| Summary: | Recently, two novel S-nitrosothiols, N-(S-nitroso-<i>N</i>-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6,tetra-<i>O</i>-acetyl-β-D-glucopyranose (RIG200) and S-nitroso-<i>N</i>-valerylpenicillamine (SNVP), have been described to have selectivity for endothelium-denuded blood vessels. Therefore, they are particularly appealing in the treatment of conditions where the vascular endothelium is damaged. This thesis describes experiments which further elucidate the mechanism of action and therapeutic of these novel S-nitrosothiols, by comparison to conventional NO donors. The key findings were that S-nitrosothiol-mediated vasodilator activity is a complex process that is dependent on intracellular antioxidant molecules, particularly glutathione. The site of NO release influenced both its susceptibility to inactivation by reactive oxygen species and the extent of sGC involvement. Evidence is also presented to show that the novel S-nitrosothiols do no induce self-tolerance with prolonged administration and remain fully active in nitrate-tolerant vessels. Experiments then focused on the sustained actions of lipophilic S-nitrosothiols in models of endothelial damage. Firstly, GlycoSNAP, an analogue of RIG200 with poor lipophilicity, failed to produce a sustained vasodilatation in endothelium-denuded rat femoral arteries. This result lends weight to the hypothesis that lipophilic S-nitrosothiols exert a sustained vasodilatation in arteries with damaged endothelium through retention in lipid-rich sub-endothelial layers. In the model of balloon angioplasty, the conventional NO donor, glyceryl trinitrate, had no significant effect on platelet adhesion to damaged carotid arteries and also caused a substantial and potentially undesirable fall in blood pressure. In contrast, SNVP caused a >60% reduction in platelet adhesion at a concentration that had minimal effects on blood pressure. The results suggest that these novel compounds may have applications in the treatment of a range of cardiovascular conditions, including atherosclerosis, thrombosis and the prevention of restenosis following bypass grafting and stenting.
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