Assessment of sympathetic nervous function in humans from noradrenaline plasma kinetics.

Noradrenaline is the neurotransmitter of the sympathetic nervous system. Many attempts have been made, in research spanning two decades 11-41, to utilize tracer methodology and the mathematical techniques of compartmental analysis 15, 61 to elucidate the kinetics of noradrenaline in humans. These studies have often been hampered by technical problems, such as the impracticability of assaying tissue noradrenaline levels in humans, and in earlier experiments, by the unavailability of radiolabelled L-noradrenaline, and the lack of a sufficiently sensitive and specific assay for plasma noradrenaline. The disposition of noradrenaline in fact is complex, defying precise compartmental analysis 141, and in the past this has frustrated attempts to measure noradrenaline turnover. Noradrenaline in plasma is derived in the main from transmitter released by sympathetic nerves, to a very small degree from the adrenal medulla 171, and probably not at all from the central nervous system [81. Faced with this lack of an acceptable method for determining noradrenaline turnover, investigators have turned to the plasma concentration of the transmitter as an index of overall sympathetic nervous system ‘activity’ (nerve firing rate) in studies of human physiology and disease [9-141. There are several possible objections, however, to this application of plasma noradrenaline values, not the least being that the plasma concentration is determined in part by the rate at which noradrenaline is removed from the circulation, and not solely by the rate of noradrenaline release. provide such an ambiguous guide to sympathetic nervous system activity, kinetic techniques for estimating the rate of release of noradrenaline to plasma have recently been developed 115-191. These methods for studying plasma noradrenaline kinetics differ from the earlier, more ambitious studies of whole-body noradrenaline kinetics in several respects, in particular in their independence from complex mathematical models of noradrenaline disposition. The central feature of these methods is the determination of the metabolic clearance rate of plasma noradrenaline, clearance being calculated after either a bolus intravenous injection of noradrenaline I171 or intravenous infusion to steady state 115, 16, 18, 191. Published methods differ in their use of either radiolabelled 115, 17, 181 or unlabelled noradrenaline 116, 191, and if a tracer is used, in the use of either Lor DL-noradrenaline. The use of either pharmacological doses of unlabelled noradrenaline [ 16, 191 or radiolabelled DL-IIOTadrenaline [ 151 carries potential disadvantages. If pressor doses of noradrenaline are used, clearance estimates may possibly be distorted by saturation of removal mechanisms or alteration of organ blood flow rates, and reflex suppression of endogenous noradrenaline release could occur [ 16,201. Differences in the body’s handling of the D-isomer, particularly for noradrenaline uptake [ 2 11, could influence results obtained with racemic radiolabelled noradrenaline. For infused radiolabelled noradrenaline (NA) the following relationships hold, under steadystate conditions 15, 181: