Autonomic Receptor FunctionsRichard D. Ye, Tel. 312-996-5087, E-mail: [email protected], Room 406 CMWAgonist: A structural analog that is capable of stimulating a biological responselike a natural ligand (by occupying the same receptor).Antagonist: (1) A receptor-specific blocker. (2) A molecule, such as a drug,enzyme inhibitor, or hormone, that diminishes or prevents the action of anothermolecule.Direct-acting: Molecule that physically binds to a receptor for its effect. Example: carbachol activates cholinergic receptors.Indirect-acting: Molecule that exerts effect on the target by interacting with another molecule. Example: neostigmine blocks AchE, causing Ach accumulation.PNS Receptor Classification:PNS ReceptorsCholinergic RAdrenergic RDopamine RMuscarinic RNicotinic RM1, M2, M3(M4, M5)NNNMβ1,α2α1,β2, β3D1, D2, D3, D4YE, ANS/receptors, Page 9The “Nicotinic Actions” -- similar to those induced by nicotine• stimulation of all autonomic ganglia (NN)• stimulation of voluntary muscle (NM)• secretion of epinephrine from the adrenal medulla (NN)• Pentameric receptor comprised of 4 different subunits: α2, β, γ, δ• Found in autonomic ganglions, adrenal medulla, neuromuscular junction and CNS• Ligand-gated ion (Na+) channel. Ach binds to the α subunits • Channel opening requires binding of 2 Ach molecules• Blocking gaglionic nAChR blocks all autonomic outflow. These agents lack selectivity and are now used mostly in research laboratories• These blocking agents include: Hexamethonium, tetraethylammonium, mecamylamine, and trimethaphanYE, ANS/receptors, Page 10The “Muscarinic Actions” -- reproduced by injection of muscarine, from Amanita muscaria. Similar to those of parasympathetic stimulation• Neural (M1): CNS, PNS, gastric parietal cells (excitatory; Gq)• Cardiac (M2): atria & conducting tissue; presynaptic (inhibitory; Gi)• Glandular (M3): exocrine glands; smooth muscle (excitatory; Gq)AgonistM1“neural”Gq↑ Inositol phosphates (IP3)↑ Diacyl glycerol (DAG)Depolarization↓ K+ conductanceMembrane depolarization (decrease of M1activity in CNS may be a cause ofdementia)AgonistM2“cardiac”Gi↓ cAMP↓ Calcium channels↑ K+ conductanceMostly inhibitory (responsible for the vagalinhibition of the heart)AgonistM3“glandular”Gq↑ Inositol phosphates (IP3)↑ Diacyl glycerol (DAG)↑ Intracellular calciumMostly exitatory (stimulation of glandularsecretion, contraction of visceral smotthmuscle)YE, ANS/receptors, Page 11Muscarinic agonistsDrugReceptor specificityHydrolysis by AchEmAChR nAchRAcetylcholineCarbacholBethanecholMuscarinePilocarpineMethacholine+++ +++ +++++ +++ ( − )+++ + ++++++++++( − ) ( − )( − ) ( − )( − ) ( − )Muscarinic antagonistsAtropine, scopolamine, and pirenzepine (relatively selective for M1 mAChR)YE, ANS/receptors, Page 12Two kinds of effects produced by Ach. A. Ach causes a fall in BP due to vasodilation.B. A larger dose of Ach also produces bradycardia, further reducing BP.C. Atropine blocks the effect of Ach in lowering BP.D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and tachycardia.Dale’ Experiment, using an anesthetized cat andmeasuring arterial pressure: YE, ANS/receptors, Page 13α1: postsynaptic effector cells, especially smooth muscleVasoconstriction, relaxation of gastrointestinal smooth muscle, hepaticglycogenolysisα2 presynaptic adrenergic nerve terminals (autoreceptor), platelets, lipocytes, smooth muscleInhibition of transmitter release, platelet aggregation, contraction ofsmooth muscleβ1 postsynaptic effector cells: heart, lipocytes, brain, presynaptic ad./ ch nerve term.Increased cardiac rate & force, relaxation of gastrointestinal smooth muscle β2 postsynaptic effector cells: smooth muscle, cardiac muscleBronchodilation, vasodilation, relaxation of visceral smooth muscle, hepaticglycogenolysisβ3 postsynaptic effector cells: lipocytesLipolysisDistribution and functions of adrenergic receptors:YE, ANS/receptors, Page 14Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenol inman. Norepinephrine (predominantly α-agonist) causes vasoconstriction and increased systolicand diastolic BP, with a reflex bradycardia. Isoproterenol (β-agonist) is a vasodilator, but stronglyincreases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.α -- NE > Epi > Isoβ -- Iso > Epi > NENE = norepinephrineEpi = epinephrineIso = isoproterenolHOHOCH2NHCH3OHCHEpiHOHOCH2NH2OHCHNEHOHOCH2NHOHCHIsoCH(CH3)2Classification of adrenergic receptors by agonist potencyYE, ANS/receptors, Page 15Cholinergic effects:Adrenergic effects:• Contraction of pupillary constrictor muscle-- miosis• Contraction of ciliary muscle - bulge of lens-- near vision, ↑ outflow of acqueous humor • Contraction of pupillary dilator muscle-- mydriasis• Stimulation of ciliary epithelium-- ↑ production of aqueous humor LensPupillary dilator muscle (α1)Pupillary constrictor muscle (M3)Secretion of acqueous humor (β)(M3)Trabecular meshwork(opened by pilocarpine)Cholinergic and adrenergic effects in the eye YE, ANS/receptors, Page
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