Noradrenaline regulation

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. 

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

However, as early as the 1970s, it was obvious that end-product inhibition of TH could not be the main factor regulating the rate of noradrenaline synthesis. Clearly, the hydroxylation of tyrosine takes place in the cytoplasm and so it must be cytoplasmic noradrenaline that governs enzyme activity. Yet, it is vesicle-bound transmitter that undergoes impulse-evoked release from the neuron. Also, when neurons are releasing noradrenaline, its reuptake from the synapse is increased and, even though some of this transmitter ends up in the vesicles, or is metabolised by MAO, there should be a transient increase in the concentration of cytoplasmic noradrenaline which would increase end-product inhibition of TH. 

The first clue to the processes which normally regulate TH activity came from experiments showing that electrical stimulation of sympathetic neurons increased the affinity of this enzyme for its co-factor and reduced its affinity for noradrenaline (for detailed reviews of this topic see Zigmond, Schwarzschild and Rittenhouse 1989 Fillenz 1993 Kaufman 1995 Kumar and Vrana 1996). Several lines of investigation showed that activation of TH was in fact paralleled by its phosphorylation and it was this process that accounted for the changes in the enzyme s kinetics (Table 8.2). 

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... 

By maintaining low concentrations of cytoplasmic noradrenaline, MAO will also regulate the vesicular (releasable) pool of transmitter. When this enzyme is inhibited, the amount of noradrenaline held in the vesicles is greatly increased and there is an increase in transmitter release. It is this action which is thought to underlie the therapeutic effects of an important group of antidepressant drugs, the MAO inhibitors (MAOIs) which are discussed in Chapter 20. 

The adrenal gland is located on the upper segment of the kidney (Fig. 42-1). It consists of an outer cortex and an inner medulla. The adrenal medulla secretes the catecholamines epinephrine (also called adrenaline) and norepineprhine (also called noradrenaline), which are involved in regulation of the sympathetic nervous system. The adrenal cortex consists of three histologically distinct zones zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones (Fig. 42-2). 

Some less obvious phenomena of catecholamine transport and biosynthesis further illustrate the complexities of deciphering how efferents from midbrain dopamine neurons contribute to sleep-wake regulation. The plasma membrane norepinephrine transporter (NET), which is responsible for the uptake of extracellular noradrenaline, can also readily transport dopamine, and does so in vivo. This... 

Since nicotine has wide ranging effects on the central nervous system it seems likely that pharmacogenomic effects on the development of nicotine dependence will span several neurotransmitter systems. One study found an association between a polymorphism in dopamine /1-hydroxylase and level of tobacco consumption [20]. This enzyme is important in noradrenaline synthesis and it is tempting to speculate that genetically regulated variations in activity might influence susceptibility to nicotine withdrawal symptoms mediated by noradrenergic pathways, but more information is required on the molecular effects of the polymorphism. 

Porter VA, Bonev AD, Knot HJ et al 1998 Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides. Am J Physiol 274 C1346—C1355 Pucovsky V, Gordienko D V, Bolton TB 2002 Effect of nitric oxide donors and noradrenaline on Ca2+ release sites and global intracellular Ca2+ in myocytes from guinea-pig small mesenteric arteries. J Physiol 539 25—39... 

Jenkinson DH, Morton IK 1967 The effect of noradrenaline on the permeability of depolarized intestinal smooth muscle to inorganic ions. J Physiol 188 373-386 Kamishima T, McCarron JG 1997 Regulation of the cytosolic Ca2+ concentration by Ca2+ stores in single smooth muscle cells from rat cerebral arteries. J Physiol 501.3 497-508 Karaki H, Ozaki H, Hori M et al 1997 Calcium movements, distribution, and functions in smooth muscle. Pharmacol Rev 49 157—230... 

In the integration of cardiovascular regulation in the so-called "medullary vasomotor centre" two different areas for pressor and depressor activity are involved. The main part of the depressor area is the nucleus tractus solitarii, which is rich in noradrenaline nerve terminals (DAHLSTROm and FDXE (27)). Ablation of this area leads to hypertension in rats (DOBA and REIS... 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Cortical hormones include glucocorticoids (cortisol/corticosterone) and mineralocorticoids (aldosterone) medullar hormones are adrenaline and noradrenaline Pancreas Regulates glucose in blood via production of the hormones glucagon and insulin... 

Presynaptic a2A and a2c i aceptors can be distinguished functionally and may thus serve independent presynaptic functions. In mouse atria, the a2A subtype inhibited noradrenaline release at hi stimulation frequencies whereas the a2c-receptors operated at lower levels of sympathetic nerve stimulation (Hein et al. 1999). Moreover, inhibition of noradrenaline release mediated by the a2A-suhtype occurred much faster than inhibition by the a2c-receptor. These findings indicate that two presynaptic receptors in the inhibitory feedback loop of transmitter release may differentially regulate synaptic transmission. 

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