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(Hypertension. 2004;43:1227.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Cardiac Uptake-1 Inhibition by High Circulating Norepinephrine Levels in Patients with Pheochromocytoma

Basil A. Eldadah; Karel Pacak; Graeme Eisenhofer; Courtney Holmes; Irwin J. Kopin; David S. Goldstein

From the Clinical Neurocardiology Section (B.A.E., G.E., C.H., I.J.K., D.S.G.), National Institute of Neurological Disorders and Stroke, and the Pediatric and Reproductive Endocrinology Branch (K.P.), National Institute of Child Health and Development, National Institutes of Health.

Correspondence to Dr Basil A. Eldadah, Building 10, Room 6N252, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC-1620, Bethesda, MD 20892-1620. E-mail eldadahb{at}ninds.nih.gov

	Abstract

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Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 µmol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[¹⁸F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (500 pg/mL), left ventricular myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (r=–0.77, P<0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine.

Key Words: heart • norepinephrine • pheochromocytoma • radiography

	Introduction

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Neuronal reuptake of the sympathetic neurotransmitter norepinephrine through the membrane norepinephrine transporter^1–3 (also known as uptake-1) is a key determinant of inactivation of norepinephrine in the heart and, therefore, of cardiac sympathetic neuroeffector function. Cardiac sympathetic neuroimaging, using radiolabeled sympathomimetic amines such as ¹²³I- or ¹³¹I-metaiodobenzylguanidine (MIBG) or catecholamines such as 6-[¹⁸F]fluorodopamine, depends on uptake of the imaging agent into sympathetic nerves through the cell membrane norepinephrine transporter.

Pheochromocytoma tumor cells also express the cell membrane norepinephrine transporter. Scintigraphy or single-photon emission-computed tomography after injection of radioiodinated MIBG or positron emission tomography after injection of 6-[¹⁸F]fluorodopamine aids diagnostic localization of pheochromocytoma.⁴

Preclinical studies dating back to the 1960s have demonstrated saturability of uptake-1, with a K_m in the range of 0.1 to 1 µmol/L.^5,6 Since plasma norepinephrine levels in humans normally average about 3 nmol/L, increasing by at most 10- to 20-fold in extreme situations, one might presume that circulating norepinephrine would exert little impact on the efficiency of uptake-1. Reports that patients with high circulating norepinephrine concentrations due to pheochromocytoma can have decreased myocardial MIBG-derived radioactivity, however, have called this view into question.^7–9

In the present study, we show that myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity decreased when plasma norepinephrine levels were markedly elevated in patients with pheochromocytoma. We included data from 3 patients evaluated before and after treatment for pheochromocytoma to assess the reversibility of uptake-1 inhibition by high plasma norepinephrine levels.

	Materials and Methods

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The study protocol was approved by the Institutional Review Boards of the National Institute of Neurological Disorders and Stroke, and the National Institute of Child Health and Development. Each subject gave informed, written consent prior to participation.

Subjects
The subjects included 28 patients (15 men and 13 women, mean age 41±14 years [SD]) evaluated for pheochromocytoma and 14 healthy volunteers (11 men and 3 women, mean age 51±24 years) as normal controls. A summary of the subject characteristics is available in an online table at http://www.hypertensionaha.org. Three patients were scanned before and 15 to 22 months after surgical or chemotherapeutic treatment for pheochromocytoma. There were no dietary restrictions associated with positron emission tomography scanning.

Plasma Norepinephrine
Blood was drawn through an indwelling vascular catheter after at least 15 minutes of supine rest. Subjects were not allowed caffeine-containing beverages, cigarettes, or alcohol for at least 24 hours before drawing blood. Venous blood was sampled from pheochromocytoma patients; only arterial blood was available from healthy volunteers. The latter were controls for another study in which the volunteers underwent dynamic positron emission tomography scanning of the chest with an indwelling arterial catheter.¹⁰ Plasma norepinephrine was assayed by high-pressure liquid chromatography with electrochemical detection after batch alumina extraction.¹¹

6-[¹⁸F]Fluorodopamine Scanning
6-[¹⁸F]Fluorodopamine, synthesized as described previously,¹² was infused intravenously at a constant rate for 3 minutes. Three-dimensional positron emission tomographic images were acquired on an Advance whole-body scanner (General Electric). Pheochromocytoma patients were scanned from pelvis to neck, in 136-mm segments. Each segment contained 35 contiguous transaxial slices acquired over 10 to 20 minutes. Control subjects underwent dynamic scanning at the level of the heart for up to 3 hours. Transmission scans for attenuation correction were obtained for each scanning segment over 4 to 10 minutes in all subjects, using rotating ⁶⁸Ge/⁶⁸Ga pin sources.

Data Analysis and Statistics
Images were reconstructed after correction for attenuation and physical decay of ¹⁸F. Scans acquired 45 to 60 minutes after injection were analyzed as described previously using National Institutes of Health MIRAGe software.¹² Briefly, for analysis of myocardium, 2 circular regions of interest were placed over representative areas of the interventricular septum and left ventricular free wall. The diameter of each region of interest was about half the width of the myocardial wall. For liver and left ventricular chamber, single large circular regions of interest were placed over representative areas. 6-[¹⁸F]Fluorodopamine-derived radioactivity was quantified in each region of interest. The data, expressed as nCi/cc, were normalized for the dose of injected radioactivity per unit body mass and expressed in nCi-kg/cc-mCi.

Data for each subject were graphed in scatterplots relating 6-[¹⁸F]fluorodopamine-derived radioactivity in the left ventricle, left ventricular chamber, or liver to plasma norepinephrine concentration. Data from the myocardium were averaged for all 4 areas (2 in septum and 2 in free wall). Because arterial plasma concentrations of norepinephrine in healthy individuals are approximately twice those in venous plasma,¹³ the arterial norepinephrine concentrations in normal volunteers were halved for comparison with venous concentrations in pheochromocytoma patients. Linear regression was used to identify curves of best fit.

	Results

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Plasma norepinephrine levels ranged from 0.25 to 90 nmol/L (42 to >15 000 pg/mL), and average myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity from 2160 to 7786 nCi-kg/cc-µCi (Table).

View this table: [in this window] [in a new window]   Summary of Subject Data

Above a plasma norepinephrine concentration of 3 nmol/L (500 pg/mL), corresponding to the upper limit of normal, myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity in the left ventricular myocardium was inversely related to the logarithm of plasma norepinephrine (y=–700 ln(x)+5679, r=–0.77, P<0.0001; Figures 1 and 2). Twenty-three of the 28 pheochromocytoma patients had plasma norepinephrine levels in this range. In contrast, below a plasma norepinephrine concentration of 3 nmol/L, which was found in all of the normal volunteers and in 5 of the patients with pheochromocytoma, there was no relationship between myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity and norepinephrine. From the above equation, myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity would be halved at a venous plasma norepinephrine concentration of 58 nmol/L.

View larger version (38K): [in this window] [in a new window]   Figure 1. Positron emission tomographs of a control subject (left) and a patient with pheochromocytoma (right) showing 6-[18F]fluorodopamine-derived radioactivity in transverse sections of left ventricular myocardium. Plasma concentrations of norepinephrine were 0.76 nmol/L in the control subject and 89.9 nmol/L in the pheochromocytoma patient. Scaling units at bottom are normalized for body weight and 6-[18F]fluorodopamine dose, and are expressed in nCi-kg/cc-mCi.

View larger version (21K): [in this window] [in a new window]   Figure 2. Individual values for 6-[18F]fluorodopamine-derived radioactivity in left ventricular myocardium as a function of plasma norepinephrine concentration. A, Data from all subjects. Open symbols represent patients with pheochromocytoma; • represent normal controls. The dashed line represents the line of best fit for subjects with plasma norepinephrine levels above 3 nmol/L, described by the equation y=–700 ln(x)+5679 (r=–0.77, P<0.0001). represent data from 3 pheochromocytoma patients scanned before treatment for their tumors. B, Data from the same 3 patients before ( and after () treatment for their tumors. The dashed line shows the same line of best fit as in panel A.

For statistical analyses, data were excluded from a patient with metastatic pheochromocytoma who had a very high plasma norepinephrine concentration (more than 1400 nmol/L or 240 000 pg/mL) and lack of visualization of the left ventricular myocardium by 6-[¹⁸F]fluorodopamine scanning, because including the data would have inappropriately skewed the overall results. Data were also excluded from a control subject who had very low myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity, >2 SD below the mean of the other control subjects and below the mean of patients with pure autonomic failure, a neurodegenerative condition that features diffuse sympathetic denervation and markedly decreased myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity.¹⁰

Analysis of the relationship between myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity and plasma norepinephrine was restricted to data for subjects with high plasma norepinephrine concentrations, because of substantial interindividual variability in radioactivity concentrations in the normal control subjects and in the patients who had normal plasma norepinephrine concentrations.

When radioactivity in each of the 4 left ventricular myocardial regions of interest was plotted against norepinephrine concentration, the regression slopes were within 10% of the average slope.

Three patients who had surgical or chemotherapeutic treatment for pheochromocytoma had decreased plasma norepinephrine levels and concomitant increases in myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity (Figure 2B).

In 6 pheochromocytoma patients, the liver was scanned at a different time than the heart. To avoid inappropriate comparisons, the data from these 6 were excluded from the analysis of liver radioactivity. 6-[¹⁸F]Fluorodopamine-derived radioactivity in the left ventricular chamber and liver was not related to the plasma norepinephrine concentration (Figure 3), even when subject groups with normal or high plasma norepinephrine levels were considered separately, although there was a trend toward an inverse relationship overall.

View larger version (19K): [in this window] [in a new window]   Figure 3. Individual values for 6-[18F]fluorodopamine-derived radioactivity as a function of plasma norepinephrine concentration for left ventricular chamber (A) and liver (B). represent patients with pheochromocytoma; • represent normal controls.

	Discussion

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The main finding of this study was that among patients with pheochromocytoma who had high plasma concentrations of endogenous norepinephrine (>3 nmol/L), myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity varied inversely with plasma norepinephrine. As explained later, the most likely explanation for this inverse relationship would be competition between norepinephrine and 6-[¹⁸F]fluorodopamine for neuronal uptake through the cell membrane norepinephrine transporter.

Previous studies of patients with pheochromocytoma and high plasma catecholamine levels have noted decreased myocardial concentrations of radioactivity after injection of radioiodinated MIBG.^7–9 In addition, infusion of high doses of norepinephrine in rats leads to decreased uptake and increased washout of [¹²³I]MIBG in the heart.¹⁴ Unlike 6-[¹⁸F]fluorodopamine, a catecholamine with an intraneuronal fate similar to that of norepinephrine, MIBG, a noncatechol analog of guanethidine, is not a substrate for monoamine oxidase, is a poorer substrate for uptake-1 than norepinephrine, and is cleared from the circulation much more slowly than are catecholamines. The finding of roughly similar decreases in myocardial ¹²³I-MIBG-derived radioactivity and 6-[¹⁸F]fluorodopamine-derived radioactivity supports the notion of competition of high plasma norepinephrine levels with sympathoneural imaging agents for neuronal uptake via the cell membrane norepinephrine transporter.

Results from a previous study by our group also suggest that high local norepinephrine concentrations in the heart can interfere with uptake-1.¹⁵ During infusion of yohimbine, an -2 adrenergic antagonist that increases release of norepinephrine from cardiac sympathetic nerves, cardiac extraction of ³[H]norepinephrine was decreased in those patients who had high rates of cardiac norepinephrine spillover.

Several alternative explanations might be offered to account for the inverse relationship between myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity and plasma norepinephrine in patients with pheochromocytoma. These explanations include sympathetic nerve rarefaction or degeneration, sequestration of the imaging agent by the tumor, downregulation of uptake-1 sites, decreased coronary perfusion, and medication interactions.

In patients studied before and after reduction of plasma norepinephrine by surgical resection or chemotherapeutic treatment of pheochromocytoma, myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity increased toward normal as plasma norepinephrine decreased. Similar results have been found by cardiac ¹²³I-MIBG scanning in patients before and after surgical resection of pheochromocytoma.¹⁶ These findings argue against cardiac sympathetic denervation, which could result, theoretically, from neurotoxic effects of high local concentrations of norepinephrine, as a cause of low myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity.

Sequestration of 6-[¹⁸F]fluorodopamine from plasma by the tumor could, theoretically, reduce delivery of the imaging agent to the heart. If tumor cells sequestered 6-[¹⁸F]fluorodopamine from the circulation, both the ventricular myocardial and the left ventricular chamber concentrations of radioactivity would have varied inversely with the plasma norepinephrine concentration; however, there was no relationship between left ventricular chamber radioactivity and the plasma norepinephrine concentration.

Downregulation of the cell membrane norepinephrine transporter could lead to decreased myocardial concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity. A report noted that in a diabetic rat model, both cardiac and plasma norepinephrine levels were unchanged between diabetic and control rats, but decreased ¹²³I-MIBG-derived myocardial radioactivity was related to diminished transporter density.¹⁷ Other animal studies have reported increased cardiac uptake-1 expression in the setting of high norepinephrine concentrations.^18,19 Moreover, downregulation of the transporter by pheochromocytoma would not explain normal 6-[¹⁸F]fluorodopamine-derived radioactivity in patients with normal plasma norepinephrine concentrations, nor the inverse relationship of radioactivity with plasma norepinephrine in the patients who had high norepinephrine concentrations.

Dietary sodium loading decreases expression of the transporter protein in rat adrenal glands in vivo and in rat sympathetic neurons in vitro;²⁰ however, this downregulation requires an exceedingly large amount of sodium intake. Moreover, patients with neurogenic orthostatic hypotension associated with multiple system atrophy, who are often treated by dietary salt supplements in conjunction with fludrocortisone, a salt-retaining steroid, have normal myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity.¹⁰

Coronary artery narrowing would decrease delivery of 6-[¹⁸F]fluorodopamine to myocardial uptake-1 sites. Of the 28 patients with pheochromocytoma, 3 had evidence of ischemic heart disease by history or ECG: 2 had normal cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity and 1 (patient #14) had a high plasma norepinephrine level. Among all patients, decreases in left ventricular 6-[¹⁸F]fluorodopamine-derived radioactivity were homogenous across the 4 individual myocardial regions analyzed, a finding that locally decreased myocardial perfusion would not explain. It is well established that norepinephrine increases systemic vascular resistance; however, its effects on coronary circulation are different. Under in vivo models of both animal and human coronary resistance vessels, administration of norepinephrine causes vasodilation. This effect is mediated by ß-2 receptors, and is independent of endothelial function.^21,22 Therefore, decreased cardiac perfusion from coronary artery disease or norepinephrine-mediated vasoconstriction seem unlikely explanations for diminished left ventricular 6-[¹⁸F]fluorodopamine-derived radioactivity in patients with high plasma norepinephrine levels.

Some drugs interfere with neuronal uptake of 6-[¹⁸F]fluorodopamine. Most notable among these are tricyclic antidepressants. The subjects were not taking drugs known to interfere with uptake-1.

In the liver, visual inspection of the data suggested a weak negative relationship between 6-[¹⁸F]fluorodopamine-derived radioactivity and plasma norepinephrine levels (Figure 3B). This could reflect a small contribution from hepatic sympathetic innervation.²³ While most of norepinephrine uptake in the liver occurs through the low-affinity, high-capacity uptake-2 process, blockade of uptake-1 with desipramine does reduce hepatic norepinephrine clearance in animal models.^24,25

Pheochromocytomas can secrete norepinephrine, epinephrine, or both. Although epinephrine is a substrate for the cell membrane norepinephrine transporter, epinephrine is not removed as avidly by uptake-1 as norepinephrine is. In this study, plasma epinephrine levels were unrelated to plasma norepinephrine levels. In addition, there was no relationship between plasma norepinephrine levels and 6-[¹⁸F]fluorodopamine-derived radioactivity in left ventricular myocardium. 3,4-Dihydroxy-phenylglycol, a major metabolite of norepinephrine, appears in the circulation primarily through leakage from sympathetic nerves.²⁶ Plasma 3,4-dihydroxyphenylglycol levels roughly paralleled plasma norepinephrine levels.

From the linear regression equation for the relationship between cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity and the logarithm of plasma norepinephrine, we calculated that uptake-1 in the heart would be half saturated at a venous plasma norepinephrine concentration of 58 nmol/L. Because of peripheral vasoconstriction associated with pheochromocytoma and the likely greater extraction of norepinephrine from the blood stream in passage through tissues of the forearm, the norepinephrine concentration in antecubital venous blood could have underestimated the arterial concentration by up to about 4-fold.²⁷ If so, then the arterial norepinephrine concentration at which cardiac uptake-1 is halved would be about 0.25 µmol/L. This value is within the range of concentrations for half saturation of the transporter based on preclinical studies.^5,6

Perspectives
The possibility that norepinephrine concentrations at uptake-1 sites can, indeed, reach endogenous levels high enough to saturate the transporter has implications for the interpretation of sympathetic neuroimaging results in pathophysiological states. In patients with pheochromocytoma, high local concentrations of norepinephrine might compete with radioiodinated MIBG or 6-[¹⁸F]fluorodopamine, leading to underestimation of the tumor burden. In addition, therapeutic dosing of ¹³¹I-MIBG for pheochromocytoma might be affected in the setting of elevated plasma norepinephrine. Finally, a high rate of cardiac sympathetic nerve traffic could result in high local concentrations of norepinephrine at uptake-1 sites, with relatively little change in the norepinephrine concentration in antecubital venous plasma, a situation that might occur in heart failure.²⁸ As a result, decreased myocardial radioactivity might be misinterpreted as sympathetic denervation, which could affect management decisions. The results of myocardial neuroimaging procedures that depend on uptake of the imaging agent by the cell membrane norepinephrine transporter must, therefore, be interpreted cautiously in patients with elevated norepinephrine levels.

	Acknowledgments

 
The authors thank Sandra Pechnik, RN; Beverly McElroy, RN; and the National Institutes of Health Positron Emission Tomography (PET) Department.

Received September 30, 2003; first decision November 19, 2003; accepted March 23, 2004.

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