Arterial Chemoreceptors: Mal(adaptive) Responses: O2 Dependent and Independent Mechanisms

Preface
Contents
Contributors
1: Transcriptomics of the Carotid Body
1.1 Introduction
1.1.1 Notes of Caution
1.2 Overview of Carotid Body Transcriptomic Studies
1.3 The Known Unknowns of the Carotid Body’s Transcriptome
1.4 Summary: Future Directions
References
2: The Adult Carotid Body: A Germinal Niche at the Service of Physiology
2.1 Introduction
2.2 The CB Contains Intermediate Restricted Progenitors from Both Vascular and Neuronal Lineages, to Accelerate Adaptation to Chronic Hypoxia
2.3 Mature Glomus Cells as Master Regulators of the Adult Carotid Body Germinal Niche
2.4 Clinical Implications and Concluding Remarks
References
3: Evidences That Sympathetic Overactivity and Neurogenic Hypertension Correlate with Changes in the Respiratory Pattern in Rodent Models of Experimental Hypoxia
3.1 Introduction
3.2 Wistar Ribeirão Preto Rats Submitted to Chronic Intermittent Hypoxia
3.2.1 Male Rats Submitted to Chronic Intermittent Hypoxia
3.2.2 Female Rats Submitted to Chronic Intermittent Hypoxia
3.3 Wistar Ribeirão Preto Rats Submitted to Sustained Hypoxia
3.4 Wistar Hannover Rats Submitted to Sustained Hypoxia
3.5 Sprague-Dawley Rats Submitted to Sustained Hypoxia
3.6 Mice Submitted to Sustained Hypoxia
3.7 Summary
References
4: Control of Arterial Hypertension by the AhR Blocker CH-223191: A Chronopharmacological Study in Chronic Intermittent Hypoxia Conditions
4.1 Introduction
4.2 Material and Methods
4.2.1 In Vivo Experiments
4.2.1.1 Ethics
4.2.1.2 Animals
4.2.1.3 Chronic Intermittent Hypoxia Paradigm
4.2.1.4 Study Design
4.2.1.4.1 Evaluation of the Chronopharmacology of the Antihypertensive Efficacy of the AhR Blocker CH-223191 in CIH Conditions
4.2.1.4.2 Circadian Variation of AhR Activation in the Kidney Cortex Under Normoxic Conditions
4.2.1.5 Terminal Surgeries
4.2.2 Assessment of AhR Activation Through Western Blot Analysis of CYP1A1 Levels
4.2.3 Statistical Analysis
4.3 Results
4.4 Discussion
References
5: Three Days of Chronic Intermittent Hypoxia Induce β1-Adrenoceptor Dependent Increases in Left Ventricular Contractility
5.1 Introduction
5.2 Methods
5.2.1 Ethical Approval
5.2.2 Chronic Intermittent Hypoxia Protocol
5.2.3 Anesthetized In Vivo Preparation
5.2.4 Gene Expression
5.2.5 Data and Statistical Analysis
5.3 Results
5.3.1 Baseline Cardiovascular Parameters
5.3.2 Left Ventricular Contractility in Response to Chemostimulation
5.3.3 Cardiovascular Response to β-Adrenoceptor Blockade
5.3.4 Sympathetic Nervous System Inhibition
5.3.5 Gene Expression of the β1-Adrenoceptor Pathway
5.3.6 Catecholamine Concentrations
5.4 Discussion
5.4.1 Hypoxia and the Cardiovascular System
5.5 Conclusion
References
6: The Beneficial Effect of the Blockade of Stim-Activated TRPC-ORAI Channels on Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia Is Independent of Oxidative Stress
6.1 Introduction
6.2 Methods
6.2.1 Animals and Intermittent Hypoxia Protocol
6.2.1.1 2-APB Treatment
6.2.2 Right Ventricular Systolic Pressure Measurement
6.2.3 STOC Pulmonary Gene Expression
6.2.4 Systemic and Pulmonary Oxidative Stress Measurement
6.2.5 Vascular Remodeling and Immunohistochemistry
6.2.6 Data Analysis, Pearson Correlation, and Statistical Analyses
6.3 Results
6.3.1 Pearson’s Correlation of Physiological Variables Related to Right Ventricle Systolic Pressure
6.3.2 Pearson’s Correlation of Physiological Variables Related to MDA Concentrations at the Pulmonary Level
6.4 Discussion
References
7: Intermittent Hypoxia and Weight Loss: Insights into the Etiology of the Sleep Apnea Phenotype
7.1 Introduction
7.2 Methods
7.2.1 Animals and Experimental Groups
7.2.1.1 Intermittent Hypoxia Protocol
7.2.2 Animal Monitoring and Experimental Measurements
7.2.2.1 Ventilatory Measurements
7.2.2.2 Assessment of Respiratory Reflexes
7.2.2.3 Data Analysis
7.2.2.4 Blood Sampling and Biochemical Analyses
7.2.3 Statistical Analysis
7.3 Results
7.3.1 Moderate IH Augments Respiratory Instability During Sleep and “Basal” Arterial Blood Pressure
7.3.2 IH Increases the Chemoreflex Response
7.3.3 IH Induces Weight and Fat Loss
7.3.4 IH Reduces ACTH and Testosterone Levels and Promotes Inflammation
7.4 Discussion
7.4.1 Efficiency of the Intermittent Hypoxia Protocol
7.4.2 Intermittent Hypoxia Reduces ACTH and Favors Weight Loss
7.4.3 Intermittent Hypoxia and Leptin
7.5 Conclusions
References
8: Effects of Gestational Intermittent Hypoxia on Placental Morphology and Fetal Development in a Murine Model of Sleep Apnea
8.1 Introduction
8.2 Methods
8.2.1 Animal Models and Anesthesia
8.2.2 Macroscopic and Microscopic Study of Placentas
8.2.3 Statistical Analysis
8.3 Results
8.3.1 Maternal, Placenta and Fetus Body Weight
8.3.2 Macroscopic and Microscopic Study of Placentas
8.4 Discussion
References
9: Ventilatory Effects of Acute Intermittent Hypoxia in Conscious Dystrophic Mice
9.1 Introduction
9.2 Materials and Methods
9.2.1 Ethical Approval
9.2.2 Experimental Animals
9.2.3 Whole-Body Plethysmography
9.2.4 Data and Statistical Analysis
9.3 Results
9.3.1 Effect of AIH on Ventilation
9.3.2 Effect of AIH on Metabolism
9.3.3 Effect of AIH on the Ventilatory Equivalent
9.4 Discussion
References
10: Intermittent Hypoxia and Diet-Induced Obesity on the Intestinal Wall Morphology in a Murine Model of Sleep Apnea
10.1 Introduction
10.2 Methods
10.2.1 Animal Protocols
10.2.2 Tissue Collection
10.2.3 Statistical Analysis
10.3 Results
10.3.1 Body Weight Gain and Visceral Fat Deposits
10.3.2 Basal Glycemia and Markers of Sympathetic and Inflammatory Activity
10.3.3 Morphology of Jejunum Wall
10.4 Discussion
References
11: Enhanced Peripheral Chemoreflex Drive Is Associated with Cardiorespiratory Disorders in Mice with Coronary Heart Disease
11.1 Introduction
11.2 Methodology
11.2.1 Animal Model
11.2.2 Resting Breathing and Chemoreflex Function
11.2.3 Electrocardiogram and Autonomic Balance
11.2.4 Data Analysis
11.3 Results
11.3.1 SR-B1−/−/HypoApoE Mice Display Increased Peripheral Chemoreflex Drive
11.3.2 SR-B1−/−/HypoApoE Mice Show Breathing Pattern Irregularity
11.3.3 Cardiac Sympathetic Tone Is Enhanced in SR-B1−/−/HypoApoE Mice
11.4 Discussion
References
12: Role of Peripheral Chemoreceptors on Enhanced Central Chemoreflex Drive in Nonischemic Heart Failure
12.1 Introduction
12.2 Methodology
12.2.1 Animals
12.2.2 Heart Failure Model
12.2.3 Echocardiography
12.2.4 Plethysmography
12.2.5 Carotid Body Denervation
12.2.6 Statistical Analysis
12.3 Results
12.3.1 Cardiac Morphology and Carotid Body Denervation in Heart Failure
12.3.2 Carotid Body Resection Restores Normal Hypercapnic Ventilatory Responses and Breathing Disorders in CHF Rats
12.4 Discussion
References
13: Effect of Carotid Body Denervation on Systemic Endothelial Function in a Diabetic Animal Model
13.1 Introduction
13.2 Methods
13.2.1 Animals
13.2.2 Evaluation of Endothelial Function
13.2.3 Nitric Oxide Quantification in Plasma and Aorta
13.2.4 Western Blot Analyses of eNOS, Inos, and PGF2αR Protein Levels in Aorta Artery
13.2.5 Statistical Analysis
13.3 Results
13.3.1 Effect of HFHSu Diet and CSN Resection on In Vivo Metabolic Parameters
13.3.2 Effect of HFHSu Diet and of CSN Resection on Vasoconstrictor Responses and Endothelial Function in Aorta Artery
13.3.3 Effect of HFHSu Diet and of CSN Resection on NO Levels in Plasma and Aorta Artery
13.3.4 Effect of HFHSu Diet and of CSN Resection on eNOS, iNOS, and PGF2αR Levels in Aorta Artery
13.4 Discussion
References
14: Contribution of Carotid Bodies on Pulmonary Function During Normoxia and Acute Hypoxia
14.1 Introduction
14.2 Methods
14.2.1 Ethical Considerations and Animals
14.2.2 Carotid Body Denervation
14.2.3 Noninvasive Measurement of Pulmonary Function
14.2.4 Invasive Measurement of Pulmonary Function
14.2.5 Lung Histology
14.2.6 Statistical Analysis
14.3 Results
14.3.1 Carotid Body Ablation and Resting Ventilatory Parameters
14.3.2 Carotid Body Ablation Blunted the Hypoxic Ventilatory Response in Mice
14.3.3 Lung Mechanics in Normoxia and the Effect of Carotid Body Denervation
14.3.4 Hypoxia and Lung Mechanics Following Carotid Body Denervation in Mice
14.3.5 Alveolar Morphology and Carotid Body Denervation
14.4 Discussion
References
15: Increased Abdominal Perimeter Differently Affects Respiratory Function in Men and Women
15.1 Introduction
15.2 Methods
15.2.1 Ethical Approval
15.2.2 Subjects and Study Design
15.2.3 Statistical Analysis
15.3 Results
15.3.1 Demographic and Clinical Information of the Participants
15.3.2 Effect of Overweight and Obesity on Basal Ventilation
15.3.3 Effect of Increased Abdominal Circumference on Basal Ventilation
15.4 Discussion
References
16: Carotid Body Resection Prevents Short-Term Spatial Memory Decline in Prediabetic Rats Without Changing Insulin Signaling in the Hippocampus and Prefrontal Cortex
16.1 Introduction
16.2 Methods
16.2.1 Animals
16.2.2 Insulin Tolerance Test (ITT) and Glucose Tolerance Test (OGTT)
16.2.3 Whole-Body Plethysmography Recordings of Ventilation
16.2.4 Y- Maze Test
16.2.5 Protein Analysis (Western Blot)
16.2.6 Statistical Analysis
16.3 Results
16.3.1 Impact of HFHSu Diet and CSN Resection on Glycaemia, Insulin Sensitivity, and Glucose Tolerance
16.3.2 Effect of HFHSu Diet and CSN Resection on the Responses to Hypoxia and Hypercapnia
16.3.3 Effect of HFHSu Diet Consumption and CSN Resection on Short-Term Spatial Memory
16.3.4 Impact of HFHSu Diet and CSN Resection on Insulin Signaling-Related Proteins in the Hippocampus and Prefrontal Cortex
16.4 Discussion
References
17: Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells
17.1 Introduction
17.2 HIF2α-Dependent Gene Expression Profile in Carotid Body Cells
17.3 Selective Inhibition of Acute Responsiveness to Hypoxia in Hif2α-Deficient Glomus Cells
17.4 Conclusions and Perspectives
References
18: Of Mice and Men and Plethysmography Systems: Does LKB1 Determine the Set Point of Carotid Body Chemosensitivity and the Hypoxic Ventilatory Response?
18.1 Introduction
18.2 Results and Discussion
18.2.1 LKB1 Determines a Set Point for Carotid Body Chemosensitivity
18.2.2 LKB1 and the AMPK-Related Kinases: From Synaptic Transmission to Gene Expression Regulation
18.2.3 LKB1, AMPK, and the Hypoxic Ventilatory Response
18.3 Conclusion
References
19: Analyzing Angiotensin II Receptor Type 1 Clustering in PC12 Cells in Response to Hypoxia Using Direct Stochastic Optical Reconstruction Microscopy (dSTORM)
19.1 Introduction
19.2 Methods
19.2.1 PC12 Cell Culture, Hypoxic Protocol, and Immunocytochemistry
19.2.2 Direct Stochastic Optical Reconstruction Microscopy (dSTORM) Imaging and Cluster Analysis
19.2.3 Statistical Analysis
19.3 Results
19.3.1 AT1Rs Are Clustered on the Cell Membrane of PC12 Cells with Measurable Characteristics
19.3.2 Maximum AT1R Cluster Area Is Increased by Hypoxia
19.3.3 Maximum AT1R Cluster Area Is Increased by Hypoxia
19.4 Discussion
References
20: The Carotid Body “Tripartite Synapse”: Role of Gliotransmission
20.1 Introduction
20.2 Methods
20.2.1 Cell Culture
20.2.2 Fura-2 Ratiometric Ca2+ Imaging
20.2.3 Solutions and Drugs
20.3 Results
20.3.1 Selective Chemoexcitants for Carotid Body Type I Versus Type II Cells
20.3.2 Crosstalk from Type I to Type II Cells During Chemotransduction: Paracrine Roles for ATP and Angiotensin II
20.3.3 Inhibitory Roles of Dopamine and Histamine in Type I to Type II Cross Talk
20.3.4 Evidence for ATP as a Type II Cell “Gliotransmitter”
20.4 Discussion
References
21: Carotid Body-Mediated Chemoreflex Function in Aging and the Role of Receptor-Interacting Protein Kinase
21.1 Introduction
21.2 Methodology
21.2.1 Animals
21.2.2 Breathing and Chemoreflex Function
21.2.3 Statistical Analysis
21.3 Results
21.3.1 Resting Ventilatory Physiological Parameters
21.3.2 Loss of RIPK3 Signaling Improves Peripheral and Central Chemoreflex Function in Aged Animals
21.3.3 Absence of RIPK3 Decreased the Incidence of Breathing Disorders in Aged Mice
21.4 Discussion
References
22: Chronic Metformin Administration Does Not Alter Carotid Sinus Nerve Activity in Control Rats
22.1 Introduction
22.2 Methods
22.2.1 Ethical Approval
22.2.2 Animal Procedures
22.2.3 CSN Electrophysiological Recordings
22.2.4 Statistical Analysis
22.3 Results
22.4 Discussion
References
Concluding Remarks