Steps in the synthetic pathway of epinephrine and norepinephrine.

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase (MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine.

Like the cholinergic transmitter, the noradrenergic transmitter is released by action potentials through ex-ocytosis, the contents of entire vesicles being emptied into the biophase (synaptic or junctional region). Similarly, the formation of transmitter-receptor complexes is a direct function of the concentration of transmitter in the biophase and is readily reversible. In this instance, the receptors are adrenoceptors.

Three processes contribute to the removal of nor-epinephrine from the biophase:

1. Transport back into the noradrenergic neuron (reuptake), followed by either vesicular storage or by enzymatic inactivation by mitochondrial MAO. The transport of norepinephrine into the neurons is a sodium-facilitated process similar to that for choline transport.

2. Diffusion from the synapse into the circulation and ultimate enzymatic destruction in the liver and renal excretion.

3. Active transport of the released transmitter into effector cells (extraneuronal uptake) followed by enzymatic inactivation by catechol-O-methyltransferase.

The neuronal transport system is the most important mechanism for removing norepinephrine. Any nor-epinephrine or epinephrine in the circulation will equilibrate with the junctional extracellular fluid and thus become accessible both to the receptors and to neuronal transport. Thus, neuronal transport is also an important mechanism for limiting the effect and duration of action of norepinephrine or epinephrine, whether these are released from the adrenal medulla or are administered as drugs. Neuronal uptake is primarily a mechanism for removing norepinephrine rather than conserving it. Under most circumstances, synthesis of new norepinephrine is quite capable of keeping up with the needs of transmission, even in the complete absence of neuronal reuptake.

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