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Insulin resistance is a common fmding in many disease states such as impaired glucose tolerance/diabetes mellirus, acanthosis nigricans, polycystic ovarian syndrome, precocious pseudo-puberty, Syndrome X and obesity. Hypertensive subjects have been shown to be insulin resistant but the relationship between hypertension and insulin resistance still remains to be clarified. Studies were undertaken to investigate the possible cause and effect relationship between insulin resistance and hypertension in a non-obese genetic rodent model of hypertension, the Spontaneously Hypertensive (SH) rat. Skeletal muscle and adipose tissue are the major insulin sensitive tissues with respect to glucose utilisation with skeletal muscle being quantitatively the most important. Soleus muscle and adipocytes were isolated from SH, Wistar Kyoto 0NKY) and Wistar rats at 3, 5 and 18 weeks of age. Muscle and adipocyte preparations were incubated in the presence of radiolabelled glucose in order to assess the sensitivity of individual tissues to insulin· stimulated glycogen synthesis and insulin·stimulated lipogenesis respectively. At 3 weeks of age the soleus muscle of SH and WKY rats were less sensitive to insulin than Wistar controls. This effect is present prior to the 6nset of hypertension and points to muscle insulin resistance being part of the genetic background of both the SH and WRY rats. It is unlikely therefore that the decreased sensitivity of the soleus muscle is directly involved in the aetiology of hypertension in SH rats.

The present thesis investigates the effect of cyclical mechanical strain on the expression of vascular endothelial growth factor (VEGF); a potent cytokine produced by human vascular smooth muscle cells (VSMC). The initial investigations observed the expression of VEGF mRNA and peptide over time and then the effect of increasing the magnitude of strain applied to the cells.;The second area of study was to identify the effect of strain on a candidate intracellular signalling pathway, the mitogen activated protein kinase (MAPK) cascade. The experiments observed the effect of strain on the level of phosphorylated MAPK within the cells and the actual activity of MAPK isolated from cultured human VSMC. The effect of a MAPK pathway inhibitor (PD98059) on the phosphorylated peptide activity was also analysed.;The data submitted in this thesis demonstrates that the expression of VEGF mRNA and peptide are increased in a dose-dependent manner when exposed to cyclical mechanical strain and that the level of phosphorylated MAPK increases likewise. Furthermore, the addition of a MAPK inhibitor not only reduces the level of MAPK activation, but also the expression of VEGF. Taken together, these data identify a potential mechanism whereby strain can directly effect vascular permeability by regulating the expression of VEGF peptide through the MAP kinase cascade.

Hypertension is the underlying pathology in many cardiovascular diseases including stroke, diabetes, ischemic heart disease and renal failure. In the majority of cases there is no single factor underlying the onset of hypertension. However, most recently changes within the central nervous system (CNS) and autonomic nervous system (ANS) have been suggested as major contributors in the genesis and maintenance of this complex cardiovascular disorder.

Hypertension IS a major risk factor for CVD and unequivocal evidence has demonstrated a continuous and linear relationship between elevated blood pressure (BP) and stroke. Among the many established risk factors for hypertension, a novel gene- nutrient interaction with a potential role in BP has recently emerged. A common polymorphism (677C---)oT) in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) produces a variant enzyme with decreased activity, and recent work at this centre in premature CVD patients reported that stabilisation of the variant enzyme by administration of its cofactor riboflavin may lower BP. The aim of this thesis was to further investigate the association between the MTHFR 677C---)o T polymorphism and BP and to evaluate the potential modulating role of riboflavin. The findings of this thesis demonstrated that riboflavin supplementation at the dietary level (1.6mg/dI16weeks) produced a genotype-specific lowering of BP that was clinically significant and that this effect was not confined solely to high-risk CVD patients but may in fact be applicable to hypertensive patients generally with the TT genotype. Preliminary work using 24-hour ambulatory blood pressure monitoring (ABPM) reported a non-significant trend towards higher BP in those with the TT genotype compared to those with the CC and CT genotypes. It also appeared to suggest that MTHFR genotype may have an effect on nocturnal BP characterised by non- dipping status, itself a cardiovascular risk factor independently of 24-hour blood pressure. In conclusion this thesis has confirmed that the MTHFR 677 TT genotype is a risk factor for hypertension and that optimisation of riboflavin status offers a targeted nutritional therapy with clinically relevant effects on BP specifically in this genotype group. Given the frequency of this polymorphism worldwide and the global burden of blood pressure-related disease, these findings could have important public health implications.

Within the hypertensive population, younger individuals are particularly difficult to risk stratify, as current risk prediction algorithms perform unreliably in the young. especially in those at low or intermediate risk of an event. Consequently, there is a need to identify reliable surrogate predictors of c~rdiovascula r disease in order to enhance current risk prediction algorithms and provide a substrate for therapeutic intervention. Statins have been shown to positively influence the microvasculature beyond their lipid lowering effects, and therefore, therapeutic intervention at an earlier stage than is currently recommended may be more effective in preventing the development of macrovascular complications. In the present study, normocholesterolaemic hypertensive patients were randomized to receive 12 weeks of therapy with simvastatin 40mg followed by placebo treatment, or vice versa. Novel measures of Doppler ultrasound analysis were obtained from the carotid, central retinal (CRA), ophthalmic (OA) and brachial arteries together with flow-mediated dilatation (FMD) of the brachial conduit. A control group was used for baseline comparative purposes. Significant differences were detected between health and disease states in the di screte wavelet transform (OWT) analysis along with differences in entropy. In the brachial conduit, the DWI analysis following deflation of a sphygmomanometer cuff differed significantly between controls and cases, while the measurement of FMO itself did not return such significant differences. In the crossover study, differences were detected before and after treatment in the OWT analysis of waveforms obtained from the OA and eRA that were not apparent with any of the traditional measures. In summary, this study has demonstrated the potential application of novel methods of waveform analysis in the early detection of cardiovascular disease and perhaps even to guide therapeutic intervention. The use of statins in normocholesterolaemic hypertensive patients may produce improvements in microvascular function that are not detectable with traditional methods of Doppler ultrasound analysis.

There is limited evidence of the effect of potassium on endothelial function. Three studies suggest a beneficial effect. Potassium raises aldosterone which has a negative effect on cardiovascular health. We aimed to determine the effect of potassium on endothelial function and the renin-angiotensin-aldosterone system in patients with moderate cardiovascular disease risk. We investigated potential new diagnostic and therapeutic interventions in patients with primary hyperaldosteronism (P A). Lastly we reviewed the outcomes in patients with P A who underwent adrenal venous sampling (A VS). The first study was a randomised controlled crossover study with 40 patients at > 1 0% cardiovascular disease risk. Patients took either 64mmol potassium or placebo for 6weeks with 6week washout. Endothelial function was assessed using pulse wave analysis measuring change in augmentation index to endothelial dependent (salbutamol) and independent (GTN) vasodilation. The second study explored the diagnostic potential of the 250mcg synacthen test in 9 P A patients, 26 essential hypertensives and 26 normotensives. We explored the aldosterone response to gonadotrophin releasing hormone (GnRH) in 6 patients with P A and 15 controls. The final study was a retrospective review of A VS results and adrenalectomy outcomes in 100 patients with PA. Potassium significantly improved systolic blood pressure and but did not affect endothelial function. Plasma renin activity and aldosterone both increased with potassium. Patients with P A had an exaggerated response to synacthen and GnRH ,- compared to controls. Our retrospective analysis found a cortisol corrected aldosterone affected to unaffected adrenal ratio of>2.0 with concordant C'T fmdings accurately classified 95% of P A patients. With adrenalectomy, 97% of patients with unilateral disease had improved blood pressure. Potassium had no effect on endothelial function but lowered systolic blood pressure. The increase in aldosterone did not have a negative impact on the vasculature. The synacthen and GnRH tests offer potential new diagnostic and therapeutic options in P A.

Introduction There has been renewed interest in aldosterone, with evidence that those with primary hyperaldosteronism are at great risk of cardiovascular disease and have higher mortality rates than those with essential hypertension at a similar level. However, screening for primary hyperaldosteronism can be difficult. Aldosterone is also recognised to be a pro-inflammatory hormone, its effects resulting in vascular damage and cardiac fibrosis. Mortality benefits have been demonstrated in patients with heart failure, and post-M I with LV dysfunction following treatment with mineralocorticoid receptor antagonists. There is a link between aldosterone and hypertension and impaired insulin resistance. However evidence is lacking on the effect of eplerenone on insulin action. Methods Three studies are presented. In the first two studies salivary aldosterone is measured using a newly developed assay, initially in normotensive controls and then in a hypertensive cohort. The third study was a randomised, controlled, double-blind, crossover study, investigating the effects of the selective mineralocorticoid receptor antagonist Eplerenone on insulin action in a hypertensive cohort. Results Salivary aldosterone correlated well with serum aldosterone at 1200h in both the normotensive and hypertensive cohorts. Diurnal variation in salivary aldosterone concentration was also demonstrated in both cohorts. Treatment with eplerenone did not affect insulin sensitivity as assessed by a hyperinsulinaemic euglycaemic clamp. Conclusions Salivary aldosterone is a marker for serum aldosterone and varies across the day in both normotensive and hypertensive individuals. Eplerenone has a neutral effect on insulin action in man. Overall, these studies have addressed a number of practical issues concerning screening for primary hyperaldosteronism and shown a neutral effect of MR blockade on insulin action. These issues are highly relevant to current medical practice.

Neurocardiovascular instability (NCVI) describes a group of disorders related to the autonomic control of heart rate (HR) and blood pressure (BP). Figures for the prevalence of the principal components of NCVI, orthostatic hypotension (OH) and carotid sinus hypersensitivity (CSH), among asymptomatic individuals vary widely. Population and methodological differences are likely to account for this finding. OH and CSH are recognised risk factors for falls and syncope in selected groups although the strength of this association in an unselected older population remains unclear. Vascular disease and more particularly abnormal blood pressure control (hypertension and hypotension) are associated with cognitive decline in an older population.

Background: Raised blood pressure is associated with increased risk of heart disease, impaired endothelial function, structural and functional abnormalities in large and small vessels. It has been shown that dietary sodium and potassium intake play an important role in regulating blood pressure. One of sodium's major functions is to regulate blood volume and pressure including the flexibility of the blood vessels. Increased sodium intake contributes development of hypertension. On the other hand an increased potassium intake lowers blood pressure and experimental studies have shown beneficial effect on endothelial function, vasculature and heart. Previous studies have predominantly used potassium chloride whereas potassium in fruit and vegetables - the main dietary sources of potassium - exists as other types of potassium salt. Aims: The purpose of this work is to study the effect of changing dietary sodium and potassium intake on blood pressure, heart, large and small vasculature and endothelial function. Methods: We carried out two double blind randomized control trials and included 187 subjects in modest salt reduction study and 46 subjects in potassium supplementation study. In the salt reduction study participants were allocated in random order to take 90mmol slow sodium tablets or placebo tables daily for 6 weeks then crossed over to take the opposite. Participants were on a reduced salt intake throughout the whole study. In the potassium supplementation study participants were allocated to take 64mmol potassium chloride (KCL) or bicarbonate (KHC03) or placebo tablets for 4 weeks in the randomised crossover design. We measured BP, large vessel property using PWV and 2D imaging of proximal part of ascending aorta, echocardiographic parameters of LV mass and function. Microcirculation changes were measured by capillaroscopy and orthogonal polarization spectral imaging (OPS). Endothelial function was performed using FMD. Additionally albumin excretion, renin angiotensin aldosteron system activity and bone metabolism parameters were measured. Results: Modest salt reduction study showed significant decrease in BP, urinary albumin excretion, albumin/creatinine ratio and PWV. Echocardiographic parameters remained unaltered. Subgroup analysis showed significant reductions in BP and urinary albumin/creatinine ratio and PWV in blacks. We observed an increase in capillary density in all ethnic groups. Potassium supplementation did not affect office BP and only 24-h and day-time systolic BP was lower with KCL. Compared to placebo, both potassium salts significantly improved endothelial function, increased arterial compliance, decreased LV mass, and improved LV diastolic function. Increased capillary density was seen only when measured by OPS. The study also showed that KCL reduced urinary albumin excretion, and KHC03 improved bone metabolism. Conclusions: These results demonstrate that a modest reduction in salt intake, causes significant falls in BP, reduces urinary albumin excretion and improves large artery compliance in all 3 ethnic groups. Also improvement in both functional and structural capillary rarefaction was observed. Results of potassium supplementation demonstrated that an increase in potassium intake had beneficial effects on the cardiovascular system and KHC03 may improve bone health.