Releasing norepinephrine from

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

Absence of one or both aromatic hydroxyl groups is associated with an increase in indirect sympathomimetic activity, denoting the ability of a substance to release norepinephrine from its neuronal stores without exerting an agonist action at the adrenoceptor (p. 88). 

Many other adrenomimetic drugs, such as amphetamine, do not themselves interact with adrenoceptors, yet they produce sympathetic effects by releasing norepinephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells. These adrenomimetics are called indirectly acting adrenomimetic drugs. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine. 

Dopamine is a unique adrenomimetic drug in that it exerts its cardiovascular actions by (1) releasing norepinephrine from adrenergic neurons, (2) interacting with a-and (3i-adrenoceptors, and (3) interacting with spe-cihc dopamine receptors. 

FIGURE 12—5. Here, /-amphetamine is releasing norepinephrine from presynaptic noradrenergic neurons. It also does this from dopamine neurons, just as shown for (/-amphetamine in Figure 12—3. When /-amphetamine binds to ther-presynaptic norepinephrine transporter on the norepinephrine presynaptic nerve terminal, it not only blocks norepinephrine reuptake but actually causes norepinephrine release. Thus, /-amphetamine releases both norepinephrine and dopamine, whereas (/-amphetamine is selective for dopamine. Since norepinephrine and dopamine can have different if related cognitive functions in different patients, then d- and /-amphetamine can have different cognitive effects as well. 

Mixed-action agonists Some agonists, such as ephedrine and metaraminol, have the capacity both to directly stimulate adrenoceptors and to release norepinephrine from the adrenergic neuron (see Figure 6.8). 

The precise mechanisms by which phencyclidine causes its clinical effects have not been fully delineated. Phencyclidine blocks the N-methyl-D-aspartate (NMDA) receptors and thereby calcium influx into cells. Phencyclidine inhibits the biogenic amine reuptake complex and thereby inhibits norepinephrine and dopamine reuptake. Phencyclidine also increases adrenergic activity by indirectly releasing norepinephrine from presynaptic neurons. Phencyclidine in high doses stimulates sigma receptors. 

At higher doses or faster rates of infusion, dopamine produces an increase in total peripheral resistance (TPR) and cardiac output, resulting in an increase in systemic pressure. The vasoconstriction produced may also selectively decrease perfusion to the kidney, heart, and mesentery. Dopamine also releases norepinephrine from neuronal endings, which increases the pressor effect. 

Bretylium releases norepinephrine from the sympathetic ganglia and postganglionic adrenergic nerve terminals, and blocks norepinephrine reuptake. 

Pharmacology The actions of ephedra products are those of ephedrine and pseudoephedrine, which release norepinephrine from sympathetic nerve endings. In addition to nasal decongestion, the established clinical use of ephedrine is as a pressor agent Ephedra herbal products are commonly used for treatment of respiratory dysfunction (including bronchitis and asthma) and as mild CNS stimulants. In Chinese medicine, ephedra products are also used for relief of cold and flu symptoms, for diuresis, and for bone or Joint pain. 

A) Chemical constituents release norepinephrine from sympathetic nerve endings... 

Blood pressure increase is due to its ability to release norepinephrine from sympathetic nerve terminals... 

Dam, K., Seidler, F, J, and Slolkin, T, A. (1999b). Chlorpyrifos releases norepinephrine from adult and neonatal rat brain synaptosomes. Dev Brain Res. 118, 120-133,... 

Peripheral presynaptic anti-adrenergics inhibit norepinephrine release from the presynaptic terminal. Guanadrel and reserpine deplete norepinephrine from presynaptic vesicles. As a result, guanadrel initially releases norepinephrine from the terminal causing a transient increase in adrenergic transmission. 

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

So ephedrine releases norepinephrine, and aspirin prevents the release from being turned off. 

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. 

Compared to a,-receptors, a2-receptors have only moderate distribution on the effector tissues however, they have important presynaptic effects. Alpha-one receptors are found on effector tissue cells at the neuroeffector junction the a2-receptors are found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron not only binds to the a.j-receptors on the effector tissue to cause some physiological effect but also binds to the a2-receptors on the neuron. Alpha-two receptor stimulation results in presynaptic inhibition" or in a decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the sympathetic postganglionic neuron and controls its own activity. Both ar and a2-receptors have equal affinity for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released from the adrenal medulla. 

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... 

The third important feature distinguishing catecholamines from neu-ronally released norepinephrine involves epinephrine s affinity for -receptors. Norepinephrine has a very limited affinity for these receptors. Therefore, circulating epinephrine causes effects that differ from those of direct sympathetic innervation, including ... 

Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. 

The second factor that exerts control on heart rate is the release of the catecholamines, epinephrine and norepinephrine, from the adrenal medulla. Circulating catecholamines have the same effect on heart rate as direct sympathetic stimulation, which is to increase heart rate. In fact, in the intact heart, the effect of the catecholamines serves to supplement this direct effect. In a denervated heart, circulating catecholamines serve to replace the effect of direct sympathetic stimulation. In this way, patients who have had a heart transplant may still increase their heart rate during exercise. 

Angiotensin II causes vasoconstriction by direct stimulation of ATj receptors on the vascular smooth muscle. It also enhances release of the neurotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active. 

Sympathetic nerves. The afferent and efferent arterioles are densely innervated with sympathetic nerves. Norepinephrine released directly from the nerves or circulating epinephrine released from the adrenal medulla stimulates a, adrenergic receptors to cause vasoconstriction. The predominant site of regulation is the afferent arteriole. Under normal resting conditions, there is little sympathetic tone to these vessels so that RBF is comparatively high. As discussed previously, this facilitates glomerular filtration. 

Azzaro, A.J., Ziance, R.J., and Rutledge, C.O., The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue,. /. Pharmacol. Exp. Ther., 189, 110, 1974. 

Li+ has been reported to affect virtually every component of the endocrine system to some extent however any resulting clinical manifestations are very rare [169]. Although these influences do not appear to be related to its mechanism of action in manic-depression, some are involved in the side effects experienced by Li+-treated patients. Apart from elevated levels of thyroid stimulating hormone (TSH), Li+ does not appear to affect the basal levels of hormones significantly however some hormone responses are reported to be altered by Li+ treatment of bipolar patients [170]. Neuronal activity stimulates the adrenal medulla to release norepinephrine and epinephrine into the blood and, consequently, the plasma from people with mania and depression shows increased levels of both neurotransmitters [171]. 

Reserpine depletes norepinephrine from sympathetic nerve endings and blocks the transport of norepinephrine into its storage granules. When the nerve is stimulated, less than the usual amount of norepinephrine is released into the synapse. This reduces sympathetic tone, decreasing peripheral vascular resistance and BP. 

Guanethidine and guanadrel deplete norepinephrine from postganglionic sympathetic nerve terminals and inhibit the release of norepinephrine in response to sympathetic nerve stimulation. This reduces cardiac output and peripheral vascular resistance. 

Kowarski D, Shuman H, Somlyo AP, Somlyo AV 1985 Calcium release by norepinephrine from central sarcoplasmic reticulum in rabbit main pulmonary artery smooth muscle. J Physiol 366 153-175... 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Nicotine causes a release of norepinephrine from the locus coeruleus and facilitates release of norepinephrine in the hippocampus (Gallardo and Leslie 1998 Mitchell 1993 Sershen etal. 1997 Fu et al. 1999). The norepinephrine released by nicotine, in turn, modulates raphe neurons (Li et al. 1998). 

Lobeline also increases basal release of norepinephrine, but norepinephrine release may be reduced at higher lobeline concentrations (Rao et al. 1997). Unlike acetylcholine, lobeline does not reduce the release of dopamine or norepinephrine by NMDA receptors, but it does block nicotine-induced release of norepinephrine from the locus coeruleus (Gallardo and Leslie 1998). Lobeline also evokes release of serotonin, which is mediated by uptake transporters and unaffected by mecamylamine (Lendvai et al. 1996). 

Another psychoactive constituent of lobelia, beta-amyrin palmitate, causes a release of norepinephrine in mouse brain synaptosomes, possibly releasing it from newly synthesized pools (Subarnas et al. 1993b). 

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