Storage of catecholamines
Synaptic vesicles actively take up DA, as well as NE (and EPI, if present).
Thus, there is a high concentration of catecholamines in synaptic vesicles and
a relatively low concentration of catecholamines in the cytosol of catecholaminergic
cells. In addition to catecholamines and DBH, some vesicles contain substantial
amounts of ATP, ascorbic acid and some specific proteins, chromogranins. Almost
all of the catecholamine content of a sympathetically innervated tissue is contained
in the synaptic vesicles inside the catecholaminergic nerves. There is a normal
background leak of catecholamines out of the vesicles, but the balance is very
much in favor of vesicular storage. Reserpine is a drug that inhibits the vesicular
catecholamine pump. By preventing the active uptake of catecholamines into the
synaptic vesicles, reserpine can result in depletion of catecholamines. This causes
some degree of failure of catecholaminergic transmission at essentially all catecholamine
junctions because reserpine is a lipid soluble drug that penetrates the blood-brain
barrier (BBB). In experimental animals reserpine can cause in essentially total
depletion of tissue catecholamines and complete failure of catecholaminergic transmission.
At much lower doses in humans, reserpine has been used in the treatment of hypertension.
The low concentration of catecholamines in the cytosol of catecholaminergic nerves
is maintained in part by the vesicular amine uptake pump and in part by the mitochondrial
enzyme, monoamine oxidase (MAO). If cytosolic concentrations of catecholamines
increase (for example, as caused by reserpine), then metabolism by MAO inactives
them inside the nerve. Thus, reserpine normally results in depletion of catecholamines,
not release. Release of catecholamines, means release in physiologically or pharmacologically
active form that results in effector organ responses. The MAO metabolites of catecholamines
are essentially inactive. Postganglionic sympathetic nerves (except to sweat glands)
release mainly NE into the neuroeffector junction. This NE thus acts as a neurotransmitter.
Release of catecholaminesNerve-induced release of catecholamines, like
synaptic release at other junctions, is based on quantal release of vesicles
containing preformed neurotransmitter molecules. Vesicular release depends on
depolarization of the nerve terminal and the influx of calcium ion. In ways not
yet understood in detail, the influx of calcium promotes simultaneous exocytosis
of many vesicles. The release of vesicular contents allows release of
catecholamines and ATP (both have short life spans outside the cell) and DBH.
The plasma level of DBH has been used as a measure of the turnover of
catecholaminergic vesicles, or as a way of trying to quantify the integral of
recent sympathetic nerve activity. The release of catecholamines can also be
promoted by certain drugs. In the adrenal medulla, ACh acting as the
neurotransmitter of the sympathetic ganglion acts on nicotinic receptors and
promotes the release of catecholamines into the circulation. Under certain
experimental conditions it is possible to mimic this nicotinic effect of
acetylcholine not only at the adrenal medulla but at other sympathetic ganglia.
Thus, agonists of nicotinic cholinergic receptors of the ganglionic, or
neuronal, type (Nn) can cause substantial catecholamine release at postganlionic
sympathetic neuroeffectors junctions as well as massive release of
catecholamines from the adrenal medulla into the circulation.
Dimethylphenylpiperazinium (DMPP) is a classical
drug that is a relatively selective agonist of Nn receptors. Epibatadine is a more recent and more selective
example. Another mechanism of release of catecholamines is based on an action
at the sympathetic nerve terminal. It is not applicable in the adrenal medulla.
Indirectly acting sympathomimetic amines such as tyramine, ephedrine and amphetamine are taken up into sympathetic
nerve terminals by the amine uptake pump. Normally, this pump serves to inactivate
catecholamines in the catecholaminergic neuroeffector juction. However, structurally
related compounds can be taken up into the nerve terminal by this transporter.
Once inside the catecholaminergic nerve terminal, the indirectly acting sympathomimetic
amines cause displacement of catecholamines from storage sites in vesicles, or
from other binding sites. The release of catecholamines can be blocked by certain
drugs, most notably bretylium (Bretylol®) and guanethidine (Ismelin®).
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