Inactivation and metabolic disposition of catecholamines
Inactivation of the effects of
catecholamines at the sympathetic neuroeffector junction can take place by one
or more of several mechanisms:
- uptake or reuptake
- O-methylation
- oxidative deamination
Uptake or reuptake of catecholamines including NE into (postganglionic)
sympathetic nerve terminals is facilitated by an amine uptake pump. This is a
part of a family of membrane proteins that transport different transmitter
substances across the plasma membrane of the nerve terminal. This pump is driven
indirectly by a sodium gradient, which is in turn generated by another plasma
membrane protein, the Na+,K+-ATPase, or sodium, potassium 'pump'. The amine
uptake pump is selective for NE > Epi but does not take up isoproterenol.
Catecholamines which diffuse into the circulation or are released as
neurohormones may also be taken up into sympathetic nerve terminals. For
example, the small content of epinephrine in postganglionic sympathetic nerve
terminals is probably provided by epinephrine from the adrenal medulla that has
been taken up.
The amine uptake pump is inhibited by cocaine or tricyclic antidepressants, such
as imipramine. Uptake of NE is a major mechanism
for terminating sympathetic neuroeffector transmission. For this reason, inhibitors
of the amine uptake pump potentiate responses to stimulation of the sympathetic
nervous system, or to injected compounds that are taken up by the sympathetic
nerve terminals. In a sympathetically innervated tissue, such as the heart, the
major uptake of catecholamines is neuronal uptake, or so-called uptake-1.
An extraneuronal uptake of catecholamines can occur; so-called uptake-2 (not
shown). This uptake is into the parenchymal cells of the organ. It is not
blocked by cocaine or imipramine. The importance of uptake-2 is uncertain.
Both inside catecholaminergic cells, and in the circulation, oxidative
deamination of NE is facilitated by the enzyme monoamine oxidase (MAO). The
product of the oxidative deamination of EPI or NE is
3,4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is subject to reduction to the
corresponding alcohol (3,4-dihydroxyphenylethylene glycol, DOPEG) or oxidation
to the corresponding carboxylic acid (3,4-dihydroxymandelic acid, DOMA); the
latter being the major pathway.
The product of oxidative deamination of NE (or Epi) is DOPGAL. DOPGAL may be
reduced to DOPEG or oxidized to DOMA.
Metabolic disposition of catecholamines is important for circulating
compounds. Catechol-O-methyl transferase (COMT) plays a major role in
terminating catecholamines in the circulation following injection or release
from the adrenal medulla. Methylation at the 3 position of the ring of
catecholamines is facilitated by COMT. There are no clinically useful inhibitors
of COMT. Pyrogallol has been used as an in vitro inhibitor.
Final metabolic disposition of catecholamines typically involves the action
of both COMT and MAO. MAO is important in regulating the levels of
catecholamines in tissues (particularly intraneuronally), but can also act on
the 3-O-methyl metabolites of catecholamines (i.e., COMT then MAO). Thus, the
major metabolite of norepinephrine and epinephrine that appears in the urine is
3-methoxy-4-hydroxymandelic acid, also called vanillylmandelic acid, or VMA.
Metabolic disposition of catecholamine also includes pathways in which COMT
acts on the respective MAO-derived metabolites (MAO then COMT). By this process
the final product that ends up in the urine is also VMA.
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