Catecholamines

1: Introduction. Catecholamines 1922-1971.- 2: The Chromaffin System.- I. Introduction.- II. Distribution of Chromaffin Cells in Vertebrates.- 1. Invertebrates.- 2. Vertebrates.- 3. The Carotid Body.- 4. Peripheral Chromaffin Cells.- III. The Functional Anatomy of the Chromaffin Cell.- 1. Structure of Chromaffin Granules.- 2. Cell Organelles.- 3. Formation of Chromaffin Granules.- 4. Adrenalin-Noradrenaline Storage.- 5. Adrenaline versus Noradrenaline Storage.- 6. Discharge of Contents of Chromaffin Granules.- IV. Innervation of Chromaffin Cells.- 1. Adrenal Medulla.- 2. Extra-Adrenal Chromaffin Cells.- References.- 3: Electron Microscopy of Catecholamine-Containing Structures.- I. Introduction.- II. Identifying Catecholamine-Containing Cellular Organelles.- 1. Identification Criteria.- 2. Chemical Basis for the Selective Staining of Catecholamines.- III. Localization of Catecholamines in Nervous Tissues.- 1. Peripheral Sympathetic Nerve Terminals.- a) Small Granular Vesicles.- b) Large Granular Vesicles.- 2. Central Nerve Terminals.- 3. Localizing Catecholamines in Neuronal Cell Bodies and Non-terminal Axons.- IV. Cytology of Catecholamine-Containing Cells.- 1. The Chromaffin Cells.- 2. Chromaffin Neurons.- 3. Carotid Body Chemoreceptors.- 4. Sympathetic Neurons.- 5. Sympathetic Axons and Terminals.- 6. Central Neurons and Terminals.- V. Conclusions.- References.- 4: Catecholamines in the Invertebrates.- I. Introduction.- II. Catecholamines in the Major Invertebrate Phyla.- 1. Protozoa.- 2. Porifera (Sponges).- 3. Coelenterata.- 4. Platyhelminthes (Flatworms).- 5. Nemertinea (Ribbon Worms).- 6. Annelida (Segmented Worms).- 7. Mollusca.- 8. Arthropoda.- 9. Echinodermata.- 10. Hemichordata, Urochordata, Cephalochordata.- III. Summary and Concluding Remarks.- References.- 5: The Distribution of Catecholamines in Vertebrates.- I. Introduction.- II. Methods Used for the Estimation and Identification of Catecholamines in Tissues and Body Fluids.- III. Distribution of Catecholamines in Tissues and Body Fluids.- 1. Catecholamines in Cyclostomata (Hagfishes and Lampreys).- 2. Catecholamines in Euselachii.- 3. Catecholamines in Teleostii (Bony Fishes).- 4. Catecholamines in Amphibia.- 5. Catecholamines in Reptilia.- 6. Catecholamines in Birds.- 7. Catecholamines in Mammals.- a) Nervous System (Brain, Spinal Cord, Pineal Gland, Cerebrospinal Fluid, Peripheral Nerves and Ganglia).- b) Eye.- c) Adrenal Gland (Adrenal Medulla, Dopamine in the Adrenal Gland, N-methyladrenaline.- d) Extramedullary Chromaffin Tissue.- e) Heart.- f) Lung.- g) Kidney.- h) Thyroid Gland.- i) Reproductive Organs (Male Sex Organs, Female Sex Organs).- j) Gastro-intestinal Tract.- k) Liver.- l) Spleen.- m) Salivary Glands.- n) Pancreas.- o) Catecholamines in the Walls of Blood Vessels.- p) Carotid Body.- q) Adipose Tissue.- r) Skeletal Muscle.- s) Skin.- t) Catecholamines in Blood.- u) Catecholamines in Urine.- v) Cells which Can Form Catecholamines.- Annex: Tables 1-44.- References.- 6: Synthesis, Uptake and Storage of Catecholamines in Adrenergic Nerves. The Effect of Drugs.- A. Introduction.- B. Adrenergic Nerves.- I. Synthesis.- 1. Main Synthetic Pathway.- a) Tyrosine Hydroxylase.- b) DOPA-Decarboxylase.- c) Dopamines ?-hydroxylase.- 2. Other Synthetic Pathways.- 3. Localization of Synthesis. Effect of Precursors.- 4. Synthesis Inhibitors.- a) Tyrosine Hydroxylase Inhibitors.- b) DOPA-Decarboxylase Inhibitors.- ?) Derivatives of Hydrazine and Hydroxylamine.- ?) Decaborane.- c) Dopamine ?-hydroxylase Inhibitors.- ?) Hydroxybenzyloxyamine.- ?) Disulfiram, Tropolone.- d) Reserpine.- 5. Induction and Regulation of Synthesis.- 6. Synthesis Rate and Kinetics.- II. Uptake.- 1. Introduction.- 2. Uptake of Catecholamines in Organs and Tissues.- 3. Uptake in Adrenergic Nerves.- 4. Specific Uptake in Storage Particles.- 5. Bulk Uptake of Catecholamines after Depletion.- 6. Uptake Estimated by Perfusate Deficit Studies.- 7. The Uptake Process.- 8. Uptake of False Transmitters. Multi Amine Storage.- 9. Effect of Drugs on Catecholamine Uptake in Organs, Nerves and Isolated Particles.- a) Sympathomimetic Amines.- b) Adrenergic Blocking Agents.- c) Neuronal and Ganglionic Blockers.- d) Psychotropic Drugs.- ?) Reserpine 209 - ?) Cocaine 211 - ?) Imipramine, Desipramine, Amitriptyline 212 - ?) d-Lysergic Acid Diethylamide.- e) Enzyme and Metabolic Inhibitors.- f) Various Drugs.- III. Storage.- 1. Storage in Subcellular Particles.- 2. Storage Capacity, Noradrenaline Content in Particles.- 3. Stability of Storage Particles.- 4. Free and Particle-bound Noradrenaline in Homogenates of Adrenergic Nerves and in Organs.- 5. Effect of Drugs.- References.- 7: The Synthesis, Uptake and Storage of Catecholamines in the Adrenal Medulla. The Effect of Drugs.- A. Synthesis.- 1. Formation of Adrenaline; N-methylation of Noradrenaline.- 2. Role of Organelles in Synthesis.- 3. Rate of Synthesis in Adrenal Medulla, and Availability of Newly Formed Hormone for Secretion.- 4. Regulation of Catecholamine Synthesis.- 5. Effect of Precursors.- 6. Inhibitors of Synthesis.- 7. Diagrammatic Illustration of Catecholamine Synthesis and Levels of Physiological and Pharmacological Regulation.- B. Uptake.- 1. Uptake at the Cellular Level.- a) Circulating Amines.- b) Reuptake of Catecholamines Secreted.- c) Functional Significance of Uptake of Circulating Catecholamines into Adrenal Medulla.- d) "False Hormones" in Adrenal Medulla.- 2. Uptake in Granules.- a) Methods.- b) Exchange versus Net Uptake.- c) Uptake at High Concentrations of Amine.- d) ATP-and Mg++-dependent Uptake.- e) Other Amine Uptake Mechanisms.- f) Role of ATPase.- 3. Inhibitors of Uptake in Chromaffin Amine Storage Vesicles.- a) Inhibition of ATPase.- b) Competition for Inward Transport.- c) Block of Transport Sites.- 4. Diagrammatic Illustration of Catecholamine Uptake, and Levels of Drug Action.- C. Storage.- 1. Origin of Storage Vesicles.- 2. Isolation of Chromaffin Amine Storage Vesicles.- 3. Chemical Composition.- 4. Storage Complex.- a) Stability of Storage Complex at 0 C.- b) Osmotic Lysis.- c) Stability of Storage Complex at Higher Temperature.- d) Differences between Dopamine, Noradrenaline and Adrenaline Storage.- e) Importance of Medium for Stability.- f) Permeability of Vesicle Membrane. Role of ATPase in Amine Transport.- g) Ca++ as Promoter of Release: In vitro Models of Secretion by Exocytosis ?.- h) Cl?-dependent Acceleration of Spontaneous Release Induced by ATP plus Mg++.- i) Homogeneity of Store.- 5. Effect of Drugs.- a) Stabilizers.- b) Promoters of Release.- c) Depleters.- 6. Diagrammatic Representation of Dynamics of Catecholamine Storage.- References.- 8: Metabolic Degradation of Catecholamines. The Relative Importance of Different Pathways under Physiological Conditions and after Administration of Drugs.- I. Introduction.- II. Metabolic Fate.- 1. Deamination by MAO.- 2. O-Methylation by COMT.- III. Use of Radioactive Catecholamines to Study Metabolic Routes.- 1. Metabolism of Adrenaline.- 2. Metabolism of Administered and Endogenous Noradrenaline.- 3. Effect of Drugs.- IV. Summary.- References.- 9: The Classification of Adrenoceptors (Adrenergic Receptors). An Evaluation from the Stand-point of Receptor Theory.- A. Introduction.- B. Historical Background.- C. Procedures for the Pharmacological Characterization and Classification of Adrenoceptors.- I. General Comments.- II. Theoretical Concepts Related to the Procedures for Pharmacological Characterization.- 1. Concepts Related to the Relative Potencies of Agonists.- 2. Concepts Related to Reversible Competitive Antagonism.- 3. Concepts Related to Irreversible Antagonism.- III. Experimental Conditions and their Control.- 1. Desired Optimal Conditions.- 2. Changes in Sensitivity to Agonists not Due to Treatment with Antagonists.- 3. Responses Complicated by an Indirect Action of the Agonist.- 4. Responses which are the Resultant of Actions of an Agonist on More than One Type of Receptor.- a) Actions on Both ?-and ?-Receptors.- b) Actions Other than Those on a?or ?-Receptors.- 5. Removal of the Agonist from the Region of the Receptor.- a) Removal Processes and their Influence on Relative Potencies of Agonists..- b) Influence of Removal Processes on Potencies of Competitive Antagonists..- 6. Modification of the Response to the Agonist by Actions of an Antagonist at Sites Other than the Receptor.- 7. Lack of Equilibrium Conditions for Agonist or Antagonist at the Time a Response is Measured.- 8. Loss of Free Drug from the External Solution.- D. Present Status of Classification of Adrenoceptors.- I. General Comments.- II. ?-Receptors.- 1. The Proposal for Two Types - ?1 and ?2.- 2. Evidence for Multiple Sub-types of ?-Receptors.- III. a-Receptors.- IV. Conclusions.- References.- 10: Classification of Sympathomimetic Amines.- I. Introduction.- II. The Mode of Action of Tyramine.- III. Experimental Approaches to the Classification.- a) Cocaine.- b) Denervation.- c) Pretreatment with Reserpine.- IV. Factors Determining the Magnitude of Direct and of Indirect Effects.- 1. Affinity of ?-and ?-Receptors.- 2. The Morphology of the Synaptic Region.- 3. Affinity to the Membranal Uptake Mechanism.- 4. Role of Intraneuronal MAO.- 5. Affinity to Vesicular Uptake Mechanisms.- 6. Affinity to Vesicular Binding Sites.- V. Various Agents with Indirect Actions.- a) Aliphatic Amines.- b) Aldehydes.- c) ?-Receptor Blocking Agents.- d) Cocaine.- e) Methylphenidate.- f) Adrenergic Neurone Blockers.- g) Noradrenaline-Depleting Agents.- h) Monoamine Oxidase Inhibitors.- i) Nicotine Agents.- k) 5-Hydroxytryptamine.- 1) 6-Hydroxydopamine.- VI. Conclusions.- References.- 11: Effects of Catecholamines on Metabolism.- A. Introduction.- B. Effects of Catecholamines on Metabolism and Function of Individual Tissues.- I. Liver.- a) Adenyl Cyclase.- b) cAMP-dependent Protein Kinases.- c) Glycogen Cycle.- d) Gluconeogenesis.- e) Lipid Metabolism.- f) Protein Synthesis.- g) Ion Movements.- h) Summary: Effects of Catecholamines on Liver.- II. White Adipose Tissue.- 1. Events at the Cell Membrane.- a) Functional Components of the Cell Membrane.- b) The Nature of the Adrenergic Receptor.- 2. Events Occurring Intracellularly.- a) Known Effects of cAMP on White Adipose Tissue.- ?) Triglyceride Lipase 387 - ?) Phosphofructokinase 388 - ?) Enzymes of the Glycogen Cycle 388 - ?) Protein Kinases.- b) Metabolic Consequences of the Action of Catecholamines on White Adipose Tissue.- III. Cardiac Muscle.- a) Adenyl Cyclase.- b) Effects of cAMP on Cardiac Muscle Enzymes.- ?) Enzymes of the Glycogen Cycle 393 - ?) Enzymes of Glycolysis 394 - ?) Enzymes of Lipolysis 394 - ?) Protein Kinases.- c) Relation of the Inotropic Response to cAMP Formation.- d) Summary: Metabolic Consequences of the Action of Catecholamines on the Heart.- IV. Skeletal Muscle.- a) Adenyl Cyclase.- b) Effect of cAMP on Skeletal Muscle Enzymes.- ?) Enzymes of the Glycogen Cycle 401 - ?) Enzymes of Glycolysis 402 - ?) Enzymes of Lipolysis.- c) Relation of Effect of Catecholamines on Contraction of Skeletal Muscle to cAMP Formation.- d) Regulation of Metabolic Processes in Skeletal Muscle.- V. Smooth Muscle.- a) Adenyl Cyclase.- b) Effect of cAMP on Smooth Muscle Enzymes.- c) Relation of Effects of Catecholamines on Contraction and Relaxation of Smooth Muscle to cAMP Formation.- VI. Brown Adipose Tissue.- a) Events at the Cell Membrane.- b) Changes in Lipid and Carbohydrate Metabolism.- c) Respiratory Processes.- d) Ultrastructural Changes and Growth.- e) Contribution of the Brown Adipose Tissue to Heat Production in Intact Animals.- f) Summary: Thermogenic and Endocrine Functions of the Brown Adipose Tissue.- VII. ?-Cells of Pancreatic Islets.- Adenyl Cyclase.- Effects of Changes in Adenyl Cyclase Activity on the Secretion of Insulin.- Role of Catecholamines in the Regulation of Insulin Secretion in Intact Animals.- VIII. Salivary Glands.- a) Adenyl Cyclase.- b) Metabolic Changes Associated with the Secretion and Resynthesis of Amylase.- c) Metabolic Changes Associated with the Catecholamine-Induced Growth of Salivary Glands.- IX. Brain.- a) Adenyl Cyclase.- b) Metabolic Consequences of the Formation of cAMP in Brain.- X. Pineal Gland.- a) Adenyl Cyclase.- b) cAMP and Enzymes of the Pineal Gland.- c) Effects of Noradrenaline and/or cAMP on Pathways of Indolalkylamine Metabolism in Pineal Gland.- d) Relation of Metabolic Effects of Noradrenaline to Regulation of Pineal Gland Function.- e) Summary: Regulation of Metabolic Processes in the Pineal Gland by Catecholamines.- XI. Tissues which Contain Unusual Adenyl Cyclases.- a) Red Blood Cells.- b) Tumour Cells.- c) Kidney Cortex and Medulla.- d) Toad Bladder.- e) FrogSkin.- C. Effects of Catecholamines on Metabolism of Intact Animals.- I. Mobilization of Energy Reserves.- a) Hyperglycemic Effect.- b) Fat-mobilizing Effect.- II. Calorigenic Effect.- D. Concluding Remarks.- I. Metabolic Effects of Catecholamines.- II. Nature of Adrenergic Receptors for Metabolic Effects of Catecholamines.- References.- 12: Central Actions of Catecholamines.- I. Introduction.- II. Blood-Brain and Cerebrospinal Fluid-Brain Barriers.- 1. Blood-Brain Barrier.- 2. Cerebrospinal Fluid-Brain Barrier.- III. Uptake, Storage and Release of Catecholamines and Catecholamine Precursors.- IV. Effect of Catecholamines on Innate Behaviour and Cerebral Electrical Activity.- 1. Catecholamines as Central Depressants.- a) Intracisternal Injection.- b) Intraventricular Injection.- c) Injections into the Brain Substance.- d) Intravenous Injections in Immature Animals.- 2. Catecholamines as Central Excitants.- a) Intact Animals.- b) Encephale isole Preparations and Curarized Animals.- V. Effect of Catecholamines on Learnt Behaviour.- a) Classical Conditioning.- b) Instrumental Conditioning.- c) Operant Conditioning.- VI. Effect of Catecholamines on Body Temperature.- 1. Mice.- Intraventricular Injection.- 2. Rats.- a) Intraventricular and Intracisternal Administration.- b) Intracerebral Injection.- 3. Rabbits.- a) Intraventricular Administration.- b) Intracerebral Administration.- 4. Cats.- a) Intraventricular Administration.- b) Intracerebral Injection.- 5. Dogs.- Intraventricular Administration.- 6. Sheep.- Intraventricular Administration.- 7. Goats.- Intraventricular Administration.- 8. Oxen.- Intraventricular Administration.- 9. Monkeys.- a) Intraventricular Administration.- b) Intracerebral Administration.- 10. Chicks.- a) Intravenous or Intraventricular Administration.- b) Intracerebral Administration.- 11. Discussion.- VII. Effect of Catecholamines on Food and Water Intake.- Relations of Temperature Regulation to Food and Water Intake.- VIII. Oxygen Consumption.- IX. Shivering, Tremor and Electromyographic Activity.- X. Effect of Catecholamines on Central Control of Blood Pressure.- XI. Drugs Affecting Catecholamine Synthesis, Storage, Release and Metabolism.- 1. Monoamine Precursors and Inhibitors of DOPA Decarboxylase.- a) Mechanism of Action.- b) Behaviour, Temperature and Electrocortical Activity.- 2. Inhibitors of Monoamine Storage.- a) Mechanism of Action.- b) Behaviour and Electrocortical Activity.- c) Conclusion.- 3. Inhibitors of Monoamine Uptake.- a) Mechanism of Action.- b) Behaviour, Temperature and Electrocortical Activity.- 4. Inhibitors of Tyrosine Hydroxylase.- a) Mechanism of Action.- b) Behaviour.- 5. Inhibitors of Dopamine ?-Hydroxylase.- a) Mechanism of Action.- b) Behaviour, Temperature and Electrocortical Activity.- 6. Inhibitors of Monoamine Oxidase.- a) Mechanism of Action.- b) Behaviour, Temperature and Electrocortical Activity.- 7. Inhibitors of Catechol-O-Methyl Transferase.- a) Mechanism of Action.- b) Behaviour.- XII. Antagonism.- 1. Electrocortical Activity and Innate Behaviour.- 2. Learnt Behaviour.- 3. Body Temperature.- 4. Food and Water Intake.- 5. Blood Pressure.- XIII. Structure - Activity Studies.- 1. Innate Behaviour and Cerebral Electrical Activity.- a) Intracisternal Injection.- b) Intraventricular and Intracerebral Injections.- c) Intravenous Injection.- 2. Learnt Behaviour.- 3. Temperature.- Effects of Catecholamines on Spinal Cord Reflexes.- 1. Effects of Catecholamines.- a) Extensor Reflexes.- b) Flexor Reflexes.- 2. Reserpine.- 3. Inhibitors of Monoamine Oxidase.- 4. Catecholamine Antagonists.- 5. Monoamine Precursor.- XV. Conclusions.- References.- 13: Fundamental Mechanisms in the Release of Catecholamines.- A. Origin of Catecholamines Released from the Cell.- I. Localisation of the Catecholamine Store.- 1. In the Adrenal Medulla.- a) Is there an Extragranular Store of Catecholamines ?.- b) Heterogeneity of the Particulate Store of Catecholamines.- c) Conclusions.- 2. In the Sympathetic Nerves.- II. Type of Binding in the Store: its Relation to the Mechanism of Release.- Possible Modes of Release of Catecholamines from the Store.- III. Fate of Components of the Store Following Stimulation: Biochemical Evidence of Exocytosis in the Adrenal Medulla.- 1. Fate of the Adenine Nucleotides.- 2. Fate of the Soluble Proteins (Chromogranins) of Chromaffin Granules.- 3. Fate of the Insoluble Proteins and Lipids of Chromaffin Granules.- 4. Correlation of the Biochemical Evidence with Ultrastructural Observations.- a) Further Permeability Barriers.- b) Resting Secretion.- IV. The Role of Noradrenergic Vesicles in the Release of Catecholamines from Sympathetic Neurons: Evidence that Some of the Neurotransmitter Is Released by Exocytosis.- 1. Quantal Release of Noradrenaline.- 2. Amount of Noradrenaline Released per Stimulus.- 3. Failure of Nerve Impulses to Release Noradrenaline Stored in the Cytosol..- 4. Release of False Adrenergic Transmitters.- 5. Release of Proteins from Noradrenergic Vesicles upon Stimulation of the Splenic Nerve.- a) What is the Origin of the Released Proteins ?.- b) How are the Proteins Released from the Nerve ?.- 6. Hypothesis: Exocytosis from Large Dense-Cored Vesicles.- 7. Exocytosis from All Vesicles, or Only from Some ?.- B. Subcellular and Molecular Mechanisms of Exocytosis.- I. The Cell Membrane as the Site of Stimulus-Secretion Coupling.- 1. Cholinoceptors.- 2. Depolarization.- 3. Entry of Calcium.- 4. Attachement of the Vesicle to the Plasma Membrane.- What Can we Conclude About the Role of Calcium ?.- 5. Membrane Fusion.- What is the Function of Lysolecithin in Chromaffin Granules ?.- 6. Release by Diffusion, or by Active Expulsion, of Vesicle Contents ?..- 7. Membrane Fission.- II. Subcellular Dynamics of Catecholamine-Containing Vesicles.- 1. Chromaffin Cell.- a) Origin of the Chromaffin Granules.- b) Transport of the Chromaffin Granules.- c) Ultimate Fate of the Chromaffin Granules.- 2. Sympathetic Neuron.- a) Origin of Noradrenergic Vesicles.- b) Transport of Noradrenergic Vesicles.- c) Fate of Large Dense-Cored Vesicles.- C. Conclusions.- References.- 14: Adrenergic False Transmitters.- I. Introduction.- II. Survey of Amines Acting as False Transmitters.- 1. Structural Requirements for Formation and Metabolism.- 2. Retention, Storage and Uptake.- 3. Stereochemical Considerations.- III. Formation of False Transmitters.- 1. Direct Incorporation of an Amine as False Transmitter.- 2. Formation of False Transmitters from Foreign Precursors.- a) Formation by a Single Metabolic Step.- b) Formation of False Transmitters by Several Metabolic Steps.- 3. Formation of False Transmitters by Inhibition of Enzymes Involved in Biosynthesis and Metabolism of Catecholamines.- IV. Release of False Transmitters.- 1. Spontaneous Release ("Leakage") of False Transmitters.- 2. Release of False Transmitters by Nerve Stimulation.- 3. Release of False Transmitters by Nicotinic Agents.- 4. Release of False Transmitters by Indirectly Acting Amines.- V. Consequences of Incorporation of False Transmitters.- 1. Depletion of Noradrenaline.- 2. Effects on Noradrenaline Synthesis.- 3. Diminished Release of Noradrenaline by Sympathetic Nerve Stimulation.- 4. Differential Depletion of Noradrenaline and False Transmitters by Reserpine and Guanethidine.- 5. Altered Sensitivity Towards Exogenous Noradrenaline.- VI. Consequences of Combined Release of Noradrenaline and False Transmitters.- 1. Effect of False Transmitters on Adrenoceptors.- 2. Effect of False Transmitters on Re-uptake of Amines.- 3. Interactions of Noradrenaline and False Transmitters at Adrenoceptors.- References.- 15: Electrophysiology of the Adrenergic Neuron.- I. The Problem of Identifying Adrenergic Neurons in Electrophysiological Investigations.- II. Electrophysiological Techniques Used for the Study of Adrenergic Neurons.- 1. Intraganglionic Part: Soma and Dendrites (SD1), Axon Hillock and Initial Segment (IS).- a) Extracellular Techniques.- b) Intracellular Recording.- 2. Non-terminal Axon.- 3. Axon Terminals.- III. Electrophysiological Properties of the Adrenergic Nerve Cell Body.- 1. The Resting Neuron.- ?) Resting Membrane Potential.- ?) Electric Time Constant.- ?) Cell Resistance.- ?) Specific Membrane Capacitance.- ?) Delayed Rectification.- 2. Direct Excitation.- 3. The Invasion of the Adrenergic Nerve Cell Body by Antidromic Impulses.- 4. Synaptic Excitation.- a) The Fast Excitatory Postsynaptic Potential (EPSP).- b) The Orthodromic Ganglionic Action Potential.- c) Slow Synaptic Potentials.- d) Ganglionic Transmission through Muscarinic Receptors and Slow Synaptic Potentials.- e) Post-activation Phenomena.- f) Patterns of Innervation and Integrative Activity of Adrenergic Neurons..- 5. Changes of Electrical Properties of Adrenergic Ganglion Cells Following Denervation and Axotomy.- IV. Electrical Properties of the Adrenergic Cell Axon.- 1. Conduction Velocity.- 2. Action Potential.- 3. Posttetanic Hyperpolarization.- 4. Possible Interaction of Neighbouring Fibres During Activity.- V. Electrical Properties of the Adrenergic Nerve Terminals; Electrical Events Involved in Transmitter Release.- 1. Invasion of the Terminal Varicosities by the Action Potential.- 2. Electrosecretory Coupling at Adrenergic Nerve Endings.- 3. Facilitated Transmitter Release and Hyperpolarizing Afterpotential.- 4. Posttetanic Changes in Adrenergic Nerve Endings.- VI. Electrical Changes Induced in the Adrenergic Neuron by Various Chemical Agents.- 1. Cholinoceptors.- a) Nicotinic Receptors.- ?) Som6a-dendritic Part 695 - ?) Axonal Part 703 - ?) Terminal Part.- b) Muscarinic Inhibitory Receptors.- ?) Soma-dendritic Part 704 - ?) Axonal Part 705 - ?) Terminal Part.- c) Muscarinic Excitatory Receptors.- ?) Soma-dendritic Part 705 - ?) Axonal Part 706 - ?) Terminal Part.- d) Interaction Between Nicotinic and Muscarinic Receptors.- 2. Adrenoceptors of the Adrenergic Neuron.- 3. 5-Hydroxytryptamine (5-HT)-Receptors.- 4. Histamine Receptors.- 5. Polypeptides.- 6. Amino Acids.- 7. Prostaglandins.- 8. Tetraethylammonium (TEA).- 9. Local Anaesthetics and Tetrodotoxin.- 10. Adrenergic Neuron Blocking Agents.- 11. Veratrum Alkaloids.- Concluding Remarks.- Abbreviations.- References.- 16: Factors Influencing the Concentration of Catecholamines at the Receptors.- I. Introduction.- II. Methods.- III. Morphological Relation between Adrenergic Nerve Endings and Effector Cells.- a) The Neuro-muscular Interval.- b) The Density of Adrenergic Innervation.- IV. The Role of Neuronal Uptake.- a) Surgical Denervation.- b) Chemical Denervation.- c) Immunosympathectomy.- d) Cocaine.- e) Sympathomimetic Amines.- f) Supersensitivity Induced by Nerve Stimulation.- g) Reserpine.- h) Conclusions.- V. The Importance of Vesicular Uptake and of Monoamine Oxidase for the Net Uptake across the Neuronal Membrane.- VI. Saturation of Neuronal Uptake.- a) Slopes of Dose-Response Curves.- b) The Apparent Potency of Competitive Antagonists.- c) Stereospecificity of Cocaine Supersensitivity.- d) The Magnitude of Decentralization Supersensitivity.- e) Conclusions.- VII. The Role of Extraneuronal Uptake.- VIII. The Role of Catechol-O-methyl Transferase.- IX. The Role of Monoamine Oxidase.- X. The Concentration of Transmitter at the Receptors after its Release from Adre-nergic Nerves.- XI. Supersensitivity versus Additive Effects.- XII. Conclusions.- References.- 17: Interrelationships between Adrenergic and Cholinergic Mechanisms.- A. Effect of Acetylcholine on Adrenergic Nerve Terminals.- I. Introduction.- II. Presence of Cholinergic Fibres in Mammalian Sympathetic Nerves.- III. Cholinergic Link Hypothesis.- 1. Effects of Acetylcholine and Nicotine on Sympathetically Innervated Effector Organs.- 2. Effects of Acetylcholine on the Responses to Electrical Stimulation of Sympathetic Nerves.- 3. Effects of Hemicholinium on the Responses to Stimulation of Sympathetic Nerves.- 4. Effects of Sympathetic Denervation on Choline Acetyltransferase Content..- 5. Effects of Botulinum Toxin on the Response to Stimulation of Sympathetic Nerves.- 6. Effects of Anticholinesterases on the Responses to Stimulation of Sympathetic Nerves and on Release of Noradrenaline.- 7. Effects of Acetylcholine and Other Cholinomimetic Compounds on the Release of Noradrenaline.- 8. Effects of Dimethylphenylpiperazinium on the Responses to Stimulation of Sympathetic Nerves and on the Release of Noradrenaline.- 9. Effects of Adrenergic Neurone Blocking Agents on the Responses of Sympathetic Neuroeffectors to Acetylcholine or Nerve Stimulation and on the Release of Noradrenaline.- IV. Morphological and Physiological Evidence for an Interaction between Cholinergic and Adrenergic Nerve Terminals.- V. The Role of Ca2+ for the Noradrenaline-Releasing Effect of Acetylcholine on Adrenergic Nerve Terminals.- VI. Conclusions.- B. Effects of Catecholamines on Cholinergic Nerve Terminals.- I. Effects on Transmission in Autonomic Ganglia.- 1. Introduction.- 2. Intraganglionic Location of Catecholamine-containing Structures.- a) Electron Microscopic Evidence.- b) Histochemical Evidence.- 3. Mode of Action of Catecholamines on Ganglionic Transmission.- II. Effects of Catecholamines on the Output of Acetylcholine in the Small and Large Intestines.- III. Effects on Transmission at the Neuromuscular Junction.- 1. Introduction.- 2. Direct Effects on Muscle.- 3. Effects on Neuromuscular Transmission.- 4. Electrophysiological Analysis of Junctional Effects.- References.- 18: Surgical, Immunological and Chemical Sympathectomy. Their Application in the Investigation of the Physiology and Pharmacology of the Sympathetic Nervous System.- I. Introduction.- II. Surgical Sympathectomy.- III. Immunosympathectomy.- IV. Chemical Sympathectomy.- V. Comparison between Surgical, Immunological, and Chemical Sympathectomy.- VI. Compensatory Mechanism.- VII. Concluding Remarks.- References.- 19: Catecholamine Synthesis and Metabolism in Man: Clinical Implications (With Special Reference to Parkinsonism).- I. Introduction.- II. Parkinsonism.- 1. Anatomical Considerations.- a) Man.- b) Animal Models.- 2. Aetiological Factors.- a) Idiopathic.- b) Postencephalitic.- c) Arteriosclerotic.- d) Toxic.- 3. Biochemical Considerations.- a) Tyrosine Hydroxylase.- b) DOPA.- c) L-DOPA Decarboxylase.- d) Dopamine.- e) Melanin Formation.- f) Catechol-O-methyltransferase.- g) Monoamine Oxidase.- h) Conjoint Pathway Metabolites.- III. L-DOPA Treatment of Parkinsonism.- 1. Response of Different Clinical Subgroups.- a) Idiopathic Parkinsonism.- b) Postencephalitic Parkinsonism.- c) Drug-induced Parkinsonism.- d) Manganism.- e) Miscellaneous Diseases.- 2. L-DOPA plus Peripheral Decarboxylase Inhibitor.- 3. Major Side-effects of L-DOPA Treatment.- a) Nausea and Vomiting.- b) Hypotension.- c) Adventitious Movements.- d) Psychiatric Aspects.- e) Sexual Aspects.- f) Drug Incompatibilities.- IV. Other Treatments of Parkinsonism in Relation to Catecholamine Metabolism.- a) Surgery.- b) Amantadine.- c) Anticholinergic Drugs.- L-DOPA Treatment: Metabolic Pathway Considerations.- 1. Compartmental Factors.- 2. Brain Dopamine.- 3. Urinary Metabolite Pattern.- 4. N-Acetylation: Possible Enterohepatic Circulation.- 5. The Role of Transamination.- 6. The Special Properties of 3-O-methylDOPA.- 7. p-Dehydroxylation: The Role of Gut Flora.- 8. Interrelationship with 5-Hydroxytryptamine.- VI. Some Further Problems.- References.- 20: Phaeochromocytoma and Other Catecholamine-Producing Tumours.- I. Introduction.- II. Phaeochromocytomas and Phaeochromoblastomas.- 1. Occurrence.- 2. Synthesis and Metabolism of Catecholamines in Tumours.- a) Synthesis of Catecholamines.- b) Metabolism of Catecholamines.- 3. Storage of Catecholamines in Tumours.- a) Tissue Content of Catecholamines and Metabolites.- b) Isolation of Chromaffin Granules from Phaeochromocytoma.- c) Properties of Chromaffin Granules from Phaeochromocytoma.- d) Electron-Microscopical Observations.- 4. Release of Catecholamines from Phaeochromocytomas.- a) Clinical Biochemistry.- ?) Plasma Catecholamines 911 - ?) Urinary Catecholamines and Metabolites 912 - ?) Biochemical Aspects of Malignancy.- b) Mechanism of Release of Amines from Phaeochromocytoma.- ?) Drug-induced Release of Catecholamines 914 - ?) Cellular Mechanisms.- III. Neuroblastomas and Ganglioneuromas.- 1. Synthesis of Catecholamines in Tumours.- 2. Metabolism of Catecholamines in Tumours.- 3. Storage of Catecholamines in Tumours.- a) Tissue Content of Catecholamines and Metabolites.- b) Isolation of Storage Organelles.- c) Microscopical Observations.- 4. Release of Catecholamines and Related Substances.- IV. Tumours of the Carotid Body and Related Structures.- V. Conclusion.- References.- Author Index.