BIOL2048-49 ANS Lecture 3 DGN 24-25 PDF

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 w...

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 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 4. synthesis and release of acetylcholine 5. ganglionic neurotransmission, nicotinic receptors 6. post-ganglionic neurotransmission, muscarinic  Cholinergic transmission in the autonomic nervous system carbonyl oxygen nitrogen ether oxygen (also at skeletal NMJ)  Cholinergic transmission in the autonomic nervous system AT ALL GANGLIA Something to think about when revising: at which sites is ACh the neurotransmitter? what are the physiological consequences of interfering with cholinergic transmission in the ANS? cardiovascular system gastrointestinal tract eye function secretions etc.... Synthesis & release Inactivation Receptors nicotinic transmission: receptors and ganglion blockers muscarinic transmission: receptors- subtypes, tissue distribution and physiological roles Drugs that interfere with cholinergic transmission and their therapeutic uses  The Synthesis of Acetylcholine substrates are choline and acetylCoA choline is taken up into nerve terminal by choline transporter, this is the rate limiting step for synthesis the enzyme is choline acetyltransferase (CAT) AcetylCoA + choline  Acetylcholine + CoA  The Synthesis of Acetylcholine Acetylcholine is taken up into presynaptic vesicles by an active transport process (blocked by vesamicol) Acetylcholine is released in response calcium entry into the presynaptic terminal Synthesis & release Inactivation Receptors nicotinic transmission: receptors and ganglion blockers muscarinic transmission: receptors- subtypes, tissue distribution and physiological roles Drugs that interfere with cholinergic transmission and their therapeutic uses  The Inactivation of Acetylcholine Following release into the synaptic cleft, ACh is available to activate receptors (these will be discussed later) The synaptic cleft is also rich in the enzyme Acetylcholinesterase which breaks ACh down into choline and acetic acid Choline is taken back up into the nerve terminal by the choline transporter. This is blocked by hemicholinium. Synthesis & release Inactivation Receptors nicotinic transmission: receptors and ganglion blockers muscarinic transmission: receptors- subtypes, tissue distribution and physiological roles Drugs that interfere with cholinergic transmission and their therapeutic uses  The Pharmacological Actions of Acetylcholine Dale, HH. (1914). The action of certain esters and ethers of choline and their relation to muscarine. J Pharm Exp Therap. 6, 147-190. 'sympathomimetic' 'parasympathomimetic' le characterized cholinergic transmission usin uscarine Nicotine Atropine " two distinct types of action can be detected- a 'muscarine' action, paralysed by atropine, and a 'nicotine' action,  Dale's experiment showing that ACh produces 2 different effects on blood pressure BP atropine 2µg 50µg 50µg5mg ACh injected IV with bradycardia MUSCARINIC tachycardia NICOTINIC Why the same compound triggers two dose- dependent opposite responses?  Parasympathetic Organ Synapse Acetylcholinesterase Ca 2+ Effector Organ Na+ K+ G Action Potential ACH Muscarinic Receptor Postganglionic neuron Muscarinic Transmission: Agonists MUSCARINE  Muscarinic Receptors: Agonists Drug Muscarinic Nicotinic Hydrolysis action action by AChe ACh +++ +++ +++ Carbachol* +++ +++ - Bethanechol +++ - - Muscarine +++ - - Pilocarpine +++ - - Oxotremorine ++ - - *  Muscarinic Receptors: Effects of Agonists cardiovascular decreased HR, CO and vasodilation gastrointestinal actions increased activity exocrine gland secretion increased sweating, lacrimation and salivation effects on the eye: treatment of glaucoma  effects on the eye: treatment of glaucoma rasympathetic innervation of constrictor pupil rasympathetic innervation of ciliary muscle: e of pilocarpine in glaucoma to relieve pressur  Muscarinic receptor subtypes: overview All are G protein coupled receptors M1 M2 M3 Type neural cardiac glandular main location CNS atria exocrine glands, presynaptic smooth muscle, terminals vascular endothelium cellular action ↑IP3, DAG ↓cAMP ↑IP3, DAG function gastric acid cardiac inhibition secretion secretion neural inhibition smooth muscle gut motility contraction vasodilation (via NO)  Muscarinic receptor subtypes: overview M1 M2 M3 Type neural cardiac glandular Function -gastric acid -cardiac -secretion secretion inhibition -smooth muscle -gut motility -neural inhibition contraction -vasodilation (via NO) Muscarinic receptor antagonists atropine pirenzepine Effects of muscarinic antagonists inhibition of secretions effect on heart rate effects on the eye effects on the gut effects on other smooth muscle effects on the CNS CLINICAL USES