Adrenergic nerve terminal

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Since the discovery that norepinephrine release at the adrenergic nerve terminal is the mechanism whereby the human body maintains sympathetic tone, medicinal scientists have searched for agents which reduce sympathetic tone through interference with norepinephrine peripherally. Reduction of the effect of norepinephrine should lead to a lowering of blood pressure which might be achieved in the following ways ... 

Although this drug is categorized as a local anesthetic, I have chosen to put it in with the hallucinogens because of the psychotomimetic effects that it produces. Cocaine is not a phenylethyl-amine, but it produces central nervous system arousal or stimulant effects which closely resemble those of the amphetamines, the methylenedioxyamphetamines in particular. This is due to the inhibition by cocaine of re-uptake of the norepinephrine released by the adrenergic nerve terminals, leading to an enhanced adrenergic stimulation of norepinephrine receptors. The increased... 

Pharmacology Bretylium tosylate inhibits norepinephrine release by depressing adrenergic nerve terminal excitability, inducing a chemical sympathectomy-like state. Bretylium blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade causes orthostatic hypotension but has less effect on supine blood pressure. It has a positive inotropic effect on the myocardium. Pharmacokinetics Peak plasma concentration and peak hypotensive effects are seen within 1 hour of IM administration. However, suppression of premature ventricular beats is not maximal until 6 to 9 hours after dosing, when mean plasma concentration declines to less than 50% of peak level. Antifibrillatory effects occur within minutes of an IV injection. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration. 

Chapter 28). Stimulation of nicotinic receptors in adrenergic nerve terminals leads to the release of norepinephrine and activation of nicotinic chemoreceptors in the aortic arch and carotid bodies causes nausea and vomiting. Nicotinic receptors in the central nervous system mediate a complex range of excitatory and inhibitory effects. 

The effects of nicotine on the cardiovascular system mimic those seen after activation of the sympathoadrenal system, and they are principally the result of a release of epinephrine and norepinephrine from the adrenal medulla and adrenergic nerve terminals. These effects include a positive inotropic and chronotropic effect on the myocardium as well as an increase in cardiac output. In addition, both systohc and diastolic blood pressures are increased secondary to stimulation of the sympathoadrenal system. These effects are the end result of a summation of adrenergic and chohnergic stimulation. 

A. K. Cho, G. S. Takimoto (1985). Irreversible inhibitors of adrenergic nerve terminal function. Trends Pharmacol. Sci. 6 443 47. 

Alpha2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP... 

Tyramine, amphetamine Adrenergic nerve terminals Promote transmitter release... 

Transmitter reuptake after release Cocaine, tricyclic antidepressants Adrenergic nerve terminals Inhibit uptake increase transmitter effect on postsynaptic receptors... 

Tranylcypromine Adrenergic nerve terminals (monoamine oxidase) Inhibits enzyme increases stored transmitter pool... 

Phenoxybenzamine binds covalently to receptors, causing irreversible blockade of long duration (14-48 hours or longer). It is somewhat selective for Ki receptors but less so than prazosin (Table 10-1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (Hi), acetylcholine, and serotonin receptors as well as receptors (see Chapter 16). 

Ang II also interacts with the autonomic nervous system. It stimulates autonomic ganglia, increases the release of epinephrine and norepinephrine from the adrenal medulla, and—what is most important—facilitates sympathetic transmission by an action at adrenergic nerve terminals. The latter effect involves both increased release and reduced reuptake of norepinephrine. Ang II also has a less important direct positive inotropic action on the heart. 

Factors that influence the disposition of catecholamines will affect the toxicity. For instance, compounds that inhibit the uptake of noradrenaline reduce the destruction of adrenergic nerve terminals but not of dopaminergic ones. Interference with the oxidative metabolism of catecholamines also influences the toxicity of 6-hydroxydopamine. 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

Methyl tyrosine (metyrosine) Adrenergic nerve terminals and adrenal medulla cytoplasm Blocks synthesis... 

Hydroxydopamine Adrenergic nerve terminals Destroys the terminals... 

At adrenergic nerve terminals norepinephrine and epinephrine can be taken up, oxidized [via MAO] to 3,4-dihydroxymandelic aldehyde and thence oxidized to 3,4-dihydroxymandelic acid (DOMA) and 3,4-dihydroxyphenylglycol (DHPG). Extracellular DOMA and DHPG can then be converted via COMT to the methylated derivatives VMA and MHPG. 

Phenylephrine is a synthetic sympathomimetic amine structurally similar to epinephrine. It acts primarily on ai receptors and has little or no effect on (3 receptors. A minor part of its pharmacologic effects may be attributed to release of norepinephrine from adrenergic nerve terminals. 

Noradrenaline is synthesised and stored in adrenergic nerve terminals and can be released from these stores by stimulating the nerve or by drugs (ephedrine, amfetamine). These noradrenaline stores may be replenished by i.v. infusion of noradrenaline, and abolished by reserpine or by cutting the sympathetic neuron. 

Interactions of sympathomimetics with other vasoactive drugs are complex. Some drugs block the reuptake mechanism for noradrenaline in adrenergic nerve terminals and potentiate the pressor effects of noradrenaline e.g. cocaine, tricyclic antidepressants or highly noradrenaline-selective reuptake inhibitors such as roboxetine. Others deplete or destroy the intracellular stores within adrenergic nerve terminals (e.g. reserpine and guanethidine) and thus block the action of indirect S5unpathomimetics. 

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