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Title: The endothelin system in human cardiovascular physiology and pathophysiology
Author: Webb, D. J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Section 1 is concerned with exploring pharmacological responses to the ET family of peptides, the sarafotoxin analogue peptides, and ET antagonists, in human blood vessels in vivo. This was amongst the first work with ET-1 in humans, and certainly the first to use the sarafotoxins, ET receptor antagonists and ET converting enzyme (ECE) inhibitors. After characterisation of the pharmacological tools, it was possible to show clearly that endogenous ET-1 plays a physiological role in the control of peripheral resistance and blood pressure in healthy humans, suggesting important clinical applications for these agents. It was also shown that the ETA receptor is the major vasocontrictor receptor and that the major role in health of the ETB receptor is endothelium-dependent vasodilatation, enhancement of which may contribute to the beneficial clinical attributes of ETA receptor antagonism. In addition, local ET-1 infusion in the forearm circulation was shown to be a system whereby the clinical efficacy of systematically administered ET receptor antagonists could be modelled pharmacodynamically. Section 2-4 cover work confirming the substantial clinical utility of ET receptor antagonists and ECE inhibitors as vasodilators, particularly in essential hypertension, heart failure and renal failure. Other work, following congenital heart surgery, suggests that a cautious approach may be needed in some cases of pulmonary hypertension. Studies with neutral endopeptidase (NEP) inhibitors show unequivocally, but unexpectedly, that these agents are peripheral vasoconstrictors, and the evidence presented is consistent with this effect occurring because endogenously generated vascular ET-1 is an important substrate for NEP. Section 5 contains some miscellaneous but related studies, together with a series of review articles written from 1991-98 synthesising the literature at each stage and drawing conclusions about potential areas of major clinical interest in cardiovascular disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available