[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Two randomised controlled trials were conducted to explore the relationship between the consumption of alcoholic beverages and cardiovascular disease risk factors. Study 1 was primarily designed to test the hypothesis that the cardio-protective effect of light alcohol could be mediated, in part, via improvements in endothelial function. Study 1 was also designed to explore the effect of alcohol on both traditional risk factors for cardiovascular disease, such as changes in lipid profile, haemostatic factors and blood pressure, and novel risk factors such as homocysteine, markers of inflammation and oxidative stress. The experimental design of this study also allowed us to determine whether reducing alcohol intake in these moderate-to-heavy drinkers could improvement insulin sensitivity, a component of the metabolic syndrome. In this group of sixteen healthy middle-aged men with a history of moderate to heavy alcohol intake of seven standard drinks per day, reducing intake down to approximately one standard drink per day for four weeks had no beneficial effects on conduit vessel endothelial function as assessed by post-ischaemic brachial artery flow-mediated dilatation, nor were there any detectable changes in soluble E-selectin, endothelin-1 and von Willebrand Factor, which are considered biomarkers of endothelial activation. As this study did not investigate the effect of alcohol on endothelial function in resistance vessels, it cannot exclude the possibility that alcohol may affect endothelial cells resident in that vascular bed. This study does show and confirm, however, that the relationship between alcohol and risk factors for cardiovascular disease is an extremely complex one. On the one hand it demonstrated that alcohol was potentially harmful, increasing blood pressure, plasma F2-isoprostane (oxidative stress), and homocysteine. On the other hand it showed that increasing alcohol intake led to significant reductions in two (i.e. fibrinogen and IL-6) of five inflammatory markers, in addition to improving the HDL-cholesterol profile of these subjects. Although the effects of alcohol on blood pressure, fibrinogen and HDL-cholesterol are not in themselves new, they support our choice of study design and strengthen the argument in favour of accepting the more novel findings of this study, specifically, the lack of effect on endothelial function and insulin sensitivity, and the harmful effect of alcohol in increasing oxidative stress and homocysteine. Study 2 was primarily designed to test the hypothesis that the consumption of red wine may confer greater cardio-protection than beer via improvements in endothelial function. Simultaneously, the study was also designed to determine whether drinking red wine for 4-weeks would have different effects than beer on either traditional risk factors for cardiovascular disease (i.e. blood pressure and lipid profile) or the more novel risk factors, homocysteine and oxidative stress. Using a randomised controlled cross-over study design, Study 2 provides evidence that the regular daily consumption of 4 standard drinks of either beer or red wine does not alter endothelial function, as measured by post-ischaemic flow-mediated vasodilatation of the brachial artery in healthy middle-aged men, nor was there evidence of any beneficial effect of de-alcoholised red wine on brachial artery response. As compliance with drinking protocol was confirmed with increased serum γ-GT and HDL during red wine and beer periods, and increased 24-hr urinary excretion of 4OMGA during red wine and de-alcoholised red wine periods, we are confident that there was excellent compliance with the beverage treatments. Study 2 also provides the first evidence from a carefully controlled intervention study that both red wine and beer elevate blood pressure to a similar degree, with no detectable difference in the magnitude of either treatment. As with endothelial function, there was also no evidence of any beneficial effect of de-alcoholised red wine on blood pressure. In addition, although post hoc analysis found evidence that alcohol increased both plasma homocysteine and urinary excretion of F2-isoprostane and endothelin-1, there was no apparent protective effect conferred from either red wine or de-alcoholised red wine on these cardiovascular risk markers. The results from this study cannot disprove the hypothesis that red wine is more beneficial for cardiovascular health; however, they suggest that if red wine has properties beyond those of beer to confer protection, they are not via any interactions with the nitric oxide regulatory function of the endothelium in conduit vessels nor are they via moderation of the vasopressor, homocysteine-raising, and oxidative stress effects of alcohol. The interpretation of the findings from both intervention studies and their place in the context of our current understanding of the role that alcoholic beverages play in the development and/or prevention of cardiovascular disease are explored in this thesis.

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