浙江大学医学院：神经系统药理学（PPT讲稿）Pharmacology of the nervous system

Pharmacology of the nervous system Shi-Hong Zhang(张世红,PhD Dept of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn

Pharmacology of the nervous system Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn 1

Pharmacology of efferent nervous system Cholinergic Pharmacology Adrenergic Pharmacology

• Cholinergic Pharmacology • Adrenergic Pharmacology Pharmacology of efferent nervous system 2

ACh ACh Parasympathetic Medulla Cardiac and smooth muscle land cells, nerve terminals ACh N Sympathetic ACh Sweat glands ACh N NE Sympathetic Cardiac and smooth muscle gland cells, nerve terminals Spinal cord ACh N Sympathetic Renal vascular smooth muscle ACh Epi. NE ACh Adrenal medulla Somatic Skeletal muscle Voluntary motor nerve Copyright @2006 by The McGraw-Hill Companies, Inc. All rights reserved

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NE synthesis in nerve terminals and turnover 1 SYNTHESIS OF NOREPINEPHRINE Hydroxylation of tyrosine In COOH 2 UPTAKE INTO STORAGE VESICLES Norepinephrine is protected hydroxylase om degradation in ahydrobiopterin, O,) vesicle is metabolise CH2C-COOH RELEASE OF L-DOPA 3 NEUROTRANSMITTER DopamIne DOPA decarboxylase cell membrane (Pyridoxal phosphate) CH, CH NH2 5 REMOVAL OF NOREPINEPHRINE Dopamine rapidly taken into neuron · Uptake Is inhibited by Dopamine B-hydroxylase cocaine and imipramine BINDING TO (Ascorbate, O, 4 RECEPTOR Postsynaptic receptor Inactive Urn● of neurotransmitter bolites SYNAPTIC Norepinephrine 6 METABOLISM SPACE Catecholamine Biosynthetic Pathway and oxidized by mo amine oxida INTRACELLULAR RESPONSE

NE synthesis in nerve terminals and turnover Catecholamine Biosynthetic Pathway 4

NH2 HO- CH2C-COOH Norepinephrine and Epinephrine H L-Tyrosine Synthesis in the Adrenal Medulla Tyrosine hydroxylase (Tetrahydrobiopterin, 0,) PNMT苯氨基乙醇N甲基转移酶 is located in the CH2C-COOH cytosol L-DOPA DBH多巴脱羧酶 is located in vesicles DOPA decarboxylase EPl is stored in vesicles (Pyridoxal phosphate) EPI(-80%) and NE (20%)are released into blood HO CH2 NH PNMT Dopamine B-hydroxylase NE)→NE—EPI→(EPI (Ascorbate, O2) H CHCH2 NH2 Norepinephrine Chromaffin cel enylethanolamine methyltransferase (s-adenosylmethionine CHCH2NHCH Epinephrine

Norepinephrine and Epinephrine Synthesis in the Adrenal Medulla - PNMT苯氨基乙醇N-甲基转移酶 is located in the cytosol - DBH 多巴脱羧酶 is located in vesicles - EPI is stored in vesicles. - EPI (~80%) and NE (~20%) are released into blood Chromaffin cell NE PNMT NE EPI EPI 5

Norepinephrine and Epinephrine Metabolism 9o-t-9- Mo MHPG(3-甲氧4羟苯乙二醇): was used as CH3 an index of cns ne turnover Norepinephrine DOPGAL Epinephrine but generated mostly from aldehyde aldehyde reductase dehydrogenase COMT raphe MMA香草扁桃酸) sometimes used as an index of ne turnover Normetanephrine DOPEG DOMA Metanephrine Sulfate conjugates COMT COMT also prevalent CH,o OH H Elimination by kidneys MOPEG or MHPG VMA Urine MIPG-SO aldehyde reductase NMN-SO MN-SO CHao MAO MAO Relative amounts excreted MOPGAL

Norepinephrine and Epinephrine Metabolism MHPG (3-甲氧4-羟苯乙二醇): was used as an index of CNS NE turnover but generated mostly from periphery VMA(香草扁桃酸): sometimes used as an index of NE turnover Sulfate conjugates also prevalent or MHPG 6

Adrenergic Receptor Subtypes& G-Protein Coupled Mechanisms a Adrenergic Receptors Phospholipase C activation, IP3 increase through G Mechanism mobilize and increase intracellular free calcium Effects: primarily smooth muscle contraction a Adrenergic Receptors nhibition of adenyl cyclase through Gi proteins Mechanism decrease intracellular cAMP levels Effects: decrease protein phosphorylation, decrease cellular function

1 Adrenergic Receptors: Phospholipase C activation, IP3 increase through Gq Mechanism: mobilize and increase intracellular free calcium Effects: primarily smooth muscle contraction 2 Adrenergic Receptors: Inhibition of adenyl cyclase through Gi proteins Mechanism: decrease intracellular cAMP levels Effects: decrease protein phosphorylation, decrease cellular function Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms 7

Adrenergic Receptor Subtypes& G-Protein Coupled Mechanisms B Adrenergic Receptors Activation of adenyl cyclase through Gs proteins Mechanism increase intracellular camp levels Effects: phosphorylation of intracellular proteins, smooth muscle relaxation cardiac muscle contraction

β Adrenergic Receptors: Activation of adenyl cyclase through Gs proteins Mechanism: increase intracellular cAMP levels Effects: phosphorylation of intracellular proteins, smooth muscle relaxation, cardiac muscle contraction Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms 8

Receptor 可乐定 Subtypes 去氧肾上腺素 CLor> 异丙肾上腺素 G IRAC PLC DG 工 acAMP |↑cAMP ↑Ca ∠④ KA P 9

q 去氧肾上腺素 异丙肾上腺素 可乐定 9

Four Major activators of the adrenergic system Hypoxia-response is mainly cardiovascular: increase in heart rate contractility(1); vasodilation of blood vessels in muscle(β2) Hypoglycemia -response is mainly metabolic glycogenolysis 阝2anda, gluconeogenesisβ2anda12, ypolysisβesp.阝3, a,), but B2 vasodilation in muscle increases glucose delivery Hypothermia-piloerection(M), peripheral vasocontraction (a), thermogenesis(B Hypotension - baroreceptor reflex 10

• Hypoxia - response is mainly cardiovascular: increase in heart rate & contractility (b1 ); vasodilation of blood vessels in muscle (b2 ). • Hypoglycemia - response is mainly metabolic (glycogenolysis b2 and 1 , gluconeogenesis b2 and 1,2, lypolysis b esp. b3 , 2 ), but b2 vasodilation in muscle increases glucose delivery. • Hypothermia - piloerection (M), peripheral vasocontraction (1 ), thermogenesis (b) • Hypotension – baroreceptor reflex Four Major Activators of the Adrenergic System 10