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Study of Vitamin D and Hidroximetilglutaril CoA Redutase inhibitors administration on Endothelial Function and Renin-Angiotensin-Aldosterona System in patients with hypertension: a Double-Blind Placebo-Controlled Study.


Hypertension, a major risk factor for cardiovascular diseases entails a large impact on morbidity and social cost of the affected population. For over two decades, it has been evaluated potential benefits of vitamin D supplementation in hypertension treatment. Publications based on cross-sectional observations demonstrate an inverse association between serum vitamin D levels and blood pressure values. However, the number of intervention studies is limited and casts inquiries about the causal relationship, long-term interaction and benefit of cholecalciferol supplementation on blood pressure control. One of the possible mechanisms attributed to potential hypotensive effect of cholecalciferol relates to the stabilization of endothelial function and interaction with the renin - angiotensin system. Endothelial dysfunction marker and promoter, the asymmetric dimethyl-arginine (ADMA) is a potent competitive inhibitor of nitric oxide synthase, the enzyme responsible for nitric oxide (NO) synthesis. Recently, it was demonstrated that patients with low serum 25 -OH vitamin D exhibit high levels of ADMA relating the vitamin insufficiency with endothelial dysfunction mediated by absolute or relative deficiency of NOS. In the context of endothelial function study, we highlight the growing evidence of inhibitors of 3 - hydroxymethylglutaryl CoA reductase inhibitors (statins) in reducing inflammation through pleiotropic effects involved in the benefits provided in primary and secondary prevention of cardiovascular events. Recent publications report a relation between statin and vitamin D, demonstrating that the addition of HMG-CoA reductase inhibitors provides an increase in serum levels of the latter and in which high levels of vitamin D are associated with beneficial changes in lipid profile, characterized by the preponderance of particles of HDL cholesterol of greater diameter.This study, divided into clinical and experimental protocol, aims to investigate the effect of the association between atorvastatin and vitamin D3, compared with their respective placebos, on blood pressure, endothelial function measured by asymmetric dimethyl arginine (ADMA), inflammatory profile and bone metabolism in patients with hypertension. The clinical protocol, in a double-blind placebo-controlled study, sixty-treated hypertensive patients will be randomized into four groups (2x2 factorial design study) and followed for 20 weeks. Eligible subjects will be randomized in a 1:1:1:1 ratio. Blood pressure will be evaluated by pressure measurements during consultations and through MAP and tonometry (ATCOR) and bone metabolism will be assessed. The experimental protocol consists in the study of endothelial function measured by ADMA and the renin-angiotensin system in cultured endothelial cells (HUVEC) exposed to a serum pool from the four groups of subjects selected for clinical protocol. Inflammatory activity and reactive oxygen species measurement produced by HUVEC will be analyzed by flow cytometry. Reactions using primers specific for ADMA, VDR, TNF-alpha, IL-10 and angiotensin II genes and genes housekeepers will be systematically performed and all values obtained for genes of interest are normalized by these results. (AU)