Noradrenaline metabolism

Effect of guanidines on enzymes involved in noradrenaline metabolism 193... 

Another interesting effect of pyrazole in vivo is to reduce brain noradrenaline levels in treated animals. This activity is shared by 4-methylpyrazole (70) but not by 4-hydroxypyrazole (71), suggesting that this effect is not related to the inhibition of brain catalase activity (81MI10503). Studies have been performed which suggest that pyrazole inhibits dopamine (3- hydroxylase (a copper-containing enzyme implicated in noradrenaline metabolism) in vivo but not in vitro, but methodological problems make these results equivocal (80MI10506). The mechanism by which pyrazole reduces brain noradrenaline levels is therefore as yet unknown. 

A direct influence of proinflammatory cytokines on the serotonin and noradrenalin metabolism... 

The adrenergic system is an essential regulator that increases cardiovascular and metabolic capacity during situations ofstress, exercise, and disease. Nerve cells in the central and peripheral nervous system synthesize and secrete the neurotransmitters noradrenaline and adrenaline. In the peripheral nervous system, noradrenaline and adrenaline are released from two different sites noradrenaline is the principal neurotransmitter of sympathetic neurons that innervate many organs and tissues. In contrast, adrenaline, and to a lesser degree noradrenaline, is produced and secreted from the adrenal gland into the circulation (Fig. 1). Thus, the actions of noradrenaline are mostly restricted to the sites of release from sympathetic nerves, whereas adrenaline acts as a hormone to stimulate many different cells via the blood stream. 

In smooth muscle, by contrast, one sympathetic nerve fibre can influence a number of muscle fibres by releasing noradrenaline from varicosities along its length without there being any defined end-plate junctions. The result of receptor activation is a slow change in potential and inactivation of the NT is initially by uptake and then metabolism. In other words, the NT function is geared to the slower phasic changes in tone characteristic of smooth muscle. 

Experiments of this kind have provided a great deal of evidence in favour of exocytotic release of vesicular noradrenaline. For example, by administering reserpine (which causes noradrenaline to leak out of the vesicles into the cytoplasm) together with an inhibitor of the enzyme monoamine oxidase (which will prevent metabolism of cytoplasmic noradrenaline), it is possible to redistribute the noradrenaline stored within nerve terminals because it leaks from the vesicles but is preserved within the neuronal cytoplasm. Under these conditions, the total amount of transmitter in the terminals is unchanged but impulse-evoked release rapidly diminishes. 

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

Figure 8.8 The metabolic pathway(s) for noradrenaline. MAO is responsible for the oxidative deamination of noradrenaline derivatives while COMT 0-methylates noradrenaline. Most intraneuronal metabolism involves MAO while COMT is mainly found extraneuronally. However, both these enz5unes can act on each other s products, yielding a complex cocktail of metabolites. The reasons for this complex network of metabolites are not known...

Certainly, such a complex system for metabolism of noradrenaline (which is shared with the other catecholamines) strongly suggests that its function extends beyond that of merely destroying transmitter sequestered from the synapse. However, as yet, little is known about the regulation of this pathway and any influence it might have on noradrenergic transmission. One crucial, additional role for MAO appears to be the... 

HT is metabolised primarily by MAO to 5-hydroxyindoleacetic acid (5-HIAA) (Fig. 9.4). In vitro, 5-HT is the preferred substrate for the MAOa, rather than the MAOb isoenzyme (see Chapter 8) and this appears to be the case in vivo since MAOa, but not MAOb, knock-out mice have increased concentrations of 5-HT in the brain. Obviously, because of its indole nucleus, 5-HT is not a substrate for the enzyme COMT which metabolises the catechol derivatives, dopamine and noradrenaline. However, other metabolic products of 5-HT are theoretically possible and one, 5-hydroxytryptophol,... 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Dostert, P, Benedetti, MS and Poggesi, I (1997) Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur. Neuropsychopharmacol. 1 (Suppl. 1) S23-S35. 

These types of antidepressant were introduced around 10 years after the SSRIs. They include the serotonin noradrenaline reuptake inhibitor venlafaxine and the selective noradrenaline reuptake inhibitor reboxetine. Although there are fewer data about these drugs, clinical experience has shown they are well tolerated and, unlike the SSRIs, they are only weak inhibitors of drug metabolism (Kent, 2000). Depression is a common psychiatric disorder seen in the elderly and often remains untreated or inadequately treated (Forsell and Fastbom, 2000). Venlafaxine was shown to improve the mood in a group of 36 older patients without any effect on cognitive function, an important consideration where there is the possibility of the coexistence of mild or undiagnosed dementia (Tsolaki et al., 2000). 

Hormones and neuronal activity affect brain glycogen metabolism. Glycogen is affected by hormones endogenous to the brain including vasoactive intestinal peptide and noradrenaline, as well as circulating hormones, such as insulin [61, 63, 64]. The mechanism whereby insulin exerts an effect on glycogen metabolism in brain has not been determined [63]. Glycogen metabolism in brain, unlike in other tissues, is controlled locally, due to differential local metabolic rates. 

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