Reserpine Noradrenaline

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. 

Reserpine irreversibly inhibits the triphosphatase that maintains the proton gradient and so it depletes neurons of their vesicular store of transmitter. This explains why restoration of normal neuronal function rests on delivery of new vesicles from the cell bodies. Some amphetamine derivatives, including methylenedioxymethamphetamine (MDMA), are also substrates for the transporter and, as a result, competitively inhibit noradrenaline uptake. Another way of inhibiting the transporter is by dissipation of the pH gradient across the vesicular membrane i-chloroamphetamine is thought to act in this way. 

A link between the central monoamines, 5-hydroxytryptamine (5-HT) and noradrenaline, and depression was forged some 40 years ago and arose from clinical experience with the drugs, reserpine and iproniazid. At that time, reserpine was used as an... 

Although some studies show that noradrenaline inhibits neuronal firing it is generally considered to increase behavioural activity and arousal. This impression is borne out to the extent that CNS stimulants, like amphetamine, increase release of noradrenaline and produce behavioural and EEG arousal, while reserpine, which reduces noradrenaline storage and hence release, causes psychomotor retardation. It is also supported by... 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Involvement of endogenous 5-HT in emesis was investigated. It was found that reserpine, p-chlorophenylalanine (PCPA) and fenfluramine antagonized cisplatin-induced emesis in the ferret [109]. The real role of 5-HT was difficult to assess, as all these agents with a possible exception of PCPA, depleted 5-HT, dopamine (DA) and noradrenaline (NE), unselectively. Cisplatin, the potent emetogenic agent, moderately increased brain levels of DA and decreased NE, while it had no significant effect on 5-HT or 5-hydroxyindoleacetic acid. 

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methyl-paratyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central... 

An unexpected discovery also arose during the therapeutic use of reserpine in the treatment of hypotension when it was found that approximately 15% of patients became clinically depressed. As it has been shown that reserpine depletes both the central and peripheral nervous system of noradrenaline, it was postulated that depression would be a consequence of the defective synthesis of noradrenaline and possibly serotonin. This helped to form the basis of the amine therapy of depression. 

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

In the sympathetic nervous system there is the possibility to reduce the release of noradrenaline. The alkaloid reserpine is known to interfere with the ability of the postganglionic sympathetic nerves to store noradrenaline. This results in a reduction of the sympathetic tone which is a useful measure in the treatment of essential hypertension. These type of drugs are classified as antisympathotonics. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

The Rauwolfla alkaloid reserpine was originally used as a neuroleptic/antipsychotic agent. It was then discovered to be an effective antihypertensive agent. Reserpine causes depletion of the noradrenaline stores in peripheral postganglionic sympathetic neurons. In addition it causes depletion of noradrenalin in central nervous structures involved in the regulation of blood pressure. 

In addition to serotonin, reserpine also releases other neurotransmitters, especially dopamine and noradrenaline, from their stores in presynaptic nerve raidings. Furthermore, the action on the synapse of the neurotransmitters released in this way is limited because they undergo intracellular enzymatic degradation. 

It is an alkaloid obtained from an African plant Yohimbehe. Chemically it is an indolealkylamine related to reserpine. It has selective blocking property with short duration of action and also blocks 5-hydroxytryptamine receptors. It produces increase in heart rate and blood pressure due to increase in noradrenaline release. It does not have any role in clinical practice. 

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