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 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. Related Collections Congestive Cardiovascular Pharmacology

(Circulation. 1999;99:2402-2407.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Inotropic and Sympathetic Responses to the Intracoronary Infusion of a ß₂-Receptor Agonist

A Human In Vivo Study

Gary E. Newton, MD; Eduardo R. Azevedo, MD; John D. Parker, MD

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

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

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—On the basis of the presence of ß₂-receptors within the sympathetic nervous system, ß₂-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory ß₂-receptors are present in the human left ventricle.

Methods and Results—The ß₂-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no ß-blocker therapy), group 2 (n=7, ß₁-selective blockade with atenolol), and group 3 (n=6, nonselective ß-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44±6% increase in +dP/dt in group 1, a 25±6% increase in group 2 (P<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124±37% increase in cardiac norepinephrine spillover in group 1 (P<0.05).

Conclusions—Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by ß₁-receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac ß₂-receptors.

Key Words: salbutamol • atenolol • nadolol • ventricles • norepinephrine

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Stimulation of ß₂-adrenergic receptors increases both ventricular contractility and sympathetic outflow to the heart. Activation of ß₂-receptors on ventricular myocytes directly increases contractility.¹ Activation of ß₂-receptors within the peripheral vasculature causes vasodilation, which results in reflex sympathetic activation and parasympathetic withdrawal,^{2 3} both of which can augment contractility.⁴ ß₂-Receptors have also been described at various sites within the efferent sympathetic nervous system. In animal studies, stimulation of ß₁- and ß₂-receptors within intrathoracic sympathetic ganglia and on intrinsic cardiac neurons increases postganglionic cardiac sympathetic nerve discharge rate.^{5 6 7} ß₂-Receptors have been reported to be present on postganglionic cardiac sympathetic nerve terminals.^{8 9 10 11 12} Stimulation of these prejunctional receptors in animal experiments also facilitates norepinephrine release from cardiac sympathetic nerves.^{11 12} Thus, in addition to ß₂-receptor–mediated positive inotropism and vasodilation, stimulation of ß₂-receptors within the efferent sympathetic nervous system may result in a direct (nonreflexive) increase in cardiac sympathetic outflow.

Stimulation of sympathoexcitatory cardiac ß₂-receptors has the potential to contribute to the increase in cardiac sympathetic activity, which occurs in the setting of congestive heart failure.¹³ These receptors may also be involved in the mechanism of action of widely used cardiac medications, including ß-agonists and antagonists. Despite their potential importance, the physiological and pathophysiological role of sympathoexcitatory ß₂-receptors in the human heart is not well understood. Human studies have demonstrated that the inotropic response to intravenous ß₂-agonists is mediated in part by postsynaptic ß₁-receptors, as evidenced by partial inhibition of the ß₂-inotropic response by selective ß₁-antagonists.^{14 15 16} Although consistent with augmented norepinephrine release due to stimulation of sympathoexcitatory ß₂-receptors, this observation may also be explained by reflex sympathetic activation resulting from ß₂-receptor–mediated vasodilation. Studies of patients with congestive heart failure also provide indirect evidence for sympathoexcitatory cardiac ß₂-receptors. In congestive heart failure, ß₁-selective antagonists increase cardiac sympathetic activity, an effect that does not occur with nonselective ß-blockade.^{17 18} To date, human studies examining direct cardiac stimulation with ß₂-receptor agonists have been limited. Hall et al¹⁹ examined the heart rate response to right coronary artery injections of the ß₂-agonist salbutamol. They observed that practolol, a ß₁-selective agent, did not increase the mean dose of salbutamol required to augment heart rate by 30 bpm. This result suggests that ß₂-receptor stimulation does not facilitate norepinephrine release from sympathetic nerves at the level of the sinoatrial node.

In the present study, we addressed the hypothesis that sympathoexcitatory ß₂-receptors are present in the left ventricle. To answer this hypothesis, we used a left main coronary artery infusion technique for the direct application of a ß₂-agonist to the left ventricle. This approach was chosen to avoid activation of reflex systems associated with systemic ß₂-agonist infusions. Using this method, we measured the inotropic response, both ß₁- and ß₂-mediated, and the cardiac norepinephrine spillover response to an intracoronary ß₂-agonist.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The study population consisted of 22 subjects with a stable chest pain syndrome who had been referred for a diagnostic heart catheterization. All subjects had normal ventricular function by either 2-dimensional echocardiography or left ventriculography, and none had symptoms of congestive heart failure.

Three groups were studied. Subjects in group 1 (n=9; 8 men, 1 woman; mean age, 52±4 years; range, 32 to 61 years) were not receiving ß-blocker therapy. Medical therapy in this group included calcium channel blockers (n=5), nitrates (n=1), and ACE inhibitors (n=1). By coronary angiography, 4 subjects in group 1 did not have coronary disease, 1 had single-vessel disease involving the left anterior descending coronary artery (LAD), 3 had 2-vessel disease (LAD and circumflex coronary artery in 2, LAD and right coronary artery in the third), and 1 had 3-vessel disease. Group 2 (n=7; 6 men, 1 woman; mean age, 57±4 years; range, 44 to 71 years) included subjects receiving the ß₁-selective ß-blocker atenolol at a dose of 50 mg po daily for at least 1 week before the study. Medical therapy in this group, in addition to atenolol, included calcium channel blockers (n=2) and nitrates (n=2). Two subjects in group 2 did not have coronary disease, 1 had single-vessel disease (LAD), 2 had 2-vessel disease (LAD and circumflex in both), and 2 had 3-vessel disease. Subjects in group 3 (n=6; 5 men, 1 woman; mean age, 62±4 years; range, 53 to 74 years) received the nonselective ß-blocker nadolol at a dose of 40 mg po daily for at least 1 week before the study. Medical therapy in this group, in addition to nadolol, included calcium channel blockers (n=1), nitrates (n=1), and ACE inhibitors (n=1). One subject in group 3 did not have coronary disease, 2 had 1-vessel disease (LAD and right coronary artery), and 3 had 3-vessel disease. Subjects in groups 2 and 3 received their usual dose of atenolol or nadolol, respectively, 1 hour before beginning the cardiac catheterization.

This protocol was approved by the University of Toronto ethical review committee for experimentation involving human subjects. Written informed consent was obtained in all cases.

Hemodynamic and Inotropic Measurements
After a diagnostic heart catheterization, 20 minutes elapsed before we began this investigation. A 7F micromanometer-tipped catheter (Millar Industries) was placed in the left ventricle. A 7F left Judkins catheter (Cordis Laboratories), placed from the opposite femoral artery, was advanced to the ostium of the left main coronary artery for intracoronary drug infusions. Femoral artery pressure was monitored via an 8F side-arm sheath (Cordis Laboratories). The ECG, left ventricular pressure, and its first derivative (dP/dt, continuous electronic differentiation) were recorded on a strip chart recorder at a paper speed of 100 mm/s. Measurements of heart rate, left ventricular pressure, and femoral artery pressure were made by averaging at least 15 beats under each experimental condition. Left ventricular pressure and the ECG were digitally recorded at 300 Hz with a Macintosh personal computer equipped with a multichannel analog-to-digital converter. Data files were stored to disk for later analysis. With customized software developed in Labview (Version 3.0, National Instruments Corp), left ventricular peak +dP/dt was calculated offline. In all cases, +dP/dt values represent the mean calculated from a minimum of 20 cardiac cycles during each experimental condition.

Experimental Approach
The effect of the ß₂-agonist salbutamol on left ventricular function and cardiac norepinephrine spillover was assessed by the intracoronary drug infusion technique.^{4 20} The sequence of intracoronary infusions was as follows: (1) control 5% dextrose in water (D₅W), the vehicle for intracoronary drug infusion, at 1.25 mL/min; (2) intracoronary salbutamol sulfate (Glaxo Canada Inc) at infusion rates of 0.125, 0.625, 1.25, 2.5, and 5.0 µg/min: (3) recontrol D₅W. Intracoronary drugs were administered into the left main coronary artery via the Judkins catheter with a Harvard pump for 4 to 5 minutes, with measurements made in the final minute. All solutions were infused at 1.25 mL/min. After completion of the protocol, radiographic contrast was injected to confirm the continued position of the catheter in the left main coronary ostium. Indications for discontinuation of salbutamol included chest discomfort and ventricular extrasystoles. In group 1 (no ß-blocker therapy), 6 subjects received the maximum salbutamol infusion (5.0 µg/min), 1 subject received a maximum infusion of 2.5 µg/min, and 2 subjects received a maximum infusion of 1.25 µg/min. In group 2 (atenolol-treated), 5 subjects received the maximum salbutamol infusion, and 1 subject received a maximum infusion of 2.5 µg/min. All subjects in group 3 (nadolol-treated) received the maximum salbutamol infusion.

Cardiac Norepinephrine Spillover Measurements
To evaluate the effect of salbutamol on norepinephrine release from cardiac adrenergic nerves, cardiac norepinephrine spillover was measured in 5 patients in group 1. Cardiac norepinephrine spillover is the rate at which norepinephrine from the heart appears in plasma and as such is an indirect index of norepinephrine release from cardiac sympathetic nerves. This index was measured at control, at peak dose of salbutamol, and at recontrol. In these patients, in addition to the instrumentation described above, a 7F coronary sinus thermodilution flow catheter (type CCS-7U-90B, Webster Laboratories) was inserted from an antecubital vein. Coronary sinus blood flow measurements were performed in triplicate at each measurement point according to the method of Ganz et al.²¹ A tracer dose of tritiated norepinephrine (1 to 1.2 µCi/min, with a 16 µCi priming bolus of L-[2,5,6-³H]NE; New England Nuclear) was infused into a peripheral vein to steady-state concentration in plasma. Cardiac norepinephrine spillover and clearance rates were calculated as follows^{13 22} : Cardiac NE spillover (pmol/min)=[NE_cs- NE_art+(NE_extxNE_art)]xCSPF, and cardiac NE clearance (mL/min)= NE_extxCSPF, 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. Catecholamine concentrations were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Fractions from the HPLC effluent containing tritium-labeled norepinephrine were assayed by liquid scintillation spectroscopy. These analyses were performed by established methods in our laboratory.^{17 23}

Statistical Analysis
Baseline characteristics and peak salbutamol responses were compared by 1-way ANOVA. Within-group and between-group comparisons of the effects of salbutamol on hemodynamics and left ventricular contractility were performed with a 2-way repeated-measures ANOVA with Student-Newman-Keuls test performed post hoc to identify significant differences. The effect of salbutamol on cardiac norepinephrine spillover and related variables was assessed with a 1-way repeated-measures ANOVA with Student-Newman-Keuls test performed post hoc to identify significant differences. All data are presented as mean±SEM. Statistical analysis was performed in Sigmastat (Version 1, Jandel Scientific).

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
Baseline hemodynamic characteristics in the 3 study groups are provided in Table 1. There were no significant differences between the study groups in age, any hemodynamic parameter, or left ventricular +dP/dt.

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

Hemodynamic Responses to Intracoronary Salbutamol
In the 3 study groups, there were no significant changes in systemic arterial blood pressure, left ventricular end-diastolic pressure, or heart rate in response to any dose of salbutamol infused into the left coronary artery (Table 2).

View this table: [in this window] [in a new window]   Table 2. Hemodynamic and Inotropic Responses to Intracoronary Salbutamol

Inotropic Responses to Intracoronary Salbutamol
In group 1 (no ß-blocker therapy), intracoronary salbutamol resulted in a large dose-dependent increase in left ventricular contractility as assessed by +dP/dt. The increase in left ventricular +dP/dt was significant at all doses of salbutamol >0.125 µg/min (Table 2, Figure 1). The maximal increase in left ventricular +dP/dt in group 1 was 578±78 mm Hg/s, or 44±6% (Figure 2).

View larger version (17K): [in this window] [in a new window]   Figure 1. Left ventricular (LV) +dP/dt responses to salbutamol, shown as change from control, for group 1 (no ß-blocker therapy, ), group 2 (atenolol treated, ), and group 3 (nadolol treated, ). *P<0.05 for within-group comparison (vs control values), P<0.05 vs group 1, and P<0.05 vs group 2. Data are mean±SEM.

View larger version (12K): [in this window] [in a new window]   Figure 2. Individual patient peak inotropic responses to salbutamol, presented as absolute (A) and percent (B) increases in left ventricular +dP/dt in group 1 (no ß-blocker therapy), group 2 (atenolol-treated), and group 3 (nadolol-treated). *P<0.05 vs group 1, P<0.05 vs group 2. Data also presented as means.

Background ß-blocker therapy resulted in smaller increases in contractility in response to intracoronary salbutamol. In group 2 (atenolol-treated), salbutamol resulted in a dose-dependent increase in left ventricular peak +dP/dt. The increase in +dP/dt was significant at all doses of salbutamol >0.625 µg/min (Table 2, Figure 1). However, compared with group 1, patients in group 2 demonstrated a significantly smaller inotropic response to salbutamol: left ventricular +dP/dt was significantly less in group 2 than in group 1 at the 2.5- and 5.0-µg/min salbutamol doses. Furthermore, in group 2 the maximal increase in +dP/dt was only 372±60 mm Hg/s, or 25±6% (P<0.05 versus group 1 for both absolute and percent increases in +dP/dt, Figure 2).

The inotropic response to intracoronary salbutamol was completely inhibited in group 3 (nadolol-treated). There were no significant increases in left ventricular +dP/dt in response to any dose of salbutamol. The lack of an increase in contractility in group 3 was significantly different from the responses in both group 1 and group 2 (Table 2, Figures 1 and 2).

Cardiac Norepinephrine Spillover Responses to Intracoronary Salbutamol
Cardiac sympathetic responses to peak doses of salbutamol were assessed in 5 patients in group 1 (1.25 µg/min in 1 subject, 5 µg/min in 4 subjects). Salbutamol resulted in a 124±37% increase in cardiac norepinephrine spillover (P<0.05), an index that provides an indirect assessment of norepinephrine release from cardiac adrenergic nerve terminals (Table 3, Figure 3). Salbutamol, a potent vasodilator, also resulted in a 72±23% increase in coronary sinus plasma flow (P<0.05) and a 22±2% reduction in the cardiac extraction of tritium-labeled norepinephrine (P<0.05). Probably as a result of these 2 opposite effects, the change in cardiac norepinephrine clearance in response to salbutamol was not significant.

View this table: [in this window] [in a new window]   Table 3. Cardiac Norepinephrine Spillover Responses to Salbutamol

View larger version (16K): [in this window] [in a new window]   Figure 3. Individual patient cardiac norepinephrine spillover (CANESP) in group 1 (no ß-blocker therapy) at control, in response to peak dose of salbutamol, and at recontrol. P<0.05 for salbutamol vs control.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This investigation provides the first human in vivo description of the inotropic and cardiac sympathetic effects of an intracoronary infusion of a ß₂-agonist. Salbutamol was infused directly into the left coronary artery to prevent the stimulation of peripheral vascular ß₂-receptors and the confounding effects of systemic vasodilation. Furthermore, direct inotropic responses were assessed by use of left ventricular +dP/dt, a method that provides a sensitive and relatively load-independent measure of contractility in human in vivo studies.^{4 17 23 24 25 26} By these methods, the central findings of this study are that a directly infused ß₂-agonist increases contractility through activation of both cardiac ß₁- and ß₂-receptors and that a ß₂-agonist increases cardiac norepinephrine spillover rate. These observations support our hypothesis that sympathoexcitatory ß₂-receptors are present in the human left ventricle.

The intracoronary infusion of salbutamol resulted in a 44±6% increase in left ventricular +dP/dt in the group without ß-blocker therapy, a 25±6% increase in +dP/dt in the group receiving atenolol, and no increase in +dP/dt in the group receiving nadolol. The much smaller +dP/dt response in patients receiving atenolol, a ß₁-selective antagonist, provides evidence that both ß₁- and ß₂-receptors mediated the inotropic response to salbutamol. ß₂-Receptors, presumably on ventricular myocytes, have previously been demonstrated to mediate a positive inotropic response.^{14 15 16 27 28 29} The ß₁-component of the inotropic response suggests that there was an increase in norepinephrine release from cardiac sympathetic nerves, a mechanism that is supported by the observed increase in cardiac norepinephrine spillover in response to salbutamol. Salbutamol may have enhanced norepinephrine release by directly stimulating sympathoexcitatory ß₂-receptors within the cardiac efferent sympathetic nervous system. Such receptors have been described on intrinsic cardiac neurons and on cardiac adrenergic nerve terminals.^{6 7 11 12} Both of these receptor systems may have been stimulated by intracoronary salbutamol. Of note, sympathoexcitatory ß-receptors have also been described in locations that are not accessible to the intracoronary infusion technique, specifically within intrathoracic sympathetic ganglia.^{5 30} An alternative explanation for a salbutamol-mediated increase in norepinephrine release is that peripheral ß₂-receptor stimulation caused vasodilation, which resulted in reflex cardiac sympathetic activation. This seems unlikely, because salbutamol was infused locally to avoid peripheral ß₂-stimulation.

Other explanations for the ß₁-receptor–mediated inotropic response to salbutamol should be considered. Salbutamol may have increased contractility by directly stimulating cardiac ß₁-receptors. The ß₂-selectivity of this agent has been demonstrated in vitro in human atrial myocardium.³¹ In human in vivo studies, ICI 118,551, a selective ß₂-antagonist, was shown to abolish the cardiovascular responses to oral salbutamol.³² Furthermore, the heart rate effects of intracoronary salbutamol were shown not to be blocked by the selective ß₁-antagonist practolol.¹⁹ In the present study, the inotropic response in the atenolol group was reduced by nearly 50%. Therefore, the magnitude of the inotropic response that was ß₁-receptor–mediated is unlikely to have resulted entirely from the nonspecificity of salbutamol. In addition, a ß₁-receptor–mediated contractile response was apparent even at low salbutamol concentrations, when its action would be expected to be highly ß₂-specific. A reduced inotropic response to salbutamol might have occurred if atenolol nonselectively blocked ß₂-receptors. This does not appear to be the case, because atenolol 50 mg/d has been shown to be highly ß₁-selective in human studies.^{14 15} Furthermore, in humans, chronic ß₁-receptor blockade has been shown to sensitize cardiac ß₂-receptors,³³ although this observation has been questioned.¹⁶ If ß₁-receptor antagonism increases cardiac responsiveness to ß₂-receptor stimulation, the inotropic response to salbutamol probably would have been augmented, not reduced, in patients treated with atenolol.

The increase in cardiac norepinephrine spillover provides evidence that intracoronary salbutamol resulted in increased norepinephrine release from cardiac sympathetic nerves. Although cardiac norepinephrine spillover does not provide a direct measure of norepinephrine release, animal studies have demonstrated that cardiac norepinephrine spillover is representative of the cardiac sympathetic nerve firing rate.³⁴ Furthermore, human studies from our laboratory have shown that stimuli that result in baroreflex-mediated increases in sympathetic activity also cause increases in cardiac norepinephrine spillover.²⁴ However, variables other than cardiac sympathetic activity may affect cardiac norepinephrine spillover. Relevant to the present study is the relationship found in animal studies between changes in coronary blood flow and changes in cardiac norepinephrine spillover rate.³⁵ In the present study, salbutamol resulted in a significant increase in coronary sinus blood flow, which may have accounted for the increase in spillover. However, we have shown the flow independence of cardiac norepinephrine spillover in humans in response to various interventions.^{17 23 24} Similarly, we recently demonstrated that after coronary angioplasty, a large increase in coronary sinus blood flow was not associated with an increase in cardiac norepinephrine spillover.³⁶

Limitations to the experimental approach used in this study should be considered. Patients were not randomly assigned to either ß-blocker or no ß-blocker therapy. However, patients had similar clinical and hemodynamic characteristics. Plasma concentrations of atenolol and nadolol were not measured in this study. However, the doses of atenolol and nadolol used in this study have previously been demonstrated to provide ß₁-selective and nonselective ß-blockade, respectively.^{14 15 37} The limitations of the cardiac norepinephrine spillover technique have been discussed above. The cardiac norepinephrine spillover measurement was performed only in patients not receiving ß-blocker therapy. Therefore, whether the sympathoexcitatory response to salbutamol resulted from the stimulation of only ß₂-receptors or from the stimulation of both ß₁- and ß₂-receptors cannot be determined from this study. This is relevant, given the description of ß₁- and ß₂-receptors within the efferent sympathetic nervous system.^{5 7}

In summary, we have provided evidence that an intracoronary ß₂-agonist increases contractility through stimulation of both ß₁- and ß₂-receptors in the left ventricle and also increases sympathetic outflow from the heart. This result provides human in vivo evidence for the role of sympathoexcitatory cardiac ß₂-receptors. Activation of these receptors may provide a partial explanation for the observation of sympathetic activation directed at the heart in conditions such as heart failure¹³ and the striking clinical effects of ß-blockers, which antagonize these receptors.³⁸

	Acknowledgments

 
This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Ontario (A2811) and by Bayer Inc. Dr Newton is a research scholar of the Heart and Stroke Foundation of Canada. 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 September 30, 1998; revision received February 8, 1999; accepted February 12, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. 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]
   
2. 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]
   
3. Arnold JMO, McDevitt DG. Heart rate and blood pressure responses to intravenous boluses of isoprenaline in the presence of propranolol, practolol and atropine. Br J Clin Pharmacol. 1983;16:175–184.[Medline] [Order article via Infotrieve]
   
4. Newton GE, Parker AB, Landzberg JS, Colucci WS, Parker JD. Muscarinic receptor modulation of basal and ß-adrenergic stimulated function of the failing human left ventricle. J Clin Invest. 1996;98:2756–2763.[Medline] [Order article via Infotrieve]
   
5. Watson-Wright W, Boudreau G, Cardinal R, Armour JA. ß₁- and ß₂-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart. Am J Physiol. 1991;261:R1269–R1275.[Abstract/Free Full Text]
   
6. 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]
   
7. Armour JA. Intrinsic cardiac neurons involved in cardiac regulation possess ₁-, ₂-, ß₁-, and ß₂-adrenoceptors. Can J Cardiol. 1997;13:277–284.[Medline] [Order article via Infotrieve]
   
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. Review: 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. 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]
    
12. 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]
    
13. 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]
    
14. Strauss MH, Reeves RA, Smith DL, Leenan FHH. The role of cardiac ß₁-receptors in the hemodynamic response to a ß₂-agonist. Clin Pharmacol Ther. 1986;40:108–115.[Medline] [Order article via Infotrieve]
    
15. Levine MAH, Leenan FHH. Role of ß₁-receptors and vagal tone in cardiac inotropic and chronotropic responses to a ß₂-agonist in humans. Circulation. 1989;79:107–115.[Abstract/Free Full Text]
    
16. Schafers RF, Adler S, Daul A, Zeitler G, Vogelsang M, Zerkowski H-R, Brodde O-E. Positive inotropic effects of the ß₂-adrenoceptor agonist terbutaline in the failing human heart: Effects of long-term ß₁-adrenoceptor antagonist treatment. J Am Coll Cardiol. 1994;23:1224–1233.[Abstract]
    
17. Newton GE, Parker JD. Acute effects of ß₁-selective and nonselective ß-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation. 1996;94:353–358.[Abstract/Free Full Text]
    
18. Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, Larrabee P, Bristow MR. 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]
    
19. Hall JA, Petch MC, Brown MJ. Intracoronary injections of salbutamol demonstrate the presence of functional ß₂-adrenoceptors in the human heart. Circ Res. 1989;65:546–553.[Abstract/Free Full Text]
    
20. 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]
    
21. 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]
    
22. 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]
    
23. Newton GE, Tong JS, Schofield AM, Baines AD, Floras JS, Parker JD. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol. 1996;28:155–161.[Abstract]
    
24. Newton GE, Parker JD. Cardiac sympathetic responses to acute vasodilation: normal ventricular function versus congestive heart failure. Circulation. 1996;94:3161–3167.[Abstract/Free Full Text]
    
25. Starling MR, Montgomery DG, Mancini GBJ, Walsh RA. Load independence of the rate of isovolumic relaxation in man. Circulation. 1987;76:1274–1281.[Abstract/Free Full Text]
    
26. Jaski BE, Fifer MA, Wright RF, Braunwald E, Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure: dose-response relationships and comparison to nitroprusside. J Clin Invest. 1985;75:643–649.
    
27. Noguchi K, Ojiri Y, Chibana T, Moromizato H, Sakanashi M. Cardiac effects of ß₂-adrenoceptor stimulation with intracoronary procaterol in the absence and presence of regional myocardial ischemia in dogs. J Pharmacol Exp Ther. 1991;259:732–737.[Abstract/Free Full Text]
    
28. Kaumann AJ, Lemoine H. ß₂-Adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium: quantitative discrepancies with binding and adenylate cyclase stimulation. Naunyn Schmiedebergs Arch Pharmacol. 1987;335:403–411.[Medline] [Order article via Infotrieve]
    
29. Motomura S, Zerkowski H-R, Daul A, Brodde O-E. On the physiologic role of ß₂-adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J. 1990;119:608–619.[Medline] [Order article via Infotrieve]
    
30. Butler CK, Smith FM, Nicholson J, Armour JA. Cardiac effects induced by chemically activated neurons in canine intrathoracic ganglia. Am J Physiol. 1990;259:H1108–H1117.[Abstract/Free Full Text]
    
31. Hall JA, Kaumann AJ, Brown MJ. Selective ß₁-adrenoreceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through ß₂-adrenoreceptors in human atrial myocardium. Circ Res. 1990;66:1610–1623.[Abstract/Free Full Text]
    
32. McCaffrey PM, Riddell JG, Shanks RG. The selectivity of xamoterol, prenalterol, and salbutamol as assessed by their effects in the presence and absence of ICI 118,551. J Cardiovasc Pharmacol. 1988;11:543–551.[Medline] [Order article via Infotrieve]
    
33. Hall JA, Petch MC, Brown MJ. In vivo demonstration of cardiac ß₂-adrenoreceptor sensitization by ß₁-antagonist treatment. Circ Res. 1991;69:959–964.[Abstract/Free Full Text]
    
34. Eisenhofer G, Smolich JJ, Cox HS, Esler MD. Neuronal reuptake of norepinephrine and production of dihydroxyphenylglycol by cardiac sympathetic nerves in the anesthetized dog. Circulation. 1991;84:1354–1363.[Abstract/Free Full Text]
    
35. 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]
    
36. Newton GE, Adelman AG, Lima VC, Seidelin PH, Schampeart E, Parker JD. Cardiac sympathetic activity in response to acute myocardial ischemia. Am J Physiol. 1997;41:H2079–H2084.
    
37. Leenan FHH, Davies RA, Fourney A. Role of cardiac ß₂-receptors in cardiac responses to exercise in cardiac transplant patients. Circulation. 1995;91:685–690.[Abstract/Free Full Text]
    
38. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349–1355.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				N. Sotoodehnia, D. S. Siscovick, M. Vatta, B. M. Psaty, R. P. Tracy, J. A. Towbin, R. N. Lemaitre, T. D. Rea, J. P. Durda, J. M. Chang, et al. {beta}2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death Circulation, April 18, 2006; 113(15): 1842 - 1848. [Abstract] [Full Text] [PDF]

				T. Nieminen, T. Lehtimaki, J. Laiho, R. Rontu, K. Niemela, T. Koobi, R. Lehtinen, J. Viik, V. Turjanmaa, and M. Kahonen Effects of polymorphisms in beta1-adrenoceptor and {alpha}-subunit of G protein on heart rate and blood pressure during exercise test. The Finnish Cardiovascular Study J Appl Physiol, February 1, 2006; 100(2): 507 - 511. [Abstract] [Full Text] [PDF]

				D. Kaye and M. Esler Sympathetic neuronal regulation of the heart in aging and heart failure Cardiovasc Res, May 1, 2005; 66(2): 256 - 264. [Abstract] [Full Text] [PDF]

				J. G. Burniston, L.-B. Tan, and D. F. Goldspink {beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle J Appl Physiol, April 1, 2005; 98(4): 1379 - 1386. [Abstract] [Full Text] [PDF]

				E. Barbato, F. Piscione, J. Bartunek, G. Galasso, P. Cirillo, G. De Luca, G. Iaccarino, B. De Bruyne, M. Chiariello, and W. Wijns Role of {beta}2 Adrenergic Receptors in Human Atherosclerotic Coronary Arteries Circulation, January 25, 2005; 111(3): 288 - 294. [Abstract] [Full Text] [PDF]

				D. M. Kaye, B. Smirk, S. Finch, C. Williams, and M. D. Esler Interaction between cardiac sympathetic drive and heart rate in heart failure: Modulation by adrenergic receptor genotype J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2008 - 2015. [Abstract] [Full Text] [PDF]

				K. Foerster, F. Groner, J. Matthes, W. J. Koch, L. Birnbaumer, and S. Herzig Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through {beta}2-adrenoceptors PNAS, November 25, 2003; 100(24): 14475 - 14480. [Abstract] [Full Text] [PDF]

				S. Velez-Roa, M. Renard, J.-P. Degaute, and P. van de Borne Peripheral sympathetic control during dobutamine infusion: effects of aging and heart failure J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1605 - 1610. [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]

				D. S. Goldstein, C. Holmes, S. M. Frank, R. Dendi, R. O. Cannon III, Y. Sharabi, M. D. Esler, and G. Eisenhofer Cardiac Sympathetic Dysautonomia in Chronic Orthostatic Intolerance Syndromes Circulation, October 29, 2002; 106(18): 2358 - 2365. [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]

				M D Lowe, E Rowland, M J Brown, and A A Grace {beta}2 Adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium Heart, July 1, 2001; 86(1): 45 - 51. [Abstract] [Full Text] [PDF]

				D. M. Kaye, L. Johnston, G. Vaddadi, H. Brunner-LaRocca, G. L. Jennings, and M. D. Esler Mechanisms of Carvedilol Action in Human Congestive Heart Failure Hypertension, May 1, 2001; 37(5): 1216 - 1221. [Abstract] [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]

				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]

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 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.