Noradrenergic transmission

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Noradrenergic transmission

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Noradrenergic transmission. Learning outcome:. After this lecture session the students will be able to demonstrate an understanding of the following:. Classification of adrenoceptors. Physiology of noradrenergic transmission. Drugs acting on adrenoceptors. - PowerPoint PPT Presentation

Transcript of Noradrenergic transmission

Page 1: Noradrenergic transmission

Noradrenergic transmission

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Learning outcome:

After this lecture session the students will be able to demonstrate an understanding of the following:

Classification of adrenoceptors

Physiology of noradrenergic transmission

Drugs acting on adrenoceptors

Drugs that affect noradrenergic neurons

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Classification of adrenoceptorsAdrenoceptors are divided into two main α- adrenoceptor subtypes (α-1 and α-2 ) and three subtypes (β1, β2, β3,).

All adrenoceptors are typical G- protein coupled receptors, and cloning has revealed that α-1 and α-2 adrenoceptors each comprise three further sub classes.

Which are expressed in different locations but have functions that are, for the most still unclear.

Each of these receptors classes is associated with a specific second messenger system,

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for example, α-1 adrenoceptor are coupled to phospholipase C and produce their effects mainly by the release of intracellular Ca2+

α2 – adrenoceptors are negatively coupled to a adenylate cyclase and reduce cAMP formation, as well as inhibiting calcium channels.

All three types of β- adrenoceptors act by stimulation of adenylate cyclase.

The distinction between β1,- and β2-adrenoceptors is an important one, for β1,- adrenoceptors are found mainly in the heart, where they are responsible for inotropic and chronotropic effects of catecholamines.

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The β2- adrenoceptors, in contrast, are responsible for causing smooth muscle relaxation in many organs. β2- is often a useful therapeutic effects, while β1 is more often harmful.

Consequently, considerable efforts have been made to find selective β2- agonists, which will relax smooth muscle without affecting the heart

A selective β1 antagonists, which would exert a useful blocking effect on the heart without at the same time blocking β2- adrenoceptors in bronchial smooth muscle

It is important to realise that the selectivity of these drugs is relative rather than absolute. Thus compounds used as selective β1 antagonists invariably have some action on β2- adrenoceptors as well, which can cause unwanted effect such as bronchocontriction.

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In relation to vascular control, it is broadly true that α1 and β2-adrenoceptors act mainly on the smooth muscle cells themselves, while α2-adrenoceptor act on presynaptic terminals, but different vascular beds deviate from this general rule.

Both α- and β- adrenoceptors are expressed in smooth cells, nerve terminals and endothelial cells, and their role in physiological regulation and pharmacological response of the cardiovascular system is only partly understood.

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Physiology of noradrenergic transmission.

The noradrenergic neuron

Noradrenergic neurons in the periphery are postganglionic sympathetic neurons; their cell bodies lie in sympathetic ganglia.

They generally have long axons that end in a series of varicosities strung along the branching terminals network, these varicosities contain numerous synaptic vesicles, which are the site of synthesis and release of noradrenaline and of coreleased mediators such as ATP and neuropeptides Y.

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In most peripheral tissue, and also in the brain, the tissue content of noradrenaline closely parallels the density of the sympathetic innervations.

With the exception of adrenal medulla, sympathetic nerve terminals accounts for all of the noradrenaline content of the peripheral tissues.

Organs such as the heart, spleen, vas deferens and some blood vessels are particularly rich in noradrenaline and have been widely used for studies of noradrenergic transmission.

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Noradrenaline synthesisThe metabolic precursor for noradrenaline is L-tyrosine, an aromatic amino acid present in the body fluids, which is taken up by adrenergic neurons.

Tyrosine hydroxylase, a cytosolic enzyme that catalyses the conversion of tyrosine to dihydroxyphenylalanine (dopa).

Tyrosine hydroxylase, is only found in catecholamine containing cells. It is rather selective enzyme; unlike other enzymes involved in catecholamine metabolism, it does not accept indole derivatives as substrates and so is not involved in 5-hydroxytryptamine (5-HT) metabolism.

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This first hydroxylation step is the main control point for noradrenaline synthesis. Tyrosine hydroxylase is inhibited by the end- point of the biosynthetic pathway, noradrenaline

This provides the mechanism for the moment -to –moment regulation of the rate of synthesis; much slower regulation, taking hours or days, occurs by changes in rate of production of the enzyme.

The tyrosine analogue α- methyltyrosine strongly inhibits tyrosine hydroxylaes; it is used clinically in patients with the rare problem of inoperateable phaeochromocytoma and may be used experimentally to block noradrenaline synthesis.

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Conversion of dopa to dopamine, is catalysed by dopa decarboxylase, a cytosolic enzyme that is by no means confined to catecholamine- synthesising cells.

It is a relatively non-specific enzyme and catalyses the decarboxylation of various other L-aromatic amino acids, such as L – histidine and L- tryptophan, which are precursors in the synthesis of histamine and 5-HT, respectively.

Activity of dopa decarboxylase is not rate limiting for noradrenaline synthesis. Though various factors including certain drugs, affect the enzymes, it is not effective means of regulating noradrenaline synthesis.

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Dopamine-β-hydroxylase (DBH) is also a relatively non specific enzyme but is restricted to catecholamine – synthesising cells. DBH catalyses the conversion of dopamine to noradrenaline. It located in synaptic vesicles, mainly in membrane form.

Many drugs inhibit DBH, including copper – chelating agents and disulfiram ( a drug used mainly for its effect on ethanol metabolism). Such drugs can cause a partial depletion of noradrenaline stores and interference with sympathetic transmission.

Phenylethanolamine N-methyltransferase (PNMT) catalyses the N- methylation of noradrenaline to adrenaline. The main location of this enzyme is in the adrenal medulla, which contains a population of adrenaline – releasing (A) cells separate from the smaller proportion of noradrenaline – releasing (N) cells.

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The A cells, which appear only after birth, lie adjacent adrenal cortex, and the production of PNMT is induced by steroid hormones secreted by the adrenal cortex.

PNMT is also found in certain part of the brain, where adrenaline may function as a transmitter, but little is known about its role.

Noradrenaline storage

Most of the noradrenaline in nerve terminals or chromaffin cells is contained in vesicles; only a little is free in the cytoplasm under normal circumstance.

Certain drugs such as reserpine, block the reuptake of noradrenaline and cause nerve terminal to became depleted of their noradrenaline.

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Noradrenaline release

Regulation of noradrenaline release

Noradrenaline release is affected by a variety of substances that act on presynaptic receptors. Many different type of nerve terminals (cholinergic, noradrenergic, dopaminergic, 5-HT-ergic, etc) are subject to this type of control

Many different mediators (e.g. acetylcholine acting through muscarinic receptor, catecholamine acting through α – and β- adrenoceptors; angiotensin II; prostaglandins; purine nucleotides; neuropepetides; etc.) can act on presynaptic terminals.

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Presynaptic modulation represents an important physiological control mechanism throughout the nervous system.

Noradrenaline, by acting on the presynaptic receptors, can regulate its own release and that of coreleased ATP. This is believed to occur physiologically, so that released noradrenaline exerts a local inhibitory effect on the terminals from which it came- the so called autoinhibitory feedback mechanism

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Uptake and degradation of catecholamine

Uptake of catecholamine

Uptake 1 is a high – affinity system, relatively selective for noradrenaline and with a low maximum rate uptake, whereas uptake 2 has low affinity and transports adrenaline, and isoprenaline as well as noradrenaline, but at a much higher maximum rate.

Metabolic degradation of catecholamine

Endogenous and exogenous catecholamine are metabolised mainly by two enzymes, monoamine oxidase (MAO) and catechol –O –meythl transferase

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MOA occurs within cells surface membrane of mitochondria

It is also abundant in noradrenanergic nerve terminals, liver and intestinal epithelium

They converts catecholamines to aldehydes – aldehyde dehydrogenase to decarboxylic. For noradrenaline it yields dihydroxymandelic acid.

Within the sympathetic neurons, MAO controls the content of dopamine and noradrenaline, and releasable store of noradrenaline increase if the enzyme is inhibited.

The second major pathway for catecholamine metabolism involves methylation of one of the catechol hydroxyl groups to give a metaoxy derivative. COMT is a widespread enzyme that occurs in both neuronal and non-neuronal tissues.

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It acts on both the catecholamine themselves and deaminated products such as DOMA, that are produced by the action of MOA.

The main final metabolite of adrenaline and noradrenaline is 3-methoxy -4 – hydroxymandelic acid (VMA)

Adrenoceptor agonists

Smooth muscle: All types of smooth muscle, except that of GI tract , contract in response to stimulation of α1. Stimulation of β-receptors causes relaxation of most kinds of smooth by increasing cAMP formation. Bronchial smooth muscle is strongly dilated by activation of β2, selective β2 agonist are important in treatment of asthma. Uterine smooth muscle responds similarly, and these drugs are also used to delay premature labour.

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Heart: Catecholamine, acting on β1- receptors, exert a powerful stimulant effect on the heart. Both the heart rate ( chronotrophic effect) and force of contraction (inotrophic effect) are increased resulting in a marked increased cardiac out put and cardiac oxygen consumption. The cardiac efficiency is reduced.

Catecholamine can also cause disturbance of cardiac rhythm, culminating in ventricular fibrillation. Cardiac hypertrophy occurs in response to activation of α1-receptor, probably by mechanism similar to the hypertrophy of vascular and prostatic smooth muscle.

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Metabolism: Catecholamines encourages the conversion of energy stores ( glycogen and fat) to freely available fuels (glucose and free fatty acids), and cause an increase in plasma concentration of glucose and fatty acid this effect is mediated by β1. Stimulation lipolysis is produced by β3-receptors . Stimulation of α2- receptor causes the release of insulin secretion and inhibition of leptin.

Nerve terminals

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α - Adrenoceptor Antagonist; The main group of adrenal are: non-selective α – receptor antagonist (e.g. phenoxybenzamine, phentoalmine), selective α1 -

antagonist, selective α2 – antagonist and ergot derivatives.

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