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Neurohumoral transmission in ans
The document details noradrenergic transmission, focusing on the release and synthesis of catecholamines such as noradrenaline, dopamine, and adrenaline. It explains the mechanisms of noradrenaline release, reuptake, and degradation, as well as the classification and effects of adrenoceptors. Additionally, it describes how various agonists interact with these adrenoceptors for therapeutic purposes.
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Introduction to neurohumoral transmission involving synapse and neuro-effector junctions.
Explains catecholamines, including noradrenaline, adrenaline, dopamine, and their roles.
Describes physiology of noradrenergic neurons, their axons, varicosities, and neurotransmitter release.
Details the synthesis of noradrenaline from L-tyrosine, enzymes involved, and factors affecting synthesis.
Mechanisms of noradrenaline release, including Ca2+ mediated exocytosis and feedback control.
Feedback control mechanisms of noradrenaline release using Ca2+ influx, GPCR activities.
Overview of uptake and enzymatic degradation of noradrenaline and the roles of MAO/COMT.
Information on adrenoceptors' types, classifications, and their cellular signaling mechanisms.
Selective agonists for adrenoceptors, their clinical uses, and physiological effects.
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Neurohumoral transmission in ans
- 1. NORADRENERGIC TRANSMISSION NEUROHUMORAL TRANSMISSION IN ANS -By Lalita shahgond B.pharm SSR COLLEGE OF PHARMACY , SILVASSA
- 2. The transmission ofimpulse through synapse and neuro-effector junction by the release of humoral (chemical) substances… What is neurohumoral transmission
- 3. CATECHOLAMIN ES Catecholamine's arecompounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side chain the most important ones are: • noradrenaline (norepinephrine), a transmitter released by sympathetic nerve terminals • adrenaline (epinephrine), a hormone secreted by the adrenal medulla • dopamine, the metabolic precursor of nor adrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system • isoprenaline (isoproterenol), a synthetic derivative of nor adrenaline, not present in the
- 4. PHYSIOLOGY OF NORADRENERGIC TRANSMISSION Thenoradrenergic neuron: Noradrenergic neurons in the periphery are postganglionic sympathetic neurons whose cell bodies are situated in sympathetic ganglia.
- 5. - they generallyhave long axons that end in the series of varicosities strung along the branching terminal network These varicosities contain numerous synaptic vesicles, which are the sites of synthesis and release of nor adrenaline and of co-released mediators such as ATP and neuropeptide Y which are stored in vesicles and released by exocytosis.
- 6. NORADRENALINE SYNTHESIS Themetabolic precursor for noradrenaline is L-tyrosine, an aromatic amino acid that is present in the body fluids and is taken up by adrenergic neurons. Tyrosine hydroxylase, a cytosolic enzyme that catalyses the conversion of tyrosine to dihydroxyphenylalanine (dopa). This above hydroxylation step is the main control point for noradrenaline synthesis (rate limiting step). Tyrosine hydroxylase is inhibited by the end product of the biosynthetic pathway, noradrenaline.
- 7. The biosynthetic pathwayfor nor adrenaline synthesis
- 8. • The tyrosineanalogue α-methyltyrosine strongly inhibits tyrosine hydroxylase and has been used experimentally to block nor adrenaline synthesis. • The next step, conversion of dopa to dopamine, is catalyzed by dopa decarboxylase, a cytosolic enzyme that is by no means confined to catecholamine-synthesising cells. • Dopa decarboxylase activity is not rate-limiting for noradrenaline synthesis • 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.
- 9. • Dopamine-β-hydroxylase (DBH)is also a relatively nonspecific enzyme, that catalyses the conversion of dopamine to noradrenaline. • Many drugs inhibit DBH, including copper- chelating agents and disulfiram (a drug used mainly for its effect on ethanol metabolism. • Phenylethanolamine N-methyl transferase (PNMT) catalyses the N-methylation of nor adrenaline to adrenaline. The main location of this enzyme is in the adrenal medulla.
- 10. NORADRENALINE STORAGE• Most ofthe nor adrenaline is stored in nerve terminals or chromaffin cells is contained in synaptic vesicles; only a little is free in the cytoplasm under normal circumstances. • The concentration in the vesicles is very high (0.3–1.0 mol/l) and is maintained by the vesicular monoamine transporter (VMAT), which is similar to the amine transporter responsible for nor adrenaline uptake into the nerve terminal.• The vesicles contain two major constituents besides nor adrenaline, namely ATP (about four molecules per molecule of nor adrenaline). This substance is released along with nor adrenaline.
- 11. NORADRENALINE RELEASE • Transmitterrelease occurs normally by Ca2+ mediated exocytosis from varicosities on the terminal network. • Non-exocytotic release occurs in response to indirectly acting sympathomimetic drugs (e.g. amphetamine), which displace nor adrenaline from vesicles. • Noradrenaline escapes via the NET transporter (reverse transport). • Transmitter action is terminated mainly by reuptake of nor adrenaline into nerve terminals via • Nor adrenaline with ATP are released by exocytosis.
- 12. • NET isblocked by tricyclic antidepressant drugs and cocaine. • Noradrenaline release is controlled by autoinhibitory feedback mediated by α2 receptors. • Co-transmission occurs at many noradrenergic nerve terminals, ATP and neuropeptide Y being frequently co-released with NA. • ATP mediates the early phase of smooth muscle contraction in response to sympathetic nerve activity. • Noradrenaline, by acting on presynaptic β2 receptors, can regulate its own release, and also that of co-released ATP.
- 13. Feedback control ofnoradrenaline (NA) release. The presynaptic α2 receptor inhibits Ca+2 influx in response to membrane depolarisation via an action of the βγ subunits of the associated G protein on the voltage- dependent
- 14. • The depolarizationof the nerve terminal causes activation of the calcium channel. • The calcium channel opens and ca+2 ion enters into the cell, the calcium ions influx causes depolarization inside the cell. • Depolarization leads to exocytosic release of nor adrenaline with ATP from the vesicle. • Released NA bind to the postsynaptic receptors and produce respective effects. • NA bind to the α2 adrenoceptor which is auto receptor it inhibits the NA release.
- 15. • Gi /Go that are the α subunit of GPCR they are responsible for 3 activities :- - Gi regulates the opening of potassium channel and the inhibition of adenyl cyclase. - Go regulates the opening of the calcium channel. -The potassium channel opens and the K+ ions move outside the cell this causes repolarisation of the cell. This inhibits exocytosis of NA - The inhibition of the adenyl cyclase inhibits the conversion of ATP to C AMP this inhibits the opening of calcium channel. This inhibits exocytosis of NA.
- 16. UPTAKE AND DEGRADATIONOF CATECHOLAMINES (nor adrenaline) The action of released nor adrenaline is terminated mainly by reuptake of the transmitter into noradrenergic nerve terminals. Circulating adrenaline and noradrenalin are degraded enzymically, but much more slowly than acetylcholine.
- 17. UPTAKE OF CATECHOLAMINESAbout 75%of the nor adrenaline released by sympathetic neurons is recaptured and repackaged into vesicles. This serves to cut short the action of the released nor adrenaline, as well as recycling it. The remaining 25% is captured by non-neuronal cells in the vicinity, limiting its local spread. These two uptake mechanisms depend on distinct transporter molecules. Neuronal uptake is performed by the plasma membrane nor adrenaline transporter (generally known as NET, the nor epinephrine transporter), which belongs to the family of neurotransmitter
- 18. THE UPTAKE OFNOR ADRENALINE IS OF 3 TYPES :- 1. AXONAL UPTAKE 2. VESICULAR UPTAKE 3. EXTRANEURONAL UPTAKE
- 19. AXONAL UPTAKE Anactive amine pump (NET) is present at the neuronal membrane which transports NA by a Na+ coupled mechanism. It takes up NA at a higher rate than Adrenaline and had been labelled uptake-1. The indirectly acting sympathomimetic amines like tyramine, but not isoprenaline, also utilize this pump for entering the neurone. This uptake is the most important mechanism for terminating the postjunctional action of NA. From 75% to 90% of released NA is retaken back into the neurone. This pump is inhibited by cocaine, desipramine and few
- 20. VESICULAR UPTAKE Themembrane of intracellular vesicles has another amine pump the ‘vesicular monoamine transporter’ (VMAT-2), which transports NA from the cytoplasm to the interior of the storage vesicle. The VMAT-2 transports monoamines by exchanging with H+ ions. The vesicular NA is constantly leaking out into the axoplasm and is recaptured by this mechanism. This carrier also takes up DA formed in the axoplasm for further synthesis to NA. Thus, it is very important in maintaining the NA content of the neurone. This uptake is inhibited by reserpine, resulting in
- 21. Extraneuronal uptake Extraneuronaluptake of CAs (uptake-2) is carried out by extraneuronal amine transporter (ENT or OCT3) and other organic cation transporters OCT1 and OCT2 into cells of other tissues. In contrast to NET this uptake transports Adrenaline at a higher rate than NA, is not Na+ dependent and is not inhibited by cocaine, but inhibited by corticosterone. It may capture circulating Adr, but is quantitatively minor and not of physiological or pharmacological importance.
- 22. METABOLIC DEGRADATION OF CATECHOLAMINES(NOR ADRENALINE) - Endogenous and exogenous catecholamines are metabolised mainly by two intracellular enzymes:- - Monoamine oxidase (MAO) - Catechol-O-methyl transferase (COMT). - MAO (of which there are two distinct isoforms) MAO-A and MAO-B is bound to the surface membrane of mitochondria. - It is abundant in noradrenergic nerve terminals but is also present in liver, intestinal epithelium and other tissues. - MAO converts catecholamines to their corresponding aldehydes, which in the periphery, are rapidly metabolised by aldehyde dehydrogenase to the corresponding carboxylic acid.
- 24. • NA Convertedto NM by COMT • MAO catalyses conversion of NM to NM aldehyde • NM aldehyde is directly converted to VMA by ADH, VMA is the major metabolite which is excreted through urine. • when MAO enzyme acts on the NA it gets converted to NA aldehyde • AR converts the NM aldehyde directly into the MHPG, which is a minor metabolite of NA and it is excreted through urine. • ADH converts NA aldehyde to DHMA further the DHMA is converted to VMA by COMT • AR catalyses the conversion of NA aldehyde to DHPG which is catalysed to MHPG by COMT.
- 26. The catecholamine's should bindto the adrenoceptors to produce effects… ADRENOCEPTORS
- 27. CLASSIFICATION OF ADRENOCEPTORS αβ α1 α2 β1 β2 β3 А В Ϲ А В Ϲ α: nor adrenaline > adrenaline > isoprenaline
- 28. Classification of adrenoceptors •Main pharmacological classification into α and β subtypes, based originally on order of potency among agonists, later on selective antagonists. • Adrenoceptor subtypes: – two main α- adrenoceptor subtypes, α1 and α2, each divided into three further subtypes (1-/2- A,B,C) – three β-adrenoceptor subtypes (β1, β2, β3) – all belong to the super family of G protein-coupled receptors.
- 29. • Second messengers: –α1 receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers – α2 receptors inhibit adenylyl cyclase, decreasing cAMP formation – all types of β receptor stimulate adenylyl cyclase
- 30. •. • Themain effects of receptor activation are as follows: – α1 receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary secretion and hepatic glycogenolysis – α2 receptors: inhibition of: transmitter release (including nor adrenaline and acetylcholine release from autonomic nerves); platelet aggregation; vascular smooth muscle contraction; insulin release – β1 receptors: increased cardiac rate and force – β2 receptors: bronchodilatation; vasodilatation; relaxation of visceral smooth muscle; hepatic glycogenolysis; muscle tremor – β3 receptors: lipolysis and thermogenesis; bladder detrusor muscle relaxation.
- 33. ADRENOCEPTOR AGONISTS • Selectiveα1 agonists include phenylephrine and oxymetazoline. • Selective α2 agonists include clonidine and α- methylnoradrenaline. They cause a fall in blood pressure, partly by inhibition of nor adrenaline release and partly by a central action. • Selective β1 agonists include dobutamine. Increased cardiac contractility may be useful clinically, but all β1 agonists can cause cardiac dysrhythmias. • Selective β2 agonists include salbutamol, terbutaline and salmeterol; used mainly for their bronchodilator action in asthma. • A selective β3 agonist, mirabegron, is used to treat overactive bladder; β3 agonists promote lipolysis and have potential in the treatment of