Noradrenaline depletion

Relationship between noradrenaline depletion and adrenergic neurone blockade 200 ADDENDUM 203... 

Noradrenaline-depleting (e.g. reserpine) Blocked Blocked Normal Not No... 

Table 3.25. NORADRENALINE-DEPLETING ACTIVITY OF GUANETHIDINE ANALOGUES AND MISCELLANEOUS GUANIDINES...

Table 3.27. NORADRENALINE-DEPLETING ACTIVITY OF OXYGEN-CONTAINING GUANIDINE DERIVATIVES...

The major routes for the synthesis and metabolism of noradrenaline in adrenergic nerves [375], together with the names of the enzymes concerned, are shown in Figure 3.1. Under normal conditions the rate controlling step in noradrenaline synthesis is the first, and the tissue noradrenaline content can be markedly lowered by inhibition of tyrosine hydroxylase [376]. Tissue noradrenaline levels can also be lowered, but to a lesser extent, by inhibition of dopamine-(3-oxidase [377, 378]. However, the noradrenaline depletion produced by guanethidine is unlikely to result from inhibition of synthesis, since intra-cisternal injection of guanethidine does not prevent the accumulation of noradrenaline which follows brain monoamine oxidase inhibition, even though it does cause depletion of brain noradrenaline [323]. 

Lundborg and Stitzel [410] have suggested that giianethidine-induced noradrenaline depletion can be adequately accounted for solely by the inhibition of noradrenaline uptake at both the cellular and vesicular membranes but if this... 

N.E. Anden, On the mechanism of noradrenaline depletion by ot-methyl metatyrosine and metaraminol, Acta Pharmacol. Toxicol. 21 (1964) 260-271. 

Marien M, Briley M, Colpaert F (1993) Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice. Eur.J. Pharmacol. 236 487-489. 

The toxin 6-OHDA does not cross the blood brain barrier after peripheral administration in the adult animal, and so must be administered centrally in order to yield effective lesions. This restriction does not apply in neonates. Thus, 6-OHDA can produce profound depletions of central catecholamines when administered subcutaneously or intracisternally to neonatal rats or mice (Breese and Traylor, 1971). Moreover, greater selectivity for individual amine pathways can be achieved by refinements of the route of delivery or by pharmacological manipulation, and different protocols of administration can allow relatively selective depletions. For example, several small repeated injections of 6-OHDA spare dopamine and preferentially deplete dopamine, whereas dopamine toxicity after a single large injection can be enhanced by pargyline treatment, in particular if the noradrenaline depletion is concurrently blocked with pargyline (Breese and Traylor, 1971 Cooper et al., 1973 Smith et al., 1973 Luthman et al., 1989). 

Carter CJ, Pycock, CJ (1980) Behavioral and neurochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat. Brain Res 792 163-176. 

Reserpine is a Rauwolfia alkaloid that has been used for centuries to treat insanity, insomnia and hypertension in humans. Reserpine inhibits normal sympathetic activity in both the CNS and the peripheral nervous system by binding to catecholamine storage vesicles, causing catecholamines to leak into the synapse so that they are not available for release when the presynaptic neuron is stimulated. This prevents the normal magnesium and ATP-dependent storage of catecholamines and 5-hydroxytryptamine in nerve cells, the result being catecholamine (norepinephrine (noradrenaline)) depletion. This results in the inhibition of normal sympathetic activity. 

Another Beecham compound, BRL 13776 (25) has shown antihypertensive properties due to noradrenaline depletion in DOCA rats and renal hypertensive cats.98 Only the medulla/pons region of brain showed significant drops in noradrenaline, in contrast to reserpine. There were no behavioural effects and the compound is being taken to clinical trial. A novel hypotensive peptide, hypotensin, has been isolated from the venom of the Western diamondback rattlesnake.99 It contains approximately 20 amino-acid residues and appears unrelated to the kinins. The hypotensive effect is said to be dose-related after oral administration in normal rats and SHRs and is not consequent upon histamine release. Brief details of a clinical trial of a PGEp analogue (26) are available.100 Eleven of seventeen hypertensives responded with lower blood pressure to oral doses (10-20 pig) of 26. A recent studylOl of the marked antihypertensive properties of the diuretic Indapamide (27)(SE 1520, Servier) in rats and cats shows it to reduce vascular reactivity on chronic dosing. 

It is, however, interesting to observe that a good number of sympathomimetics in fact do not really mimic the actions of noradrenaline or adrenaline at the effector receptor. They merely induce the release of noradrenaline from the sympathetic postganglionic adrenergic nerves. Such sympathomimetics which exert their action indirectly are comparatively less effective in patients treated with noradrenaline depleting drugs, for instance, the rauwolfia alkaloids, or other adrenergic neuron blockers. 

In this condition females still respond to pheromones producing the olfactory block to pregnancy, but fail to recognise or become imprinted to pheromones of the male that mated, and consequently the stud male s pheromones block such a pregnancy (Keverne and de la Riva, 1982). Hence, females with noradrenaline depleted from their accessory olfactory bulbs would fail to become pregnant unless they were isolated from all male odours after mating. 

The antihypertensive effects of a-methylated catecholamine analogs have been studied.In renal hypertensive rats, prolonged treatment with a-methyldopa, a-methyl- m-tyrosine, a-meth-yltyrosine or metaraminol produces dose-dependent decreases in blood pressure and dose-dependent depletion of myocardial catecholamines. The same order of relative activities was found in regard to noradrenaline depletion and antihypertensive effect, but there was no relationship between the degree of catecholamine depletion and the intensity of the hypotensive effect. 

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