Catecholamine uptake process

Drugs that block the catecholamine uptake process (e.g., cocaine, tricyclic antidepressants, and phenothiazines) are apt to block the anti hypertensive action of which of the following drugs ... 

Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6) block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine. 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

The catecholamines and serotonin share similar pathways of biosynthesis and metabolism, including in some steps, the same enzymes. Catecholamines and serotonin are sequestered and stored in vesicular granules from where they are released mto the extracellular environment by calcium-dependent exocytosis. Termination of the physiological effects of both the catecholamines and serotonin is dependent on active uptake processes, facilitated by specific... 

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-0-methyl transferase. 

Some inhibitors of the vesicle uptake process are listed in Table IS. The most potent inhibitors are reserpine and related substances. Kinetic studies indicate that reserpine has an affinity for the vesicle uptake sites some 10,000 times higher than that of the catecholamines. Another compound with very high affinity is prenylamine (segontin), which is about 10 times less potent than reserpine. Imi-pramine and chlorpromazine are both active as inhibitors, but are very much less potent on the vesicle system than on the neuronal membrane uptake. Other inhibitors include substances, such as N-ethylmaleimide, which block free sulphydryl groups. The action of such compounds appears to be related to an inhibition of the storage vesicle ATP-ase (Para. 5.2.4). 

Various sympathomimetic amines can be taken up into storage vesicles, leading to the stoichiometric displacement of part of the endogenous NA content (p-tyramine and -phenylethylamine). It is not clear that such amines are taken up by the same mechanism which is responsible for catecholamine uptake. For example, metaraminol is taken up by medullary vesicles by a process which does not require ATP. and is insensitive to inhibition by reserpine. Some amines, such as DA and -methylNA. appear to be taken up both by the reserpine-sensitive and reserpine-insensitive mechanisms. It may be that the latter mechanism can account for the uptake of exogenous catecholamines into storage vesicles in reserpine-treated animals, leading to a temporary restoration of adrenergic transmission. 

Amphetamine has several important central actions, it causes a well-known central excitation accompanied by increased motor activity, it also has temperature-elevating and appetite-suppressing actions. This amine is classified as an indirectly acting sympathomimetic in peripheral adrenergic systems, and there is considerable evidence that it may act centrally by displacing NA and/or DA. The main evidence in favour of this view is that the locomotor stimulating actions of amphetamine are blocked in animals pretreated with inhibitors of catecholamine biosynthesis, such as a-methyl-p-Tyr. On the other hand, the central actions of amphetamine are not markedly reduced, and may even be enhanced, in reserpine-treated animals, in which the central catecholamine stores are severely depleted. However, even in reserpinized animals, a small pool of newly synthesized NA may still be available for release by amphetamine. In addition to the possibility of catecholamine release, amphetamine also has other actions on central adrenergic neurons. It is an inhibitor of MAO, and a potent inhibitor of both the NA and DA uptake processes. 

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in intemeuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine. 

Catecholamines can be transported into effector cells extraneuronal uptake). These cells generally contain both COMT and MAO. The combined processes of extraneuronal uptake and 0-methylation are believed to be a minor but functionally significant, site of irreversible loss of catecholamines. The precise role of extraneuronal MAO in transmitter inactivation remains unknown. 

Wliile the cyclics block the uptake of amines, MAOls prc cnt the breakdown of the neurotransmitters (Cohen, 1997 Cooperrider, 1988 Meyer Quenzer, 2005). The enzyme monoamine oxidase metabolizes a variety of neurotransmitters, including norepinephrine and serotonin. MAOls inhibit this degradation process and thus enhance the availability of the transmitter within the neuron. Thii.s, the actions of the cyclics and MAOls each arc consistent u ith the hypothesis that decreased brain catecholamine activity causes depression and that these antidepressants (using different mechanisms) reverse this process by increasing catecholamine activity in the brain. 

The action of NE at adrenergic receptors is terminated by a combination of processes, including uptake into Ihe neuron and into cxtraneuronal lis.sucs. diffusion away from the synapse. and metabolism. Usually. Ihe primary mechanism for termination of Ihe action of NE is rcuplakc of the catecholamine into tlie nerve terminal. This procc.ss is termed upuike-l and involves a Na /Cl -dcpendenl transmembrane transporter that has a high affinity for NE. This uptake system also transparts certain amines other than NE into the... 

The neuronal monoamme transporters provide the principal mechanism for rapid termmation of the signal in neuronal transmission, whereas the transporters at extraneuronal locations are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. For the norepinephrine released by sympathetic nerves, about 90% is removed back into nerves by neuronal uptake, 5% is removed by extraneuronal uptake, and 5% escapes these processes to enter the bloodstream. In contrast, for the epinephrine released directly into the bloodstream from the adrenals, about 90% is removed by extraneuronal monoamine transport processes that are particularly important in the liver. The presence of these highly active transport processes means that monoamines are rapidly cleared from the bloodstream with a circulatory half-life of less than 2 minutes. 

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