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The Effect of High Salt Intake on Osmoreceptor Gain in Salt

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The Effect of High Salt Intake on Osmoreceptor Gain in Salt The Effect of High Salt Intake on Osmoreceptor Gain in Salt-Sensitive Hypertension David Levi Integrated Program in Neuroscience McGill University Montreal, QC August 2018 A thesis submitted to McGill University in partial fulfillment of the requirement of the degree of Master of Science. © David Levi 2018 Table of Contents Abstract ....................................................................................................................................... i Resumé ....................................................................................................................................... ii Acknowledgements .................................................................................................................. iii Preface and Contribution of Authours .................................................................................. iv Symbols and Abbreviations ..................................................................................................... v 1. Introduction ............................................................................................................................... 1 1.1 General Introduction to Hypertension .............................................................................. 1 1.1.1 Epidemiology of Hypertension ...................................................................................... 1 1.1.2 Risk Factors of Hypertension ......................................................................................... 2 1.2 Homeostasis of Blood Pressure .......................................................................................... 3 1.2.1 Introduction to Blood Pressure Regulation .................................................................... 3 1.2.2 The Nervous System as an Initial Regulator of Blood Pressure .................................... 4 1.2.3 The Kidney: Bridging Blood Pressure Regulation and Fluid Balance .......................... 5 1.3 Regulation of Fluid Balance ............................................................................................... 7 1.3.1 Osmosis in the Context of a Single Cell ........................................................................ 7 1.3.2 Systemic Osmoregulation .............................................................................................. 7 1.3.3 The OVLT as the Central Osmoreceptor ....................................................................... 8 1.3.4 Neuroendocrine Mechanisms Underlying Vasopressin Secretion ................................. 9 1.3.5 Electrophysiological Characterization of VP-Containing MNCs ................................ 10 1.3.6 Intrinsic and Extrinsic Modulation of Vasopressin MNCs .......................................... 11 1.3.6.1 Intrinsic Osmosensitivity of VP MNCs ................................................................ 11 1.3.6.2 Glial-MNC Interactions ........................................................................................ 13 1.3.6.3 Afferent Modulation of VP MNCs ....................................................................... 13 1.3.6.3a Osmotic Modulation: OVLT ............................................................................... 13 1.3.6.3b Cardiovascular Modulation: Baroreceptors ........................................................ 14 1.3.7 Fluid Balance and Plasma Sodium .............................................................................. 14 1.4 High Dietary Sodium Intake as a Risk Factor for Hypertension ................................. 16 1.4.1 Changes in the Perception and Intake of Salt Throughout Human History ................. 16 1.4.2 Forming the Relationship between High Dietary Salt Intake and Hypertension ......... 17 1.4.3 Sodium Reduction as a Strategy to Reduce Blood Pressure ........................................ 19 1.4.4 Projected Effect of Reducing Sodium Intake on Cardiovascular Health ..................... 20 1.5 Mechanisms Underlying Salt Sensitive Hypertension ................................................... 22 1.5.1 Salt Sensitivity: An Overview ..................................................................................... 22 1.5.2 Salt-Sensitive Hypertension as a Continuous, Multifactorial Disease ......................... 24 1.5.3 Renal Dysfunction in Salt-Sensitive Hypertension ...................................................... 26 1.5.3.1 Overview of Pressure Natriuresis ......................................................................... 26 1.5.3.2 Impaired Pressure-Natriuresis in Salt Sensitive Hypertension ............................. 26 1.5.4 Role of the Autonomic Nervous System in Salt Sensitivity ........................................ 28 1.5.4.1 Sympathetic Control of Cardiovascular and Renal Function ............................... 28 1.5.4.2 Abnormally Elevated SNA Following High Salt Intake ....................................... 29 1.5.4.3 Detection of Plasma Hypernatremia as the Mediator of Sympathoexcitation ...... 30 1.5.5 Role of Vasopressin in Rat Models of Salt-Sensitive Hypertension ........................... 31 1.5.5.1 Exaggerated Release of Vasopressin in Models of Salt-Sensitive Hypertension . 31 1.5.5.2 GABA is Excitatory in Salt-Sensitive Hypertension ............................................ 32 1.5.5.3 Increased Osmoreceptor Drive in Salt Sensitive Hypertension? .......................... 34 1.5.6 Specific Aim ................................................................................................................ 35 1.5.7 AngII-Salt Model of Salt-Sensitive Hypertension ....................................................... 36 2. Methods .................................................................................................................................... 38 2.1 Animal Care ...................................................................................................................... 38 2.1.1 Salt Loading Model of Salt-Sensitive Hypertension ................................................... 38 2.1.2 AngII-Salt Model of Salt-Sensitive Hypertension ....................................................... 38 2.2 Electrophysiology in Acute Hypothalamic Slices ........................................................... 39 2.2.1 Acute Slice Preparation and Recording Conditions ..................................................... 39 2.2.2 Chemicals and Drugs ................................................................................................... 40 2.2.3 Spontaneous Current Clamp Recordings ..................................................................... 41 2.2.4 Spontaneous Voltage Clamp Recordings ..................................................................... 41 2.2.5 Evoked Voltage Clamp Recordings ............................................................................. 41 2.3 Statistics ............................................................................................................................. 42 3. Results ...................................................................................................................................... 43 3.1 Results Overview ............................................................................................................... 43 3.2 Effects of Salt Loading (SL) ............................................................................................. 43 3.2.1 SL Increases SONVP MNC Osmoresponsiveness ........................................................ 43 3.2.2 SL Increases SONVP MNC Intrinsic Osmosensitivity ................................................. 44 3.2.3 Salt Loading Does Not Enhance Osmoreceptor Signalling ......................................... 45 3.2.4 SL Discussion .............................................................................................................. 46 3.2.4.1 Summary of SL Results ........................................................................................ 46 3.2.4.2 Possible Mechanisms Underlying Increased Osmoresponsiveness in SL ............ 46 3.3 Effects of AngII-Salt Hypertension ................................................................................. 53 3.3.1 AngII-Salt Hypertension Increases SONVP MNC Overall Osmoresponsiveness ........ 53 3.3.2 AngII-Salt Does Not Increase SONVP MNC Intrinsic Osmoresponsiveness ............... 54 3.3.3 AngII-Salt Increases Synaptic Gain in the OVLT→SONVP Pathway ......................... 55 3.3.4 AngII-Salt Increases Probability of Release of the OVLT→SONVP Connection ....... 56 3.3.5 AngII-Salt Increases Quantal Size of SONVP MNCs ................................................... 57 3.3.6 AngII-Salt Increases the Frequency and Amplitude of Asynchronous EPSCs ........... 58 3.3.6 AngII-Salt Discussion .................................................................................................. 59 3.3.6.1 Summary of AngII-Salt Results ............................................................................ 59 3.3.6.2 Possible Mechanism Underlying Increased Synaptic Gain in AngII-Salt ............ 60 4. General Discussion and Conclusion ...................................................................................... 70 4.1 Summary of Thesis Motivation and Results ....................................................................... 70 4.2 Comparison of the Salt-Sensitive Hypertension Models .................................................... 70 4.3 Perspectives of Thesis Results in Regards to Global Health .............................................
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