Associate editor: D.R. SibleyThe role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines
Section snippets
Neuronal catecholamine transporters
The presence of an active transport system for the cellular uptake of norepinephrine (NE) at sympathetic nerve endings initially was suggested by findings that the tissue uptake and retention of [3H]-labeled NE administered intravenously to experimental animals could be blocked by sympathectomy Whitby et al., 1961, Hertting & Axelrod, 1961. Uptake was also blocked by certain psychotropic drugs, notably tricyclic antidepressants and cocaine, pointing to the mechanism of action of these agents
Removal or cellular accumulation of substrate
Measurements of the cellular accumulation of exogenous radiolabeled substrates provide the most convenient and time-honored method for analysis of transporter function. While such measurements are particularly appropriate and useful in synaptosomal preparations or cell culture systems, due consideration must be given to possible confounding influences of variations in the intracellular disposition of radiolabeled substrates after their uptake into cells (Fig. 1).
Consideration of the
Transporters as modulators of neuronal transmission
As neurotransmitters, catecholamines act as chemical messengers that relay signals from neuron to end-organ in the periphery. In addition to being released from nerves promptly on demand, catecholamines must be cleared quickly after release for rapid termination of the signal. Since the enzymes involved in the inactivation of catecholamines are located intracellularly and since the catecholamines are highly polar chemicals that do not readily cross cell membranes, termination of the signal
Neuronal versus extraneuronal uptake of catecholamines released by neurons
In general, neuronal reuptake is quantitatively more important than extraneuronal uptake for clearance of catecholamines released by neurons. In isolated rat atria and the vas deferens, 90% of the NE released by sympathetic nerves was calculated to be recaptured by neuronal reuptake (Schömig et al., 1989). In the human heart, 92% of the NE released by sympathetic nerves is recaptured by neuronal reuptake, whereas only 4% is removed by extraneuronal uptake, leaving another 4% to escape into the
Hypertension and aging
The possibility that impaired neuronal reuptake of NE by sympathetic nerves might contribute to essential hypertension initially was suggested by findings of decreased uptake of [3H]-labeled NE in tissues of hypertensive rats De Champlain et al., 1967, LeLorier et al., 1976. Subsequent clinical studies involving NE radiotracer-dilution analyses indicated that a subgroup of patients with essential hypertension might have impaired sympathoneuronal reuptake of NE Esler et al., 1981a, Goldstein et
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