School of Medicine

University of Washington School of Medicine
CVANS: The Structural Function

HUBIO 543
UW Restricted

CVANS MODULE

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ANS Nerve Functions

Like all nerves, ANS fibers engage in certain fundamental processes. Knowing these processes and drugs that affect them is very useful. Each nerve uses one (or more) transmitters, and for each there is:
  • synthesis
  • storage
  • release
  • postsynaptic (& presynaptic) action
  • inactivation

Synthesis of ACh requires the uptake into the nerve terminal of choline. Hemicholinium-3 inhibits the plasma membrane pump for choline. In the absence of choline uptake, cholinergic nerves eventually become depleted of ACh. The more cholinergic nerves are stimulated in the presence of HC-3, the more rapidly they fail.

Storage of ACh in synaptic vesicles requires its uptake into synaptic vesicles. Vesamicol is a drug that prevents the uptake pump for ACh in synaptic vesicles. Similar to the effects of HC-3, once a cholinergic nerve is depleted of preformed ACh, then transmission fails.

The release of synaptic vesicles from cholinergic nerve terminals is blocked by botulinus toxin (Botox®). This effect is useful both experimentally and clinically.

The multistep synthesis of catecholamines takes place in various compartments in the catecholaminergic cell. Tyrosine is taken up into the nerve terminal by a specific transporter. Tyrosine hydroxylase and DOPA decarboxylase are located in the cytoplasm of the cell. DBH is located in the synaptic vesicles. Thus, the final step in the synthesis of NE occurs in the vesicle. In addition to new synthesis, NE taken up by the nerve terminal is recycled into the vesicles for re-release.

In adrenal medulla cells, NE in the cytosol is acted upon by phenylethanolamine-N-methyltransferase. This adds a methyl group to the amino nitrogen and forms epinephrine (EPI). Most of the EPI formed in this process is taken into synaptic vesicles and stored for subsequent release into the blood. In humans, about 80% EPI and 20% NE is the mix of catecholamines released during the fight or flight response.

Release of catecholamines (be sure to differentiate release and depletion of catecholamines) can be prompted by a number of different agents. Ganglionic stimulants such as agonists of the NN receptors on ganglion cells (for example, DMPP) promote the release of catecholamines from adrenal medulla and postganglionic sympathetic fibers. Likewise, agonists of the M1 muscarinic receptor of ganglion cells (for example McN-A-343) may also promote release from adrenal medulla and postganglionic sympathetic fibers. The triggering receptors differ, but distally the same mechanisms are involved; influx of calcium and exocytosis.

Indirectly-acting sympathomimetic amines such as tyramine and amphetamine release catecholamines from the terminals of postganglionic sympathetic fibers. These indirectly acting agents are taken up into the sympathetic nerve terminals (by the amine uptake pump) and then cause release of catecholamines. Indirectly acting sympathomimetic amines must be taken up into the nerve terminal to promote release. Thus agents that inhibit the uptake pump (for example, cocaine or imipramine) antagonize responses to these agents. Likewise, because these indirectly acting agents cause the release of catecholamines from a small pool, repeated exposure may result in tachyphylaxis. Finally, agents that cause depletion of catecholamines from the sympathetic nerve terminals (e.g., reserpine) antagonize indirectly acting agents because there is a lack of catecholamines to be released.

Inhibitors of normal catecholamine synthesis act by blocking the synthesis of NE and epinephrine and/or by inducing the synthesis of false transmitter.

Inhibition of synthesis is caused by alphamethyl-para-tyrosine. Alphamethyl-DOPA (Aldomet®) promotes the synthesis of alphamethylNE. It was suggested that alphamethylNE is a poor agonist at postsynaptic adrenergic receptors. More likely, alphamethylNE acts as a somewhat selective agonist of presynaptic alpha2 receptors, thereby reducing the release of NE (and alphamethylNE). It may also have CNS actions that are useful in the treatment of hypertension.

Inhibitors of catecholamine storage act by blocking the granular catecholamine transport-storage mechanism within the adrenergic neuron. This leads to depletion of catecholamines. Such agents include reserpine (Serpasil®) and guanethidine (Ismelin®).

Inhibitors of catecholamine release act by preventing the release of catecholamine from the nerve terminal following a nerve action potential. Such agents include bretylium (Bretylol®) and guanethidine (Ismelin®). Like reserpine, guanethidine causes depletion of catecholamines. Thus, guanethidine causes both inhibition of the release of catecholamines and depletion of catecholamines. Guanethidine is concentrated in adrenergic nerve terminals by the amine uptake pump. Therefore, agents which inhibit the amine uptake pump, such as imipramine, can antagonize the effects of guanethidine.