This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Azevedo, E. R. Articles by Parker, J. D. Search for Related Content PubMed PubMed Citation Articles by Azevedo, E. R. Articles by Parker, J. D. Related Collections Congestive Cardiovascular Pharmacology

(Circulation. 2001;104:2194.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Nonselective Versus Selective ß-Adrenergic Receptor Blockade in Congestive Heart Failure

Differential Effects on Sympathetic Activity

Eduardo R. Azevedo, MD; Toshihiko Kubo, MD; Susanna Mak, MD; Abdul Al-Hesayen, MD; Anne Schofield, RN; Rebecca Allan, RN; Susan Kelly, RN; Gary E. Newton, MD; John S. Floras, MD, DPhil; John D. Parker, MD

From the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario, and the Section of Cardiology, Department of Medicine, St Boniface Hospital, University of Manitoba (E.R.A.), Winnipeg, Canada.

Correspondence to John D. Parker, MD, Associate Professor of Medicine, Division of Cardiology, Mount Sinai Hospital, University of Toronto, 600 University Ave, Suite 1609, Toronto, Ontario, Canada M5G-1X5. E-mail jdp{at}inforamp.net

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective ß-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional ß₂-adrenergic receptors.

Methods and Results —— Thirty-six patients with chronic heart failure were randomized to the nonselective ß-blocker carvedilol or the selective ß-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (-1.7±0.5 nmol/min, P<0.01) and cardiac norepinephrine spillover (-87±29 pmol/min, P<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group.

Conclusions— Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective ß-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional ß-adrenergic receptors.

Key Words: heart failure • receptors, adrenergic, beta • nervous system, autonomic • norepinephrine

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The beneficial effect of ß-blockers in the treatment of patients with chronic congestive heart failure (CHF) has now been demonstrated. Several ß-blockers, including metoprolol, bisoprolol, and carvedilol, improve clinical outcome in CHF compared with placebo.^1–3 To date, few trials have compared the relative efficacy of these agents. The fact that there may be clinically relevant differences between ß-blockers has recently been highlighted by the BEST study, in which bucindolol, compared with placebo, failed to show a clear beneficial effect on mortality.⁴

There have been a few reports comparing metoprolol with carvedilol in patients with chronic CHF. Two studies reported no important differences in the effect of these drugs on symptoms, exercise capacity, or left ventricular function.^5,6 Another larger, randomized study demonstrated that carvedilol had beneficial effects on hemodynamics and left ventricular function compared with metoprolol.⁷ At the moment, there is no available data concerning the relative impact of these 2 agents on long-term outcome in patients with chronic CHF.

The rationale for the use of ß-adrenergic receptor antagonists in CHF is based on observations that sympathetic efferent neuronal activity is increased in CHF and that this sympathoexcitation has independent prognostic value.^8,9 These drugs may provide cardiac protection in CHF via blockade of postjunctional ß-adrenergic receptors on cardiac myocytes. Another mechanism by which ß-blockers may be beneficial is through the antagonism of prejunctional ß₂-adrenergic receptors, which facilitate neural norepinephrine release. In a previous report from our laboratory, we demonstrated an acute reduction in cardiac norepinephrine spillover with an intravenous infusion of the nonselective ß-antagonist propranolol compared with the ß₁-selective antagonist metoprolol.¹⁰ Gilbert et al,¹¹ examining results from previous placebo-controlled CHF studies, found that chronic therapy with carvedilol reduces coronary sinus norepinephrine levels whereas metoprolol does not. Both observations suggest that there may be important differences in the effect of selective versus nonselective ß-adrenergic blockers on cardiac sympathetic efferent neuronal activity.

The purpose of the present experiment was to document the effect of chronic therapy with a selective versus a nonselective ß-blocker on cardiac and systemic sympathetic efferent neuronal activity in patients with CHF. We hypothesized that the nonselective ß-blocker carvedilol would cause a significant and larger reduction in cardiac norepinephrine spillover compared with the selective ß₁-adrenergic receptor antagonist metoprolol. In an effort to determine whether any observed change in spillover was mediated by prejunctional modulation of norepinephrine release versus a change in central sympathetic efferent neuronal outflow, we performed direct neural recordings as well as neurochemical assessments.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patients
The study population consisted of 36 patients with a diagnosis of CHF. Included were patients who were between 18 and 80 years of age with symptoms of CHF and with left ventricular ejection fraction 35% and stable medical therapy for >1 month. Exclusions were patients with an acute coronary syndrome or myocardial revascularization within the preceding 3 months, those who had a contraindication to ß-blocker therapy, and those with primary valvular heart disease or systolic blood pressure <85 mm Hg. In the carvedilol group, 15 patients were taking an ACE inhibitor and 2 patients were taking an angiotensin receptor blocker (ARB). In the metoprolol group, there were 13 patients taking an ACE inhibitor and 1 taking an ARB. Twelve patients in the carvedilol group and 12 in the metoprolol group were receiving a loop diuretic. The protocol was approved by the Ethical Review Committee for Human Experimentation of the University of Toronto.

Study Protocol
Patients who agreed to participate in this study were submitted to a right heart catheterization and measurements of cardiac and systemic norepinephrine kinetics. The microneurographic study was performed on the day preceding or subsequent to the cardiac catheterization in a quiet temperature-controlled room at the same time of the day with subjects resting supine. These measurements will be referred to as baseline measurements. Once baseline measurements were obtained, patients were randomized to carvedilol (n=18) or metoprolol (n=18) in a double-blind fashion. All patients were initiated on 3.125 mg of carvedilol or 6.25 mg of metoprolol twice a day and slowly uptitrated to a maximum dose of 25 mg of carvedilol or 50 mg of metoprolol twice a day. Patients were followed closely in the heart failure clinic until a maintenance dose of ß-blocker was achieved and monthly thereafter until the completion of the study. After 4 months of therapy, repeat measurements of hemodynamics, norepinephrine kinetics, and microneurography were obtained. Thereafter, all patients were followed in a clinic by a physician not involved in the acquisition or analysis of these data.

Hemodynamic Measurements
Instrumentation for hemodynamic measurements included the insertion of a pulmonary artery catheter for recording right heart pressures and cardiac output. An arterial line was placed in the femoral or radial artery for blood sampling and measurement of arterial pressure. All pressures and electrocardiographic tracings were recorded on a strip chart recorder.

A coronary sinus thermodilution catheter was inserted through the internal jugular or brachial vein and positioned using fluoroscopy. Five percent dextrose at room temperature was infused at 35 mL/min by a Harvard pump for coronary blood flow measurements, which were performed in triplicate.

Norepinephrine Spillover Measurements
Sympathetic efferent neuronal outflow was estimated by the measurement of cardiac and total body norepinephrine spillover, using techniques developed by Esler et al¹² that are well established in our laboratory.¹⁰ For these measurements, tritiated norepinephrine (1.6 µCi/min with a 16-µCi priming bolus of L-[2,5,6-³H] norepinephrine; New England Nuclear) was infused into the femoral vein via a Harvard pump (model 33, Harvard Apparatus Canada) to steady-state concentration in plasma. Norepinephrine clearance and spillover rates were calculated as in our previous reports.¹⁰

Analysis of Plasma Catecholamines
Plasma catecholamines were analyzed using high-performance liquid chromatography, as previously described.¹⁰ Fractions from the HPLC effluent containing tritium-labeled norepinephrine were assayed by liquid scintillation spectroscopy. Personnel blinded to patient status performed the biochemical analysis.

Muscle Sympathetic Nerve Activity
Blood pressure was measured from the right arm by an automatic cuff recorder. Heart rate was derived from lead II of the ECG. Muscle sympathetic nerve activity (MSNA) was recorded from the right peroneal nerve using the microneurographic technique, also well established in our laboratory.¹³ Blood pressure, lead II of the ECG, and MSNA were recorded simultaneously on paper and stored on computer for analysis with the use of a Laboratory View–based program (National Instruments). After instrumentation, subjects lay quietly for 15 minutes to achieve steady state before the recording signals were recorded over a 7-minute pre–ß-blocker period. MSNA was expressed as bursts/min (burst frequency), bursts/100 cardiac cycles (burst incidence).

Statistical Analysis
All data are presented as mean±SEM. Statistical analysis was performed in Statview 5.0 (SAS Institute). Paired t tests were used for within group comparisons when data were distributed normally. Wilcoxon’s rank sum test was used when tests of normality failed. Between groups, comparisons were made using ANCOVA. Comparisons of baseline characteristics were made using unpaired t tests and the Fisher exact test. A P value <0.05 was required for statistical significance.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
Baseline characteristics are shown in Table 1. All patients had New York Heart Association functional class II or III symptoms. The mean left ventricular ejection fraction (radionuclide angiography) was 19±2% in the carvedilol group and 20±2% in the metoprolol group. Baseline heart rate was 81±2 bpm in the carvedilol group and 71±4 bpm in the metoprolol group, a difference that was statistically significant (Table 2; P<0.05). There were no significant differences in baseline mean pulmonary artery pressure, pulmonary capillary wedge pressure, arterial pressure, cardiac index, coronary sinus blood flow, total body, or cardiac norepinephrine spillover between the carvedilol and metoprolol groups.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

View this table: [in this window] [in a new window]   Table 2. Hemodynamic and Neurochemical Responses to Carvedilol and Metoprolol

Thirty-one patients completed the study, 17 in the carvedilol group and 14 in the metoprolol group. The mean maximum dose of study medication was 43±3 mg per day in the carvedilol group and 68±8 mg per day in the metoprolol group. Five patients did not complete the study. One patient died suddenly 4 weeks after randomization to carvedilol. Four patients assigned to the metoprolol group withdrew consent because of extreme fatigue from study medication (n=2) or for nonmedical reasons.

Changes in Concomitant Medication
As was specified in the protocol, changes in concomitant medication were kept to a minimum. The dose of vasodilator therapy was changed in 2 patients in the carvedilol group during the course of the study (increased in 1 and reduced in the other). The mean daily dose of furosemide was increased by 1±8 mg in the carvedilol group and decreased by 10±12 mg in the metoprolol group. These changes were not statistically significant.

Hemodynamic Responses to ß-Blockade
Carvedilol caused a highly significant reduction in heart rate, from 81±2 to 66±2 bpm (P<0.001). There were no changes in filling pressures after 4 months of therapy with carvedilol (Table 2). Despite the absence of a significant change in systolic or diastolic arterial pressure, carvedilol led to an increase in pulse pressure from 58±5 to 64±4 mm Hg (P=0.01). Cardiac output did not change during the study. There was, however, a significant increase in stroke volume, from 62±4 to 79±5 mL (P=0.001).

Metoprolol also caused a significant reduction in heart rate, from 71±4 to 62±4 bpm (P=0.007). Except for a small increase in right atrial pressure, which was of no clinical significance, there were no other significant changes in filling pressures in response to metoprolol. As was observed with carvedilol, therapy with metoprolol was associated with a significant increase in pulse pressure, from 61±5 to 69±5 mm Hg (P=0.02). Cardiac output did not change in response to metoprolol, although there was a modest increase in stroke volume, from 73±5 to 82±8 mL (P=0.05).

Neurohormonal Response to ß-Blockade
In the carvedilol group there was a large reduction in total body norepinephrine spillover, from 4.5±0.5 to 2.8±0.2 nmol/min (P<0.01; Table 2). There was no significant change in total body clearance of norepinephrine (2.1±0.1 versus 2.0±0.1 L/min, P=0.88). Cardiac norepinephrine spillover was also significantly reduced from 236±44 to 149±24 pmol/min (P<0.01; Table 2) after 4 months of therapy with carvedilol. There was no significant change in cardiac extraction or clearance of norepinephrine. Metoprolol caused no significant change in either total body norepinephrine spillover or clearance. Furthermore, there was no significant change in cardiac norepinephrine spillover in response to metoprolol (151±34 versus 176±57 pmol/min, P=0.96).

ANCOVA revealed that the decrease in cardiac norepinephrine spillover in the carvedilol group was significantly greater than the change observed in the metoprolol group (P<0.03, Figure,panel B). A similar result was obtained for total body norepinephrine spillover; the between-group analysis revealed that the difference between the effect of carvedilol and metoprolol was significant (P<0.04, Figure, panel A).

View larger version (15K): [in this window] [in a new window]   A, Change in total body norepinephrine spillover (TBNESP) in the carvedilol versus metoprolol groups during the 4-month treatment period. B, Change in cardiac norepinephrine spillover (CANESP) in the carvedilol and metoprolol groups during the 4-month treatment period. *P<0.05 vs before treatment; P<0.05 vs the change observed in the metoprolol group. Values are mean±SEM.

Endogenous plasma norepinephrine concentrations were significantly reduced in the arterial and coronary sinus blood of patients randomized to carvedilol. There were no significant changes observed in the group taking metoprolol. Coronary sinus blood flow did not change significantly in either group (Table 2).

Muscle Sympathetic Nerve Activity in Response to ß-Blockade
In patients who completed the microneurographic component of the study (carvedilol, n=13; metoprolol, n=10), there were no significant differences in age, sex, or other baseline characteristics between the carvedilol and the metoprolol groups. Table 3 shows the effect of 4 months of ß-blockade on hemodynamic variables and MSNA. Neither carvedilol nor metoprolol affected blood pressure in these subjects. Both drugs lowered heart rate significantly, whereas there was no significant difference between the effect of carvedilol and metoprolol in this response. Neither ß-adrenergic blocker altered MSNA.

View this table: [in this window] [in a new window]   Table 3. Hemodynamics and Muscle Sympathetic Nerve Activity

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, two groups of heart failure patients were randomized in a double-blind fashion to 4 months of therapy with carvedilol or metoprolol. The nonselective ß-adrenergic antagonist carvedilol caused a significant reduction in cardiac and systemic norepinephrine spillover, an effect that was not observed with the selective ß₁-adrenergic receptor antagonist metoprolol (Table 2, Figure). We postulate that these significant reductions in cardiac and systemic norepinephrine spillover resulted from blockade of prejunctional ß₂-adrenergic receptors associated with sympathetic efferent neurons that release norepinephrine.^14–16 Studies performed in humans have suggested that prejunctional ß₂-adrenergic receptors facilitate noradrenergic neurotransmission.^17–19 It has been suggested that in states of chronic sympathoadrenal activation, such as chronic CHF, circulating epinephrine plays an important sympathoexcitatory role via its effects on prejunctional ß₂-adrenergic receptors.²⁰ Evidence for cardiac prejunctional sympathoexcitatory ß₂-adrenergic receptors comes from studies in dogs,^21,22 although this has been challenged.²³ Human studies of cardiac sympathoexcitatory ß-adrenergic receptors are limited. Recently, our laboratory provided evidence of cardiac sympathoexcitatory ß₂ receptors using intracoronary infusions of salbutamol.²⁴ Several placebo-controlled studies have demonstrated that nonselective ß-adrenergic receptor blockade reduces plasma norepinephrine concentrations in patients with heart failure.^25,26 Previous studies of the effects of ß₁-selective adrenergic blockade on sympathetic efferent neuronal activity in the setting of heart failure have provided conflicting results.^27–30

It is possible that the observed decrease in systemic and cardiac norepinephrine spillover in response to carvedilol could have occurred secondary to a decrease in central sympathetic efferent neuronal outflow. This could have been mediated by the arterial baroreflex responding to the observed increase in arterial pulse pressure. This explanation would seem unlikely, because a similar increase in pulse pressure was observed in the metoprolol group. A direct, central sympathoinhibitory effect of ß-adrenergic receptor blockade is also possible; such an effect has been suggested to contribute to the antihypertensive effect of these medications as well as their effects in chronic heart failure.²⁰ Although this possibility has some appeal, particularly in light of the greater lipophilicity of carvedilol,¹⁵ it also seems unlikely, because the direct recording of muscle sympathetic nerve activity demonstrated no change in central sympathetic outflow. In light of these findings, we conclude that the reduction in systemic (total body) and cardiac norepinephrine spillover in the carvedilol group was a postganglionic effect, involving the release of norepinephrine that is regulated, in part, by prejunctional ß₂-adrenergic receptors.

It is now recognized that facilitatory ß-adrenergic receptors involved in the modulation of cardiac sympathetic activity may be located at more than one level within the sympathetic nervous system and not limited to a strictly presynaptic or prejunctional distribution. Armour and colleagues^31,32 have demonstrated the presence and functional significance of intrathoracic ganglia and intrinsic cardiac sympathetic neurons. These neurons have been demonstrated to contain both ß₁- and ß₂-adrenergic receptors that are involved in neurotransmission and have sympathoexcitatory effects. Carvedilol may have caused more complete (ß₁ and ß₂) ß-adrenergic receptor blockade at the level of the intrathoracic ganglia and intrinsic cardiac neurons, providing another potential mechanism for the results observed.

It is important to discuss some limitations of our study. First, although the study was double blind and randomized, it was not placebo controlled. Therefore, it is not possible to account for the effect of time on the neurochemical endpoints. In light of this, it might be suggested that some of the sympathoinhibitory effects observed with carvedilol might not have been specific to the drug but, rather, an effect of time. This possibility seems unlikely, because there was no change in peripheral nerve activity during the course of the study. Although we did document a decrease in cardiac norepinephrine spillover, this is only an indirect measure of cardiac efferent sympathetic nerve traffic. Because it is not possible to directly measure efferent cardiac nerve activity in conscious humans, we cannot completely exclude a centrally mediated decrease in efferent cardiac sympathetic nerve activity. Finally, it cannot be concluded that potent reductions in sympathetic activity are associated with improved outcome in chronic heart failure. Indeed, the results of the MOXCON study using the central sympathoinhibitory agent, moxonidine, suggest that at some level reductions in sympathetic outflow may have adverse consequences.³³

In summary, in this randomized, double-blind study, we have demonstrated that therapy with carvedilol caused significant decreases in systemic and cardiac sympathetic activity whereas metoprolol did not. The importance of potential differences between different ß-adrenergic blocking agents has been highlighted by the results of the recently published BEST study.⁴ These data provide a rationale for potential differences in the long-term impact of nonselective versus selective ß-adrenergic antagonists on clinical outcome of patients with chronic CHF. Indeed, the results of the present study will be helpful in interpreting the results of ongoing comparative studies. If these studies demonstrate a favorable effect of a nonselective agent on outcome, then we provide a potential explanation. On the other hand, if no difference is observed with selective versus nonselective agents, then our results will call into question basic assumptions concerning the mechanism of treatment effects during long-term ß-adrenergic blocking therapy in heart failure.

	Acknowledgments

 
Dr Azevedo held a Research Fellowship Award from Astra Zeneca/Heart and Stroke Scientific Research Corporation of Ontario. Dr Mak holds a Research Fellowship from the Canadian Institute for Health Research. Dr Newton holds a Research Scholarship Award. This study received financial support from GlaxoSmithKline and Roche Pharmaceuticals. The authors wish to thank the staff of the Bayer Cardiovascular Clinical Research Laboratory of the Mount Sinai Hospital for their help in the completion of these studies.

Received June 22, 2001; revision received August 22, 2001; accepted August 24, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999; 353: 9–13.[Medline] [Order article via Infotrieve]
   
2. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.[Medline] [Order article via Infotrieve]
   
3. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med. 1996; 334: 1349–1355.[Abstract/Free Full Text]
   
4. The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001; 344: 1659–1667.[Abstract/Free Full Text]
   
5. Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation. 1999; 99: 2645–2651.[Abstract/Free Full Text]
   
6. Sanderson JE, Chan SK, Yip G, et al. Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. J Am Coll Cardiol. 1999; 34: 1522–1528.[Abstract/Free Full Text]
   
7. Metra M, Giubbini R, Nodari S, et al. Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation. 2000; 102: 546–551.[Abstract/Free Full Text]
   
8. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984; 311: 819–823.[Abstract]
   
9. Kaye DM, Lefkovits J, Jennings GL, et al. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995; 26: 1257–1263.[Abstract]
   
10. Newton GE, Parker JD. Acute effects of beta 1-selective and nonselective beta-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation. 1996; 94: 353–358.[Abstract/Free Full Text]
    
11. Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation. 1996; 94: 2817–2825.[Abstract/Free Full Text]
    
12. Esler M, Jennings G, Korner P, et al. Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol. 1984; 247: E21–E28.[Abstract/Free Full Text]
    
13. Abramson BL, Ando S, Notarius CF, et al. Effect of atrial natriuretic peptide on muscle sympathetic activity and its reflex control in human heart failure. Circulation. 1999; 99: 1810–1815.[Abstract/Free Full Text]
    
14. Lands AM, Arnold A, Mcauliff JP, et al. Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967; 214: 597–598.[Medline] [Order article via Infotrieve]
    
15. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists.In: Hardman JG, Goodman Gilman A, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. McGraw-Hill; 1996: 199–248.
    
16. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000; 101: 558–569.[Free Full Text]
    
17. Vincent HH, Man In’t Veld AJ, Boomsma F, et al. Elevated plasma noradrenaline in response to b-adrenoceptor stimulation in man. Br J Pharmacol. 1982; 13: 717–721.
    
18. Persson B, Andersson OK, Hjemdahl P, et al. Adrenaline infusion in man increases muscle sympathetic nerve activity and noradrenaline overflow to plasma. J Hypertens. 1989; 7: 747–756.[Medline] [Order article via Infotrieve]
    
19. Chang PC, Grossman E, Kopin IJ, et al. On the existence of functional beta-adrenoceptors on vascular sympathetic nerve endings in the human forearm. J Hypertens. 1994; 12: 681–690.[Medline] [Order article via Infotrieve]
    
20. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol. 1993; 22: 72A–84A.
    
21. Yamaguchi N, De Champlain J, Nadeau RA. Regulation of norepinephrine release from cardiac sympathetic fibers in the dog by presynaptic a- and b-receptors. Circ Res. 1977; 41: 108–117.[Abstract/Free Full Text]
    
22. Boudreau G, Peronnet F, De Champlain J, et al. Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs. Am J Physiol. 1993; 265: H205–H211.[Abstract/Free Full Text]
    
23. Cousineau D, Goresky CA, Bach GG, et al. Effect of ß-adrenergic blockade on in vivo norepinephrine release in canine heart. Am J Physiol. 1984; 246: H283–H292.[Abstract/Free Full Text]
    
24. Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a ß₂-receptor agonist: a human in vivo study. Circulation. 1999; 99: 2402–2407.[Abstract/Free Full Text]
    
25. Gilbert EM, Anderson JL, Deitchman D, et al. Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990; 88: 223–229.[Medline] [Order article via Infotrieve]
    
26. Woodley SL, Gilbert EM, Anderson JL, et al. Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991; 84: 2426–2441.[Abstract/Free Full Text]
    
27. Andersson M, Lomsky m, Waagstein F. The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure: a study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol. Eur Heart J. 1993; 14: 1375–1385.[Abstract/Free Full Text]
    
28. Rahman MA, Hara K, Daly PA, et al. Reductions in muscle sympathetic nerve activity after long term metoprolol for dilated cardiomyopathy: preliminary observations. Br Heart J. 1995; 74: 431–436.[Abstract/Free Full Text]
    
29. Eichorn EJ, Heesch CM, Barnett JH, et al. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind placebo-controlled study. J Am Coll Cardiol. 1994; 24: 1310–1320.
    
30. Andersson B, Hamm C, Persson S, et al. Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment. J Am Coll Cardiol. 1994; 23: 1397–1404.[Abstract]
    
31. Watson-Wright W, Boudreau G, Cardinal R, et al. Beta 1- and beta 2-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart. Am J Physiol. 1991; 261: R1269–R1275.[Abstract/Free Full Text]
    
32. Huang MH, Sylven C, Pelleg A, et al. Modulation of in situ canine intrinsic cardiac neuronal activity by locally applied adenosine, ATP, or analogues. Am J Physiol. 1993; 265: R914–R922.[Abstract/Free Full Text]
    
33. Jones CG, Cleland JG. Meeting report: the LIDO, HOPE, MOXCON and WASH studies. Heart outcomes prevention evaluation: the Warfarin/Aspirin Study of Heart Failure. Eur J Heart Fail. 1999; 1: 425–431.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				T. J. Vittorio, R. Zolty, M. E. Kasper, R. M. Khandwalla, D. S. Hirsh, C.-H. Tseng, U. P. Jorde, and K. Ahuja Differential Effects of Carvedilol and Metoprolol Succinate on Plasma Norepinephrine Release and Peak Exercise Heart Rate in Subjects With Chronic Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2008; 13(1): 51 - 57. [Abstract] [PDF]

				G. Grassi, G. Seravalle, F. Quarti-Trevano, F. Scopelliti, R. Dell'Oro, G. Bolla, and G. Mancia Excessive Sympathetic Activation in Heart Failure With Obesity and Metabolic Syndrome: Characteristics and Mechanisms Hypertension, March 1, 2007; 49(3): 535 - 541. [Abstract] [Full Text] [PDF]

				A. Al-Hesayen and J. D. Parker Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2377 - H2379. [Abstract] [Full Text] [PDF]

				L. A. Nikolaidis, I. Poornima, P. Parikh, M. Magovern, Y.-T. Shen, and R. P. Shannon The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1871 - 1881. [Abstract] [Full Text] [PDF]

				J. Spaak, Z. J. Egri, T. Kubo, E. Yu, S.-I. Ando, Y. Kaneko, K. Usui, T. D. Bradley, and J. S. Floras Muscle Sympathetic Nerve Activity During Wakefulness in Heart Failure Patients With and Without Sleep Apnea Hypertension, December 1, 2005; 46(6): 1327 - 1332. [Abstract] [Full Text] [PDF]

				V. K. Somers, A. S. Gami, and L. J. Olson Treating Sleep Apnea in Heart Failure Patients: Promises But Still No Prizes J. Am. Coll. Cardiol., June 21, 2005; 45(12): 2012 - 2014. [Full Text] [PDF]

				B. F. McBride and C. M. White Critical Differences Among Beta-Adrenoreceptor Antagonists in Myocardial Failure: Debating the MERIT of COMET J. Clin. Pharmacol., January 1, 2005; 45(1): 6 - 24. [Abstract] [Full Text] [PDF]

				S. Nemoto, P. Razeghi, M. Ishiyama, G. De Freitas, H. Taegtmeyer, and B. A. Carabello PPAR-{gamma} agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H77 - H82. [Abstract] [Full Text] [PDF]

				C. Cogliati, S. Colombo, T. G. Ruscone, D. Gruosso, A. Porta, N. Montano, A. Malliani, and R. Furlan Acute {beta}-Blockade Increases Muscle Sympathetic Activity and Modifies Its Frequency Distribution Circulation, November 2, 2004; 110(18): 2786 - 2791. [Abstract] [Full Text] [PDF]

				J. Neumann, G. Ligtenberg, L. Oey, H. A. Koomans, and P. J. Blankestijn Moxonidine Normalizes Sympathetic Hyperactivity in Patients with Eprosartan-Treated Chronic Renal Failure J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2902 - 2907. [Abstract] [Full Text] [PDF]

				G. Grassi, A. Vincenti, R. Brambilla, F. Q. Trevano, R. Dell'Oro, A. Ciro, G. Trocino, A. Vincenzi, and G. Mancia Sustained Sympathoinhibitory Effects of Cardiac Resynchronization Therapy in Severe Heart Failure Hypertension, November 1, 2004; 44(5): 727 - 731. [Abstract] [Full Text] [PDF]

				S. Satwani, G. W. Dec, and J. Narula {beta}-Adrenergic Blockers in Heart Failure: Review of Mechanisms of Action and Clinical Outcomes Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2004; 9(4): 243 - 255. [Abstract] [PDF]

				P. J. Blankestijn Sympathetic hyperactivity in chronic kidney disease Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1354 - 1357. [Full Text] [PDF]

				W. S. Akers and L. A. Cassis Presynaptic modulation of evoked NE release contributes to sympathetic activation after pressure overload Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2151 - H2158. [Abstract] [Full Text] [PDF]

				L. N. Graham, P. A. Smith, R. J. Huggett, J. B. Stoker, A. F. Mackintosh, and D. A.S.G. Mary Sympathetic Drive in Anterior and Inferior Uncomplicated Acute Myocardial Infarction Circulation, May 18, 2004; 109(19): 2285 - 2289. [Abstract] [Full Text] [PDF]

				J. L. Bauman and R. L. Talbert Pharmacodynamics of{beta}-Blockers in Heart Failure: Lessons from the Carvedilol Or Metoprolol European Trial Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 117 - 128. [Abstract] [PDF]

				H. A. Koomans, P. J. Blankestijn, and J. A. Joles Sympathetic Hyperactivity in Chronic Renal Failure: A Wake-up Call J. Am. Soc. Nephrol., March 1, 2004; 15(3): 524 - 537. [Abstract] [Full Text] [PDF]

				F. Roveda, H. R. Middlekauff, M. U. P. B. Rondon, S. F. Reis, M. Souza, L. Nastari, A. C. P. Barretto, E. M. Krieger, and C. E. Negrao The effects of exercise training on sympathetic neural activation in advanced heart failure: A randomized controlled trial J. Am. Coll. Cardiol., September 3, 2003; 42(5): 854 - 860. [Abstract] [Full Text] [PDF]

				A. Aggarwal, M. D. Esler, M. J. Morris, G. Lambert, and D. M. Kaye Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure Hypertension, March 1, 2003; 41(3): 553 - 557. [Abstract] [Full Text] [PDF]

				T. J. Vittorio, C. C. Lang, S. D. Katz, M. Packer, D. M. Mancini, and U. P. Jorde Vasopressor Response to Angiotensin II Infusion in Patients With Chronic Heart Failure Receiving {beta}-Blockers Circulation, January 21, 2003; 107(2): 290 - 293. [Abstract] [Full Text] [PDF]

				L. N. Graham, P. A. Smith, J. B. Stoker, A. F. Mackintosh, and D. A.S.G. Mary Time Course of Sympathetic Neural Hyperactivity After Uncomplicated Acute Myocardial Infarction Circulation, August 13, 2002; 106(7): 793 - 797. [Abstract] [Full Text] [PDF]

				S. Nemoto, M. Hamawaki, G. De Freitas, and B. A. Carabello differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation J. Am. Coll. Cardiol., July 3, 2002; 40(1): 149 - 154. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Azevedo, E. R. Articles by Parker, J. D.