Sympathetic Nervous Activation in Essential Hypertension
2010; Lippincott Williams & Wilkins; Volume: 55; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.110.151506
ISSN1524-4563
Autores Tópico(s)Cardiovascular Syncope and Autonomic Disorders
ResumoHomeHypertensionVol. 55, No. 5Sympathetic Nervous Activation in Essential Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSympathetic Nervous Activation in Essential HypertensionCommonly Neglected as a Therapeutic Target, Usually Ignored as a Drug Side Effect Murray Esler Murray EslerMurray Esler From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Originally published5 Apr 2010https://doi.org/10.1161/HYPERTENSIONAHA.110.151506Hypertension. 2010;55:1090–1091Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 5, 2010: Previous Version 1 Inappropriate and excessive activation of the sympathetic nervous system has been invoked as a cause of coronary heart disease. This pathophysiological linkage can take 2 forms. The most direct and explicit is when acute sympathetic nervous activation triggers adverse cardiac events (myocardial infarction, atrial fibrillation, ventricular arrhythmias, and Takotsubo cardiomyopathy have all been documented) during acute severe mental stress.1 Systematic evidence has been gathered at times of disasters, including war, missile attacks on civilians, and earthquakes, that strongly supports this proposition. The recently published and already celebrated analysis of coronary heart disease clinical presentations in German nationals in Munich during the 2006 Fédération Internationale de Football Association World Cup provides a telling example in demonstrating a dose-response relationship of the level of acute mental stress (judged from the closeness of the contest and the particular relevance of the result to Germany), and presumably sympathetic nervous activation, to cardiac events.2The case is no less strong that chronic sympathetic activation is similarly adverse. In patients with heart failure, the cardiac sympathetic outflow is preferentially and often very highly activated. The level of this stimulation of the cardiac sympathetic outflow is directly related to reduced survival.3 β-Adrenergic blocking drugs break this link. Similarly, in patients with end-stage renal disease, the very high level of sympathetic activity, which is equal to that present in heart failure, almost certainly contributes directly to cardiovascular mortality.4 A similar claim has been made for depressive illness that the sympathetic activation present in the heart5 underlies the increased cardiovascular mortality that exists, but here the case is less certain.In patients with essential hypertension, sympathetic activation is also common, present in perhaps 50% of patients.6 Recent evidence with endovascular radiofrequency ablation of the renal sympathetic nerves in patients with drug-resistant hypertension suggests that this activation of the sympathetic nervous system sustains the blood pressure elevation.6 Perhaps this sympathetic nervous activation in essential hypertension, much as for cardiac failure, contributes directly to mortality, having a detrimental influence in addition to the blood pressure elevation?7 If this is true, the sympathetic nervous system stimulation produced by some antihypertensive drugs (diuretics and dihydropyridine calcium channel blockers being examples8,9) might be harmful.These considerations provide the backdrop to the interesting article by Wray and Supiano,10 who studied the effect of chronic oral dosing with hydrochlorothiazide on sympathetic nervous system activity in patient with hypertension and compared this with the effect of aldosterone antagonism with spironolactone. The patients with hypertension studied were elderly, the authors reasoning that, in the elderly, any drug-induced sympathetic activation would be doubly pertinent, superimposed as it would be on the sympathetic activation, which accompanies aging. Very emphatically, the sympathetic nervous activation anticipated with spironolactone was not seen, with clear cut sympathetic inhibition being documented. This was surprising given the contrary effect on sympathetic tone seen with sodium depletion produced by either a diuretic8 or dietary sodium restriction.11 Brain mineralocorticoid receptors mediating excitation of central nervous system sympathetic outflow have been described12; the effect of antagonizing these (lowered sympathetic tone) must have overridden any sympathetic stimulation from sodium depletion. Perhaps this sympathetic inhibition contributed to the blood pressure reduction being greater with spironolactone than hydrochlorothiazide in the study by Wray and Supiano.10 The sympathetic activation from sodium depletion, which preferentially involves the renal sympathetic outflow,11 is adaptive, promoting a counterbalancing renal retention of sodium.6Of the differing methods used for investigating the sympathetic nervous system in clinical research, each have strengths and weaknesses.8 The method used by Wray and Supiano,10 a 2-compartment radiotracer kinetic method, has definite strengths, but perhaps one weakness. The principal strength is that the appearance rate of the sympathetic transmitter, norepinephrine, in the extravascular space, "NE2" in the authors' notation, can be measured. This provides very specific information on whole body norepinephrine flux into the sympathetic synapse and beyond into the interstitial space. The measured value is larger, and the measurement has somewhat greater analytic power than the commonly used whole body norepinephrine "spillover" measurement,8,11 which represents the appearance rate of norepinephrine in the plasma (vascular) compartment. Wray and Supiano10 found that spironolactone lowered the appearance rate of norepinephrine in the extravascular space but did not materially reduce norepinephrine spillover to plasma. The former is the more instructive measurement, and the finding is to be trusted.But there is one limitation with their technique that, in contrast to measurement of regional norepinephrine spillover from individual organs and clinical microneurography measuring the sympathetic neural discharge in efferent fibers passing to the skeletal muscle vasculature, provides no information on regional sympathetic outflows. Sympathetic nervous system responses are sometimes regionalized, where one sympathetic outflow may be activated although another may be unchanged or inhibited.8,11,13 Sodium depletion in humans, in fact, provides a case in point, activating the renal sympathetic outflow but leaving the cardiac sympathetic outflow unchanged.11 What effect spironolactone has on regional sympathetic outflows would be of particular interest. Does the drug inhibit the renal sympathetic outflow, which would contribute directly to the antihypertensive effect by minimizing adaptive renal mechanisms of sodium retention? In addition, does spironolactone inhibit the cardiac sympathetic outflow, which might reduce cardiac risk in those elderly patients with essential hypertension who have prevailing high levels of cardiac sympathetic activity? The answer to both questions may well be "yes," but the methodology does not allow us to be sure.Let us return to the premise that persisting high sympathetic nervous system activity constitutes a cardiac "risk factor." This is plausible but perhaps needs to be established on a case-by-case basis. One determinant might be the regional pattern of sympathetic activation, specifically whether the cardiac sympathetic outflow is activated. This applies with the sympathetic activation accompanying cardiac failure3 and depressive illness5 but not with that caused by sodium depletion11 or obesity.13 Another prerequisite might be whether myocardial injury exists, as it does in heart failure, to provide a fertile field for sympathetically mediated cardiac complications. Another factor of importance no doubt is the level of cardiac sympathetic nerve firing, which is very high indeed in cardiac failure.3 In essential hypertension, the level of activation of the cardiac sympathetic outflow is sufficient to contribute to the development of left ventricular hypertrophy7 and perhaps also to atrial fibrillation. Consideration of the efficacy and safety of dihydropyridine calcium channel blocking antihypertensive drugs, however, indicates that chronic sympathetic nervous system stimulation is not invariably harmful. Suspicions that the chronic sympathetic activation produced by this drug class9 may be toxic to the heart, even with the currently used longer acting drug formulations, were soundly disproved in the recent Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension Trial.14The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresM.E. has received research grants, consultancy fees, and served as a study clinical investigator for Ardian Corporation.FootnotesCorrespondence to Murray Esler, PO Box 6492, St Kilda Road, Central Melbourne, Vic 8008, Australia. E-mail [email protected] References 1 Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999; 99: 2192–2217.CrossrefMedlineGoogle Scholar2 Wilbert-Lampen U, Leistner D, Greven S, Pohl T, Sper S, Volker C, Guthlin D, Plasse A, Knez A, Kuchenhoff H, Steinbeck G. Cardiovascular events during World Cup soccer. N Engl J Med. 2008; 358: 475–383.CrossrefMedlineGoogle Scholar3 Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995; 26: 1257–1263.CrossrefMedlineGoogle Scholar4 Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Cataliotti A, Stancanelli B, Malatino LS, Cateliotti A. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation. 2002; 105: 1354–1359.CrossrefMedlineGoogle Scholar5 Barton DA, Dawood T, Lambert EA, Esler MD, Haikerwal D, Hotchkin E, Brenchley C, Socratous F, Kaye DM, Schlaich MP, Hickie I, Lambert GW. Sympathetic activity in major depressive disorder: Identifying those at increased cardiac risk? J Hypertens. 2007; 25: 2117–2124.CrossrefMedlineGoogle Scholar6 DiBona GF, Esler MD. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2010; 298: R245–R253.CrossrefMedlineGoogle Scholar7 Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003; 108: 560–565.LinkGoogle Scholar8 Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions. Physiol Rev. 1990; 70: 963–985.CrossrefMedlineGoogle Scholar9 Ruzicka M, Leenen FHH. Relevance of intermittent increases in sympathetic activity for adverse outcome on short acting calcium antagonists. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press; 1995: 2815–2825.Google Scholar10 Wray DW, Supiano MA. Impact of aldosterone receptor blockade compared with thiazide therapy on sympathetic nervous system function in geriatric hypertension. Hypertension. 2010; 55: 1217–1223.LinkGoogle Scholar11 Friberg P, Meredith I, Jennings G, Lambert G, Fazio V, Esler M. Evidence of increased renal noradrenaline spillover rate during sodium restriction in man. Hypertension. 1990; 16: 121–130.LinkGoogle Scholar12 Gomez-Sanchez EP. What is the role of the central nervous system in mineralocorticoid hypertension. Am J Hypertens. 1991; 4: 374–381.CrossrefMedlineGoogle Scholar13 Vaz M, Jennings G, Turner A, Cox H, Lambert G, Esler M. Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation. 1997; 96: 3423–3429.CrossrefMedlineGoogle Scholar14 Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359: 2417–2428.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bardsley E and Paterson D (2018) Neurocardiac regulation: from cardiac mechanisms to novel therapeutic approaches, The Journal of Physiology, 10.1113/JP276962, 598:14, (2957-2976), Online publication date: 1-Jul-2020. Bardsley E, Davis H, Ajijola O, Buckler K, Ardell J, Shivkumar K and Paterson D (2018) RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity, Scientific Reports, 10.1038/s41598-018-26651-7, 8:1, Online publication date: 1-Dec-2018. 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Lenders J and Eisenhofer G (2014) Pathophysiology and Diagnosis of Disorders of the Adrenal Medulla: Focus on Pheochromocytoma Comprehensive Physiology, 10.1002/cphy.c130034, (691-713) Charkoudian N and Wallin B (2014) Sympathetic Neural Activity to the Cardiovascular System: Integrator of Systemic Physiology and Interindividual Characteristics Comprehensive Physiology, 10.1002/cphy.c130038, (827-850) May 2010Vol 55, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.110.151506PMID: 20368501 Originally publishedApril 5, 2010 PDF download Advertisement SubjectsClinical StudiesPharmacology
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