Heart failure is associated with significant morbidity, mortality and economic cost. Over the past 30 years our understanding of the pathophysiology of heart failure has advanced greatly. However, morbidity and mortality remain high and further improvements in therapy are necessary. Pre-clinical data suggest that the novel peptide apelin, acting through the APJ receptor, has anti-hypertensive, vasodilator, diuretic and inotropic actions and an antagonistic relationship with angiotensin-II. These findings are of obvious interest in heart failure, particularly as plasma and myocardial apelin concentrations are reduced in patients with advanced heart failure. Consequently, it is hypothesised that upregulation of the apelin-APJ system may be of therapeutic value. The aims of this doctoral thesis were therefore to delineate the actions, mechanisms of action and relative efficacy of apelin; compare the arterial vasodilator action of apelin in health and heart failure; and examine the interactions of apelin with other key neurohormones in health and heart failure. This was achieved using wire myography and organ bath techniques in an array of animal and human blood vessels and in a validated rabbit model of post-myocardial infarction heart failure. Apelin is a modest nitric oxide and prostanoid dependent vasodilator at supra-physiological concentrations in small arteries. No such effect was noted in larger arteries or veins. This vasodilator action is abolished in heart failure, whilst response to acetylcholine is preserved suggesting an apelin-APJ specific abnormality in this syndrome. Apelin has an antagonistic relationship with endothelin-1 and synergistic relationship with B-type natriuretic peptide in normal small arteries. Again, these putative cardioprotective properties are lost in heart failure. These data suggest that the putative cardioprotective properties of apelin are lost in heart failure.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:569598 |
| Date | January 2012 |
| Creators | Dalzell, Jonathan |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=192161 |
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