Published online before print March 6, 2008, doi: 10.1161/CIRCRESAHA.107.165183
© 2008 American Heart Association, Inc.
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Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart
From the Department of Physiology, University College London, United Kingdom.
Correspondence to Alexander V. Gourine, PhD, Department of Physiology, University College London, Gower St, London WC1E 6BT, United Kingdom. E-mail a.gourine{at}ucl.ac.uk
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Abstract |
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Heart failure patients are routinely given β-adrenoceptor antagonists (β-blockers), although the mechanism(s) underlying their beneficial effects is not fully resolved. It is not entirely clear how long-term application of negative inotropic compounds improves cardiac performance, slows remodeling processes, and decreases mortality. All β-blockers, which produce a beneficial effect in heart failure, have in common a high degree of lipophilicity and, therefore, have the ability to cross the blood–brain barrier. Here, we show that blockade of β-adrenoceptors directly in the brain (chronic intracerebroventricular administration of metoprolol) attenuates the progression of left ventricular remodeling in a rat model of myocardial infarction-induced heart failure. These results provide the first direct evidence that the action of certain β-blockers in the brain could contribute to their beneficial effect on the failing heart.
Key Words: central nervous system • β-blockers • heart failure • left ventricular remodeling • myocardial infarction
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Mortality associated with heart failure (HF) still remains high, despite considerable achievements in medical therapy, device technology, and cardiac surgery. The use of β-adrenoceptor (β-AR) antagonists (β-blockers) pioneered in the 1970s for the treatment of arterial hypertension became one of the most important advances in HF therapy.1,2 The efficacy of 3 β-blockers, bisoprolol, carvedilol, and metoprolol, in HF treatment have been demonstrated in large placebo-controlled clinical trials.3–5 These studies have revealed a reduction in the number of deaths from worsening HF in patients treated with carvedilol and metoprolol resulting from an improvement in left ventricular (LV) function and a delayed progression of LV remodeling.3,4 In contrast, bisoprolol decreased mortality mainly by preventing sudden cardiac death,5 whereas several β-blockers (eg, bisindolol and others) have been found to be insufficiently effective to be used in HF therapy.2
A number of mechanisms explaining variable effects of β-blockers in HF patients have been proposed (including polymorphism in the genes encoding β-ARs, modulation of systemic neurohormonal activity, antagonism of the toxic actions of norepinephrine on the myocardium, favorable effects on myocardial energetics, etc).2,6,7 Interestingly, it appears that the β-blockers, which produce a beneficial effect in HF, all have in common a high degree of lipophilicity and, as a result, have the ability to cross the blood–brain barrier.2,8 Beneficial actions of certain lipophilic β-blockers in preventing ventricular fibrillation have already been attributed to their possible action within the brain.9 We, therefore, suggested that the favorable effects of β-blockers in HF may be attributable, at least in part, to their central nervous system (CNS) effects. To test this hypothesis, we infused metoprolol (a β1-blocker widely used in HF therapy) directly into the brain and determined the effect of this treatment on the progression of LV remodeling after myocardial infarction (MI) in rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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MI in rats was induced using a permanent coronary occlusion (CO) technique.10 Metoprolol was given into the third cerebral ventricle (ICV) 48 hours after the MI and twice daily thereafter for 6 weeks. The rats were randomized into 5 groups: (1) post-MI/artificial cerebrospinal fluid (aCSF) (animals with CO receiving ICV injections of aCSF [3 µL]); (2) post-MI/metoprolol (rats with CO receiving ICV injections of metoprolol [25 µg, 3 µL]); (3) sham/aCSF (sham-operated animals receiving ICV injections of aCSF [3 µL]); (4) sham/metoprolol (sham-operated animals receiving ICV injections of metoprolol [25 µg, 3 µL]); and (5) post-MI/metoprolol, IP (rats with CO receiving metoprolol [25 µg, 0.1 mL] intraperitoneally). Hemodynamic studies were performed 6 weeks after the surgery. Arterial pressure, heart rate (HR), LV pressure, the maximum rate of rise of LV pressure (LV dP/dtmax), LV end-diastolic pressure were recorded under urethane (1.5 g/kg) anesthesia. At the end of the hemodynamic studies, LV pressure–volume relationships, LV volume, and LV infarct sizes were determined. In separate experiments in control rats, the effects of metoprolol applied ICV or into the specific hypothalamic and brain stem regions on HR were determined. Distribution of β1-ARs in the brain stem regions involved in cardiovascular control was evaluated using specific antibodies. Data (means±SEM) were compared by ANOVA, followed by the Tukey–Kramer’s post hoc test to determine the main group effect. Values of P<0.05 were considered to be significant. An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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LV remodeling is defined as progressive loss of ventricular function along with LV dilatation.11 In this study, rats from all post-MI groups were assigned into 2 groups (those with small infarcts [
30%] and those with large infarcts [>30%] representing patients with different degrees of ischemic myocardial damage). Progression of LV remodeling and development of HF in rats is associated with elevated LV end-diastolic pressure, increased LV volume, and a shift to the right of the LV pressure–volume relationship curve (greater LV volume at any given LV pressure) (Figure 1). These data are consistent with previous observations in rats.10,12–14 In rats with small infarcts, β-AR blockade in the brain maintained nearly normal LV end-diastolic pressure (P=0.008 compared with values obtained in post-MI animals treated ICV with aCSF), LV volume to LV weight ratio (P=0.005 in comparison with post-MI/aCSF group) and prevented the right shift of the LV pressure–volume curve (Figure 1A). In rats with large infarcts, metoprolol attenuated the rise in LV end-diastolic pressure (P=0.047, compared with post-MI/aCSF group), although changes in LV geometry and LV pressure–volume relationships were unaffected (Figure 1B). There were no differences between experimental groups with comparable infarcts in heart weights and hemodynamic variables examined (Table I in the online data supplement).
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Metoprolol given systemically in this exact dose (25 µg) was completely ineffective (Figure 1), excluding the possibility that when infused into the third cerebral ventricle, it was "leaking" out of the brain and exerting its beneficial action at some peripheral target(s). This result was somewhat predictable because the amounts of metoprolol given in this study were at least 1000 times lower than the doses required to attenuate LV remodeling in HF rats during chronic systemic administration.14 We conclude, therefore, that attenuation of LV remodeling occurs when metoprolol is acting at the sites located within the brain. The effect of central nervous β-AR blockade appears to be more prominent when ischemic myocardial damage is less severe. These results correlate well with the recent clinical data indicating that metoprolol is highly effective in patients with asymptomatic LV systolic dysfunction.4
Development of HF is associated with an increase in the activity of the sympathetic nervous system,6,15,16 which is believed to be maladaptive and detrimental, contributing to the progression of LV remodeling.6,17 Therefore, we determined whether β-AR blockade in the brain has an effect on sympathetic outflow to the heart. We analyzed metoprolol-induced changes in HR following systemic pretreatment with atenolol, a hydrophilic β1-blocker with a limited ability to cross the blood–brain barrier,8 or the M-cholinoreceptor antagonist atropine. It was found that the magnitude of the decrease in HR evoked by injection of metoprolol into the brain was not affected in conditions when parasympathetic input to the heart was interrupted by atropine (Figure 2A). In contrast, when sympathetic drive was blocked by atenolol, metoprolol had no effect on HR (Figure 2A), indicating that blockade of β-ARs in the brain decreases sympathetic outflow to the heart.
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) indicate locations in which microinjection of metoprolol (1 µg) decreased HR (*P=0.0005). Arterial blood pressure was not affected (data not shown). D and E, Low- and high-power photomicrographs of the dorsal part of the medulla oblongata showing profound expression of β1-ARs in the cNTS. Scale bars=250 µm (d); 50 µm (e). AH indicates anterior hypothalamus; AP, area postrema; CC, central canal; DVN, dorsal motor nucleus of the vagus nerve; NA, nucleus ambiguus; PVN, paraventricular nucleus of the hypothalamus; RN, raphe nucleus; rNTS, rostral NTS; RVLM, rostroventrolateral medulla; and XII, hypoglossal nucleus.To reveal the putative site(s) of β1-blocker action within the brain, we microinjected metoprolol into the main hypothalamic and brain stem structures involved in cardiovascular control (Figure 2B). A significant decrease in HR was observed only when metoprolol was injected into the caudal part of the medullary nucleus of the solitary tract (cNTS) (Figure 2B and 2C). Metoprolol injected into the paraventricular nucleus of the hypothalamus, anterior hypothalamus, rostral NTS, nucleus ambiguus, raphe nucleus, area postrema, dorsal motor nucleus of the vagus nerve, or rostroventrolateral medulla had no effect on HR. The presence of β1-ARs in the cNTS was confirmed immunohistochemically (Figure 2D and 2E).
The data demonstrating the importance of the brain mechanisms in progression of HF have been reviewed recently.16 This study is from the same genre; it provides the first direct evidence that an action of β-blockers within the CNS could contribute to their beneficial effect on the failing heart. The decrease in sympathetic outflow to the heart following blockade of β1-ARs in the CNS seems particularly significant because detrimental sympathetic activation is believed to play an important role in the pathophysiology of HF. The cNTS is one of the possible sites of β-blockers action. Taken together, this study demonstrates the existence of previously unrecognized central nervous β-AR mechanism, the blockade of which is beneficial in HF, and may help to identify novel therapeutic strategies for HF treatment aimed at targeting sites within the brain. An expanded Discussion section is available in the online data supplement.
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Acknowledgments |
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We thank Prof Arnfinn Ilebekk, Prof Per-Ove Sjöquist, and Dr Oleg Osadchii for helpful discussions and critical reviews of the manuscript.
Sources of Funding
This study was supported by The Peter Samuel Royal Free Fund.
Disclosures
None.
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Footnotes |
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Original received October 3, 2007; revision received January 16, 2008; accepted February 25, 2008.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
1. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. 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. 2005; 112: e154–e235.
2. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen C. Expert consensus document on β-adrenergic receptor blockers. Eur Heart J. 2004; 25: 1341–1362.
3. Poole-Wilson PA, Swedberg K, Cleland JG, Di LA, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A. 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. Lancet. 2003; 362: 7–13.[CrossRef][Medline] [Order article via Infotrieve]
4. Colucci WS, Kolias TJ, Adams KF, Armstrong WF, Ghali JK, Gottlieb SS, Greenberg B, Klibaner MI, Kukin ML, Sugg JE. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation. 2007; 116: 49–56.
5. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999; 353: 9–13.[CrossRef][Medline] [Order article via Infotrieve]
6. Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of β-adrenergic signaling in heart failure? Circ Res. 2003; 93: 896–906.
7. Feldman DS, Carnes CA, Abraham WT, Bristow MR. Mechanisms of disease: β-adrenergic receptors-alterations in signal transduction and pharmacogenomics in heart failure. Nat Clin Pract Cardiovasc Med. 2005; 2: 475–483.[CrossRef][Medline] [Order article via Infotrieve]
8. Neil-Dwyer G, Bartlett J, McAinsh J, Cruickshank JM. β-Adrenoceptor blockers and the blood-brain barrier. Br J Clin Pharmacol. 1981; 11: 549–553.[Medline] [Order article via Infotrieve]
9. Parker GW, Michael LH, Hartley CJ, Skinner JE, Entman ML. Central β-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs. Circ Res. 1990; 66: 259–270.
10. Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E. Myocardial infarct size and ventricular function in rats. Circ Res. 1979; 44: 503–512.
11. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990; 81: 1161–1172.
12. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction. Effects on systolic function. Circ Res. 1981; 49: 618–626.
13. Wang H, Huang BS, Ganten D, Leenen FH. Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen. Circ Res. 2004; 94: 843–849.
14. Prabhu SD, Chandrasekar B, Murray DR, Freeman GL. β-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation. 2000; 101: 2103–2109.
15. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984; 311: 819–823.[Abstract]
16. Leenen FH. Brain mechanisms contributing to sympathetic hyperactivity and heart failure. Circ Res. 2007; 101: 221–223.
17. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992; 20: 248–254.[Abstract]
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