Saudi Cultural Missions Theses & Dissertations
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Item Restricted INVESTIGATING CHANGES IN ANGIOTENSIN II SIGNALLING, RESPIRATORY VARIABILITY AND CAROTID BODY FUNCTION IN RESPONSE TO CHRONIC HYPOXIA(University of Birmingham, 2024-08-05) Aldossary, Hayyaf Saad; Holmes, Andrew; Coney, AndrewChronic hypoxia (CH) and rises in circulating angiotensin II (Ang II) are key features of chronic obstructive pulmonary disease (COPD), an illness associated with respiratory dysfunction. Hypertension is an important co-morbidity in COPD. It has recently been suggested that the carotid body (CB) has an important role in causing vascular dysfunction in COPD patients. In response to CH, the CB undergoes extensive structural and functional adaptation, leading to hyperactivity. It is proposed that CB hyperactivity contributes to hypertension development in CH/COPD. The CB serves as a peripheral chemoreceptor located at the common carotid artery bifurcation, sensing and reacting to alterations in arterial O2, CO2, and pH levels. Previous studies have suggested the involvement of Ang II and its G Protein-Coupled Receptor (GPCR) member, AT1R, in mediating CB activity. It is currently unknown if the membrane arrangement of AT1Rs is altered by CH. It is not clear if Ang II stimulation involves activation of TRPC channels. Furthermore, a role for heightened Ang II-AT1R-TRPC signalling in mediating CB hyperactivity in response to CH remains uncertain. Key aims of this thesis were to: 1. Assess if AT1R membrane protein expression is increased in CH, 2. Explore how single molecule organisation of AT1R is modified by CH, 3. Provide a detailed evaluation of respiratory changes induced by CH, 4. Identify if CB Ang II-TRPC signalling is upregulated in CH and 5. Determine if targeting Ang II-TRPC signalling in vivo decreases the blood pressure in CH animals. In Chapter 2 and 3, utilizing the PC12 cell line as a surrogate for CB type I cells, it was revealed that AT1R protein expression was elevated by CH, accompanied by modifications in cell size, suggesting adaptive responses to prolonged hypoxia. Subsequent investigations utilising super-resolution microscopy demonstrated that AT1Rs form distinct clusters in the cell membrane. Furthermore, the maximum cluster size is increased under CH, indicating enhanced supercluster formation. In Chapter 4, expanding beyond cellular responses, the impact of CH on respiratory variables was evaluated using whole body plethysmography. It revealed key alterations, such as rises in respiratory frequency, shortening of respiratory timings and elevations in inspiratory and expiratory drive. Furthermore, a decrease in breath to breath interval variability was observed after CH exposure. In Chapter 5, carotid sinus nerve (CSN) activity measurements showed augmented, more consistent responses to Ang II that were apparent in a greater proportion of fibres in the CH group, suggesting increased Ang II sensitivity. In the presence of Ang II, the TRPC channel blocker, specifically 2-APB, produced exaggerated inhibition of CB activity in the CH group, suggestive of a rise in Ang II-TRPC signalling. Lastly, in Chapter 6, cardiovascular measurements showed that single bolus injection of 2-APB did not successfully decrease the mean arterial pressure (MAP) or heart rate (HR) in CH animals. This is likely due to it not reaching a high enough concentration in the CB. These investigations provide comprehensive information regarding AT1R, CB and respiratory adaptations to CH. The findings should help guide the development of novel therapeutic interventions, based on targeting Ang II-AT1R-TRPC signalling, to treat CB hyperactivity in conditions such as COPD.11 0