Catecholamines and related compounds radioactively labeled at high specific activity have been useful tools for the study of various aspects of adrenergic function.
A portion of administered labeled NE is transported into sympathetic neurons and mixes with the endogenous store of neurotransmitter and thus serves as a valid tracer for endogenous NE. This tracer is mainly destroyed by deamination within the neuron. NE that is released from the neuron by nerve impulses or by drugs is metabolized primarily by O-methylation. Most of the injected dose which is not taken into neurons at all is similarly O-methylated.
The major means for limiting the action of NE released by nerve stimulation appears to be active transport back into the sympathetic neuron, where it is stored for reuse, or destroyed by MAO if the storage processes are interrupted. There is evidence to suggest multiple intraneuronal storage sites, but these theoretical functional compartments do not appear to be associated with the segregation of catecholamines into particulate and soluble fractions as defined by centrifugation of tissue homogenates.
Detailed studies of the uptake process indicate that it satisfies Michaelis-Menten kinetics and that a number of amines can compete with NE. In vivo uptake of labeled NE into a tissue from the blood is proportional to local blood flow and the density of sympathetic innervation. Studies of the specific activity of labeled tissue NE in a steady state during infusions of labeled NE have led to the conclusion that synthesis exceeds uptake as a source of endogenous NE.
The particulate storage site for NE is relatively specific but it will retain other phenylethylamine derivatives which have a β-hydroxyl or catechol group. Such stored compounds, whether formed spontaneously or after the administration of precursors, can be released by nerve stimulation. Replacement of NE by such "false neurochemical transmitters" may explain the partial adrenergic blockade which follows the administration of α-methyl dopa or MAO inhibitors, or the tachyphylaxis to sympathomimetic amines.
Labeled compounds have provided an extremely sensitive means for assaying substances released by nerve stimulation. Not all of these necessarily replace stored NE. Bretylium, for example, is released during nerve stimulation but may replace some substance other than NE involved in the chain of chemical events between the arrival of the nerve impulse and the release of neurotransmitter.
Thus, labeled compounds have provided an important means for study of the uptake, storage, release, transport, and metabolism of NE and of drugs which affect this adrenergic neurotransmitter.