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Characterisation of endothelial function in conduit and resistance arteries in chronic renal failure

Cross, Jenny; (2003) Characterisation of endothelial function in conduit and resistance arteries in chronic renal failure. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Cardiovascular disease remains the leading cause of death in patients with renal failure. In common with other risk factor groups associated with accelerated atherogenesis such as diabetes mellitus and hyperlipidaemia, atherosclerosis is preceded by vascular dysfunction in renal failure. This thesis investigates the mechanisms of vascular dysfunction in renal failure, with particular reference to reduced bioactivity of the nitric oxide (NO) pathway. I have used in vivo techniques to study the activity of the NO pathway in both conduit and resistance arteries. To assess the effect of circulating uraemic toxins on endothelial function, flow-mediated vasodilatation (FMD) of the brachial artery was measured before and after dialysis. I demonstrated that haemodialysis resulted in rapid clearance of uraemic toxins from plasma and transiently increased FMD; in contrast, automated peritoneal dialysis treatment did not reduce levels of uraemic toxins or improve FMD. These data suggest that acute reduction of circulating inhibitors of endothelial function is associated with improved endothelial function in conduit vessels. To explore this further, the role of competitive inhibition of NO synthase by L-arginine analogues was investigated by administering the natural substrate, L-arginine. Despite normalising the ratio of plasma arginine/NO synthase inhibitors, there was no improvement in either conduit or resistance artery endothelial function. These findings imply that in renal failure, impaired endothelium-dependent vasodilatation is not solely due to competitive inhibition of NOS. I examined whether reactive oxygen species may contribute to impaired endothelial function in uraemia. The acute administration of the anti-oxidant, vitamin C, reduced biochemical markers of oxidant stress and improved endothelial function of resistance, but not conduit arteries. In conclusion, the mechanisms responsible for endothelial dysfunction in uraemia remain obscure. I have shown, however, that endothelial function can be corrected by both acute haemodialysis and by an acute increase in plasma anti-oxidant capacity. The observed beneficial effect of haemodialysis on vascular function may explain reports of improved cardiovascular outcome in patients who routinely undergo long hour or daily haemodialysis treatments. It remains to be seen whether other interventions, such as statin therapy, which are known to improve endothelial function can confer similar outcome benefit in this high risk patient group.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Characterisation of endothelial function in conduit and resistance arteries in chronic renal failure
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Chronic renal failure
URI: https://discovery.ucl.ac.uk/id/eprint/10107296
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