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An Investigation Into the Cerebral Autoregulatory Upper Limit: Normal Control Mechanisms and Changes Associated with Ageing

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An Investigation Into the Cerebral Autoregulatory Upper Limit: Normal Control Mechanisms and Changes Associated with Ageing AN INVESTIGATION INTO THE CEREBRAL AUTOREGULATORY UPPER LIMIT: NORMAL CONTROL MECHANISMS AND CHANGES ASSOCIATED WITH AGEING by EMMA LOUISE THOMPSON Student ID: 874535 A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Supervisors: Professor Janice Marshall and Dr Andrew Coney Institute of Cardiovascular Sciences College of Medical and Dental Sciences University of Birmingham October 2017 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Cerebral autoregulation (CA) is the process by which cerebral arterial vessels constrict or dilate, in order to maintain cerebral blood flow (CBF) in the face of changes in arterial blood pressure. This thesis aimed to investigate the mechanisms that normally control CA, with specific reference to the upper limit (UL); the point at which autoregulatory vasoconstriction is overcome. The UL is associated with an increase in CBF, which can potentially cause damaging cerebrovascular hyperperfusion. Ageing is associated with a general decrease in regulatory mechanisms, and an increased risk of stroke. Therefore we sought to assess whether changes in CA at the UL may predispose older rats to haemorrhagic stroke. We assessed CA by infusion of phenylephrine to increase ABP in an anaesthetised rat model, whilst measuring CBF to enable identification of the UL. This protocol was repeated in young (6-8 weeks) and old (12-15 months) rats in control conditions, or during removal of regulatory inputs. The UL in young, control rats was 168±4mmHg. Removal of nitric oxide- mediated dilatation and sympathetically-mediated vasoconstriction increased the UL. In old rats, the increase in UL was even greater. Thus we propose a new working hypothesis to explain the control of CA and the UL. DEDICATION I would like to dedicate this thesis to a number of people. Firstly, to my wonderful family; my parents Neil and Julie, my sister Ellen, my grandparents Pam and Malcolm, my great aunt Joyce, and my extended family, who have all supported me throughout my time at university. Secondly, to my kind and patient fiancé, Chris, who has been there for me during this challenging and amazing experience. And finally in loving memory of my grandparents Jean and Brian, who always believed in me. ACKNOWLEDGMENTS Firstly, I wish to acknowledge my supervisors Professor Janice Marshall, and Dr Andrew Coney, for their invaluable advice, patience, encouragement, expertise, experimental abilities, and vast knowledge. Their help and support has been instrumental throughout my PhD, and I want to express my sincere and heartfelt gratitude for their part in such a rewarding experience. Secondly I want to acknowledge my colleagues, who have become dear friends; Professor Prem Kumar, Dr Clare Ray, Dr Andrew Holmes and Dr Clare Box. Their kindness and friendship throughout my PhD has kept me going during difficult times, brought me happiness and laughter, and created memories that will last me a lifetime. I would also like to acknowledge Dave Westwood, for his excellent technical support during my experiments. Finally, I would like to acknowledge the British Heart Foundation for their generous funding of this PhD. I would also like to thank the Physiological Society, the College of Medical and Dental Sciences overseas travel fund, and the Elizabeth Watson Davidson award, for travel grants that enabled me to attend national and international conferences to present my work. TABLE OF CONTENTS CHAPTER 1: GENERAL INTRODUCTION ................................................................................................... 1 1.1 The Cerebral Circulation ................................................................................................................ 1 1.2 Methods for Investigation of Cerebral Autoregulation ................................................................ 3 1.2.1 Cerebral blood flow measurements in humans ..................................................................... 3 1.2.2 CBF measurement in animals ................................................................................................. 7 1.3 Mechanisms involved in the control of cerebral blood flow ...................................................... 15 1.3.1 Autoregulation ..................................................................................................................... 15 1.3.2 Metabolic/chemical control of cerebral blood flow ............................................................ 18 1.3.3 Autonomic control of cerebral blood flow ........................................................................... 22 1.3.4 Endothelial mediators affecting cerebral blood flow: Nitric oxide ...................................... 31 1.3.5 Regional differences in cerebral autoregulation .................................................................. 37 1.3.6 Summary: Mechanisms involved in the control of cerebral blood flow .............................. 39 1.4 Ageing .......................................................................................................................................... 42 1.4.1 The ageing population .......................................................................................................... 42 1.4.2 The use of animal models to study ageing ........................................................................... 44 1.4.3 The effects of age on the cardiovascular system and cerebral vasculature ........................ 48 1.4.4 The effects of ageing on cerebral endothelial structure and function ................................ 50 1.4.5 Ageing and oxidative stress .................................................................................................. 56 1.4.6 The effects of age on autonomic control of the cerebral vasculature ................................. 61 1.4.7 The effects of ageing on cerebral blood flow and autoregulation ....................................... 67 1.4.8 Ageing and the upper autoregulatory limit: Clinical implications for haemorrhagic stroke 71 1.5 Aims and Hypotheses .................................................................................................................. 72 CHAPTER 2: GENERAL MATERIALS AND METHODS .............................................................................. 82 2.1 Animals ........................................................................................................................................ 82 2.2 Anaesthesia and surgery ............................................................................................................. 83 2.2.1 General surgery .................................................................................................................... 83 2.2.2 Additional surgery ................................................................................................................ 84 2.3 Equipment and data acquisition ................................................................................................. 85 2.3.1 Using flow probes to measure global CBF ............................................................................ 86 2.3.2 Using Laser Doppler/Laser Speckle imaging to measure cortical CBF ................................. 87 2.4 Drugs and solutions ..................................................................................................................... 88 2.5 Stabilisation ................................................................................................................................. 88 2.6 Experimental protocols ............................................................................................................... 90 2.6.1 Assessment of the cerebral autoregulatory upper limit (UL) .............................................. 90 2.7 Data analysis ................................................................................................................................ 90 2.7.1 Cardiovascular and blood flow data ..................................................................................... 90 2.7.2 Laser speckle data ................................................................................................................ 91 2.7.3 Analysis of Gross and cortical UL ......................................................................................... 92 2.8 Statistical analyses ...................................................................................................................... 93 CHAPTER 3: METHOD DEVELOPMENT .................................................................................................. 98 3.1 Introduction................................................................................................................................. 98 3.1.1 Measurement of cerebral blood flow .................................................................................. 98 3.1.2 Methods for assessment of cerebral autoregulation .........................................................
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