Norepinephrine removal

Blockade of the NET, eg, by the nonselective psychostimulant cocaine or the NET selective agents atomoxetine or reBoxetine, impairs this primary site of norepinephrine removal and thus synaptic norepinephrine levels rise, leading to greater stimulation of a and 3 adrenoceptors. In the periphery this effect may produce a clinical picture of sympathetic activation, but it is often counterbalanced by concomitant stimulation of k2 adrenoceptors in the brain stem that reduce sympathetic activation. 

Activation of endothelial cell muscarinic receptors by acetylcholine releases endothelium-derived relaxing factor (nitric oxide) (EDRF [NO]), which causes relaxation of vascular smooth muscle precontracted with norepinephrine. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of acetylcholine on vascular smooth muscle. (Modified and reproduced, with permission, from Furchgott RF, Zawadzki JV The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980 288 373.)... 

Evidence from a number of systems suggests that ion flux plays a role in palytoxin action. In a wide range of systems, palytoxin effects are accompanied by a change in intracellular cation levels. For example, the influx of Na and/or Ca is associated with palytoxin-stimulated contraction of cardiac and smooth muscle, the release of norepinephrine by rat pheochromocytoma (PC12) cells, and the depolarization of excitable membranes 12—15). Palytoxin also induces K efflux from erythrocytes and thus alters ion flux in a nonexcitable membrane system as well 16-19). In both excitable and nonexcitable membranes, the ultimate action of palytoxin has been shown to be dependent on extracellular cations. The palytoxin-induced effects on smooth muscle and erythroctyes can be inhibited by removing Ca from the media, and the palytoxin-induced release of norephinephrine from PC12 cells can be blocked in Na" free media (ii, 14y 18, 20, 21)... 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Because duration of activity of the catecholamines is significantly longer than that of neuronally released norepinephrine, the effects on tissues are more prolonged. This difference has to do with the mechanism of inactivation of these substances. Norepinephrine is immediately removed from the neuroeffector synapse by way of reuptake into the postganglionic neuron. This rapid removal limits duration of the effect of this neurotransmitter. In... 

Following the release of dopamine, the primary mode of removal from the synapse is reuptake into the presynaptic neuron via the dopamine transporter (DAT). DAT is dependent upon the energy created by the Na+/K+ pump and is a member of the Na+/Cl -dependent plasma membrane transporter family, as are the norepinephrine and 7-aminobutyric acid (GABA) transporters. Imaging studies utilizing compounds with highly specific affinity for DAT... 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

Three processes contribute to the removal of norepinephrine from the biophase ... 

The neuronal transport system is the most important mechanism for removing norepinephrine. Any norepinephrine or epinephrine in the circulation will equilibrate with the junctional extracellular fluid and thus become accessible both to the receptors and to neuronal transport. Thus, neuronal transport is also an important mechanism for limiting the effect and duration of action of norepinephrine or epinephrine, whether these are released from the adrenal medulla or are administered as drugs. Neuronal uptake is primarily a mechanism for removing norepinephrine rather than conserving it. Under most circumstances, synthesis of new norepinephrine is quite capable of keeping up with the needs of transmission, even in the complete absence of neuronal reuptake. 

The second most important mechanism for removing norepinephrine from the synapse is the escape of neuronally released norepinephrine into the general circulation and its metabolism in the Uver. The liver has two enzymes that perform this function catechol-O-methyltransferase (COMT) and MAO. 

MAO is a much less discriminating enzyme in that it will catalyze the removal of an amine group from a variety of substrates. The action of MAO on norepinephrine and epinephrine also is indicated in Figure 9.5. The list of its substrates is very large, including endogenous substances (norepinephrine, epinephrine, dopamine, tyramine, 5-hydroxy-tryptamine) and many drugs that are amines. At least in the brain, two separate forms of MAO have been described MAO type A and MAO type B. The two types are differentiated on the basis of substrate and inhibitor specificity. 

Mechanism of Action A sympathomimetic amine that stimulates the release of norepinephrine and dopamine. Therapeutic Effect Decreases appetite. Pharmacokinetics Rapidly absorbed from the gastrointestinal (GI) tract. Widely distributed. Metabolized in liverto active metabolite and undergoes extensive first-pass metabolism. Excreted in urine. Unknown if removed by hemodialysis. Half-life 4-6 hr. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitters, such as norepinephrine and serotonin, at presynaptic membranes, in-creasing their concentration at postsynaptic receptor sites. Therapeutic Effect Results in antidepressant effect. Anticholinergic effect controls nocturnal enuresis, Pharmacohinetics Rapidly, completely absorbed after PO administration, and not affected by food. Protein binding 95%, Metabolized in liver (significant first-pass effect), Primarily excreted in urine. Not removed by hemodialysis. Half-life 16-40 hr. 

Norepinephrine is removed from the synapse by means of two mechanisms. In the hrst, catechol-O-methyl-transferase (COMT) degrades intrasynaptic NE. In the second, the norepinephrine transporter (NET), a Na /CH-dependent neurotransmitter transporter, is the primary way of removing NE from the synapse [(4) in Fig. 2.7]. The NET is blocked selectively by desipramine and nortriptyline. Once internalized. 

FIGURE 2.7 Noradrenergic synapse. The release of norepinephrine (1) can be enhanced by compounds such as amphetamine. Once released, norepinephrine binds to a2 receptors (2a), al receptors (2b), and pi receptors (3). Norepinephrine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the norepinephrine transporter (4). 

Despite the documented efficacy and safety of the psychostimulants, their mechanism of action is not fully understood. Stimulants affect central nervous system (CNS) dopamine (DA) and norepinephrine (NE) pathways crucial in frontal lobe function. The stimulants act by causing release of catecholamines from the DA axons and blocking their reuptake. Methylphenidate releases catecholamines from long-term stores, so its effects can be blocked by pretreatment with reserpine. Amphetamines, on the other hand, release catecholamines from recently formed storage granules near the surface of the presynaptic neuron, so their action is not blocked by reserpine. In addition, the stimulants bind to the DA transporter in striatum (see Figures 2.6 and 2.7) and block the reuptake of both DA and NE. This action reduces the rate that catecholamines are removed from the synapse back into the axon and leads... 

Wellhoner et al. 2 reported that intravenous injection of III at 25 mg/kg led to marked hypotension in rats, guinea pigs, rabbits, and cats. The hypotensive effect was particularly marked in old cats that had high blood pressures initially it was not altered by bilateral vagotomy, evisceration, or removal of the carotid bodies, but was reduced or abolished by decapitation. These investigators suggested that the hypotension may result from some effect of the oxime on the CNS. They found also that prior doses of III prevented the hypertensive action of norepinephrine. 

Amphetamines not only mimic the action of norepinephrine and dopamine they also boost the levels of these neurotransmitters in a synaptic cleft by blocking their removal. Normally, neurotransmitters are reabsorbed by presynaptic neurons after they have exerted their effect on postsynaptic receptor sites. This process, commonly called neurotransmitter reuptake and illustrated in Figure 14.24, is the body s way of recycling neurotransmitters, molecules that are difficult to synthesize. Special membrane-embedded proteins are required to pull once-used neurotransmitter molecules back into a presynaptic neuron. Amphetamines inactivate norepinephrine and dopamine reuptake proteins by binding to them. As a consequence, the concentration of these stimulating neurotransmitters in the synaptic cleft is maintained at a higher-than-normal level. 

FIGURE 6-48. Shown here is the icon of a norepinephrine and dopamine reuptake inhibitor (NDRI). In this case, four of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Only the norepinephrine reuptake inhibitor (NRI) portion remains to this is added a dopamine reuptake inhibitor action (ORI). 

Glutamate removal. Glutamate s actions ate stopped not by enzymatic breakdown, as in other neurotransmitter systems, but by removal by two transport pumps. The first of these pumps is a presynaptic glutamate transporter, which works as do all the other neurotransmitter transporters already discussed for monoamine neurotransmitter systems such as dopamine, norepinephrine, and serotonin. The second transport pump, located on nearby glia, removes glutamate from the synapse and terminates its actions there. Glutamate removal is summarized in Figure 10—22. 

FIGURE 12—9- Acetylcholine (ACh) destruction and removal. Acetylcholine is destroyed by an enzyme called acetylcholinesterase (AChE), which turns ACh into inactive products. The actions of ACh can also be terminated by a presynaptic ACh transporter, which is similar to the transporters for other neurotransmitters already discussed earlier in relation to norepinephrine, dopamine, and serotonin neurons. 

Norepinephrine is secreted by neurons that originate in the locus caeruleus of the pons and projects throughout the reticular formation. Norepinephrine is generally regarded as an inhibitory transmitter within the CNS, but the overall effect following activity of norepinephrine synapses is often general excitation of the brain, probably because norepinephrine directly inhibits other neurons that produce inhibition. This phenomenon of disinhibition causes excitation by removing the influence of inhibitory neurons. 

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