Autonomic Nervous System Neurotransmission Lecture Notes PDF

Neurotransmission in the Autonomic Nervous System IMPORTANT POINT NO 1: excitatory transmission at ALL the autonomic ganglia, sympathetic and parasympathetic, involves the transmitter Acetylcholine acting on Nicotinic acetylcholine receptors IMPORTANT POINT NO 2: transmission at the postga...

Neurotransmission in the Autonomic Nervous System IMPORTANT POINT NO 1: excitatory transmission at ALL the autonomic ganglia, sympathetic and parasympathetic, involves the transmitter Acetylcholine acting on Nicotinic acetylcholine receptors IMPORTANT POINT NO 2: transmission at the postganglionic sympathetic synapse usually involves Noradrenaline acting on either -adrenoceptor or -adrenoceptors IMPORTANT POINT NO 3: transmission at the postganglionic parasympathetic synapse usually involves Acetylcholine acting on Muscarinic receptors Overview of neurotransmission in the Autonomic Nervous System Topics: Transmission at the post-ganglionic sympathetic synapse 1. synthesis, release, uptake and metabolism of noradrenaline 2. classification and pharmacology of noradrenaline receptors 3. drugs that interfere with post-ganglionic sympathetic transmission Transmission at cholinergic synapses in the autonomic nervous system 1. synthesis and release of acetylcholine 2. ganglionic neurotransmission, nicotinic receptors 3. post-ganglionic neurotransmission, muscarinic  Sympathetic Organ Synapse Ca 2+ Effector Organ Na+ G NE Action Potential Adrenergic Receptor Postganglionic neuron Transmission at the post-ganglionic sympathetic synapse Historical: Adrenaline was identified from adrenal extracts Adrenaline was shown to mimic sympathetic nerve stimulation The Finkelman preparation provided evidence that the sympathetic nervous system releases an adrenaline like compound Von Euler demonstrated that nor-adrenaline is the main endogenous catecholamine in the sympathetic nerves  THE FINKELMAN PREPARATION sympathetic nerve stimulation noradrenaline  Noradrenaline is the main transmitter at the post- ganglionic sympathetic synapse Except..........  in sweat glands (ACh, therefore atropine blocks sweating)  resistance blood vessels in skeletal muscle; activation of the sympathetic nervous system causes vasodilation in this tissue  n.b. there are other neurotransmitters (NANC, for non-adrenergic, non-cholingergic) these will be OU SHOULDdiscussed LEARN THE later STRUCTURE OF NORADRENALINE  noradrenaline is a CATECHOLAMINE α CARBON β CARBON this carries a +ve charge at physiological pH CATECHOL GROUP THE SYMPATHETIC SYNAPSE Synthesis Release Inactivation Receptors  TYROSINE from diet tyrosine hydroxylase L-DOPA dopadecarboxylase DOPAMINE dopaminebetahydroxylase NORADRENALINE PNMT ADRENALINE YOU SHOULD REMEMBER THIS SYNTHETIC PATHWAY  'false' transmitters DDC tyramine DBH octopamine PNMT synephrine  Drugs that interfere with catecholamine synthesis α methyl-tyrosine is a competitive inhibitor of tyrosine hydroxylase used in the treatment of phaeochromocytoma α methyl-DOPA is a drug that can be used to interfere with NAdr transmission as it leads to the synthesis of the false transmitter α methyl-NAdr  Drugs that interfere with catecholamine synthesis Carbidopa inhibits dopa decarboxylase (DCC) and is used in the treatment of Parkinson's disease: -co-adminstered with L-DOPA -stop the peripheral metabolism of L-DOPA -carbidopa doesn't cross the BBB Drugs that interfere with catecholamine synthesis LeWitt, NEJM, 2008 THE SYMPATHETIC SYNAPSE Synthesis Release Inactivation Receptors  NADR is STORED IN VESICLES By a transport mechanism driven by a PROTON GRADIENT Stored with ATP AND CHROMOGRANIN DRUGS THAT INTERFERE WITH NADR STORAGE Rauwolfia Reserpine antihypertensive: side-effect, depression  Guanethidi ne antihypertensive: side-effect orthostatic hypotension THE SYMPATHETIC SYNAPSE Synthesis Release Inactivation Receptors  INACTIVATION OF NAdr FOLLOWING RELEASE Presence of UPTAKE mechanisms for NAdr demonstrated by IVERSEN Used radiolabelled Noradrenaline And tissue receiving sympathetic innervation, cardiac tissue Measured amount of Noradrenaline accumulated by the tissue intact denervated  INACTIVATION OF NAdr FOLLOWING RELEASE intact Intact - denervated Uptake denervated nmol min-1 Concentration of noradrenaline M INACTIVATION OF NAdr FOLLOWING RELEASE: TWO mechanisms UPTAKE 1 UPTAKE 2 High affinity Low affinity Low capacity High capacity NERVE TERMINAL EXTRANEURONAL  INACTIVATION OF NAdr FOLLOWING RELEASE Uptake 1 2 components at nerve terminal Uptake 2 INACTIVATION OF NAdr FOLLOWING RELEASE Presence of UPTAKE mechanisms for NAdr demonstrated b IVERSEN UPTAKE 1- NAT (Noradrenaline transporter) High affinity, low capacity, present on nerve termina Requires Na+ gradient and ATP Substrate specificity UPTAKE 2- Low affinity, high capacity, present on extraneurona tissue Inhibited by cortisol  DRUGS THAT BLOCK UPTAKE 1 Will POTENTIATE the action of Nadr) ostly clinically used as ANTIDEPRESSANTS OCAINE IPRAMINE- First Tricyclic Antidepressant ESIPRAMINE and AMITRYPTALINE are closely related drugs UANETHIDINE also weakly blocks uptake 1)  DRUGS THAT STIMULATE NAdr RELEASE direct sympathominetics YRAMINE naturally occurring in foodstuffs PHEDRINE used in cold remedies MPHETAMINE psychostimulant  NAdr METABOLISM TWO IMPORTANT ENZYMES  Monoamine Oxidase (MAO)  Catechol-O-Methyl Transferase (COMT) Major metabolites are 3-methoxy-4-hydroxymandelic acid (VMA) 3-methoxy-4-hydroxyphenylglycol (MHPG) Plasma levels of the metabolites can be useful biomarkers of disease DRUGS THAT INTERFERE WITH NAdr METABOLISM Monoamine Oxidase Inhibitors (MAOIs) Iproniazid THE SYMPATHETIC SYNAPSE Synthesis Release Inactivation Receptors  Sympathetic Organ Synapse Ca 2+ Effector Organ Na+ G NE Action Potential Adrenergic Receptor Postganglionic neuron  Adrenoceptor subtypes Alqhuist 1948 Effects of noradrenaline on smooth muscle Vascular smooth muscle contraction Bronchial smooth muscle relaxation Different receptors? Agonist profile  Adrenoceptor subtypes α β Isoforms 1 – 2 1,2,3 ALL ARE GPCR S  Adrenoceptor subtypes DIVIDED INTO α AND β Evidence for adrenoceptor subtypes at the noradrenergic synapse from neurochemical experiments by S Langer IMPORTANT CONCEPTS: There is feedback inhibition of neurotransmitter release at the synapse mediated by AUTORECEPTORS (α2) α1 - predominantly postsynaptic α2- predominantly presynaptic  Adrenoceptor agonists Phenylephrine α1> α2 Methoxamine α1 Clonidine α2 which drug will have antihypertensive action?  Adrenoceptor antagonists Phentolamine α1 = α2 Phenoxybenzamine α1 Prasozin α1 > α2 Yohimbine α2 > α1 which drug(s) will be antihypertensive? what effect will yohimbine have on noradrenergic transmission?  β Adrenoceptors all are GPCRs and stimulate cAMP formation β1 cardiac acceleration lipolysis decreased gut motility & secretion renin release β2 bronchodilation vasodilation of blood vessels to skeletal muscle glycogen breakdown  β Adrenoceptor agonists isoprenaline β1 > β2 sed for treatment of asthma ssociated with high incidence of heart failure salbutamol β2 > β1 an effective bronchodilator by inhalation dobutamine β1 > β2 used as cardiac stimulant  β Adrenoceptor antagonists oxymethylene bridge Sir James Black PROPRANOLOL n-selective beta blocker tihypertensive as local anaesthetic action; can cause bronchoconstriction) β Adrenoceptor antagonists oxymethylene bridge ATENOLOL β1 antagonist; cardioselective THE SYMPATHETIC SYNAPSE Summary ummary for postganglionic sympathetic synapse You should be able to describe the process of noradrenergic transmission (synthesis, storage, release, inactivation and receptors) You should be able to describe the action of drugs which interact with noradrenergic transmission with reference to autonomic processes especially the regulation of blood pressure