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Inhibition of uptake‐1 activity in the human heart in a hypernoradrenergic state
Author(s) -
Eldadah B. A.,
Pacak K.,
Eisenhofer G.,
Holmes C.,
Kopin I. J.,
Goldstein D. S.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.206
Subject(s) - pharmacology , medicine
Uptake‐1, mediated by the cell membrane norepinephrine transporter (NET), constitutes the main route of inactivation of norepinephrine at sympathetic nerve terminals. In vitro , the NET can be saturated with a K M between 0.1 and 1 μmol/L. This study addressed whether endogenous norepinephrine levels can attain high enough plasma concentrations in humans to inhibit cardiac uptake‐1. patients with pheochromocytoma, a catecholamine‐secreting tumor, were imaged by 6‐[ 18 F]fluorodopamine positron emission tomography. Above 3 nmol/L (about 500 pg/ml) in antecubital venous plasma, left ventricular myocardial 6‐[ 18 F]fluorodopamine‐derived radioactivity varied inversely with the logarithm of plasma norepinephrine concentration (R = −0.77, P <0.0001). Treatment of the pheochromocytoma resulted in decreased norepinephrine levels and increased myocardial 6‐[ 18 F]fluorodopamine‐derived radioactivity. In the liver and left ventricular chamber, there was no significant relationship between 6‐] 18 F]fluorodopamine‐derived radioactivity and plasma norepinephrine. Therefore, at sufficiently high plasma concentrations, endogenous norepinephrine competes with sympathetic imaging agents at uptake‐1 sites. As a result, this competition could lead to erroneous conclusions of sympathetic denervation, net dysfunction, or, in the case of pheochromocytoma, tumor burden. drawing quantitative conclusions about uptake‐1 activity in hypernoradrenergic states should be approached with caution. Clinical Pharmacology & Therapeutics (2004) 75 , P54–P54; doi: 10.1016/j.clpt.2003.11.206