttime BP profile to lower levels than those at baseline. Soy food intake did not change the nighttime BP profile after 8 weeks. Miso intake also tended to reduce nighttime BP in a subgroup with stage 1 hypertension compared with the results of the soy food group participants and shifted the nighttime BP profile toward lower levels than those recorded at baseline. Miso intake did not influence lipid or glucose metabolism. In conclusion, this is the first report showing that miso reduces nighttime BP in humans. Miso may do so by shrinking the fluid spaces in the body and/or deactivating the adrenergic nervous system.

Cardiovascular diseases such as heart failure and metabolic syndrome have high prevalence in the elderly population and are leading causes of death, disability, hospitalization, driving high healthcare costs worldwide. To reduce this social and economic burden there is urgency to find effective therapeutic targets. Several studies have linked the dysfunction of the Sympathetic Nervous System and β-adrenergic receptor signaling with the pathogenesis of age-related cardiovascular diseases. Therapeutic treatments that restore their functions have been shown to be effective in subjects with cardiovascular comorbidities. In fact, lifestyle interventions (such as exercise training and diet) as well as pharmacologic treatments (e.g. β-blockers or moxonidine) and mini-invasive interventions (renal sympathetic denervation) have beneficial effects on age-related cardiovascular diseases. In the current "Medicine in focus" article we will discuss the pathogenic role of the Sympathetic Nervous System in age-related cardiovascular diseases as well as current and new therapeutic approaches.

The prevalence of heart failure (HF) has increased in the last decades, particularly in the older population. In parallel with the increase in prevalence, costs with infrastructure to hospitalize and treat these patients have also increased. Coronary heart disease remains the most directly related to HF; however, other causes and comorbidities should be taken into account depending on the region studied. Cardiac adrenergic assessment through imaging examinations allows us to get a few robust parameters using semiquantitative analysis which have a great potential in the evaluation of abnormal findings. Myocardial scintigraphy with 123I-mIBG plays an important role in the assessment of HF for risk-stratifying cardiac events. mIBG is an analog of norepinephrine (NE), which can be used to evaluate cardiac sympathetic activity by analyzing the decrease in adrenoreceptor expression in HF. Standardization and validation may contribute to its acceptance and routine use in clinical practice.

Natural killer (NK) cells are critical for protection against viruses. Diaz-Salazar et al. show that adrenergic neurons modulate the adaptive NK cell response in a cell-intrinsic manner. This study identifies the nervous system as a novel axis through which antigen-specific NK cell responses are regulated., Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by the adrenergic nervous system, and demonstrate that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the β2-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell–specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Taken together, we propose a novel role for the adrenergic nervous system in regulating circulating lymphocyte responses to viral infection.

A new report shows that upregulation of the receptor TREM1 on macrophages and neutrophils, dependent on the adrenergic nervous system, links stroke to systemic inflammation and gut barrier dysfunction, which result in bacterial translocation and exacerbation of neurological damage.

Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.

Acute stressor states are linked to neurohormonal activation that includes the adrenergic nervous system. Elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K+ and Mg2+ based on their regulation of a large number of Mg2+-dependent Na+-K+-ATPase pumps present in skeletal muscle. The hyperadrenergic state accounts for a sudden translocation of cations into muscle with the rapid appearance of hypokalemia and hypomagnesemia. The resultant hypokalemia and hypomagnesemia will cause a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for supraventricular and ventricular arrhythmias. In this review, we focus on the interdependency between K+ and Mg2+, which is clinically relevant to acute hyperadrenergic stressor states found in patients admitted to intensive care units.

Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during β-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the β-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of β1 and β2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under β-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the β-adrenergic modulation of Ca2+ handling in failing hearts., MF-V is Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). This work was supported by grants PI14/01078, CP15/00129, PI17/01093, and PI17/01344 from ISCIII, Fondo Europeo de Desarrollo Regional (FEDER Ministerio de Economía y Competitividad of Spain (SAF2014-57190-R; SAF2017-84777-R), FSE, and CIBER-CV, a network funded by ISCIII.

Purpose Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since $\alpha$1-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the $\alpha$2-adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective $\alpha$-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration o a non-selective $\alpha$-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives. Methods The $\alpha$1- and $\alpha$2-adrenoreceptor affinities of the tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl) pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a highfat diet, and additionally we measured the spontaneous activity and body temperature. Results The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of $\alpha$1B and $\alpha$2A-adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals' spontaneous activity and body temperature. Conclusion Non-selective $\alpha$-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe $\alpha$2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.

Heightened cardiac adrenergic nervous system (ANS) activity and progression of left ventricular (LV) remodeling are temporally related in patients with systolic heart failure. Whether cardiac ANS activation directly contributes to or merely accompanies LV remodeling remains an unresolved issue. Human and experimental data that directly link cardiac ANS activation to LV remodeling and worsening heart failure are first reviewed, including cardiac norepinephrine spillover. Alterations of beta adrenergic receptor signaling pathways are then addressed with emphasis on the mechanisms that may mediate the beneficial effect of beta adrenergic receptor blockade on LV remodeling. Lastly, alternative approaches to beta adrenergic receptor blockade for lessening cardiac ANS activation and reversing cardiac ANS-induced LV remodeling are discussed. A large body of work now links LV remodeling to cardiac ANS activation. However, the precise mechanisms that link cardiac ANS activation to LV remodeling are still to be fully understood. Fully understanding of these mechanisms may uncover new therapeutic approaches.

I-metaiodobenzylguanidine (mIBG) Echocardiography Myocardial imaging Adrenergic nervous system Cardiac resynchronization therapy (CRT)

Oxidative stress and transcriptional pathways of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) are critically involved in the etiopathology of amebic liver abscess (ALA). In this work, we studied the relationship between the adrenergic nervous system and ALA in the hamster. ALA was visible at 12 h of infection. While 6-hydroxidopamine (6-OHDA) decreased infection, propranolol (β-adrenergic blocker) treatment was associated with less extensive liver damage, and phentolamine treatment (α-adrenergic blocker) significantly reduced ALA compared to 6-OHDA and propranolol. Serum enzymatic activities of alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GTP) were increased at 12 h post-infection. Chemical denervation and α and β-adrenergic blockers decreased ALT to normal levels, while 6-OHDA and propranolol showed a trend to decrease γ-GTP but phentolamine significantly reduced γ-GTP. Amebic infection increased oxidized glutathione (GSSG) and decreased both reduced glutathione (GSH) and the GSH/GSSG ratio. Propranolol and 6-OHDA showed a tendency to decrease GSSG. However, GSH, GSSG and GSH/GSSG returned to normal levels with phentolamine. Furthermore, amebic infection increased pNF-κB and interleukin-1β (IL-1β), and showed a tendency to decrease hemoxigenase-1 (HO-1), but not Nrf2. Chemical denervation showed a trend to decrease pNF-κB and IL-1β, and neither Nrf2 nor HO-1 increased significantly. In addition, NF-κB and IL-1β were attenuated by propranolol and phentolamine treatments, although phentolamine showed significant overexpression of Nrf2 and HO-1. This suggests that the adrenergic system may be involved in oxidative stress and in modulation of the Nrf2 and NF-κB pathways during ALA development.

Several studies have investigated the behavior of sympathetic cardiovascular drive in essential hypertension, providing conclusive evidence of the adrenergic activation characterizing this condition. These studies have also shown the importance of neuroadrenergic overdrive in the development and progression of the hypertensive state as well as in the pathogenesis of hypertension-related end-organ damage. The information available on the sympathetic nervous system's behavior in 'pseudo-resistant' and 'true resistant' hypertension is much more scarce. This paper will review the available knowledge on this issue by examining the data collected via indirect and direct approaches to investigate adrenergic function in resistant hypertension as well as the effects of pharmacological and non-pharmacological interventions.

Acute stressor states are inextricably linked to neurohormonal activation which includes the adrenergic nervous system. Consequent elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K+, Mg2+ and Ca2+. Catecholamines, for example, regulate the large number of Mg2+-dependent Na/K ATPase pumps present in skeletal muscle. A hyperadrenergic state accounts for a sudden translocation of K+ into muscle and rapid appearance of hypokalemia. In the myocardium, catecholamines promote Mg2+ efflux from cardiomyocytes, whereas intracellular Ca2+ influx and overloading account for the induction of oxidative stress and necrosis of these cells with leakage of their contents, including troponins. Accordingly, acute stressor states can be accompanied by nonischemic elevations in serum troponins, together with the concordant appearance of hypokalemia, hypomagnesemia and ionized hypocalcemia, causing a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for arrhythmias, including atrial fibrillation and polymorphic ventricular tachycardia. In this review, we focus on the interdependency between K+, Mg2+ and Ca2+ which are clinically relevant to acute stressor states.

The progressive nature of heart failure is linked to multiple factors, including an ongoing loss of cardiomyocytes and necrosis. Necrotic cardiomyocytes leave behind several footprints: the spillage of their contents leading to elevations in serum troponins; and morphologic evidence of tissue repair with scarring. The pathophysiologic origins of cardiomyocyte necrosis relates to neurohormonal activation, including the adrenergic nervous system. Catecholamine-initiated excessive intracellular Ca accumulation and mitochondria Ca overloading in particular initiate a mitochondriocentric signal-transducer-effector pathway to necrosis and which includes the induction of oxidative stress and opening of their inner membrane permeability transition pore. Hypokalemia, ionized hypocalcemia and hypomagnesemia, where consequent elevations in parathyroid hormone further account for excessive intracellular Ca accumulation, hypozincemia and hyposelenemia each compromise metalloenzyme-based antioxidant defenses. The necrotic loss of cardiomyocytes and adverse structural remodeling of myocardium is related to the central role played by a mitochondriocentric pathway initiated by neurohormonal activation.

Heart failure is an epidemic disease which affects about 1% to 2% of the population worldwide. Both, the etiology and phenotype of heart failure differ largely. Following a cardiac injury (e.g., myocardial infarction, increased preload or afterload) cellular, structural and neurohumoral modulations occur that affect the phenotype being present. These processes influence the cell function among intra- as well as intercellular behavior. In consequence, activation of the sympathoadrenergic and renin-angiotensin-aldosterone-system takes place leading to adaptive mechanisms, which are accompanied by volume overload, tachycardia, dyspnoea and further deterioration of the cellular function (vicious circle). There exists no heart failure specific clinical sign; the clinical symptomatic shows progressive deterioration acutely or chronically. As a measure of cellular dysfunction, the level of neurohormones (norepinephrine) and natriuretic peptides (e.g., NT-pro BNP) increase. For the diagnosis of heart failure, noninvasive (echocardiography, NMR, NT-proBNP) and invasive (heart catheterization, biopsy) diagnostic procedures are implemented. Modulation of the activated systems by ß-blocker, ACE-inhibitors and ARNI improve outcome and symptoms in heart failure patients with left ventricular dysfunction. Interventional and surgical therapy options may be performed as well. The understanding of the underlying pathophysiology of heart failure is essential to initiate the adequate therapeutic option individually for each patient. Furthermore, prevention of cardiovascular risk factors is essential to lower the risk of heart failure.

The effect of morphine on the cat choledochoduodenal junction was studied by means of different in vivo and in vitro methods. In vivo: Morphine (1-100 μg/kg) induced increased duodenal activity and increased resistance to flow through the sphincter of Oddi when given intravenously. Atropine (5 mg/kg intravenously) counteracted the effect of 1 μg/kg morphine intravenously on the choledochoduodenal tract, but was ineffective in preventing the spasm caused by slightly increased doses of morphine. Effective α-adrenoceptor blockade with dibenzyline (2 mg/kg) did not affect the action of morphine. Morphine (0.001–0.02 μg/kg) consistently produced increased duodenal activity and increased passage pressure through the sphincter when administered i.a. in the pancreatic duodenal artery. In vitro: The isolated sphincter and the isolated duodenum were insensitive to morphine in concentrations up to 80 μg/ml in the bath fluid. In vivo morphine is active locally in the cat choledochoduodenal tract but inactive when added to the bath fluid of the isolated sphincter of Oddi or duodenum. The results support the view that morphine exerts its spasmogenic effect on the sphincter region by the release of some endogenous contracting agent. This agent does not belong to the cholinergic or adrenergic nervous system but may be released from the vascular compartment by morphine.

Newborn rats were treated for 30 days with the adrenergic neurone-blocking drug debrisoquin sulphate. The doses used (50, 75 and 100 mg/kg intraperitoneally on days 1 to 5, 6 to 19 and 20 to 30, respectively) caused a high mortality rate during the first 10 days and a retardation of normal body weight development. A decrease in the formaldehyde-induced catecholamine fluorescence of the terminal adrenergic axons in the irides was observed 24 hours after termination of the treatment. This was reversible within 3 days. Histological, fluorescence histochemical and morphometric studies, and determinations of the activities of tyrosine hydroxylase and dopamine-β-hydroxylase performed 4 days after termination of the treatment did not reveal any changes in the classical long adrenergic neurones and in the adrenergic neurones innervating the vas deferens. In this respect, debrisoquin differs from certain other adrenergic neurone blocking drugs such as guanethidine, guanacline and bretylium, which all have been reported to damage sympathetic neurones. Hence the present results obtained with developing symphathetic neurones, which are more sensitive than mature neurones to various toxic influences, support the conclusion reached after experiments with adult rats (Haeusler et al. 1974), namely that induction of degeneration of adrenergic neurones is not a hazard common to all adrenergic neurone-blocking drugs.

Objective and methods Left ventricular hypertrophy in human and experimental hypertension is not always associated with pressure overload but seems to precede an increase in blood pressure. In this study, performed in male 5-week-old prehypertensive spontaneously hypertensive rats (SHR; n=65) and age-matched Wistar-Kyoto rats (n = 56), the relationship between myocardial structure and activation of the adrenergic and nitric oxide systems was evaluated. Results Body weight, blood pressure and heart rate were similar in both groups. A higher left ventricle/body weight ratio was found in SHR, as a result of greater mononuclear (+47%) and binuclear (+43%) myocyte volumes, without changes in interstitial collagen. Both adrenergic and nitric oxide pathways were activated in SHR, as expressed by higher myocardial norepinephrine content, tyrosine hydroxylase activity, myocardial nitric oxide synthase 3 expression and protein nitration, indicating greater peroxynitrite (ONOO - ) generation from nitric oxide and superoxide. No difference was measured in nitric oxide synthase 1 expression, whereas nitric oxide synthase 2 was undetectable. A positive correlation between myocardial tyrosine hydroxylase activity and protein nitration was observed in SHR (r2 = 0.328; P

This observational prospective study analyzed the effect of an incremental cardiopulmonary exercise test (CPET) on the secretion of salivary biomarkers of the adrenergic nervous system and hypothalamus-pituitary-adrenal (HPA) axis activity by measuring salivary α-amylase and cortisol diurnal trajectories in the setting of long-term hormone replacement therapy (HRT).Fifteen healthy sedentary postmenopausal women who were current HRT users and 15 women who had never used HRT were consecutively recruited. α-Amylase and cortisol were measured in salivary samples collected on the CPET day and on a rest day. Cardiovascular and respiratory fitness parameters were recorded during the CPET challenge.The participants had very homogeneous somatic characteristics, and they were all in generally good health. The postmenopausal never-HRT users presented an abnormal diurnal pattern of α-amylase at baseline and a flattened response to CPET. In contrast, women on HRT had a physiological α-amylase diurnal pattern and increased salivary α-amylase production during the CPET-induced challenge. The CPET challenge physiologically activated the HPA axis activity, as shown by the increase in the concentration of salivary cortisol during the effort test. HPA axis activity was not affected by long-term HRT. Postmenopausal women using HRT exhibited a cardiorespiratory functional capacity that was significantly (p0.05) higher than that of non-users.Our findings show that healthy postmenopausal women present an asymmetry between adrenergic nervous system and HPA axis activities under both basal and stress conditions. HRT was able to modify the abnormal adrenergic nervous system activity, most likely by reducing the sympathetic hyperactivity that characterizes menopause.

The adrenergic (or sympathetic) branch of the autonomic nervous system plays an integral role in the regulation of cardiovascular physiology. Although not essential for life (as the cholinergic or parasympathetic nervous system is), the adrenergic nervous system (ANS) is evolutionarily selected to prepare the cardiovascular system of mammals, so that the whole organism can orchestrate a whole-body response to an acute stress condition (the so-called fight or flight response). Thus, cardiovascular ANS activation results in increased cardiac function (stronger and more frequent contraction to pump more blood to the periphery), constriction of cutaneous or subcutaneous (body surface) vessels, and dilatation of skeletal muscle and renal vessels, so that more blood gets sequestered from the periphery into the central circulation, thereby increasing venous blood return to the heart (which also increases cardiac function via the Frank–Starling mechanism) in order for more blood to be pumped out upon the next cardiac contraction. These ANS effects, in conjunction with its effects in other organ systems (e.g., bronchodilatation in the lungs), prime the cardiovascular system for participation in the whole body’s response to a stressful stimulus. In pathological conditions, however, the cardiovascular ANS gets aberrantly and chronically activated, contributing significantly to the morbidity and the mortality of almost every chronic cardiovascular disease, including heart failure, angina pectoris (coronary artery disease), and hypertension. This introductory chapter discusses some of the basic principles of ANS biology and function in the mammalian cardiovascular system (heart and blood vessels).

The adrenergic system is an important regulator of cardiovascular function. Noradrenaline is secreted from sympathetic nerves and activates postsynaptic G-protein-coupled receptors, adrenoceptors, in the heart and vasculature. Adrenaline is released from chromaffin cells of the adrenal medulla and it reaches its target cells as a hormone via the blood stream. Adrenaline and noradrenaline stimulate cardiovascular function by raising blood pressure, heart rate, and cardiac output. The release of noradrenaline and adrenaline is modulated by short feedback loops containing α2-adrenoceptors. Presynaptic α2A-adrenoceptors inhibit catecholamine secretion from sympathetic nerves and from adrenal chromaffin cells. In heart disease, structure and function of the adrenergic system are altered. In heart failure, diminished cardiac function activates baroreflex mechanisms leading to increased sympathetic outflow to sympathetic nerves and the adrenal gland. Desensitization of inhibitory feedback α2-adrenoceptors further enhances catecholamine release. In addition, signaling molecules including nerve growth factor (NGF) or leukemia inhibitory factor (LIF) which are produced by cardiomyocytes modulate sympathetic structure and neuronal phenotypes. Further insights into the molecular mechanisms of the function and structure of the adrenergic nervous system are expected to result in novel therapeutic strategies for heart failure and other cardiovascular diseases.

The adrenergic nervous system is a crucial regulator of cardiovascular homeostasis, both in physiological and pathological conditions. It fine-tunes heart rate, cardiac contractility, vascular constriction/relaxation as well as atrioventricular conduction. The actions of the adrenergic nervous system are mediated by catecholamine binding to the different adrenergic receptor (AR) subtypes. The ARs belong to the superfamily of G-protein-coupled receptors. To date, a total of three types and nine subtypes of ARs have been identified and classified into α1-AR (α1A, α1B, α1D), α2-AR (α2A, α2B, α2C), and β-AR (β1, β2, β3). All ARs primarily signal through heterotrimeric G proteins. Importantly, signaling through these receptors is finely regulated, and receptor activation also triggers regulatory processes that are responsible for receptor dysfunctional signaling in several cardiovascular diseases, including chronic heart failure (HF). The present chapter discusses the role of the adrenergic nervous system in cardiac physiology and in the pathophysiological model of HF, the mechanisms of regulation of sympathetic activity, and how they are dysfunctional in HF, the molecular alterations in heart physiology that occur in HF.