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Title: A role for brain adrenomedullin receptors in hypertension?
Author: Milosavljevic, Snezana
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Hypertension (elevated arterial blood pressure) is a major risk factor for cardiovascular disease. Despite the prevalence and menace of essential hypertension, little is known about the fundamental pathophysiological aetiology. Recently, the concept of neurogenic hypertension has placed the kidney into a feedback network that involves hypothalamic and brainstem structures that generate hormonal and sympathetic tone, and directly influence long-term pressure regulation. I have studied neurogenic hypertension in genetically spontaneously hypertensive rats (SHRs), as compared to normotensive controls. Previous comprehensive microarray analysis of six different brain regions identified 396 transcripts differentially expressed between normotensive Wistar Kyoto (WKY) rats and SHRs, revealing candidate genes that correlate with the dysregulation of cardiovascular parameters in hypertension. My studies have focussed on G-protein-coupled receptor (GPCR) GPR182, which is thought to mediate adrenomedullin (ADM) peptide signalling. GPR182 is up-regulated in the rostral ventrolateral medulla (RVLM) of SHR compared to WKY rats. Chronic attenuation of GPR182 receptor expression in the RVLM of SHR and Wistar rats aimed to examine a potential novel target associated with the pathogenesis of neurogenic hypertension. A comprehensive study demonstrated that ADM peptide administration in the RVLM of SHR and Holtzman rats significantly increased mean arterial blood pressure (MAP). Additionally, ADM antagonist administered bilaterally in the RVLM produced a significant decrease in MAP in SHR, but in contrast, no change in Hotzman rats. These results suggest that higher RNA transcript levels reflect potent endogenous ADM mediated activation of cognate receptors (maybe GPR182) in the RVLM of SHR. Finally, I have studied the effects of hypoperfusion of the brainstem, induced by increased cerebrovascular resistance, which activates the sympathetic nervous system, generating hypertension. Hyperbaric oxygenation in neonatal rats is proposed to improve blood flow and oxygen distribution in the brain of SHR. The hyperbaric experimental protocol had an influence on blood pressure in SHR and Wistar rats.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available