Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentrationtime curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p<0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p<0.001), whereas the spillover rate of NE increased from 33±5 to 63±11 pmol-min'1 (p<0.05). Nitroprussideinduced increments in blood flow increased the spillover of NE from 18±4 to 35±6 pmolmin"1 (/7