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Title: Mechanisms of glucocorticoid programmed disease
Author: O'Regan, David
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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This thesis investigates the role of the renin-angiotensin (RAS), and sympathetic nervous systems (SNS) in determining programmed hypertension, and further seeks to determine whether programming effects are sexually dimorphic. DEX administration in the last week of gestation reduces offspring birth weight and programmes adult cardiovascular and metabolic physiology in a sex specific manner. In male offspring, prenatal glucocorticoid exposure programmes elevated basal circulating corticosterone, elevated PEPCK activity, and produces adulthood postglucose hyperglycaemia and hyperinsulinaemia. Whilst in female offspring, prenatal DEX programmes elevated hepatic angiotensinogen mRNA expression, elevated plasma angiotensinogen and renin activity, and produces hypertension, when measured by tail-cuff plethysmography. Unlike previous studies, offspring blood pressure was subsequently assessed with radiotelemetry, which is unmarred by any stress artefact. We no demonstrate that prenatal DEX-treated male and female offspring actually display lower basal blood pressure in adulthood; with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to any stressor. Moreover, DEX-treated offspring sustain their stress-induced hypertension for longer. These hypertensive responses are mediated by alterations in the responsitivity of the sympathetic nervous system, being ameliorated by the inhibition of catecholamine synthesis, and further exaggerated by the promotion of systemic catecholamine release. Additionally, we demonstrate that DEX-treated offspring display greater sensitivity to various vasoconstrictors in the isolated mesenteric vasculature. These findings demonstrate that in utero over-exposure to glucocorticoids actually results in stress-induced hypertension, and support a role for both RAS and SNS in mediating this. Furthermore, it appears that the programming of cardiovascular physiology may reflect distinct processes in each gender, whilst the programming of metabolic physiology is male specific.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available