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Title: Regulation of vascular tone and renal function by endothelin in health and renal disease
Author: Goddard, Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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After confirming, in a dose ranging study, that ETA receptor blockade produces vasodilatation in healthy subjects, I have shown, in patients with chronic renal failure (CRF), that selective ETA but not combined ETA/B receptor antagonism produces substantial reductions in blood pressure that are associated with renal vasodilatation, a reduction in filtration fraction and a reduction in proteinuria, suggesting a renoprotective action. These data show that ET-1 plays a major role in regulating blood pressure and renal vascular resistance in CRF, consistent with activation of the ET system in this condition. By contrast, selective ETB receptor antagonism alone produced substantial systemic and renal vasoconstriction in both healthy subjects and CRF. Thus the effects of ETB receptor blockade, whether in the presence of ETA receptor blockade or not, suggest the net effect of ETB receptor activation on the circulation, in health and renal disease, is to produce vasodilatation. Clearance of ET-1 from the circulation is also reduced during ETB receptor blockade and studies of urinary ET-1 excretion under conditions of ET receptor blockade suggest that renal tubular excretion of ET-1 is at least partly mediated through the ETB receptor. I have also explored the interaction between the ET and renin-angiotensin systems, demonstrating that, while ETA receptor antagonism does not alter the pressor effect of angiotensin II, prior angiotensin converting enzyme inhibition will enhance the effect of ETA receptor blockade in healthy subjects to produce a picture similar to that seen in CRF, an action mediated by nitric oxide, and abolished by concomitant ETB receptor blockade.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available