Main description:

Catecholamines 1922 -1971 H. BLASCHKO Adrenaline and related substances were discussed in the 1924 edition of Hefl'ter's Handbook by PAUL TRENDELENBURG. On 164 pages he described what was then known not only of adrenaline and its closest relatives but also of the sympathomimetic compounds such as tyramine and ephedrine. When the present Editors of the Handbook entrusted us with the task of editing the present Volume it was decided to restrict it to adrenaline and the other naturally occurring catecholamines. The sympathomimetic amines in general will be discussed only in their relation to the catecholamines. Since TRENDELENBURG completed his review this field has undergone an enormous expansion. There has been a wealth of new findings, and a succession of new ideas. The new theories that have been built into contemporary thought will be fully discussed in the succeeding contributions. But many of the hypotheses that have been put forward since 1924 have long been discarded and yet, they have often led to important observations that we still consider as valid.

Contents:

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 DegreesC.- 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.