The Effects of Dobutamine on Cardiac Sympathetic Activity in Patients with Congestive Heart Failure Abdul Al-Hesayen, MD, Eduardo R

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Journal of the American College of Cardiology Vol. 39, No. 8, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01783-7 The Effects of Dobutamine on Cardiac Sympathetic Activity in Patients With Congestive Heart Failure Abdul Al-Hesayen, MD, Eduardo R. Azevedo, MD, Gary E. Newton, MD, John D. Parker, MD, FACC Toronto, Canada

OBJECTIVES The goal of this work was to study the effects of short-term infusion of dobutamine on efferent cardiac sympathetic activity. BACKGROUND Increased efferent cardiac sympathetic activity is associated with poor outcomes in the setting of congestive heart failure (CHF). Dobutamine is commonly used in the therapy of decompensated CHF. Dobutamine, through its effects on excitatory beta-receptors, may increase cardiac sympathetic activity. METHODS Seven patients with normal left ventricular (LV) function and 13 patients with CHF were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) before and during an intravenous infusion of dobutamine titrated to increase the rate of rise in LV peak positive pressure (ϩdP/dt) by 40%. RESULTS Systemic arterial pulse pressure increased significantly in response to dobutamine in the normal LV function group (74 Ϯ 3mmHgto85Ϯ 3 mm Hg, p ϭ 0.005) but remained unchanged in the CHF group. Dobutamine caused a significant decrease in LV end-diastolic pressure in the CHF group (14 Ϯ 2mmHgto11Ϯ 2 mm Hg, p ϭ 0.02), an effect not observed in the normal LV group. In the normal LV function group, CANESP did not change in response to dobutamine (75 Ϯ 22 pmol/min vs. 72 Ϯ 22 pmol/min, p ϭ NS). In contrast, dobutamine infusion was associated with a significant reduction in CANESP in patients with CHF (199 Ϯ 43 pmol/min to 128 Ϯ 30 pmol/min, p Ͻ 0.0009). CONCLUSIONS Dobutamine infusion caused a significant sympatholytic response in patients with CHF. This sympathetic withdrawal response is probably related to reduction of LV filling pressures and/or activation of ventricular mechanoreceptors with dobutamine infusion. (J Am Coll Cardiol 2002;39:1269–74) © 2002 by the American College of Cardiology Foundation

The detrimental effect of long-term oral positive inotropic quences including increased arrhythmias and myocardial therapy in patients with advanced congestive heart failure ischemia (15). Beta-agonist therapy may also increase en- (CHF) is well established (1–3). Different classes of inotro- dogenous norepinephrine release through stimulation of pic agents including beta-adrenergic receptor agonists and facilitative prejunctional beta-receptors at several sites phosphodiesterase inhibitors have been evaluated in clinical within the sympathetic nervous system (16,17). We have

trials with neutral or negative effects (1–6). Despite the previously demonstrated that a beta2-agonist increases car- failure of oral positive inotropic agents, intravenous positive diac sympathetic activity, presumably through an excitatory inotropic therapy continues to be used extensively in the prejunctional mechanism (18). treatment of decompensated CHF. Dobutamine, a rela- The purpose of the current study was to explore the

tively selective beta1-agonist, is one agent in widespread effects of acute beta-agonist administration on cardiac sym- clinical use for this indication (7,8). It is also used in pathetic activity. We hypothesized that dobutamine would intermittent therapeutic regimens, although its efﬁcacy and cause an augmentation in cardiac sympathetic activity safety in this setting remain controversial (9). Multiple through activation of sympathoexcitatory beta-adrenergic case-control studies and case series suggested that this receptors. To test this hypothesis we measured cardiac approach improved functional capacity and reduced hospital norepinephrine spillover (CANESP) responses during the admissions (10–13). However, a single randomized trial, acute administration of dobutamine in patients with CHF presented only in abstract form, described an increase in and normal left ventricular (LV) function. mortality (14). An important potential mechanism for adverse effects of beta-agonist therapy in patients with CHF is via sympa- METHODS thetic activation. Beta-agonists directly stimulate adrenergic Patients. The study population consisted of 20 patients. receptors on cardiac myocytes with possible adverse conse- Seven subjects with normal LV function (LV ejection fraction: 56 Ϯ 2%, mean age: 62 Ϯ 3 years) underwent From the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, coronary angiography to investigate a chest pain syndrome. University of Toronto, Toronto, Canada. Dr. Al-Hesayen holds a research fellowship award from the Heart and Stroke Foundation of Ontario. Dr. Azevedo held a research Four of these had coronary artery disease. In this group, six fellowship award from AstraZeneca/Heart and Stroke Scientiﬁc Research Corpora- of the patients received beta-blockers which included ateno- tion of Canada. This study was funded by an operating grant from the Heart and lol (n ϭ 3, daily dose 50 mg), metoprolol (n ϭ 1, daily dose Stroke Foundation of Ontario (grant No. T3696) and from Bayer Inc. ϭ Manuscript received July 31, 2001; revised manuscript received January 3, 2002, 100 mg), nadolol (n 1, daily dose 40 mg) and propranolol accepted January 18, 2002. (n ϭ 1, daily dose 80 mg), and one patient received an 1270 Al-Hesayen et al. JACC Vol. 39, No. 8, 2002 Dobutamine Heart Failure and Norepinephrine Spillover Rate April 17, 2002:1269–74

at each measurement point according the method of Ganz Abbreviations and Acronyms et al. (19). CANESP ϭ cardiac norepinephrine spillover Norepinephrine spillover measurements. Sympathetic CHF ϭ congestive heart failure activity was estimated by the measurement of CANESP and ϭ HPLC high-performance liquid chromatography total body norepinephrine spillover (20). For these measure- LV ϭ left ventricle/ventricular ␮ ϩdP/dt ϭ rate of rise in left ventricular peak positive ments, tritiated norepinephrine (1 to 1.2 Ci/min with a ␮ 3 pressure 16 Ci priming bolus of L-[2,5,6- H] norepinephrine; New England Nuclear, Boston, Massachusetts) was infused into a peripheral vein to steady-state concentration in angiotensin receptor blocker. Thirteen patients had CHF plasma. Norepinephrine clearance and spillover rates were (LV ejection fraction: 21 Ϯ 3%, mean age: 62 Ϯ 2 years). calculated as previously described (21,22). The etiology of the heart failure was ischemic in nine Analysis of plasma catecholamines. Plasma catecholamine concentrations were measured by high-performance patients and idiopathic in four patients. The medical ther- liquid chromatography (HPLC) with electrochemical de- apy consisted of metoprolol (n ϭ 4, mean dose 81 mg), tection. Fractions from the HPLC effluent containing atenolol (n ϭ 1, daily dose 50 mg), carvedilol (n ϭ 1, daily tritium-labeled norepinephrine were assayed by liquid scin- dose 25 mg), digoxin (n ϭ 7) and angiotensin-converting tillation spectroscopy. These analyses were performed by enzyme inhibitor or angiotensin receptor antagonist (n ϭ established methods in our laboratory by personnel blinded 11). The patients were on a stable dose of beta-blockers for to patient status (21,22). a minimum of eight weeks before participation in the study. Study protocol. After the diagnostic heart catheterization Eight patients had New York Heart Association functional and insertion of catheters for hemodynamic monitoring, class II symptoms; four had functional class III symptoms the patient was left undisturbed for a minimum of 20 min and one patient had functional class IV symptoms. for tritium-labeled norepinephrine to reach steady-state. All medications were held on the morning of the study. Baseline hemodynamic and coronary blood flow measure- The University of Toronto Ethical Review Committee for ments were obtained along with measures of CANESP experimentation involving human subjects approved the and total body norepinephrine spillover. Subsequently, an protocol. Written informed consent was obtained from all intravenous infusion of dobutamine was initiated starting Ϫ Ϫ participants. at 2.5 ␮g·kg 1·min 1. The dobutamine infusion rate was Hemodynamic and coronary flow measurements. A di- increased until LV ϩdP/dt had increased by 40%. Hemo- agnostic left and right heart catheterization from the fem- dynamic, coronary sinus blood flow, CANESP and total oral approach was performed without sedation. After the body norepinephrine spillover were reassessed 20 min after diagnostic procedure, the pulmonary artery catheter was left this increase in LV ϩdP/dt had been achieved. The dobut- in place. A 7F coronary sinus thermodilution catheter (type amine infusion was then discontinued, and recovery mea- CCS-7U-90B, Webster Laboratories, Baldwin Park, Cali- surements were performed once LV ϩdP/dt had returned to fornia) was inserted from an antecubital vein and positioned baseline values. under fluoroscopic guidance in the coronary sinus for flow Statistical analysis. Data are presented as the mean value measurements and blood sampling. A 7F micromanometer Ϯ SEM. The analysis was performed using SAS (release tipped catheter (Millar Industries, Houston, Texas) was 8.1, SAS Institute Inc., Cary, North Carolina). Between- placed in the LV. Femoral artery pressure was monitored via group comparisons of baseline characteristics were per- an 8F side-arm sheath (Terumo Medical Corp., Elkton, formed with unpaired t test. The effects of dobutamine were Maryland). Cardiac output was measured by the Fick analyzed using a general linear modelling procedure. The method. The electrocardiogram (ECG), right atrial pres- model allowed for analysis of the effects of dobutamine sure, pulmonary artery pressure, femoral artery pressure, LV within groups and also determined if there was significant pressure and its first derivative ([dP/dt] continuous elec- group by treatment interactions. A value of p Յ 0.05 was tronic differentiation) were recorded on a strip chart re- required for statistical significance. corder. For each variable, the results were expressed as an average measurement of 10 cardiac cycles in patients with RESULTS sinus rhythm and 15 cardiac cycles in patients with atrial fibrillation. Left ventricular pressure and the ECG were Baseline characteristics. Baseline hemodynamic and neu- digitally recorded at 300 Hz with a Macintosh personal rochemical characteristics are summarized in the Table 1. computer equipped with a multichannel analog-to-digital The CHF group had reduced cardiac index and elevated converter. Data files were stored to disk for later analysis. central filling pressures. Left ventricular peak ϩdP/dt values were calculated off-line Hemodynamic responses. The final dobutamine infusion with customized software developed in Labview (Version rate was 2.7 Ϯ 0.2 ␮g/kg per min in the normal LV 3.0, National Instruments Corp., Austin, Texas). Coronary function group and 5.6 Ϯ 0.6 ␮g/kg per min in the CHF sinus blood flow measurements were performed in duplicate group (p ϭ 0.002, normal LV vs. CHF group). The LV JACC Vol. 39, No. 8, 2002 Al-Hesayen et al. 1271 April 17, 2002:1269–74 Dobutamine Heart Failure and Norepinephrine Spillover Rate

Table 1. Baseline Hemodynamic and Neurochemical Data Normal LV CHF HR (beats/min) 60 Ϯ 477Ϯ 4* RA (mm Hg) 4 Ϯ 17Ϯ 1* Ϯ Ϯ PAmean (mm Hg) 13 1243* Ϯ Ϯ FAmean (mm Hg) 88 3853 LV ϩdP/dt (mm Hg/s) 1,217 Ϯ 103 855 Ϯ 61* CI (l/min/m2) 3.3 Ϯ 0.3 2.4 Ϯ 0.2* Ϯ Ϯ NEart (nmol/l) 0.7 0.1 1.9 0.3* Ϯ Ϯ NEcs (nmol/l) 1.3 0.5 3.2 0.6* TBNECL (l/min) 2.5 Ϯ 0.1 1.8 Ϯ 0.2* TBNESP (nmol/min) 1.9 Ϯ 0.4 2.9 Ϯ 0.5 CANESP (pmol/min) 75 Ϯ 22 199 Ϯ 43*

*p Ͻ0.05. Data are presented as mean Ϯ SEM. ϩdP/dt ϭ rate of rise in peak positive pressure; CANESP ϭ cardiac norepineph- ϭ ϭ ϭ rine spillover; CHF congestive heart failure; CI cardiac index; FAmean mean ϭ ϭ ϭ femoral artery pressure; HR heart rate; LV left ventricle; NEart arterial plasma ϭ ϭ norepinephrine; NEcs coronary sinus plasma norepinephrine; PAmean mean Figure 1. ϭ ϭ Cardiac norepinephrine spillover rate (CANESP) with dobut- pulmonary artery pressure; RA right atrial pressure; TBNECL total body amine in the congestive heart failure (CHF) group versus the normal left norepinephrine clearance; TBNESP ϭ total body norepinephrine spillover. ventricular (LV) function group. Solid triangle ϭ normal LV on no beta-blocker; open triangle ϭ normal LV on beta-blocker; open circle ϭ peak ϩdP/dt increased by 38 Ϯ 8% in the normal LV CHF on no beta-blocker; solid circle ϭ CHF on beta-blocker. C ϭ Ϯ control; Dob ϭ Dobutamine. *p Ͻ 0.05 vs. control; †p Ͻ 0.05 response in function group and by 42 5% in the CHF group (Table CHF group versus response in normal LV group. 2). The analysis revealed that there was no significant interaction between the effect of dobutamine and patient Cardiac sympathetic responses. In the normal LV func- group (p ϭ NS, normal vs. CHF). In the normal LV tion group, dobutamine caused no change in CANESP function group, systemic arterial pressure parameters in- (0 Ϯ 11%, p ϭ NS). In the CHF group, there was a large creased in response to dobutamine, with the increase in and highly significant reduction in CANESP with dobut- pulse pressure being the most prominent (74 Ϯ 3mmHgto amine (Ϫ36 Ϯ 8%, p Ͻ 0.0009). There was a significant 85 Ϯ 3 mm Hg, p ϭ 0.005). Dobutamine infusion caused group by treatment interaction indicating that the response smaller increases in systemic arterial pressure parameters in of CANESP in the CHF group was significantly different the CHF group, none of which were statistically significant. from the response observed in the normal LV function There was no significant interaction between the systemic group (p ϭ 0.01; normal LV function vs. CHF group) (Fig arterial blood pressure effects of dobutamine and patient 1). There was no difference between recontrol CANESP group. Dobutamine did cause a significant decrease in LV measurements and baseline measurements. end-diastolic pressure during dobutamine infusion in the Generalized sympathetic responses. Dobutamine had no CHF group (14 Ϯ 2mmHgto11Ϯ 2mmHg,pϭ 0.02). significant effect on total body norepinephrine spillover in There was no significant change in LV end-diastolic pres- either group (Table 3). In both the normal LV function sure in the normal LV function group; however, there was group and the CHF group, dobutamine infusion was a significant interaction between the effect of dobutamine associated with a significant increase in total body norepi- and patient group, indicating that the LV end-diastolic nephrine clearance (Table 3). pressure response in the CHF group was significantly Effects of beta-blocker treatment on responses to different from the response in the normal LV function dobutamine. Six patients in the CHF group were being group. Hemodynamic measurements returned to baseline treated with beta-blockers. There was no difference in the after discontinuation of dobutamine. final dobutamine infusion dose between the patients on

Table 2. Hemodynamic Responses to Dobutamine Normal LV CHF Control Dobutamine Control Dobutamine HR (beats/min) 60 Ϯ 465Ϯ 577Ϯ 487Ϯ 6* RA (mm Hg) 4 Ϯ 14Ϯ 17Ϯ 17Ϯ 1 Ϯ Ϯ Ϯ Ϯ PAmean (mm Hg) 13 1141* 24 3233 Ϯ Ϯ Ϯ Ϯ FAmean (mm Hg) 88 3904853864 PP (mm Hg) 74 Ϯ 385Ϯ 3* 58 Ϯ 665Ϯ 5 LVEDP (mm Hg) 10 Ϯ 212Ϯ 214Ϯ 211Ϯ 2*† LV ϩdP/dt (mm Hg/s) 1,217 Ϯ 103 1,686 Ϯ 170* 855 Ϯ 61 1,226 Ϯ 75* CI (l/min per m) 3.3 Ϯ 0.3 3.7 Ϯ 0.3* 2.4 Ϯ 0.2 2.9 Ϯ 0.2*

*p Ͻ0.05 versus control; †p Ͻ0.05 response in CHF group versus response in normal LV group. PP ϭ pulse pressure. Data are presented as mean Ϯ SEM. Other abbreviations as in Table 1. 1272 Al-Hesayen et al. JACC Vol. 39, No. 8, 2002 Dobutamine Heart Failure and Norepinephrine Spillover Rate April 17, 2002:1269–74

Table 3. Neurochemical Responses to Dobutamine Normal LV CHF Control Dobutamine Control Dobutamine CSBF (ml/min) 107 Ϯ 10 141 Ϯ 22* 130 Ϯ 15 145 Ϯ 14* Ϯ Ϯ Ϯ Ϯ NEart (nmol/l) 0.7 0.1 1.0 0.2 1.9 0.3 1.7 0.3 Ϯ Ϯ Ϯ Ϯ NEcs (nmol/l) 1.3 0.5 1.1 0.4 3.2 0.6 2.3 0.6* TBNECL (l/min) 2.5 Ϯ 0.1 2.9 Ϯ 0.2* 1.8 Ϯ 0.2 1.9 Ϯ 0.2* TBNESP (nmol/min) 1.9 Ϯ 0.4 1.7 Ϯ 0.4 2.9 Ϯ 0.5 2.7 Ϯ 0.6 CANESP (pmol/min) 75 Ϯ 22 72 Ϯ 22 199 Ϯ 43 128 Ϯ 30*†

*p Ͻ 0.05 versus control; †p Ͻ 0.05 response in CHF group versus response in normal LV group. Data are presented as mean Ϯ SEM. CSBF ϭ coronary sinus blood flow. Other abbreviations as in Table 1. beta-blockers and those who were not (5.8 Ϯ 1.1 ␮g/kg per been termed the “intrinsic cardiac sympathetic nervous min vs. 5.3 Ϯ 0.6 ␮g/kg/min, no beta-blocker vs. beta- system” and are felt to play an important role in the blocker, p ϭ NS). Heart rate and cardiac output increased peripheral control of cardiac sympathetic responses (23). significantly in both groups with dobutamine infusion with Animal experiments have demonstrated that beta1- no effect of beta-blockade on the magnitude of response. adrenegic receptors in these neuronal systems can modulate Similarly, the CANESP responses to dobutamine were not an increase in cardiac sympathetic activity (23). affected by beta-blocker treatment (Ϫ39 Ϯ 12% vs. Ϫ33 Ϯ Dobutamine effects in the normal LV group. In the 10%, no beta-blocker vs. beta-blocker, p ϭ NS). normal LV function group dobutamine had no significant effect on CANESP. Despite this neutral response, we DISCUSSION cannot completely discount that a cardiac sympathoexcit- This investigation provides the first human in vivo descrip- atory effect occurred. Indeed, it is possible that a direct tion of the effects of dobutamine on CANESP rate, an sympathoexcitatory effect was offset by afferent reflexes that indirect index of cardiac sympathetic efferent neuronal were associated with a balanced withdrawal of central activity. Dobutamine was given intravenously and in clini- sympathetic outflow. There would appear to be two poten- cally relevant doses. We have demonstrated that dobut- tial mechanisms. First, dobutamine caused an increase in amine caused a significant reduction in CANESP, an systemic arterial pressure. Such stimulation of arterial accepted index of efferent postganglionic nerve activity in baroreceptors could have caused a reflex decrease in sympa- patients with CHF. thetic outflow. Second, the infusion of dobutamine may Sympathoexcitatory beta-adrenergic receptors. In this have caused activation of ventricular mechanoreceptors. investigation we hypothesized that dobutamine administra- Stimulation of these receptors has been shown to elicit reflex tion would cause an increase in cardiac sympathetic activity decreases in sympathetic outflow, and the activity of these receptors has been shown to increase in response to positive through its effects, primarily, on beta1-adrenergic sympathoexcitatory receptors located on intramural and juxtacar- inotropic therapy (24,25). diac sympathetic ganglia and efferent postganglionic neu- Dobutamine effects in the CHF group. Contrary to our Ϯ rons. These receptors have been described at a number of hypothesis, dobutamine caused a 36 8% reduction in levels within the intrathoracic sympathetic nervous system. CANESP in the CHF group. This observation suggests that sympathoinhibitory reflex responses are more relevant Classically, prejunctional beta2-adrenergic receptors are described that facilitate neuronal norepinephrine release. than any direct sympathoexcitatory effects of dobutamine in These receptors, and their functional significance, have been this patient population. Three possible reflex mechanisms to described in a number of animals and humans (16,17). In a account for sympathoinhibition can be suggested. As with previous report from our laboratory, we documented the the normal LV function group, it is possible that arterial presence and functional importance of cardiac, sympatho- baroreceptors played a role in the observed sympathoinhibi- excitatory beta2-adrenergic receptors in humans with nor- tory response. This seems unlikely because dobutamine had mal ventricular function (18). In that study, we demon- essentially no effect on systemic arterial blood pressure, strated that salbutamol infusion increased CANESP by while somewhat greater increases in systemic arterial pres- 124% and that the increase in norepinephrine release sure in the normal LV function group had no effect on mediated by beta2-adrenergic receptor stimulation made an CANESP. Second, it is also possible that the sympathoin- important contribution to the inotropic responses observed hibitory effect of dobutamine in patients with CHF was (18). Recently, intracardiac, pericardiac and intrathoracic caused by a reduction in LV filling pressure. Dobutamine sympathetic ganglia have been described that contain both caused a significant reduction in LV end-diastolic pressure beta1- and beta2-adrenergic receptors that are involved in without reducing systemic arterial blood pressure. In a the control of cardiac sympathetic responses (16,17,23). previous report using lower body negative suction, we These cardiac and intrathoracic sympathetic neurons have demonstrated that a decrease in ventricular filling pressure JACC Vol. 39, No. 8, 2002 Al-Hesayen et al. 1273 April 17, 2002:1269–74 Dobutamine Heart Failure and Norepinephrine Spillover Rate in the absence of a fall in systemic arterial blood pressure downregulation in the myocardium of patients with CHF was associated with a significant reduction in cardiac sym- (33). Direct measures of efferent sympathetic outflow to the pathetic activity in patients with CHF (26). In the present heart are not available in humans. We have hypothesized study, the reduction in LV filling pressure with dobutamine that the reduction in CANESP that occurred in the CHF was somewhat smaller than that seen with lower body group was mediated by a reduction in central sympathetic negative suction. Furthermore, right-sided filling pressures outflow. Because cardiac efferent nerve activity cannot be did not change with dobutamine, while they did decrease recorded in vivo, we cannot be definitive about this mech- significantly with lower body negative suction. Therefore, anism. For example, our measure of norepinephrine spill- although it is possible that the reduction in LV filling over is an indirect estimate of changes in norepinephrine pressure made some contribution to the observed result, we release, and we cannot rule out that some of the observed do not believe that the entire reduction in CANESP reduction in CANESP was mediated by changes in norepi- occurred because of this small reduction in left-sided filling nephrine uptake mechanisms. pressure. Ventricular mechanoreceptor activation in re- Conclusions. In summary, this investigation has demon- sponse to increased contractility provides a third potential strated that a short-term infusion of dobutamine caused a explanation for the observed decrease in cardiac sympathetic significant reduction in efferent cardiac sympathetic activity activity (24,27,28). Activation of these receptors is associ- in patients with CHF. These observations are relevant given ated with both attenuation in the sympathetic outflow to the the common clinical usage of dobutamine in this patient peripheral circulation and augmentation of vagal efferent population. The authors would like to emphasize that these cardiac nerve activity (24). This increase in efferent cardiac observations should not change present perceptions con- parasympathetic activity could explain the differential effects cerning the safety of using inotropic agents in the treatment of dobutamine on cardiac sympathetic norepinephrine spill- of patients with CHF. At the moment, the utility of over in the two groups. We have previously shown that dobutamine and other inotropic agents in the short-term muscarinic receptor activation caused a reduction in management of individual patients has an accepted place in CANESP in patients with CHF, an effect not observed in clinical practice. Their utility and safety when used routinely patients with normal LV function (29). In the CHF group in decompensated patients or intermittently as part of there was a significant increase in both heart rate and LV long-term maintenance care remains controversial (14,34). ϩdP/dt despite concurrent evidence of sympathetic with- Our observation serves to establish that relatively selective drawal. These differential responses are not inconsistent beta1-adrenergic agonists like dobutamine do not cause an because the former was the result of dobutamine’s postjunc- increase in cardiac sympathetic efferent neuronal activity tional beta-agonist activity. when used in patients with chronic heart failure. There have been no previous investigations of the response of the cardiac sympathetic nervous system to inotro- Acknowledgments pic agents like dobutamine. In a previous study, Colucci et The authors thank the staff of the Bayer Cardiovascular al. (30) demonstrated that systemic plasma norepinephrine Clinical Research Laboratory of Mount Sinai Hospital for decreases in response to short-term infusions of dobutamine their help in the completion of these studies. in patients with CHF. These observations suggested that dobutamine decreased systemic sympathetic activity in Reprint requests and correspondence: Dr. John D. Parker, CHF. 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