Primer on the Autonomic Nervous System (eBook)

Front Cover 1
Primer on the Autonomic Nervous System 4
Copyright Page 5
Contents 6
Preface 20
List of Contributors 22
I. Introduction 28
1 Development and Differentiation of Autonomic Neurons 30
Introduction 30
The ANS is Derived from Neural Crest Cells 30
Signaling Molecules Regulate the Developmental Processes of the ANS 30
Transcriptional Regulatory Code Underlying the Development and Phenotypic Specification of the ANS 31
Mash1 (also called Cash1) 31
Phox2 Genes 32
GATA3 32
AP2(Activator Protein 2)ß 32
Other Transcription Factors 33
Neurotransmitter Phenotypes of the ANS 33
NA Phenotype 33
Control Mechanism of DBH Gene Expression is Closely Related to the ANS Development 33
Mutations of DBH Gene are Closely Associated with the Autonomic Disorder, Orthostatic Hypotension 33
Cholinergic Phenotype and the Switch of Neurotransmitter Phenotypes by Target Cell Interactions 34
Acknowledgements 34
References 34
2 Central Autonomic Control 36
Forebrain Components 36
Insular Cortex 36
Anterior Cingulate Cortex 36
Amygdala 36
Hypothalamus 36
Brainstem Components 37
Periaqueductal Gray 37
Parabrachial Complex and Adjacent Regions of the Pons 38
Nucleus of the Solitary Tract 38
Rostral Ventrolateral Medulla 38
Caudal Ventrolateral Medulla 38
Ventromedial Medulla and Caudal Raphe 38
Autonomic Output of the Central Nervous System 38
Sympathetic Preganglionic Units 38
Parasympathetic Outputs 38
Vagal Output 39
Sacral Parasympathetic Output 39
References 39
3 Imaging of Brainstem Sites Involved in Cardiovascular Control 40
Identification of Medullary Cardiovascular Nuclei in Experimental Animals 40
Identification of Medullary Cardiovascular Nuclei in Humans 40
References 43
4 Peripheral Autonomic Nervous System 44
Sympathetic Nervous system (See Fig. 4.1) 44
Sympathoadrenal Axis and the Adrenal Gland 47
Parasympathetic Nervous System (See Fig. 4.1) 48
The Concept of Plurichemical Transmission and Chemical Coding 49
Visceral Afferent Neurons and Autonomic Nervous System 50
Functional Neuroanatomy and Biochemical Pharmacology 51
Stress and Autonomic Dysfunction 52
References 52
Further Reading 53
5 Cotransmission 54
Early Studies 54
Sympathetic Nerves 54
Parasympathetic Nerves 55
Sensory-Motor Nerves 56
Enteric and Cardiac Nerves 56
Physiological Significance of Cotransmission 57
Cotransmitters with Different Firing Patterns 57
Different Cotransmitters act on Different Postjunctional Cells 57
Neuromodulation 57
Synergism 58
Negative Cross-Talk 59
Trophic Factors 59
Excitatory and Inhibitory Cotransmitters 59
False Cotransmitters 59
Coexisting Peptides Acting as Neuromodulators 59
Cotransmitter Plasticity 59
Concluding Comments 59
References 60
II. Biochemical and Pharmacological Mechanisms 62
6 Noradrenergic Neurotransmission 64
Catecholamines, and Catechols 64
Noradrenergic Innervation of the Cardiovascular System 64
Norepinephrine: the Main Sympathetic Cardiovascular Neurotransmitter 65
Norepinephrine Synthesis 65
Norepinephrine Storage 65
Norepinephrine Release 66
Norepinephrine Disposition 66
Norepinephrine Metabolism 68
Biomarkers of Sympathetic Noradrenergic Innervation and Function 69
NE and Metabolomics 69
Differential Noradrenergic vs. Adrenergic Activation in Stress 69
Further reading 70
7 Tyrosine Hydroxylase 72
Introduction 72
Diversity of Human TH Gene Expression 72
Congenital Disease Associated with TH Mutation 73
Gene Therapy with TH Gene Function 73
Conclusion 74
References 74
8 Antidepressant-Sensitive Norepinephrine Transporters: Structure and Regulation 76
Acknowledgements 77
References 77
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& #945
Structure of & #945
Ligand Binding and Activation of & #945
Function of & #945
Signaling of & #945
Regulation of & #945
Acknowledgements 81
References 81
10 & #945
Pharmacology and functions of & #945
& #945
Regulation by Interacting Proteins 83
& #945
Acknowledgement 85
Further Reading 85
11 & #946
Introduction 86
& #946
& #946
Receptor Desensitization 87
Therapeutic Importance of & #946
Genetic Variability in & #946
ADRB1 88
ADRB2 88
ADRB3 88
Acknowledgement 88
References 88
12 Dopaminergic Neurotransmission 90
Further Reading 92
13 Dopamine Receptors 94
Introduction 94
Distribution and Expression of Dopamine Receptors 94
Central Nervous System 94
Autonomic Nervous System 94
Dopamine Receptor Structure 94
Gene Structure 94
Receptor Structure 95
Dopamine Receptor Function: Signal Transduction Pathways 96
G Protein Dependent Signaling 96
Signal Regulation 96
ß-Arrestin Dependent Signaling 96
Oligomerization 96
Dopamine Receptor Pharmacology 96
Ligand Specificity 96
Functional Selectivity 96
References 97
14 Cholinergic Neurotransmission 98
Acetylcholine Biosynthesis and Metabolism 98
Acetylcholine Receptors 98
Cholinergic Pharmacologic Agents 99
Further Reading 100
15 Acetylcholine and Muscarinic Receptors 102
Cholinergic Neurotransmission: Sites and Receptors 102
Muscarinic Agonists 103
Muscarinic Antagonists 104
Further Reading 104
16 Nicotinic Receptors 106
Structural Considerations 106
Subtype Diversity of Nicotinic Receptors 106
Electrophysiologic Events Associated with Receptor Activation 107
Distribution of Nicotinic Receptors 108
References 109
17 Serotonin Receptors and Neurotransmission 110
Localization 110
Synthesis and Metabolism 110
Neurotransmission 110
Receptors 111
Pharmacology and Role in Disease 112
Role in Autonomic Processes 112
References 113
18 Purinergic Neurotransmission and Nucleotide Receptors 114
Purinergic Neurotransmission 114
Receptors for Purines and Pyrimidines 116
P2X Receptors 117
P2Y Receptors 117
Conclusions 119
References 119
19 Adenosine Receptors and Autonomic Regulation 122
Postsynaptic Anti-Adrenergic Effects of Adenosine 122
Presynaptic Effects of Adenosine on Efferent Nerves and Ganglionic Transmission 122
Adenosine and Central Autonomic Regulation 123
Neuroexcitatory Actions of Adenosine on Afferent Pathways 123
Integrated View of Adenosine and Cardiovascular Autonomic Regulation 123
References 124
20 Nitric Oxide and Autonomic Regulation 126
No Synthesis and Actions 126
Central No–Autonomic Nervous System Interactions 126
No–Autonomic Nervous System Interactions in The Periphery 127
No–Autonomic Nervous System Interactions in Heart Rate Control 128
References 128
21 Glutamatergic Neurotransmission 130
Synthesis and Vesicular Release 130
Receptors 131
Clearance of Glutamate 132
Glutamate Metabolism 132
Glutamate in the Autonomic Nervous System 132
Summary 133
References 134
22 GABAergic Neurotransmission 136
Overview of GABA Mediated Signaling 136
GABA Responses are Mediated by Both Ionotropic and Metabotropic Receptors 136
GABAA Receptors Mediate Multiple Modes of Neuronal Signaling 136
Neurotransmission is Mediated by a Diverse Set of GABAA Receptor Subtypes 137
Subtype Preferring Drugs Allow for Selective modulation of GABA Signaling 137
References 138
23 Renin-Angiotensin 140
Introduction 140
The Classical RAS 140
Components and Features of the Classical RAS 140
Recent Advances in the Classical RAS 140
The Classical RAS and Autonomic Regulation 140
The Brain RAS 141
Components of the Brain RAS 142
Influence of the Brain RAS on Autonomic Regulation 142
Summary 143
Acknowledgement 143
References 143
24 Aldosterone and the Mineralocorticoid Receptor 144
Effects of Aldosterone That Target Distal Nephron 144
Specificity of MR for Aldosterone Role of 11-ß-Hydroxysteroid Dehydrogenase Type II (11BHSD2)
Excess Aldosterone and the Development of Hypertension 144
Low-Renin Hypertension but not Primary Aldosteronism 145
Aldosterone as a Mediator of Tissue Injury 146
References 146
25 Vasopressin and Disorders of Water Homeostasis 148
Vasopressin Secretion 148
Vasopressin Actions 148
Disorders of Body Water Homeostasis 149
Hypoosmolality 149
Decreased ECF Volume (Hypovolemia) 150
Normal ECF Volume (Euvolemia) 150
Increased ECF Volume (Hypervolemia) 150
Hyperosmolality 151
Diabetes Insipidus 151
Osmoreceptor Dysfunction 151
Disorders of Water Homeostasis and the Autonomic Nervous System 152
Further Reading 152
26 Calcitonin Gene-Related Peptide and Adrenomedullin 154
Introduction 154
Synthesis and Localization of CGRP and AM 154
Release of CGRP from Sensory Nerve Terminals 154
CGRP and AM Signaling 155
Attenuation of Oxidative Stress by CGRP and AM 155
Attenuation of Inflammation by CGRP And AM 155
Inhibition of Apoptosis by CGRP and AM 156
Conclusion 156
Further Reading 156
27 Leptin Signaling and Energy Homeostasis 158
Introduction 158
Leptin Receptor 158
Intracellular Mechanisms Associated with the Leptin Receptor 158
Sites of Leptin Action in the Brain 159
Interaction of Leptin and Neuropeptides in the Hypothalamus 160
Melanocortin System 160
Neuropeptide Y 160
Other Mediators 161
Conclusion 161
References 161
28 The Endothelin System 162
Introduction: Endothelin System Components 162
Effects of PREPROet-1 or ET Receptor Gene Deletion 162
Mechanism of Action of ET 162
Pathophysiology of the Endothelin System in Experimental Models 163
Renal Effects of ET-1 163
Cardiac Effects of ET-1 163
ET-1 in Essential Hypertension 163
Molecular Genetics of the Endothelin System 164
Endothelins and the Nervous System 164
Conclusion 165
Acknowledgements 165
References 165
29 Pharmacology of the Nucleous Tractus Solitarii 168
Nucleus Tractus Solitarii 168
Cardiovascular Effects of No in the NTS 168
Cardiovascular Effects of Adenosine in the NTS 169
Cardiovascular Effects of Insulin in the NTS 169
Cardiovascular Effects of Angiotensin II in the NTS 169
Conclusion 170
References 170
III. Autonomic Physiology 172
30 Entrainment of Sympathetic Rhythms 174
Sympathetic Rhythm 174
Cardiac- and Respiratory-related Rhythms 174
Mechanisms Underlying Rhythms 174
Phasic Inputs Generate Rhythms 174
Entrainment of Rhythms 174
How Many Central Oscillators? 175
The Spinal Cord and Sympathetic Rhythms 175
Functional Significance 175
References 176
31 Cross-talk Between Body Systems: Respiratory-Cardiovascular Coupling in Health and Disease 178
Introduction 178
Cardiovascular Autonomic Activity: Coupling to the Respiratory Pattern Generator 178
Why is the Circulatory System Respiratory-Modulated? 179
RSA 179
HFO 180
Cardiovascular Disease: Opposite Effects on RSA and HFO 180
RSA 180
HFO 181
Cardiovascular Modulation of Respiratory Activity 181
New Horizons 181
References 181
32 Circadian Rhythms and Autonomic Function 184
SCN Output and Autonomic Control 184
Circadian and Sleep-Control of the Autonomic Nervous System 185
Cardiac Events and Circadian Rhythms 186
Further Reading 186
33 Baroreceptor Reflexes 188
Neural Pathways and Effector Mechanisms 188
Arterial Baroreflex 188
Cardiopulmonary Baroreflex 188
Determinants of Afferent Baroreceptor Activity 188
Rate Sensitivity of Baroreceptors 188
Large Artery Compliance 190
Neuronal Mechanisms Mediating Sensory Transduction 190
Baroreflex Adaptation and Resetting in Acute Hypertension 190
Decreased Baroreflex Sensitivity in Disease 190
Control of HR vs. SNA and BP, and Underlying Mechanisms 190
Genetic Determinants of BRS 191
BRS: A Determinant of Cardiovascular Risk and Therapeutic Target 191
Decreased BRS and Cardiovascular Risk 191
BRS is a Therapeutic Target 191
Further Reading 192
34 Genetic Determinants of Baroreflex Function 194
References 196
35 Cardiac and Other Visceral Afferents 198
Introduction 198
Anatomical Framework 198
Afferent Stimuli 198
Ischemia 198
Autonomic Reflex Responses to Visceral Afferent Activation 200
Pathological Alterations of Visceral Afferents 201
Acknowledgments 202
References 202
36 Autonomic Control of the Heart 204
Introduction 204
The Heart 204
Autonomic Nervous Control 205
Control of the Heartbeat 206
Altered Autonomic Control 206
References 207
37 Cardiac Vagal Ganglia 208
The Vertebrate Nervous System 208
The Cardiac Conduction System 208
Anatomy of the Cardiac Vagal Ganglia 208
Atrial Ganglionated Plexuses 209
Ventricular Ganglionated Plexuses 209
The Autonomic Nervous System 210
References 212
38 Neural Control of Blood Vessels 214
Autonomic Vasomotor Control and Cardiovascular Homeostasis 214
Sympathetic Component of Autonomic Vasomotor Control 215
Neuroeffector Junction 215
Sympathetic Neurotransmitters 215
Neurotransmitter Release and Effector Action 216
Parasympathetic Component of Autonomic Vasomotor Control 216
Differential Vasomotor Control 217
Modulation of Adrenergic Vasoconstriction 218
Further Reading 218
39 Physiology of Upright Posture 220
Introduction 220
Regulatory Mechanisms Involved in the Adjustments of the Human Body to Orthostatic Stress 220
Arterial Baroreceptors 220
Local Vasoconstrictor Mechanisms 221
Role of Capacitance Vessels to Orthostatic Reflex Adjustments 221
Role of Skeletal Muscle Pump 222
Humoral Mechanisms 222
Further Reading 222
40 Cerebral Circulation 224
Neurovascular Coupling 224
Regulation of Cerebral Circulation 224
Basic Considerations 224
Cerebral Autoregulation 224
Clinical Considerations 225
Role of Autonomic Innervation 226
References 226
41 Autonomic Control of the Lower Airways 228
Overview of Airway Innervation 228
Afferent nerves 228
Cholinergic Nerves 229
Cholinergic Efferents 229
Bronchodilator Nerves 229
Neuropeptides 230
Neural Control of Airways in Disease 230
References 231
42 Gastrointestinal Function 232
Salivary Secretion 232
Gastric Secretion 232
Pancreaticobiliary Secretion 232
Bile 232
Intestinal Secretion and Absorption 233
Control of Gut Motility 233
Normal Gastrointestinal Motor Function 235
References 236
43 The Splanchnic Circulation 238
Overview 238
Local Regulation 238
Effect of Splanchnic Circulation on Overall Circulatory Function 238
Sympathetic Control of the Splanchnic Circulation – General Features 238
Sympathetic Control of the Splanchnic Circulation in Special Circumstances 239
Sympathetic Control of the Splanchnic Circulation in Disease 239
References 240
44 Autonomic Control of the Kidney 242
Introduction 242
Innervation of the Kidney 242
Autonomic Receptors in the Kidney 242
Reflex Regulation of Blood Volume 244
The Renorenal Reflex 245
Autonomic Control of the Kidney in Pathophysiological States 246
References 247
45 Dopamine Mechanisms in the Kidney 248
Renal Dopamine (DA) Formation and Excretion 248
Renal DA Receptor Expression 248
Dopaminergic Regulation of Renal Na+ Excretion 249
D1-like Receptors 249
D2-like Receptors 249
Physiologic Interactions of the Renal Dopaminergic System and the Renin-Angiotensin System (RAS) 249
Renal DA and Hypertension 250
References 250
46 Autonomic Control of the Lower Urinary Tract 252
Introduction 252
Innervation 252
Parasympathetic Pathways 252
Sympathetic Pathways 253
Somatic Motor Pathways to the Urethral Sphincter 254
Central Neural Control 254
Neuropathology 254
Therapy 254
Further Reading 255
47 Bladder Function in Health and Disease 256
Structure of the Lower Urinary Tract 256
Properties of the Healthy Lower Urinary Tract 256
Clinical Evaluation 257
Clinical Conditions 257
Incontinence 257
Bladder Outlet Obstruction 259
Neurourology 259
Painful Bladder Syndrome 259
Conclusions 259
References 259
48 Physiology and Pathophysiology of Female Sexual Function 262
Physiology of the Female Sexual Response Cycle 262
Sexual Arousal 262
Afferent and Central Pathways 262
Neurotransmitters 263
Innervation of Female Sexual Function 263
Hormones Influencing Female Sexual Function 264
Common Etiologies of Female Sexual Dysfunction 264
Neurogenic Etiologies 264
Assessment of Female Sexual Dysfunction 264
Laboratory Investigation 265
Common Therapeutic Approaches in Female Sexual Dysfunction 265
References 265
49 Control of the Pupil 266
Parasympatholytic (Anticholinergic) Drugs 266
Parasympathomimetic (Cholinergic) Drugs 266
Sympathomimetic (Adrenergic) Drugs 267
Sympatholytic Drugs (Adrenergic Blockers) 267
Other Agents 267
Iris Pigment and Pupillary Response to Drugs 268
Pupil Sympathetic Defects 268
Pupil Parasympathetic Defects 269
Pupil Combined Sympathetic and Parasympathetic Defects 269
Acknowledgements 269
References 269
50 Central Thermoregulation 270
Cutaneous Thermal Receptor Afferent Pathway 270
Thermoregulatory Sensorimotor Integration in the Preoptic Area 271
Thermoregulatory Effector Drive from the Dorsomedial Hypothalamus 272
Rostral Raphe Pallidus Area Contains Premotor Neurons for Thermoregulatory Effectors 273
Spinal Sympathetic Mechanisms Controlling Thermal Effectors 273
Summary 273
References 273
51 Sweating 276
Introduction 276
Anatomy and Function of the Sweat Gland 276
Type 276
Density and Distribution 276
Physiology of Sweat Glands 276
Function 277
Innervation of Sweat Gland 277
Denervation 277
References 278
52 Regulation of Metabolism 280
Contribution of the Sympathoadrenal System to Components of Total Daily Energy Expenditure 280
Contribution of Sympathetically Stimulated Organs/Tissues to Resting Metabolic Rate 280
Mobilization/Utilization of Specific Macronutrients: Carbohydrate 280
Mobilization/Utilization of Specific Macronutrients: Lipid 280
Mobilization/Utilization of Specific Macronutrients: Protein 281
Role of the Sympathoadrenal System in the Dysregulation of Metabolism 282
References 282
53 Autonomic Innervation of the Skeleton 284
Bone Sympathetic Innervation: Ontogeny and Anatomy 284
Effect of Sympathetic Nerves on Bone Remodeling 284
Relevance to Bone Physiology and Diseases 285
References 286
54 Sex Differences in Autonomic Function 288
Introduction 288
Sex Differences in Normal Autonomic Function 288
Orthostatic Intolerance and Hypotension 289
Sex, Aging and Hypertension 290
Overall Summary and Conclusions 290
References 290
55 Autonomic Control During Pregnancy 292
Pregnancy Activates the Sympathetic Nervous System 292
Pregnancy Impairs the Baroreceptor Reflex 292
Mechanisms of Pregnancy-Induced Baroreflex Impairment 293
Preeclampsia 294
Summary and Conclusions 294
References 294
IV. Stress 296
56 Aging and the Autonomic Nervous System 298
Cardiac Baroreflex Function 298
Sympathetic Activity 299
Parasympathetic Activity 299
Integration of Autonomic Control Networks 299
Neurotransmitters 299
Cardiac Beta-Adrenergic Receptors 299
Vascular Reactivity 300
Volume Regulation 300
Cerebral Autoregulation 300
References 300
57 Exercise 302
Introduction 302
Acute Exercise 302
Exercise Training 303
Exercise as a Non-Drug Therapy 304
Conclusion 305
References 305
58 Effects of High Altitude 308
Introduction 308
Effects of Acute Hypoxia 308
Effects of Chronic Hypoxia 309
Autonomic Nervous System and Altitude Illness 309
References 309
59 Space Physiology 310
Introduction 310
Space Motion Sickness 310
Orthostatic Intolerance 311
Clinical Interactions 312
References 312
60 Hypothermia and Hyperthermia 314
Introduction 314
Central Neural Control of Thermoregulation 314
Regulation of Body Temperature in Thermoneutral Environments 314
Hypothermia 315
Hyperthermia 315
Skin Blood Flow 315
Sweating 316
Overall Summary 316
References 316
61 Psychological Stress and the Autonomic Nervous System 318
Introduction 318
Normal Psychological Stresses and Autonomic Activity 318
Patterns of Autonomic Response to Stress 318
Cardiac Disease 319
Gastrointestinal (GI) Control 319
Psychosomatic Disorders and the Autonomic Nervous System 319
Post-Traumatic Stress Disorder, Panic, and Anxiety 319
References 320
62 Mind–Body Interactions 322
Introduction 322
Skin Conductance Response (SCR) 322
Decision-Making 322
The Somatic Marker Hypothesis 322
Electrogastrogram (EGG) 323
Emotion 323
Cardiovascular Arousal (HR and BP) 324
Emotion 324
Imagery-Induced Emotion 325
Conclusions 325
References 325
V. Pathophysiological Mechanisms 328
63 Alpha-Synuclein and Neurodegeneration 330
Alpha-SYN in Disease 330
Alzheimer’s Disease 330
Parkinson’s Disease 330
Multiple System Atrophy 330
Toxic Species of Alpha-SYN 330
Transgenic Animal Models of a-Synucleinopathy 331
Therapeutic Approaches to a-SYN Toxicity 331
Conclusion 332
References 332
64 Insulin Resistance and the Autonomic Nervous System 334
Introduction 334
Sympathetic Activity and Insulin Resistance 334
Insulin Resistance Induces Sympathetic Activation 334
Heightened SNA Induces Insulin Resistance 335
An Integrated View 336
Therapeutic Considerations 337
References 337
65 Salt Sensitivity of Blood Pressure 340
Genetics 340
Gene–Environment Interactions 341
Vasoregulatory and Natriuretic Systems 341
Renin-Angiotensin-Aldosterone System (RAAS) 341
Endothelin 343
Nitric Oxide (NO) and Oxidative Stress 343
Sympathetic Nervous System (SNS) 344
Arachidonic Acid (AA) Metabolites 344
Clinical Significance 344
References 345
66 Endothelial Dysfunction 346
Introduction 346
Normal Endothelial Cell Function 346
Endothelial Cell Dysfunction 346
Clinical Assessment of Endothelial Vasomotor Function 347
Basal NO Activity in the Healthy Human Circulation 347
Pharmacologic Endothelial Function Testing 347
Physiologic Endothelial Function Testing 347
Circulating Biomarkers of Endothelial Dysfunction 348
Markers of Endothelial Activation and Dysfunction 348
Markers of Endothelial Repair and Regeneration 348
Clinical Consequences of Endothelial Dysfunction 348
Endothelial NO, Physiologic Coronary Vasomotion, and Myocardial Ischemia 348
Endothelial Function and Cardiovascular Prognosis 349
Strategies to Improve Endothelial Function 349
Endothelial Dysfunction and Cardiovascular Pathophysiology: Interaction With the Autonomic Nervous System 349
Further Reading 350
67 Inflammation, Immunity and the Autonomic Nervous System 352
Introduction 352
General Concepts Regarding Innate and Adaptive Immunity 352
The Autonomic Nervous System, Inflammation and Hypertension 353
Conclusion and Perspectives 355
References 355
68 Oxygen Sensing 358
Morphology of the Carotid Body and Measures of O2 Sensing 358
Uniqueness of Carotid Body O2 Sensing 358
O2 Sensors and Transduction of the Hypoxic Stimulus 358
Role of Gas Messengers in Hypoxic Sensing by the Carotid Body 359
Molecular Determinants of O2 Sensing by the Carotid Body 359
Consequences of Carotid Body O2 Sensing on Autonomic Nervous System 360
Physiological Situations 360
Pathological Situations 360
Acknowledgements 360
References 360
69 Reactive Oxygen Species and Oxidative Stress 362
Introduction 362
Biology of ROS 362
Production and Metabolism of ROS 363
Xanthine Oxidase 363
Uncoupled Nitric Oxide Synthase 363
Mitochondrial Respiratory Enzymes 363
ROS-Generating Nox-Family NAD(P)H Oxidases 363
Regulation of Noxes 364
Protecting against Oxidative Stress – Antioxidant Defenses 364
ROS and Autonomic Outflow 364
Conclusions 364
Acknowledgements 365
References 365
VI. Cardiovascular Disorders 366
70 Neurally Mediated Syncope 368
Introduction 368
Pathophysiology of Neurally Mediated Syncope (NMS) 368
Diagnosis of NMS 368
TILT Table Testing 369
Natural History of NMS 369
NMS Treatment 369
References 370
71 Sympatho-Vagal Imbalance in Hypertension 372
Evidence for Autonomic Dysfunction in Hypertension and its Role in Hypertension-Related Organ Damage 372
Autonomic Dysfunction in Hypertension Complicated by Other Disease 373
Effects of Therapeutic Interventions on Hypertension-Related Autonomic Dysfunction 374
References 374
72 Baroreflex Failure 376
Introduction 376
Causes of Baroreflex Failure 376
Clinical Presentation 376
Diagnosing Baroreflex Failure 378
Treatment 379
Further Reading 379
73 Blood Pressure Variability 382
Physiologic Control of SNS Outflow 382
Clinical Patterns of BP Variation 382
Respiratory Variation 382
Diurnal Rhythms and Nocturnal change 382
Postural Adaptation 383
Food Intake and Postprandial Hypotension 383
Body Temperature 383
Emotional States 383
“White Coat” Syndromes 383
Exercise 383
Smoking 384
Salt-sensitivity 384
Drug Effects 384
Intraoperative BP Variation 384
Baroreflex Disorders 384
Further Reading 384
74 Obesity-Associated Hypertension 386
Epidemiology 386
Increased Sympathetic Activation in Obesity 386
Sympathetic Activation and Obesity in Minority Populations 387
Sympathetic Activation and Obesity-Associated Hypertension 387
References 388
75 Orthostatic Hypertension 390
Further Reading 392
76 Heart Failure 394
References 397
77 Stress Cardiomyopathy and Takotsubo Syndrome 398
Further Reading 401
78 Clinical Evaluation of Autonomic Disorders 404
Approach in History Taking 404
Assessment: Bedside and Laboratory Testing 404
Laboratory Testing 407
Final Thoughts 408
References 408
79 Tilt Table Studies 410
Questions About Head-Up Tilt Table Testing 410
1. What is a Head-Up Tilt Table Test (HUT)? 410
2. What are the Different Types of Hut that Exist? 410
3. What Types of Monitoring Should there be During HUT? 410
4. What is the Physiological Basis Underlying HUT? 410
5. How Accurate are HUT for Neurally Mediated Syncope? 411
6. How Useful are HUT in the Clinical Management of Patients? 411
7. What are the Indications for HUT? 411
8. When is Extra Monitoring Like Transcranial Doppler (TCD) or Electroencephalogram (EEG) Monitoring Useful? 411
9. Is HUT Useful in the Diagnosis of Postural Tachycardia Syndrome (POTS)? 411
10. Is HUT Useful in the Diagnosis of Orthostatic Hypotension? 413
References 414
80 Sympathetic Microneurography 416
Methodology 416
Equipment 416
Procedure 416
Analysis 418
Multiunit Activity 418
Single-Unit Activity 419
Potential Difficulties 419
Mixed Sites 419
Changes of Electrode Site 419
Acknowledgement 419
References 419
81 Clinical Applications of Microneurography 420
Neurological Diseases 420
MSNA and SSNA in Radiculoneuropathies 420
MSNA in Multiple System Atrophy 420
MSNA Withdrawal in Hypotensive Attacks 420
SSNA in Sweat Disturbances 421
MSNA in Sleep Apnea 421
Cardiovascular Diseases 422
MSNA in Hypertension 422
MSNA in Heart Failure 422
Kidney Diseases 422
Metabolic Syndrome 423
Bone Loss 423
Conclusion 423
References 424
82 Clinical Sympathetic Imaging 426
Sympathetic Imaging Methods and Agents 426
Sympathetic Imaging in Dysautonomias 428
Association of Noradrenergic Denervation with Synucleinopathy in Lewy Body Diseases 429
References 429
83 Assessment of the Autonomic Control of the Cardiovascular System by a Frequency Domain Approach 432
Introduction 432
Methodology 432
Cardiovascular Rhythms and Autonomic Neural Control 432
Differential Neural Control of Cardiovascular Variables and of their Spontaneous Variability 433
References 434
84 Assessment of Sudomotor Function 436
Tests of Sudomotor Function 436
Axon Reflex Testing 436
Skin Potentials 438
Thermoregulatory Sweating 438
Conclusion 438
References 438
85 Cutaneous Autonomic Innervation: Assessment by Skin Biopsy 440
Introduction 440
Cutaneous Neuroanatomy 440
Sweat Glands 440
Hair Follicles 440
Arrector Pilorum Muscles 441
Blood Vessels 441
Skin Biopsies to Evaluate Specific Autonomic Disorders 441
Summary 444
References 444
VII. Catecholamine Disorders 446
86 Pheochromocytoma 448
Further Reading 451
87 Deficiencies of Tetrahydrobiopterin, Tyrosine Hydroxylase and Aromatic L-Amino Acid Decarboxylase 454
Biochemistry 454
Presentation and Neurological Symptoms 454
Diagnosis 455
Tetrahydrobiopterin Deficiencies 455
Tyrosine Hydroxylase Deficiency 456
Aromatic L-Amino Acid Decarboxylase Deficiency 456
Treatment 456
BH4 Deficiencies 456
TH Deficiency 456
AADC Deficiency 456
References 456
88 Dopamine & #946
Clinical Description 458
Diagnosis 459
Differential Diagnosis 460
Genetics 460
Management 460
Mouse Model of DBH Deficiency 460
Further Reading 460
89 Menkes Disease and Other ATP7A-Related Phenotypes 462
Epidemiology 462
Clinical Phenotype 462
Biochemical Phenotypes 462
Autonomic Manifestations 463
Clinical Signs of Dysautonomia in MD and OHS 463
Neurochemical Abnormalities 464
Molecular Diagnosis 464
Treatment 464
References 464
90 Norepinephrine Transporter Deficiency 466
Net Deficiency in Cardiovascular Disease 466
Human Net Gene Polymorphisms 466
The Net A457P Variant and Orthostatic Intolerance 466
Other Net Gene Polymorphisms and Cardiovascular Disease 468
Net and Comorbidity of Cardiovascular and Neurobehavioral Disorders 469
References 469
91 Monoamine Oxidase Deficiency 470
Further Reading 471
92 Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations 472
Paired-Like Homeobox 2B (PHOX2B) Gene 472
PHOX2B Genotype and Cchs Phenotype Association 472
Continuous Ventilatory Dependence and Other Studies Pertinent to Respiratory Control 473
Hirschsprung Disease (HSCR) 473
Tumors of Neural Crest Origin 473
Cardiac Asystoles 473
Facial Dysmorphology 474
Phenotype Specific to NPARMs 474
Later-onset CCHS (LO-CCHS) 474
Comprehensive Clinical Evaluation 475
References 476
VIII. Autonomic Synucleinopathies 478
93 Multiple System Atrophy 480
Background 480
Epidemiology 480
Pathophysiology 480
Clinical Features 481
Differential Diagnosis 481
Special Tests 483
Management 483
Neuroprotective Therapy 483
Further Reading 484
94 Parkinson’s Disease 486
Conclusion 488
References 488
95 Dementia with Lewy Bodies 490
Clinical Aspects and Differential Diagnosis 490
Practical Management 490
Therapy 492
Dementia 492
Hallucinations and Psychosis 492
Parkinsonism 492
Dysautonomia 492
References 493
96 Pure Autonomic Failure 494
Differential Diagnosis 494
Catecholamine Studies 494
Neuroendocrine Studies 495
Diagnostic Imaging Techniques 495
Neuropathology 495
Management 495
References 495
IX. Peripheral Autonomic Disorders 498
97 Diagnostic Workup of Peripheral Neuropathies with Dysautonomia 500
References 502
98 Diabetic Autonomic Dysfunction 504
Iris 504
Esophagus 504
Stomach 504
Gallbladder 505
Colon 505
Bladder 505
Penis 506
Vagina 506
Adrenal Medulla 506
Sudomotor 507
Cardiovascular 507
References 508
Further Reading 508
99 Amyloidotic Autonomic Failure 510
Immunoglobulin Amyloidosis 510
Pathogenesis 511
Diagnosis 511
Treatment 512
Prognosis 512
Reactive Amyloidosis 513
Hereditary Amyloidosis 513
Pathogenesis 513
Laboratory Data and Diagnosis 513
Treatment and Prognosis 513
Further Reading 514
100 Autoimmune Autonomic Ganglionopathy 516
Autoimmune Autonomic Ganglionopathy 516
Description 516
Pathogenesis 516
Diagnosis 517
Clinical Course 517
Treatment 518
Paraneoplastic Autoimmune Autonomic Neuropathy 518
References 518
101 Guillain–Barré Syndrome 520
Clinical Features 520
Investigations 520
Etiology or Mechanisms 520
Course and Prognosis 521
Management 521
References 521
102 Hereditary Autonomic Neuropathies 522
Fabry’s Disease 522
Clinical Manifestations of Fabry’s Disease 522
Autonomic Involvement 523
Porphyria 523
Clinical Manifestations of Porphyria 524
Autonomic Involvement in Porphyria 524
Treatment of Porphyria 524
Multiple Endocrine Neoplasia Type 2B 524
Hereditary Motor and Sensory Neuropathies Type I and II (Charcot–Marie–Tooth 1 and 2) 525
Type I, II, IV, and V Hereditary Sensory and Autonomic Neuropathy 525
Further Reading 525
103 Familial Dysautonomia (Riley–Day Syndrome) 526
Introduction 526
Clinical Features 526
Genetics 526
Cardiovascular Autonomic Abnormalties 527
Pathology 528
Treatment 529
References 529
X. Autonomic Disorders 530
104 Autonomic Disturbances in Spinal Cord Injuries 532
Cardiovascular System 532
Cutaneous Circulation 534
Thermoregulation and Sudomotor Function 534
Gastrointestinal System 535
Urinary System 535
Reproductive System 535
References 535
Further Reading 536
105 Drug-Induced Autonomic Dysfunction 538
Introduction 538
Drug-Induced Hypertension 538
Drug-Induced Hypotension 539
Summary 541
References 541
XI. Orthostatic Intolerance 542
106 Postural Tachycardia Syndrome (POTS) 544
Introduction 544
Clinical Features and Phenotypes 544
Phenotypes of Pots 544
Neuropathic POTS 544
Hyperadrenergic POTS 544
POTS Associated with Poor Conditioning 545
Follow-Up 545
Management 545
Conclusions 546
Summary 546
References 546
107 Mechanisms of Postural Tachycardia Syndrome 548
Hyperadrenergic Pots 548
Central Hyperadrenergic POTS 548
Norepinephrine Transporter Deficiency 548
Mast Cell Activation Disorder 549
Neuropathic Pots 549
Hypovolemia and Blood Volume Regulation 550
Low Stroke Volume 550
References 550
108 Symptoms and Signs of Postural Tachycardia Syndrome (POTS) 552
Hemodynamics – Tachycardia 552
Reflex Tachycardia in Pots – a Classification Based on Peripheral Blood Flow 553
Low Flow POTS 553
High Flow POTS 554
Normal Flow POTS 555
Summary 555
References 555
109 Delayed Orthostatic Hypotension 556
References 557
110 Chronic Fatigue Syndrome and the Autonomic Nervous System 558
Chronic Fatigue Syndrome and Autonomic Dysfunction 558
Chronic Fatigue Syndrome and Orthostatic Intolerance 558
Postural Tachycardia Syndrome (POTS) 560
Neurally Mediated Hypotension 560
Pathophysiology 560
Conclusions 560
References 560
111 Joint Hypermobility Syndrome and Dysautonomia 562
Introduction 562
Epidemiology and Pathophysiology 562
Clinical Manifestation and Diagnosis 562
Autonomic Dysfunction in JHS 562
Management 564
References 564
XII. Special Clinical Conditions 566
112 Neuroleptic Malignant Syndrome 568
Introduction 568
Clinical Features 568
Medications and Risk Factors 568
Differential Diagnosis 570
Pathogenesis 570
Treatment 570
References 571
113 Migraine and the Autonomic Nervous System 572
Functional Anatomy of Migraine 572
Autonomic Symptoms in the Course of the Migraine Attack 572
Interictal Autonomic Dysfunction in Migraine 573
The Pain of Migraine 573
Migraine as a Bio-Behavioral Disorder 574
Migraine as a Reflection of Genetically Determined Adaptive Darwinian Behavioral Responses 574
Conclusion 574
References 574
114 Epilepsy and Autonomic Regulation 576
Supratentorial Components of the Central Autonomic Network 576
Infratentorial Components of the Central Autonomic Network 576
Ictal Autonomic Dysfunction 577
Gastrointestinal Autonomic Dysfunction 577
Urogenital Autonomic Dysfunction 577
Ictal Cutaneous and Pupillary Changes 577
Respiratory Autonomic Dysfunction 577
Cardiovascular Autonomic Dysfunction 577
Sudden Unexpected Death in Epilepsy Patients (SUDEP) 578
Autonomic Dysfunction During Status Epilepticus 578
Interictal Autonomic Dysfunction 578
Effects of Vagus Nerve Stimulation on Cardiovascular Function of Epilepsy Patients 579
References 579
115 Disorders of Sweating 580
Hyperhidrosis 580
Hypohidrosis and Anhidrosis 581
Distal Anhidrosis 583
Global Anhidrosis 584
Dermatomal, Focal, or Multifocal Anhidrosis 584
Segmental Anhidrosis 584
Hemianhidrosis 584
References 586
116 Male Erectile Dysfunction 588
Mechanism of Erection 588
Etiology of Erectile Dysfunction 589
Neurogenic Erectile Dysfunction 589
Hypogonadism 590
Medical and Surgical Treatment 590
References 590
117 Sleep Apnea 592
Autonomic Function During Physiologic Sleep 592
Obstructive Sleep Apnea 592
OSA and the Autonomic Nervous System 592
Acute Changes During Apneic Episodes 592
Chronic Changes with OSA 594
Atrial Fibrillation and OSA 594
Sudden Cardiac Death and OSA 595
Heart Rate Variability in OSA 595
Central Sleep Apnea 596
Heart Failure and CSA 596
Acknowledgments 596
References 596
118 Altered Adrenal Function and the Autonomic Nervous System 598
Crosstalk Between Adrenal Cortex and Medulla 598
Primary Adrenal Insufficiency 598
Adrenal Crisis 599
Management 599
Secondary Adrenal Insufficiency 599
Hypoaldosteronism 600
Influence of the Autonomic Nervous System on Adrenocortical Function 600
References 600
119 Mastocytosis 602
Mastocytosis and Allied Activation Disorders of the Mast Cell 602
Symptoms and Signs 602
Mast Cell Mediators Responsible for the Symptoms and Signs 602
Diagnosis 603
Summary 603
References 603
120 Cocaine Overdose 604
Effects of Cocaine on the Peripheral Circulation 604
Autonomic Effects of Cocaine on the Heart 604
Effects of Cocaine on Thermoregulation 606
Treatment of Cocaine Overdose 607
Acknowledgements 607
References 607
121 Complex Regional Pain Syndrome 610
CRPS I is a Neuronal Disorder Involving the CNS 610
Sympathetic Systems Supplying Skin 610
Cutaneous Vasoconstrictor Neurons and Blood Flow Through Skin 610
Sudomotor Neurons and Sweating 611
Sympathetic Neurons and Edema, Inflammation and Trophic Changes 611
Edema 611
Inflammation 612
Trophic Changes 612
Sensory Systems of the Skin 612
Somatomotor Changes 612
Initiating Events 613
CRPS and Sympathetically Maintained Pain (SMP) 613
Conclusions 613
Acknowledgement 614
References 614
122 Carcinoid Tumors 616
References 618
123 Paraneoplastic Autonomic Dysfunction 620
Encephalitis 620
Morvan’s Syndrome and Neuromyotonia 620
Subacute Sensory Neuronopathy 621
Enteric Neuronopathy 621
Autonomic Neuropathy 621
Lambert–Eaton Myasthenic Syndrome 622
Diagnosis 622
Treatment 623
Further Reading 623
124 Abdominal Pain and Cyclic Vomiting 624
Cyclic Vomiting Syndrome (CVS) 624
Chronic Abdominal Pain 625
References 626
125 Fecal Incontinence 628
Prevalence of the Condition 628
The Physiological Mechanisms that Sustain Continence of Feces 628
Internal Anal Sphincter (IAS) 628
External Anal Sphincter (EAS) 628
Puborectalis 628
Recto-Anal Reflexes 628
Recto-Anal Sensation and the Urge to Defecate 629
Fecal Incontinence 629
The Mechanism of Action of Sacral Neuromodulation 629
Animal Models 629
References 629
XIII. Management of Autonomic Disorders 630
126 Panic Disorder 632
Resting Sympathetic Nervous System Function in Panic Disorder 632
Sympathetic Nervous Activity and Epinephrine Secretion Rates 632
Brain Serotonin Release 632
Epinephrine Cotransmission in Sympathetic Nerves 633
Reduction in Neuronal Norepinephrine Reuptake by Sympathetic Nerves 633
Autonomic Nervous Changes During a Panic Attack 633
Sympathetic Nerve Firing and Secretion of Epinephrine 633
Release of Neuropeptide Y 634
Mediating Autonomic Mechanisms of Cardiac Risk During a Panic Attack 634
References 635
127 Physical Measures 636
Physical Countermaneuvers 636
Squatting 636
External Support 637
Respiratory Maneuvers 638
Conclusion 638
Further Reading 638
128 Water and the Osmopressor Response 640
Introduction 640
The Water-Induced Pressor Response 640
Evidence for Water-Induced Sympathetic Activation 640
A Spinal Sympathetic Reflex? 641
Evidence for an Osmosensitive Mechanism Involving Trpv4 641
Therapeutic Utility of Water Drinking 641
Further Reading 642
129 Droxidopa (L-DOPS) 644
Introduction 644
History 644
Pharmacology 644
Isomeric Structure 644
Pharmacokinetics 644
Mechanism of Action 646
Pressor Effect 646
Other Actions 646
Clinical Studies 646
DBH Deficiency 646
Other Types of Autonomic Failure 646
References 647
130 Midodrine, Adrenergic Agonists and Antagonists 648
Midodrine 648
Mechanism of Action 648
Pharmacology 648
Efficacy 648
Other Beneficial Effects 649
Adverse Effects and Disadvantages 649
Adverse effects and Precautions 650
Dosing 650
Other Special Populations 650
Ephedrine/Other Alpha Agonists 650
Mechanism of Action 650
Adverse Events and Disadvantages 651
Dosing 651
Antagonists 651
Mechanism of Action 651
Adverse Events and Disadvantages 651
Dosing 651
References 651
131 Agents Potentiating Sympathetic Tone 654
Yohimbine 654
Atomoxetine 655
Pyridostigmine 656
References 657
132 Acetylcholinesterase and its Inhibitors 658
Cholinesterases and Acetylcholine Metabolism 658
Molecular Pharmacology of Acetylcholinesterase Inhibitors 658
Quaternary Amines 658
Carbamates 659
Phenanthrene and Piperidines 659
Organophosphates 660
Therapeutic Applications 660
Further Reading 660
133 Fludrocortisone 662
Introduction 662
Mechanism of Effect 662
Clinical Pharmacology 662
Side Effects 663
Long-Term Effects of Fludrocortisone 663
Further Reading 663
134 Acarbose 666
Pathophysiology of Postprandial Hypotension in Autonomic Failure 666
Acarbose in the Treatment of Postprandial Hypotension 666
References 668
135 Erythropoietin in Autonomic Failure 670
Modulation of Erythropoietin Production by the Autonomic Nervous System 670
The Anemia of Autonomic Failure 670
Recombinant Human Erythropoietin in the Treatment of Orthostatic Hypotension 670
References 671
136 Somatostatin Agonists 672
Introduction 672
Somatostatin and Autonomic Neuropathy 672
Postural Tachycardia Syndrome and Orthostatic Intolerance 673
Postmenopausal Hot Flashes 674
Adverse Effects of Somatostatin Analogs 674
Summary 675
References 675
Further Reading 675
137 Harnessing the Autonomic Nervous System for Therapeutic Intervention 676
Pharmacological and Surgical Targeting of the Autonomic Nervous System 676
“Harnessing” the Autonomic Nervous System 676
Activation of the Sympathetic Nervous System in Essential Hypertension 676
Does this sympathetic activation cause the blood pressure elevation? 677
Drug-Resistant Hypertension 677
Anti-Adrenergic Devices for Treating Hypertension 677
The implantable barostimulator 677
Endovascular Renal Sympathetic Nerve Ablation 677
A cure for essential hypertension? 679
References 679
138 Acupuncture Regulation of Cardiovascular Function 680
Introduction 680
Western Understanding of Acupuncture 680
Neurological Substrate 680
Clinical Role of Acupuncture 683
Outstanding Issues in Acupuncture Research 684
References 684
139 Bionic Baroreflex 686
Introduction 686
Bionic Baroreflex System 686
Theoretical Background 686
Implementation of Algorithm of Artificial Vasomotor Center in BBS 687
Efficacy of BBS 687
Epidural Catheter Approach for Human BBS 688
Feasiblity Study of BBS in Patients with High Cervical Spinal Cord Injury 689
Implantable BBS 689
References 689
XIV. Experimental Autonomic Neuroscience 690
140 Anesthetic Management in Autonomic Disorders 692
Introduction 692
Clinical Presentation and Assessment 692
Pathophysiology 692
Preoperative Management 693
Anesthetic Management 693
Special Consideration for Anesthesia 693
Airway Management 693
Ventilatory Management 694
Hepatic Blood Flow and Lidocaine 694
Temperature Dysregulation 694
Response to Infection 694
Diabetic Neuropathy 694
Uremia 695
Summary 695
References 695
141 Evolution of the Cardiovascular Autonomic Nervous System in Vertebrates 696
The Autonomic Nervous System in Vertebrates 696
Comparative Aspects of the Autonomic Regulation of the Cardiovascular System 697
Anatomy of the Cardiovascular System in Vertebrates 697
Autonomic Regulation of the Heart 698
Innervation of the Systemic Vasculature 698
Cardiovascular Responses to Altered Pressure, Exercise and Hypoxia 699
Autonomic Regulation of the Pulmonary Circulation 699
References 700
142 Human Physiome 702
Introduction 702
Physiome Standards 702
Modeling the Autonomic Nervous System 704
Conclusions 706
References 707
143 Modeling the Autonomic Nervous System 708
Large-Scale Computational Model of the Brainstem Sympatho-Respiratory Network 708
Modeling the Effects of Baroreceptor Activation on the Respiratory Pattern: Insights Into Respiratory–Sympathetic Interacti ... 708
Sympathetic Nerve Activity Following Chronic Intermittent Hypoxia-induced Sensitization of Central Chemoreceptors 711
References 713
144 Optogenetics 716
Introduction 716
Optogenetic Reporters 716
Optogenetic Reporters for Ca2. 716
Optogenetic Effector Proteins 716
Light-Sensitive Cation Channel Channelrhodopsin-2 and its Derivatives 717
Optogenetic “Silencers” 717
Light-Sensitive G-protein Coupled Receptors (GPCRs) 717
Means of Gene Delivery 717
Cell-Specific Viral Targeting 718
Germline Transgenics 718
Conclusion 718
Acknowledgements 718
References 718
Index 720