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dc.contributor.authorVelmurugan, Shanti
dc.identifier.citationVelmurugan, S. 2014. Investigation of the effect of inorganic nitrate on platelet and endothelial function in healthy individuals and in patients with hypercholesterolaemia. Queen Mary University of London.en_US
dc.description.abstractIngestion of vegetables rich in inorganic nitrate (NO3-) content has emerged as an effective method, via the formation of a nitrite (NO2-) intermediate, for acutely elevating vascular nitric oxide (NO) levels. As such a number of beneficial effects of NO3- ingestion have been demonstrated including the suggestion that platelet reactivity is reduced. I initially investigated whether inorganic NO3- supplementation might also reduce platelet reactivity in healthy volunteers and have determined the mechanisms involved in the effects seen. I conducted a randomised crossover study in 24 (12 of each sex) healthy subjects assessing the acute effects of potassium nitrate capsules (KNO3, 8 mmol) vs placebo (KCl) control capsule ingestion on platelet reactivity. Inorganic NO3- ingested via supplementation raised circulating NO3- and NO2- levels in both sexes and attenuated ex vivo platelet aggregation responses to adenosine diphosphate (ADP) and, albeit to a lesser extent, collagen but not epinephrine in male but not female volunteers. These inhibitory effects were associated with a reduced platelet P-selectin expression and elevated platelet cyclic guanosine monophosphate (cGMP) levels. In addition, I have shown that NO2- reduction to NO occurs at the level of the erythrocyte and not the platelet. These results demonstrate that inorganic NO3- ingestion, whether via the diet or through supplementation, results in a modest decrease in platelet reactivity in healthy males. I then sought to examine the effects of 6 weeks daily intake of NO3--rich beetroot juice versus a placebo NO3--deplete juice on endothelial and platelet function in a cohort of otherwise healthy non-diabetic untreated hypercholesterolaemics. In this randomised double blind placebo controlled parallel study 69 subjects were recruited. The primary end point was change in endothelial function determined using ultrasound flow-mediated dilatation (FMD). Secondary endpoints included change in pulse wave analysis (PWA), aortic pulse wave velocity (aPWV), platelet P-selectin and platelet monocyte aggregate (PMA) expression and plasma, urine and salivary NO3- and NO2- levels. Baseline characteristics, including lipid levels, were similar between the groups. Dietary NO3- caused an improvement in FMD of ~24% from 4.6%±2.2% to 5.7%±2.6% in the treatment group (p<0.001) not seen in the placebo group (4.5%±1.9% versus 4.3%±1.8% p=0.07). This improvement in FMD was also noted following acute administration of dietary NO3-. Small but significant improvements also occurred in aPWV and PWA augmentation index (p=0.04). The % of platelet monocyte aggregates was significantly reduced in the NO3- limb by 7.6% versus an increase of 10.1% in the placebo group (p=0.004). No adverse effects of dietary NO3- were detected. In this study population, chronic dietary NO3- ingestion improves endothelial function, vascular stiffness and platelet markers of atherogenesis in a cohort of hypercholesterolaemics who are otherwise at increased risk of cardiovascular disease (CVD). This thesis provides strong support for assessment of the potential of dietary NO3- as a primary prevention strategy to prevent atherothrombotic and atherogenic complications in larger cohorts.en_US
dc.description.sponsorshipNIHR; British Heart Foundation
dc.publisherQueen Mary University of London
dc.subjectOrganic synthesisen_US
dc.subjectSmall ringsen_US
dc.subjectHorner–Wadsworth–Emmons procedureen_US
dc.titleInvestigation of the effect of inorganic nitrate on platelet and endothelial function in healthy individuals and in patients with hypercholesterolaemia.en_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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