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Title: Endothelin in man : studies in pharmacology, physiology and pathophysiology
Author: Ferro, Charles Joseph
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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In this thesis I review the biology of endothelin as well as discuss the evidence supporting a pathophysiological role for endothelin in a number of cardiovascular and renal diseases. In the studies described, I have further investigated the physiology of the endothelin system as well as examined the pharmacology of endothelin receptor antagonists in man. Finally, I have also examined the role of endothelin in the pathophysiology of chronic renal failure and essential hypertension. Study 1: Inhibitors of the enzyme, neutral endopeptidase cause forearm vasoconstriction when infused into the brachial artery. This enzyme appears to significantly contribute to the breakdown of endothelin in vivo. Study 2: Big ET-3 is converted to the mature peptide ET-3 in the forearm circulation, but not in capacitance vessels. This study suggests the existence of a third endothelin-converting enzyme capable of converting big ET-3. Study 3: Systemic doses of TAK-044, a non-selective endothelin receptor antagonist, lowers vascular resistance and blood pressure in man, demonstrating that endothelin contributes to the maintenance of blood pressure in health. Study 4: Systemic TAK-044 completely blocks the local vasoconstriction produced by intrabrachial artery infusion of ET-1 for up to 3 hours. This finding has implications for the treatment of acute vasospastic conditions. Study 5: Systemic doses of TAK-044 only partially block ET-1 mediated vasoconstriction for 12 hours. This has important implications for dosing schedules in potential therapeutic interventions. Study 6: TAK-044 causes renal vasodilatation and lowers effective filtration fraction by a relative decrease in glomerular filtration rate and increase in effective plasma flow in healthy volunteers. This study demonstrates that endothelin has a role in controlling the renal circulation. Study 7: TAK-044 lowers systemic vascular resistance and blood pressure in patients with chronic renal failure, with a reduction in effective filtration fraction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available