Inhibition of uptake-1 activity in the human heart in a hypernoradrenergic state

Abstract

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 KM 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-[18F]fluorodopamine positron emission tomography. Above 3 nmol/L (about 500 pg/ml) in antecubital venous plasma, left ventricular myocardial 6-[18F]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-[18F]fluorodopamine-derived radioactivity. In the liver and left ventricular chamber, there was no significant relationship between 6-]18F]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