Buckley, Christine Helen;
(1994)
The impairment of endothelium-dependent relaxations in isolated rabbit aorta and coronary arteries by low-density lipoproteins and oxidised fatty acids.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Vasodilation mediated by endothelium-derived relaxing factor (EDRF) is accounted for by the release of nitric oxide from the endothelium in response to acetylcholine and other agents. In isolated arteries from atherosclerotic and hypercholesterolaemic animals endothelium-dependent responses are attenuated. This dysfunction may result from the accumulation of oxidised low-density lipoproteins (OXLDL) within the vessel wall, a process known to contribute to the pathogenesis of atherosclerosis. Previous studies have shown that LDL oxidised by Cu2+ inhibits endothelium-dependent relaxation in isolated rabbit aorta and porcine coronary arteries. This study investigated the effects of Cu2+-oxidised LDL on relaxations in rabbit large coronary arteries and small resistance vessels which do not exhibit overt signs of atherosclerosis. The effects of lipoxygenase metabolites of linoleic and arachidonic acid, which are present in OXLDL, on vascular reactivity of rabbit aorta were also investigated. Oxidised, but not native, LDL caused a reversible inhibition of endothelium-dependent relaxations evoked by ACh in isolated rabbit coronary arteries precontracted with either PGF2α or KC1. Furthermore, the extent of the inhibitory effect was similar in both large and small coronary arteries. Relaxations evoked by the nitrovasodilator SNP were unaffected by the presence of OXLDL. Hydroperoxy and hydroxy derivatives of linoleic and arachidonic acid, which have been identified in OXLDL, caused an immediate and reversible attenuation of ACh-evoked relaxations in isolated rabbit aorta. The inhibition was prevented by the addition of the protein kinase C inhibitor chelerythrine chloride suggesting the inhibition is mediated through a mechanism involving the activation of protein kinase C. Metabolites of arachidonic but not linoleic acid inhibited endothelium-independent relaxations evoked by GTN. In addition, arachidonic acid oxidation products caused a direct contraction of rabbit aortic rings which was not altered by the presence of the endothelium. LDL modified by treatment with lipoxygenase (LO-LDL) also inhibited endothelium-dependent relaxations in rabbit aorta by a mechanism involving protein kinase C and not dependent on uptake via the scavenger receptor. Relaxations evoked by GTN were reversibly attenuated by the presence of LO-LDL. In conclusion, the inhibitory effect of OXLDL in coronary vessels suggests that the effects of atherosclerosis on vascular function may extend into the microcirculation. Products of fatty acid peroxidation may contribute, with other constituents of OXLDL, to the impairment of coronary vasodilation observed in atherosclerosis and hypercholesterolaemia. Arachidonic acid metabolites may also be involved in enhanced vasoconstrictor responses and vasospasm.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The impairment of endothelium-dependent relaxations in isolated rabbit aorta and coronary arteries by low-density lipoproteins and oxidised fatty acids |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Health and environmental sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10102515 |
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