浙江大学：《药理学》课程教学资源（PPT课件讲稿）神经系统药理学 Pharmacology of the nervous system（主讲：张世红）

Pharmacology of efferent nervous system Cholinergic Pharmacology Adrenergic Pharmacology 2

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

AC ACh N Parasympathetic Medulla Cardiac and smooth muscle gland cells, nerve terminals Sympathetic ACh Sweat glands ACh NE Sympathetic Cardiac and smooth muscle gland cells, nerve terminals Spinal ACh 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 NH2 NOREPINEPHRINE CH.C-COOH he rate-limiting step 2 UPTAKE INTO STORAGE VESICLES H Inactive 4 e Dopamine entera vesicle L-Tyrosine e Norepinephrine is protected Tyrosine hydroxylase om degradation in erin, o Transport into vesicle is HO Inactive HO CH2C-COOH L-DOPA 3 RELEASE OF NEUROTRANSMITTER DOPA decarboxylase coll membrane ( Pyridoxal phosphate) e Release blocked by HO HO 5 REMOVAL OF NOREPINEPHRINE Dopamine rapidly taken into neuron Dopamine B-hydroxylase cocaine and imlpram (Ascorbate, O) 4 BINDING TO RECEPTOR of neurotransmitter 一CHCH2NH2 SYNAPTIC Norepinephrine 6 METABOLISM SPACE Catecholamine Biosynthetic Pathway mIne oxidase INTRACELLULAR RESPONSE

NE synthesis in nerve terminals and turnover Catecholamine Biosynthetic Pathway 4

NH2 Norepinephrine and Epinephrine CH2C-COOH L-Tyrosine Synthesis in the Adrenal Medulla Tyrosine hydroxylase (Tetrahydrobiopterin, O,) PNMT苯氨基乙醇N-甲基转移酶 is located in the NH2 CH2C-COOH cytosol L-DOPA DBH多巴脱羧酶 is located in vesicles DOPA decarboxylase EPl is stored in vesicles EPl(-80%)and NE(-20%)are released into blood CH, CH NH Dopamine Dopamine B-hydroxylase PNMI NE)→NE一→EPI→EPI (Ascorbate, O2 H CHCH2 NH2 Norepinephrine Chromaffin cell Phenylethanolamine N-methyltransferase (S-adenosylmethionine CHCH NHCH 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 MAO B2b28-=b MHPG(3甲氧4羟苯乙二醇 CH2-NH2 -CH2 was used as an index of cns ne turnover Norepinephrine DOPGAL Epinephrine but generated mostly from aldehyde COMT aldehyde reducts COMT periphery CH,O VMA(香草扁桃酸) sometimes used as an index of ne turnover Normetanephrine DOPEG DOMA Metanephrine Sulfate conjugates COMT COM also prevalent Elimination by kidneys MOPEG or MHPG VMA VMA Urine MHPG-SO NMN-SO reductase dehydrogenase MN-SO 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 a2 Adrenergic Receptors: Inhibition of adenyl cyclase through G 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 <Clon he 异丙肾上腺素 a R(AC PLC 冷B DG 工 cAMP ⊙ 个cAMP 个Ca PKA)O 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(B1); vasodilation of blood vessels in muscle(β2) Hypoglycemia -response is mainly metabolic ( glycogenolysis 阝2anda1, gluconeogenesisβ2andc12, lipolysisβesp.β3, a2), but B2 vasodilation in muscle increases glucose delivery Hypothermia- piloerection( M), peripheral vasocontraction (Ol), 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

Summary: Adrenoceptors a receptors a, receptors: vasoconstriction: increased peripheral resistance, BP r, contraction of radial muscle of iris: mydriasis a2 receptors: CNS, presynaptic membranes of adrenergic nerves: vasodilatation inhibition of ne release inhibition of insulin release

 receptors • 1 receptors: vasoconstriction: increased peripheral resistance, BP↑; contraction of radial muscle of iris: mydriasis • 2 receptors: CNS, presynaptic membranes of adrenergic nerves: vasodilatation, inhibition of NE release; inhibition of insulin release Summary: Adrenoceptors 11