Plane, Frances; (1992) Low-density lipoproteins and vasomotor responses in the rabbit aorta. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The relationship between elevated plasma levels of low- density lipoproteins and the development of atherosclerosis is well established and recent evidence suggests that oxidation of LDL is a key process in atherogenesis. Clinical and experimental studies have shown that, in isolated blood vessels from hypercholesterolemic and atherosclerotic animals and humans endothelium-dependent relaxations (EDR) are inhibited whereas contractile responses to some agonists are potentiated. This study investigated the effects of human LDL and oxidized LDL (OXLDL) on EDR and contractile responses in isolated rabbit aortic rings. LDL (2 mg protein/ml) caused an immediate, reversible attenuation of EDR elicited by acetylcholine (ACh) and A23187 in tissues pre-contracted with noradrenaline (NA) and serotonin (5-HT) but not in aortic rings contracted to PE. The inhibition was abolished by the addition of the anti-oxidants probucol and ascorbic acid, indicating that an oxidative interaction between LDL and NA or 5-HT may play a role. Relaxations to nitric oxide (NO), the proposed mediator of EDR, were also attenuated in the presence of LDL, but endothelium-independent relaxations evoked by glyceryl trinitrate were unaffected indicating that LDL may directly inactivate NO but does not inhibit activation of vascular smooth muscle soluble guanylate cyclase. OXLDL also inhibits EDR but the extent and reversibility of the inhibition is dependent on the donor of the plasma from which the LDL was prepared. The inhibition of EDR by OXLDL requires 30 mins pre-incubation and is independent of the agonist used to pre-contract the tissues. High-density lipoproteins (HDL) and serum albumin decreased the inhibition of EDR by OXLDL, indicating that the transfer of lipid components from the OXLDL may be involved. All preparations of OXLDL reversibly attenuated NO evoked relaxations and caused a reversible decrease in sensitivity to GTN. LDL and OXLDL can also modulate contractile responses and in the presence of all preparations of LDL and OXLDL contractile responses to NA were reversibly attenuated whereas contractions to 5 HT were potentiated. In conclusion, both LDL and OXLDL can modulate EDR and contractile responses and thus, may contribute to the alterations in vascular reactivity observed in hypercholesterolemia and atherosclerosis.

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