Chapter 7 162 placebo 10. In the absence of large, well designed RCTs in the field of magnesium and CVD endpoints, the lack of solid data on bio-availability of magnesium and limited possibilities to judge whether observed effects are attributed to magnesium or to the counterbalancing anion, we performed a large multi-arm RCT (n=164), in which we aimed to demonstrate the effect of magnesium citrate supplementation, now with a higher dose than was used in the previous study, on arterial stiffness (Chapter 6). We also explored whether two other inorganic magnesium formulations (i.e. magnesium oxide and magnesium sulfate) have similar effects. Hypertension is the leading cause of cardiovascular disease and premature death worldwide. It has been estimated that hypertension affects ~30% of the world’s adult population. Several risk factors for the development of hypertension have been proposed, including high sodium intake, low potassium intake, obesity, alcohol intake and physical inactivity. Although not yet consistently proven in interventional studies, there is an emerging interest in the role of magnesium in blood pressure regulation. Previous epidemiological studies reported inverse associations between dietary magnesium intake or 24-h urinary magnesium excretion and risk of hypertension 25,26. Although not consistently shown, some RCTs have shown small but significant effects of magnesium supplementation on blood pressure 27,28. Yet, underlying mechanisms by which magnesium may alter blood pressure levels are not well known. In Chapter 4, we summarized available evidence linking magnesium with blood pressure. In this review, we focused on blood pressure, and its two major determinants, i.e. cardiac output and peripheral resistance.We conclude that magnesiummay affect blood pressure via several mechanisms, on the one hand including the inhibition of several vasoconstrictors, and on the other hand stimulation of vasodilators, and via suppression of the Wnt/b-catenin signaling pathway. Effects on glucocorticoid metabolism Cortisol is a glucocorticoid hormone that is secreted by the hypothalamic-pituitaryadrenal axis during a stress response. Glucocorticoid excess induces cardiovascular risk factors, such as hypertension 29 and vascular calcifications 30. Preclinical studies have shown that magnesium deficiency negatively affects the glucocorticoid metabolism in rats 31–33. In Chapter 5, we studied the effects of magnesium supplementation on glucocorticoid metabolism in human individuals. For this, we used urine samples from a previous RCT that showed a beneficial effect of oral magnesium citrate supplementation on arterial stiffness in overweight and slightly obese adults 10. We observed that, after
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