False adrenergic transmitters

S.2.9.2. Formation, Storage and Release of False Adrenergic Transmitters 52.9.2.1. Biosynthesis of False Transmitters... 

More recently a number of related amino acids have been tested as possible precursors for the formation of false adrenergic transmitters. Among these compounds the amino acids 5-hydroxyDOPA and its methoxylated derivative 4-methoxy, 3,5-dihydroxyphenylalanine (Fig. 11) have proved of interest. These compounds give rise to the corresponding decarboxylated and ) -hydroxylated amines which are stored in the adrenergic nerves. There is, however, some tissue selectivity with a much larger proportion of the NA in peripheral sympathetic nerves being replaced by the false amines than in the CNS, presumably because the parent amino acids enter the brain only slowly. 

The false adrenergic transmitters, a-methylnoreiniiephrine and metaraminol (see Sect. B, Chap. 5.2), displace the naturally occurring NAt from its binding sites in many tissues, including adipose tissue. 

Although the concept of false transmitters as substances with weaker agonist activity diluting the normal stores of adrenergic transmitter is attractively simple and elegant, the true pharmacological situation is in fact quite complex. The overall effect of the introduction of a false transmitter on adrenergic neurotransmission depends on a number of different factors. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Octopamine (4.41), which carries a p-hydroxyl group, is taken up even more readily into storage vesicles and is, in turn, released when the neuron fires. As an adrenergic agonist, octopamine is, however, only about one-tenth as active as NE therefore, it acts as a very weak neurotransmitter. Compounds such as this behave like neurotransmitters of low potency, and are called false transmitters. On the other hand, octopamine may be a true transmitter in some invertebrates, with receptors that cannot be occupied either by other catecholamines or by serotonin. 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

These drugs are best avoided in patients with cerebrovascular, cardiovascular and hepatic disorders. Some sympathomimetic effects may occur, mainly mild tremor and occasionally cardiac arrhythmias. Apparent anticholinergic effects may also occur but these are the result of sympathetic potentiation in tissues with dual cholinergic/adrenergic innervation, e.g. pupil. Sympatholytic effects can also occur, principally postural hypotension, because of synthesis of relatively inactive false transmitters, e.g. octopamine, in nerve terminals following inhibition of MAO and activation of alternative metabolic pathways. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

The action of tyramine on nerve receptors is mainly indirect by release of norepinephrine and dopamine from neuronal storage sites (363, 384). Tyramine and its /3-oxidized counterpart octopamine have been referred to as false neurotransmitters because these compounds can be taken up, stored, and released from nerve endings in a way similar to those of the principal neurotransmitters norepinephrine and dopamine (385). Octopamine was first discovered in salivary glands of octopods (386). The compound is widely distributed in the animal kingdom and is present in high amounts in the nervous system of several species of invertebrates such as molluscs and arthropods, where it acts as a specific transmitter substance (387). Octopamine may also play a role in the regulation of adrenergic neurotransmission in mammals (387). Administration of octopamine to intact animals produces a transient rise in blood pressure (388). 

Many foods and beverages (e.g., wine, cheese, and chocolate) contain tyramine. This chemical is normally degraded by MAOa, before systemic absorption. When the inhibition of MAOa occurs, due to the administration of these drugs, tyramine from ingested food is absorbed. It is then taken up into adrenergic neurons, where it enters the synthetic pathway and is converted to octopamine. a false transmitter. This results in a massive release of norepinephrine, and may result in a hypertensive crisis. 

It was demonstrated that in patients taking methyldopa, a-methylnorepinephrine is formed, stored and released as a "false transmitter" as in animals. Tests of adrenergic function in rats at the time of maximum blood pressure reduction failed to show sufficient impairment to account for the hypotension. However, the false transmitter principle may still apply to the action on central neuronsi ... 

The false-transmitter substances appear to be stored in adrenergic nerves in the same manner as NA, the amines being retained largely within the intranemonal... 

Various foreign amines which are stored by adrenergic nerves are released in response to nerve stimulation. There is a very interesting correlation between the requirements for release of a false transmitter and the requironoits outlined above for storage. It seems that only those compounds whose structure is suitable to allow their retention within the intraneuronal storage vesicles are released during nerve activity (Table 18). 

A second factor is that the presence of the false transmitter may alter the responsiveness of the effector tissue to NA and other agonists. One mechanism by which this may occur is an inhibition of the neuronal uptake mechanism by the false transmitter, a-methylated amines, in particular, are very potent inhibitors of this transport process, and in tissues containing these false amines responsiveness to N A is increased. As far as the overall effect of the false transmitter is concerned, this will tend to reduce the effect on adrenergic transmission, since the increased responsiveness of the effector tissue may counteract the effect of a diminished release of NA. 

Finally, there is the potency of the false transmitter itself as an adrenergic agonist. The direct actions of most of the amines vdiich have been shown to be... 

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