title: Cardiac uptake-1 inhibition by high circulating norepinephrine levels in patients with pheochromocytoma.
abstract: 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 micromol/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 (approximately 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.
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC-1620, Bethesda, MD 20892-1620, USA. eldadahb@ninds.nih.gov
authors.forename: Basil A
authors.initials: BA
authors.lastname: Eldadah
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kopin
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001667:Binding, Competitive; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005188:False Negative Reactions; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging* / Q000294:innervation; D006801:Humans; D021621:Imaging, Three-Dimensional; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010673:Pheochromocytoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014055:Tomography, Emission-Computed
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; D027981:Symporters; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D009638:Norepinephrine