This Article Abstract 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 Newton, G. E. Articles by Parker, J. D. Search for Related Content PubMed PubMed Citation Articles by Newton, G. E. Articles by Parker, J. D.

(Circulation. 1996;94:353-358.)
© 1996 American Heart Association, Inc.

Articles

Acute Effects of ß₁-Selective and Nonselective ß-Adrenergic Receptor Blockade on Cardiac Sympathetic Activity in Congestive Heart Failure

Gary E. Newton, MD; John D. Parker, MD

the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Correspondence to John D. Parker, MD, Cardiovascular Division, Mount Sinai Hospital, Suite 1609, 600 University Ave, Toronto, Ontario, Canada M5G 1X5.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background ß-Blockers may reduce cardiac sympathetic activity in patients with heart failure by antagonizing ß-adrenergic receptors that facilitate sympathetic outflow to the heart. To explore this possible effect of ß-blockade, we measured cardiac norepinephrine spillover responses in patients with heart failure after the acute administration of either propranolol, a nonselective ß-blocker, or metoprolol, a ß₁-selective agent.

Methods and Results Eighteen patients were studied. Repeated intravenous doses of propranolol (0.5 mg; nine patients; left ventricular ejection fraction, 14±2%) or metoprolol (1.0 mg; nine patients; left ventricular ejection fraction, 18±2%) were administered until one of the following end points was reached: a 15% decrease in heart rate, left ventricular +dP/dt, or mean arterial blood pressure or a 5 mm Hg increase in left ventricular end-diastolic pressure. Propranolol (mean dose, 2.0 mg) and metoprolol (mean dose, 3.6 mg) caused similar reductions in heart rate, +dP/dt, and coronary sinus plasma flow. Cardiac norepinephrine spillover was reduced after propranolol (277±55 to 262±53 pmol/min, P<.05) but was increased after metoprolol (233±57 to 296±82 pmol/min, P<.05). In a comparison of the two groups, the decrease in spillover after propranolol was significantly different than the increase seen after metoprolol (P<.01).

Conclusions The administration of a ß₁-selective antagonist was associated with increased cardiac norepinephrine spillover. In contrast, the administration of a nonselective ß-blocker until similar hemodynamic end points were reached caused a reduction in norepinephrine spillover. This suggests that in patients with heart failure, nonselective ß-blockade may have favorable inhibitory effects on cardiac sympathetic activity.

Key Words: heart failure • nervous system, autonomic • norepinephrine • ß-adrenergic antagonists

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Congestive heart failure is characterized by generalized and organ-specific increases in efferent sympathetic activity, with the greatest increase directed at the heart.¹ Generalized sympathetic activation is associated with poor prognosis,² and a similar observation was recently made regarding sympathetic outflow to the heart in patients undergoing evaluation for heart transplantation.³ Activation of the sympathetic nervous system, both generalized and cardiac specific, provides the rationale for the use of ß-blockers in the setting of heart failure. ß-Blockers are thought to prevent the adverse cardiac effects of sympathetic activation through blockade of ß-adrenergic receptors on cardiac myocytes.^{4 5 6}

Another potential outcome of ß-blockade is the attenuation of cardiac sympathetic activation as a result of antagonism of facilitative ß-adrenergic receptors at sites within the sympathetic nervous system. Recently, we demonstrated the functional significance of prejunctional inhibitory ₂-adrenergic receptors in the failing human heart.⁷ In contrast, stimulation of prejunctional ß₂-adrenergic receptors on adrenergic nerve terminals augments norepinephrine release,^{8 9 10 11} although the significance of these receptors in the setting of human heart failure remains unknown. ß-Adrenergic receptors have also been demonstrated in intrathoracic ganglia¹² (both ß₁ and ß₂) and on intrinsic cardiac neurons.¹³ Stimulation of these receptors in dogs increases the firing rate of postganglionic cardiac sympathetic nerves.^{12 13} Therefore, ß-blockers may reduce sympathetic outflow to the heart by antagonizing the stimulation of facilitative ß-adrenergic receptors. Furthermore, because both ß₁- and ß₂-adrenergic receptors enhance adrenergic neurotransmission,^{8 9 10 11 12} nonselective ß-blockade may inhibit cardiac sympathetic activity more effectively than ß₁-selective blockade.

The purpose of the present study was to explore the effect of acute ß-blocker administration on cardiac sympathetic activity in patients with heart failure. We hypothesized that a nonselective ß-blocker, compared with a ß₁-selective agent, would cause greater inhibition of sympathetic outflow to the heart. To test this hypothesis, we measured cardiac norepinephrine spillover responses in patients with heart failure after the acute administration of either propranolol, a nonselective ß-blocker, or metoprolol, a ß₁-selective agent.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Characteristics
Eighteen patients with heart failure participated in this investigation: nine in a propranolol-treated group and nine in a metoprolol-treated group. Both groups included eight men and one woman. Both groups included six patients with idiopathic dilated cardiomyopathy and three patients with coronary artery disease. Medical therapy in all patients included furosemide and digoxin. In the propranolol group, additional therapy included angiotensin-converting enzyme inhibitors (n=7), hydralazine (n=2), isordil (n=1), and amiodarone (n=1). In the metoprolol group, additional therapy included angiotensin-converting enzyme inhibitors (n=8) and amiodarone (n=1). All medical therapy was withheld on the morning of the study.

Study Protocol
A diagnostic right and left heart catheterization, without sedation, was performed from the femoral approach. A 7F thermodilution catheter (type CCS-7U-90B, Webster Laboratories) was then placed in the coronary sinus through an antecubital vein for flow measurements and blood sampling. A 7F micromanometer-tipped catheter (Millar Industries) was placed in the left ventricle for assessment of contractility (+dP/dt) and filling pressures. The patient was then undisturbed for a minimum of 20 minutes, until tritium-labeled norepinephrine had reached a steady-state concentration in plasma. Hemodynamic measurements were then performed, and total body and cardiac norepinephrine spillover levels were assessed. Subsequently, repeated bolus intravenous doses of either propranolol (0.5 mg) or metoprolol (1.0 mg) were administered at 5-minute intervals until one of the following end points was reached: (1) a 15% decrease in heart rate, (2) a 15% decrease in left ventricular +dP/dt, (3) a 15% decrease in mean arterial blood pressure, or (4) a 5 mm Hg increase in left ventricular end-diastolic pressure. Hemodynamic measurements and total body and cardiac norepinephrine spillover levels were then reassessed.

Norepinephrine Spillover Measurements
Sympathetic activity was estimated by the measurement of spillover to plasma of norepinephrine from the heart and from the body as a whole.¹⁴ For spillover measurements, tritiated norepinephrine (1 to 1.2 µCi/min with a 16-µCi priming bolus of L-[2,5,6-³H]norepinephrine; New England Nuclear) is infused into a peripheral vein to a steady-state concentration in plasma. Total body and cardiac norepinephrine clearance and spillover rates are calculated as follows^{1 14}

where [³H]NE is tritium-labeled norepinephrine; NE_ext is transcardiac fractional extraction of tritium-labeled norepinephrine; NE_cs and NE_art are coronary sinus and arterial plasma norepinephrine concentrations, respectively; and CSPF is coronary sinus plasma flow calculated from the hematocrit and coronary sinus blood flow.

Analysis of Plasma Catecholamines
Catecholamine analysis was performed by personnel who were blinded to patient status. Samples were transferred immediately to ice-chilled tubes containing an anticoagulant (EDTA). The plasma was separated through centrifugation at 4°C and stored at -70°C until assay. After the addition of dihydroxybenzlamine as an internal standard, catechols were extracted through adsorption on alumina. After elution from the alumina through the addition of 0.2 mol/L HClO₄, catechols were separated through the use of isocratic ion-pair chromatography on a reversed-phase column. The high-performance liquid chromatography system consisted of a multisolvent-delivery system (model 600E pump), a model 7171 automatic sample injector (Waters Associates Inc), and a Zorbax SB-C18 4.6x150-mm column (Chromatographic Specialties Inc). Detection of the compounds was performed with a model Coulochem II coulometric detector consisting of four coulometric cells in series (ESA Inc). Data analysis (electrode 4 set at -0.38 V) was performed with a Millennium 2010 chromatography manager device (Waters Associates Inc). Fractions containing tritium-labeled norepinephrine in the effluent, collected distal to the electrochemical cell, were assayed through liquid scintillation spectroscopy. Recovery of catecholamines from alumina was 75% and was corrected to the internal standard (dihydroxybenzlamine). The detection limit of the method was 0.1 nmol/L, and peak area was linear from 0.1 to 50 nmol/L. Intra-assay (n=8) and interassay (n=14) CVs were 1.7% and 2.3% for the determination of endogenous norepinephrine, respectively.

Hemodynamic and Coronary Flow Measurements
Left ventricular contractility (+dP/dt) and filling pressures were assessed with a micromanometer-tipped catheter placed in the left ventricle. Femoral artery pressure was monitored via an 8F side-arm sheath (Cordis Laboratories). The ECG, femoral artery pressure, left ventricular pressure, and its first derivative (continuous electronic differentiation) were recorded with a strip-chart recorder. For each variable, the results were expressed as an average of measurements from 15 cardiac cycles.

The coronary sinus thermodilution flow catheter was positioned with the use of fluoroscopy, and correct placement was confirmed with radiographic contrast injection. The external thermister was advanced 2 cm past the ostium of the coronary sinus to avoid reflux of right atrial blood,¹⁵ and a constant position was maintained through comparison with anatomic landmarks. Room-temperature 5% dextrose in water was infused at a rate of 35 mL/min with a Harvard pump for coronary blood flow measurements, which were performed in triplicate according to the method of Ganz et al.¹⁶

Statistical Analysis
All data are presented as mean±SEM. Within-group comparisons of the effect of ß-blockade on hemodynamics, catecholamine concentrations, and norepinephrine kinetics were made with the Wilcoxon signed rank test. Between-group comparisons of baseline characteristics and effects of propranolol versus metoprolol were performed with a Wilcoxon-Mann-Whitney test. For all comparisons, exact P values were calculated with StatXaxt3 Statistical Software for Exact Nonparametric Inference (Cytel Software Corp). Nonparametric tests were used because the data were not normally distributed. A value of P<.05 was required for statistical significance.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics and Clinical Results of ß-Blockade
All patients had New York Heart Association functional class III or IV symptoms (Table 1). The mean left ventricular ejection fraction was 14±2% in the propranolol group and 18±2% in the metoprolol group (P=NS). There were no significant differences between the two groups in any baseline characteristic, including hemodynamics, coronary sinus plasma flow, catecholamine concentrations, and spillover rates.

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

The mean total dose of propranolol was 2.0 mg (range, 1 to 3.5 mg). The mean total dose of metoprolol was 3.6 mg (range, 2 to 6 mg). One patient in the metoprolol group (patient 3 in metoprolol group; Table 3) developed pulmonary congestion requiring inotropic support in the recovery area 30 minutes after completion of the study. Otherwise, ß-blockade was well tolerated.

View this table: [in this window] [in a new window]   Table 3. Coronary Sinus Plasma Flow, Plasma Norepinephrine Concentration, and Noreprinephrine Spillover Responses to Acute ß-Blockade With Propranolol or Metoprolol

Hemodynamic Responses to ß-Blockade
ß-Blockade resulted in significant reductions in heart rate and left ventricular contractility (Table 2 and Fig 1). Heart rate decreased from 90±3 to 81±3 bpm (P<.01) and left ventricular +dP/dt decreased from 765±94 to 660±84 mm Hg/s (P<.01) after propranolol. Similar reductions were observed after metoprolol; heart rate decreased from 95±7 to 83±6 bpm (P<.01), and +dP/dt decreased from 755±52 to 655±49 mm Hg/s (P<.01). There were no changes in either mean arterial pressure or left ventricular end-diastolic pressure with either drug (Table 2). There were significant reductions in coronary sinus plasma flow with propranolol and with metoprolol (Table 3 and Fig 1). There were no significant differences in any of the hemodynamic responses to metoprolol compared with propranolol.

View larger version (28K): [in this window] [in a new window]   Figure 1. Bar graph illustrating the hemodynamic responses to ß-blockade with either propranolol (open bar) or metoprolol (hatched bar) expressed as percent changes from control measurements. HR indicates heart rate; dP/dt, left ventricular peak +dP/dt; and CSPF, coronary sinus plasma flow. *P<.01 for within-group comparison of each hemodynamic response. All data are expressed as mean±SEM.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic and Selected Autonomic Responses to ß-Blockade: Propranolol and Metoprolol Groups

Norepinephrine Kinetics in Response to ß-Blockade
There were no increases in total body norepinephrine spillover in either group (Table 2). Total body norepinephrine clearance was reduced after the administration of metoprolol (Table 2).

View larger version (44K): [in this window] [in a new window]   Figure 2. Bar graph of cardiac norepinephrine spillover at control (open bar) and after administration of either propranolol or metoprolol (hatched bar). *P<.05 vs control. P<.01 for between-group comparison of the change in spillover.

View larger version (13K): [in this window] [in a new window]   Figure 3. Plots of the percent change in cardiac norepinephrine spillover with group mean values after administration of either propranolol (triangles) or metoprolol (circles). *P<.01 vs response in the propranolol group.

There was a small but significant reduction in cardiac norepinephrine spillover after propranolol (277±55 to 262±53 pmol/min, P<.05, Fig 2). In contrast, cardiac norepinephrine spillover increased from 233±57 to 296±82 pmol/min after metoprolol (P<.05, Fig 2). In a comparison of the two groups, the decrease in cardiac norepinephrine spillover in the propranolol group was significantly different from the increase in the metoprolol group (P<.01). The individual patient spillover responses are provided in Table 3 and Fig 3. There were no changes in cardiac norepinephrine clearance despite significant reductions in coronary sinus plasma flow in both groups (Table 2).

Plasma Catecholamine Responses to ß-Blockade
Consistent with the cardiac norepinephrine spillover responses, there were smaller increases in plasma catecholamine concentrations after the administration of propranolol compared with metoprolol (Tables 2 and 3). After propranolol, there was an increase in arterial norepinephrine concentration (2.5±0.7 to 2.9±0.8 nmol/L; P<.05) as well as coronary sinus norepinephrine (from 3.5±0.8 to 4.1±1.1 nmol/L; P<.05). After metoprolol, arterial norepinephrine concentration increased from 2.3±0.6 to 3.5±0.8 nmol/L (P<.01), and coronary sinus norepinephrine concentration increased from 3.6±0.7 to 5.0±1.1 nmol/L (P<.01). A comparison of the two groups revealed that there was a smaller increase in arterial norepinephrine concentration (P<.05) and a tendency toward a smaller increase in coronary sinus norepinephrine (P=.06) after propranolol compared with metoprolol.

There were no significant changes in epinephrine concentrations after propranolol. In contrast, after metoprolol, there was a significant increase in coronary sinus epinephrine concentration (0.4±0.3 to 0.7±0.4 nmol/L, P<.05) and an increase in arterial epinephrine concentration that was of borderline statistical significance (0.6±0.2 to 0.9±0.4 nmol/L, P=.06).

Patient 3 in the metoprolol group (Table 3) developed pulmonary congestion after the study. This patient showed no clinical or hemodynamic evidence of worsening heart failure during the investigation. However, this patient had a large increase in cardiac norepinephrine spillover, which may have been related to impending decompensation. The metoprolol group was therefore reanalyzed excluding patient 3, and the increase in cardiac norepinephrine spillover (187±38 to 231±56 pmol/min, P<.05) remained significantly different from the response in the propranolol group (P<.05).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, two well-matched groups of heart failure patients received equivalent ß-blocking doses of metoprolol or propranolol. Similar overall ß-blockade was achieved through titration of both agents to identical reductions in heart rate and left ventricular contractility. These hemodynamic changes likely resulted from more postjunctional ß₁-blockade with metoprolol compared with relatively more postjunctional ß₂-blockade with propranolol. However, the purpose of titration to similar hemodynamic responses was to ensure equivalent changes in the stimulus to central sympathetic outflow. Despite equal effects on heart rate and contractility by both agents, the administration of metoprolol resulted in increases in cardiac norepinephrine spillover and plasma epinephrine concentration. In contrast, after propranolol, there was a reduction in cardiac norepinephrine spillover and no change in plasma epinephrine concentration. Therefore, these results suggest that nonselective ß-blockade, compared with ß₁-selective blockade, may favorably modify cardiac noradrenergic neurotransmission in patients with heart failure.

The increase in cardiac norepinephrine spillover in the metoprolol group probably occurred because of reflex sympathetic activation,¹⁷ possibly as a result of reduced discharge from inotropically sensitive inhibitory ventricular mechanoreceptors.¹⁸ After the administration of propranolol, this reflex sympathetic activation was probably similar because the hemodynamic responses were nearly identical. We hypothesized that the absence of an increase in spillover in the propranolol group occurred as a result of antagonism of ß₂-adrenergic receptors. This implies that facilitory ß₂-adrenergic receptors were stimulated and contributed to the increase in cardiac norepinephrine spillover seen after metoprolol. The likely ß₂-agonist in this setting would be epinephrine, arising from neuronal and/or adrenal release.¹⁹

The facilitory ß₂-adrenergic receptors responsible for these results may be located at more than one level within the sympathetic nervous system. Propranolol may have antagonized the stimulation of prejunctional ß₂-adrenergic receptors on adrenergic nerve terminals, both in the heart^{11 20} and in the adrenal medulla.²¹ Blockade of cardiac prejunctional ß₂-adrenergic receptors would likely blunt a stimulated increase in norepinephrine release.^{11 20} The cardiac norepinephrine spillover response observed after propranolol may have occurred due to the combination of ß₂-blockade and unopposed ₂-mediated negative feedback of norepinephrine release.⁷ Antagonism of adrenal prejunctional ß₂-adrenergic receptors could account for the lack of an increase in arterial plasma epinephrine concentration after propranolol.²¹ Propranolol, compared with metoprolol, may also have caused more complete (ß₁ and ß₂) ß-adrenergic receptor blockade in intrathoracic ganglia and on intrinsic cardiac neurons.^{12 13} By preventing the stimulation of ß-adrenergic receptors at these sites, propranolol may have attenuated any increase in the firing rate of postganglionic cardiac sympathetic nerves.^{12 13} Since it is not possible to measure efferent cardiac sympathetic nerve discharge rate in studies in humans, this mechanism cannot be directly assessed.

There are other possible explanations for the present observations. Propranolol, compared with metoprolol, may have had a lesser effect on arterial and/or cardiopulmonary baroreceptor reflex mechanisms and therefore may have caused less stimulus to reflex increases in central sympathetic outflow. This possibility seems unlikely since the two agents had essentially identical hemodynamic effects. Propranolol may have had a greater central sympathoinhibitory effect than metoprolol. Finally, propranolol could have prevented an increase in cardiac sympathetic nerve activity as a result of its membrane-stabilizing action. However, this possibility is unlikely due to the small doses of propranolol that were used in this study.²²

Previous investigations have demonstrated that ß-adrenergic receptors modulate both efferent sympathetic nerve activity and norepinephrine release from adrenergic nerve terminals. Long-term ß-blockade reduces efferent sympathetic nerve activity to skeletal muscle, presumably due to direct central nervous system effects.^{23 24} Stimulation of ß-adrenergic receptors in intrathoracic ganglia and on intrinsic cardiac neurons enhances cardiac efferent sympathetic nerve activity in dogs.^{12 13} However, the relevance of these receptors in humans is unknown. Studies in humans have suggested that prejunctional ß₂-adrenergic receptors facilitate noradrenergic neurotransmission.^{25 26 27 28} Evidence for prejunctional cardiac ß₂-adrenergic receptors comes from studies in dogs,^{11 29} although this has been challenged.³⁰ In a study in humans, intravenous epinephrine did not increase cardiac norepinephrine spillover.³¹ However, epinephrine had hemodynamic effects that may have caused a reflex reduction in sympathetic outflow.²⁵ In a study from the same group, intravenous metoprolol reduced cardiac norepinephrine spillover in patients with normal ventricular function.³² Prejunctional ß-adrenergic receptors are unlikely to be tonically active in the absence of either sympathetic activation or elevated epinephrine levels,^{9 10 19} so a more plausible explanation for this result was that spillover was reduced due to a decrease in coronary sinus blood flow.³⁰

The importance of the present investigation is that it provides further insights into the use of ß-blockers in the treatment of heart failure. The increase in cardiac norepinephrine spillover that occurred with metoprolol may help explain why patients with heart failure tolerate the acute administration of ß₁-selective ß-blockers.³³ An increase in cardiac adrenergic drive associated with acute ß₁-blockade may provide short-term support for cardiac function. In contrast, the present study demonstrated that nonselective ß-blockade resulted in more complete inhibition of sympathetic drive to the failing heart. This observation may help explain the apparently greater clinical effects of carvedilol,³⁴ a relatively nonselective ß-blocker, compared with previous results with metoprolol.^{35 36}

Consistent with the results of the present study, a small number of placebo-controlled studies of nonselective ß-blockade have demonstrated reductions in the plasma norepinephrine concentration in patients with heart failure.^{37 38} Previous studies that addressed the effect of ß₁-blockade on sympathetic activity in the setting of heart failure have produced conflicting results. Intravenous metoprolol administration has been shown to increase both arterial and coronary sinus norepinephrine concentrations,³⁹ which is consistent with acute sympathetic activation. Long-term metoprolol use has been shown to reduce muscle sympathetic nerve activity,²⁴ while having varying effects on coronary sinus norepinephrine concentration.^{40 41} Plasma norepinephrine concentration has been shown to be reduced in some,^{40 41} but not all,⁴² placebo-controlled studies of long-term metoprolol therapy.

The most important limitation to the present study is that we examined the acute effects of ß-adrenergic receptor blockade. The effect of long-term ß-blocker administration on cardiac adrenergic drive was not addressed and cannot be inferred from the present results. A second limitation of this study was our assessment of cardiac sympathetic activity. We used a radiotracer technique to measure norepinephrine spillover from the heart. The strength of this method is that it allows an assessment of regional sympathetic activity in internal organs that are not accessible to direct methods such as microneurography. The spillover method also accounts for regional changes in norepinephrine clearance.⁴³ However, it is not possible to distinguish whether the observed spillover responses were derived from altered neuronal reuptake of released norepinephrine or from altered norepinephrine release due to changes in efferent sympathetic nerve activity and/or prejunctional modulation. These questions of mechanism can be addressed only in more peripheral vascular beds.²⁵ Finally, cardiac norepinephrine spillover has been reported to be influenced by changes in coronary blood flow.³⁰ Flow changes do not explain our findings since spillover increased after metoprolol, whereas there was a similar reduction in coronary sinus plasma flow after both agents.

In summary, we have shown that the acute administration of a ß₁-selective ß-blocker to patients with severe heart failure is associated with increased cardiac norepinephrine spillover. In contrast, the administration of a nonselective ß-blocker until similar hemodynamic end points were reached results in a small but significant reduction in norepinephrine spillover. This suggests that nonselective ß-adrenergic receptor blockade may have favorable inhibitory effects on sympathetic outflow to the heart. These findings have potential implications for the use of nonselective versus ß₁-selective blockade in the treatment of patients with heart failure.

	Acknowledgments

 
This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Ontario (A2811) and by Bayer, Inc. Dr Parker is a scholar of the Medical Research Council of Canada. Dr Newton is supported by Boeringher Ingelheim Canada. The authors thank Dr John Floras for his thoughtful comments concerning this manuscript and Andrea B. Parker for assistance with the statistical analysis. We also 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 November 20, 1995; revision received January 16, 1996; accepted January 21, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Hasking GJ, Esler MD, Jennings GJ, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986;73:615-621.[Abstract/Free Full Text]

2. Cohn JN, Levine TB, Olivari MT, Garberg V, Tura 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]

3. 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.[Abstract]

4. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. ß₁- and ß₂-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective ß₁-receptor down-regulation in heart failure. Circ Res. 1986;59:297-309.[Abstract/Free Full Text]

5. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85:790-804.[Abstract/Free Full Text]

6. Meredith IT, Broughton A, Jennings GL, Esler MD. Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med. 1991;325:618-624.[Abstract]

7. Parker JD, Newton GE, Landzberg JS, Floras JS, Colucci WS. Functional significance of presynaptic -adrenergic receptors in the failing and nonfailing human left ventricle. Circulation. 1995;92:1793-1800.[Abstract/Free Full Text]

8. Adler-Graschinsky E, Langer SZ. Possible role of a ß-adrenoreceptor in the regulation of noradrenaline release by nerve stimulation through a positive feed-back mechanism. Br J Pharmacol. 1975;53:43-50.[Medline] [Order article via Infotrieve]

9. Majewski H. Modulation of noradrenaline release through activation of presynaptic ß-adrenoreceptors. J Auton Pharmacol. 1983;3:47-60.[Medline] [Order article via Infotrieve]

10. Misu Y, Kubo T. Presynaptic ß-adrenoreceptors. Med Res Rev. 1986;6:197-225.[Medline] [Order article via Infotrieve]

11. Boudreau G, Peronnet F, De Champlain J, Nadeau R. Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs. Am J Physiol. 1993;265:H205-H211.[Abstract/Free Full Text]

12. Watson-Wright W, Boudreau G, Cardinal R, Armour JA. ß₁- and ß₂adrenoreceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart. Am J Physiol. 1991;261:R1269-R1275.[Abstract/Free Full Text]

13. Huang MH, Smith FM, Armour JA. Modulation of in situ canine intrinsic cardiac neuronal activity by nicotinic, muscarinic, and ß-adrenergic agonists. Am J Physiol. 1993;265:R659-R669.[Abstract/Free Full Text]

14. Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P. Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol. 1984;247:E21-E28.[Abstract/Free Full Text]

15. Mathey DG, Chatterjee K, Tyberg JV, Lekven J, Brundage B, Parmeley WW. Coronary sinus reflux: a source of error in the measurement of thermodilution coronary sinus flow. Circulation. 1971;57:778-786.[Abstract/Free Full Text]

16. Ganz W, Tamura K, Marcus HS, Donoso R, Swan HJC. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation. 1971;44:181-195.[Abstract/Free Full Text]

17. Sundlof G, Wallin BG, Stromgren E, Nerhed C. Acute effects of metoprolol on muscle sympathetic activity in hypertensive humans. Hypertension. 1983;5:749-756.[Abstract/Free Full Text]

18. Thoren PN. Characteristics of left ventricular receptors with nonmedullated vagal afferents in cats. Circ Res. 1977;40:415-421.[Abstract/Free Full Text]

19. Floras JS. Epinephrine and the genesis of hypertension. Hypertension. 1992;19:1-18.[Abstract/Free Full Text]

20. Yamaguchi N, Naud M, Lamontagne D, Nadeau R, De Champlain J. Presynaptic inhibitory effects of sotalol, propranolol, and acebutolol on noradrenaline release upon cardiac sympathetic nerve stimulation in anaesthetized dogs. Can J Physiol Pharmacol. 1986;64:1076-1084.[Medline] [Order article via Infotrieve]

21. Foucart S, Nadeau R, De Champlain J. Local modulation of adrenal catecholamines release by beta-2 adrenoceptors in the anaesthetized dog. Naunyn Schmiedebergs Arch Pharmacol. 1988;337:29-34.

22. Coltart DJ, Meldrum SJ. The effect of propranolol on the human and canine transmembrane action potential. Br J Pharmacol.. 1970;40:148P.[Medline] [Order article via Infotrieve]

23. Wallin BG, Sundlof G, Stromgren E, Aberg H. Sympathetic outflow to muscles during treatment of hypertension with metoprolol. Hypertension. 1984;6:557-562.[Abstract/Free Full Text]

24. Rahman MA, Hara K, Daly PA, Wigle ED, Floras JS. 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]

25. Persson B, Andersson OK, Hjemdahl P, Wysocki M, Agerwall S, Wallin G. 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]

26. Vincent HH, Man In't Veld AJ, Boomsma F, Wenting GJ, Schalekamp MADH. Elevated plasma noradrenaline in response to ß-adrenoceptor stimulation in man. Br J Pharmacol. 1982;13:717-721.

27. Floras JS, Aylward PE, Victor RG, Mark AL, Abboud FM. Epinephrine facilitates neurogenic vasoconstriction in humans. J Clin Invest. 1988;81:1265-1274.

28. Chang PC, Grossman E, Kopin IJ, Goldstein DS. 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]

29. Yamaguchi N, De Champlain J, Nadeau RA. Regulation of norepinephrine release from cardiac sympathetic fibers in the dog by presynaptic - and ß-receptors. Circ Res. 1977;41:108-117.[Abstract/Free Full Text]

30. Cousineau D, Goresky CA, Bach GG, Rose CP. Effect of ß-adrenergic blockade on in vivo norepinephrine release in canine heart. Am J Physiol. 1984;246:H283-H292.[Abstract/Free Full Text]

31. McCance AJ, Forfar JC. Cardiac and whole-body [³H]noradrenaline kinetics during adrenaline infusion in man. Clin Sci. 1991;80:227-233.[Medline] [Order article via Infotrieve]

32. McCance AJ, Forfar JC. Noradrenaline kinetics and coronary hemodynamics during acute ß₁-adrenoceptor blockade in man. Clin Sci. 1993;84:413-417.[Medline] [Order article via Infotrieve]

33. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Beneficial effects of long-term beta-blockade in congestive cardiomyopathy. Br Heart J. 1980;44:117-133.[Abstract/Free Full Text]

34. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM. Effect of carvedilol on the survival of patients with chronic heart failure. Circulation. 1995;92(suppl I):I-142. Abstract.

35. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1994;342:1441-1446.

36. Eichorn EJ, Hjalmarson A. ß-Blocker therapy for chronic heart failure: the frog prince. Circulation. 1994;90:2153-2156.[Free Full Text]

37. Gilbert EM, Anderson JL, Deitchman D, Yanowitz FG, O'Connell JB, Renlund DG, Bartholomew M, Mealey PC, Larrabee P, Bristow MR. Long-term ß-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]

38. Woodley SL, Gilbert EM, Anderson JL, O'Connell JB, Dietchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R, Bristow MR. ß-Blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991;84:2426-2441.[Abstract/Free Full Text]

39. Andersson B, 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]

40. Eichorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield A, Marcoux LG, Malloy CR. 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.

41. Andersson B, Hamm C, Persson S, Wikstrom G, Sinagra G, Hjalmarson A, Waagstein F. Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment. J Am Coll Cardiol. 1994;23:1397-1404.[Abstract]

42. Paolisso G, Gambardella A, Marrazzo G, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Metabolic and cardiovascular benefits derived from ß-adrenergic blockade in chronic congestive heart failure. Am Heart J. 1992;123:103-110.[Medline] [Order article via Infotrieve]

43. Esler M, Jennings G, Korner P, Willett I, Dudley F, Anderson W, Lambert G. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11:3-20.[Free Full Text]

This article has been cited by other articles:

				L. Frankenstein, C. Zugck, D. Schellberg, M. Nelles, H. Froehlich, H. Katus, and A. Remppis Prevalence and prognostic significance of adrenergic escape during chronic {beta}-blocker therapy in chronic heart failure Eur J Heart Fail, February 1, 2009; 11(2): 178 - 184. [Abstract] [Full Text] [PDF]

				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]

				C. W. Hogue Jr, C. A. Palin, and J. E. Arrowsmith Cardiopulmonary bypass management and neurologic outcomes: an evidence-based appraisal of current practices. Anesth. Analg., July 1, 2006; 103(1): 21 - 37. [Abstract] [Full Text] [PDF]

				A. Al-Hesayen, E. R. Azevedo, J. S. Floras, S. Hollingshead, G. D. Lopaschuk, and J. D. Parker Selective versus nonselective {beta}-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization Eur J Heart Fail, June 1, 2005; 7(4): 618 - 623. [Abstract] [Full Text] [PDF]

				Y. Kadoi, S. Saito, F. Goto, and N. Fujita The Effect of Diabetes on the Interrelationship Between Jugular Venous Oxygen Saturation Responsiveness to Phenylephrine Infusion and Cerebrovascular Carbon Dioxide Reactivity Anesth. Analg., August 1, 2004; 99(2): 325 - 331. [Abstract] [Full Text] [PDF]

				A. Al-Hesayen and J. D. Parker Impaired Baroreceptor Control of Renal Sympathetic Activity in Human Chronic Heart Failure Circulation, June 15, 2004; 109(23): 2862 - 2865. [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]

				B. Reinsfelt, A. Westerlind, E. Houltz, S. Ederberg, M. Elam, and S.-E. Ricksten The Effects of Isoflurane-Induced Electroencephalographic Burst Suppression on Cerebral Blood Flow Velocity and Cerebral Oxygen Extraction During Cardiopulmonary Bypass Anesth. Analg., November 1, 2003; 97(5): 1246 - 1250. [Abstract] [Full Text] [PDF]

				D. H. Au, E. M. Udris, V. S. Fan, J. R. Curtis, M. B. McDonell, and S. D. Fihn Risk of Mortality and Heart Failure Exacerbations Associated With Inhaled {beta}-Adrenoceptor Agonists Among Patients With Known Left Ventricular Systolic Dysfunction Chest, June 1, 2003; 123(6): 1964 - 1969. [Abstract] [Full Text] [PDF]

				A. Al-Hesayen, E. R. Azevedo, G. E. Newton, and J. D. Parker The effects of dobutamine on cardiac sympathetic activity in patients with congestive heart failure J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1269 - 1274. [Abstract] [Full Text] [PDF]

				E. R. Azevedo, T. Kubo, S. Mak, A. Al-Hesayen, A. Schofield, R. Allan, S. Kelly, G. E. Newton, J. S. Floras, and J. D. Parker Nonselective Versus Selective {beta}-Adrenergic Receptor Blockade in Congestive Heart Failure: Differential Effects on Sympathetic Activity Circulation, October 30, 2001; 104(18): 2194 - 2199. [Abstract] [Full Text] [PDF]

				B. Stanek, B. Frey, M. Hulsmann, R. Berger, B. Sturm, J. Strametz-Juranek, J. Bergler-Klein, P. Moser, A. Bojic, E. Hartter, et al. Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction J. Am. Coll. Cardiol., August 1, 2001; 38(2): 436 - 442. [Abstract] [Full Text] [PDF]

				D. M. Farrell, C.-C. Wei, J. Tallaj, J. L. Ardell, J. A. Armour, G. R. Hageman, W. E. Bradley, and L. J. Dell'Italia Angiotensin II modulates catecholamine release into interstitial fluid of canine myocardium in vivo Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H813 - H822. [Abstract] [Full Text] [PDF]

				G. Grassi, C. Turri, G. Seravalle, G. Bertinieri, A. Pierini, and G. Mancia Effects of Chronic Clonidine Administration on Sympathetic Nerve Traffic and Baroreflex Function in Heart Failure Hypertension, August 1, 2001; 38(2): 286 - 291. [Abstract] [Full Text] [PDF]

				C. F. Notarius and J. S. Floras Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure Europace, January 1, 2001; 3(1): 29 - 38. [Abstract] [PDF]

				A. K. Agarwal, P. Venugopalan, C. Woodhouse, and D. de Bono Catecholamine levels in heart failure due to dilated cardiomyopathy and their relationship to the severity of heart failure Eur J Heart Fail, September 1, 2000; 2(3): 261 - 263. [Full Text] [PDF]

				Y. Kadoi and S. Saito Reply Ann. Thorac. Surg., July 1, 2000; 70(1): 337 - 337. [Full Text] [PDF]

				M. R. Bristow {beta}-Adrenergic Receptor Blockade in Chronic Heart Failure Circulation, February 8, 2000; 101(5): 558 - 569. [Full Text] [PDF]

				K. Shinagawa, H. Mitamura, A. Takeshita, T. Sato, H. Kanki, S. Takatsuki, and S. Ogawa Determination of refractory periods and conduction velocity during atrial fibrillation using atrial capture in dogs: Direct assessment of the wavelength and its modulation by a sodium channel blocker, pilsicainide J. Am. Coll. Cardiol., January 1, 2000; 35(1): 246 - 253. [Abstract] [Full Text] [PDF]

				O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]

				N. Dzimiri Regulation of beta -Adrenoceptor Signaling in Cardiac Function and Disease Pharmacol. Rev., September 1, 1999; 51(3): 465 - 502. [Abstract] [Full Text] [PDF]

				E. R. Azevedo and J. D. Parker Parasympathetic Control of Cardiac Sympathetic Activity : Normal Ventricular Function Versus Congestive Heart Failure Circulation, July 20, 1999; 100(3): 274 - 279. [Abstract] [Full Text] [PDF]

				G. E. Newton, E. R. Azevedo, and J. D. Parker Inotropic and Sympathetic Responses to the Intracoronary Infusion of a ß2-Receptor Agonist : A Human In Vivo Study Circulation, May 11, 1999; 99(18): 2402 - 2407. [Abstract] [Full Text] [PDF]

				E. R. Azevedo, G. E. Newton, and J. D. Parker Cardiac and systemic sympathetic activity in response to clonidine in human heart failure J. Am. Coll. Cardiol., January 1, 1999; 33(1): 186 - 191. [Abstract] [Full Text] [PDF]

				P. Lechat, M. Packer, S. Chalon, M. Cucherat, T. Arab, and J.-P. Boissel Clinical Effects of ß-Adrenergic Blockade in Chronic Heart Failure : A Meta-Analysis of Double-Blind, Placebo-Controlled, Randomized Trials Circulation, September 22, 1998; 98(12): 1184 - 1191. [Abstract] [Full Text] [PDF]

				W. Plochl, D. J. Cook, T. A. Orszulak, and R. C. Daly Critical cerebral perfusion pressure during tepid heart operations in dogs Ann. Thorac. Surg., July 1, 1998; 66(1): 118 - 123. [Abstract] [Full Text] [PDF]

				G. E. Billman, L. C. Castillo, J. Hensley, C. M. Hohl, and R. A. Altschuld ß2-Adrenergic Receptor Antagonists Protect Against Ventricular Fibrillation : In Vivo and In Vitro Evidence for Enhanced Sensitivity to ß2-Adrenergic Stimulation in Animals Susceptible to Sudden Death Circulation, September 16, 1997; 96(6): 1914 - 1922. [Abstract] [Full Text]

				G. E. Newton and J. D. Parker Cardiac Sympathetic Responses to Acute Vasodilation: Normal Ventricular Function Versus Congestive Heart Failure Circulation, December 15, 1996; 94(12): 3161 - 3167. [Abstract] [Full Text]

				S. Saito, Y. Hiroi, Y. Zou, R. Aikawa, H. Toko, F. Shibasaki, Y. Yazaki, R. Nagai, and I. Komuro beta -Adrenergic Pathway Induces Apoptosis through Calcineurin Activation in Cardiac Myocytes J. Biol. Chem., October 27, 2000; 275(44): 34528 - 34533. [Abstract] [Full Text] [PDF]

This Article Abstract 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 Newton, G. E. Articles by Parker, J. D. Search for Related Content PubMed PubMed Citation Articles by Newton, G. E. Articles by Parker, J. D.