Investigation of the effect of inorganic nitrate on the cardiovascular system in humans

Abstract

Fruit and vegetable-­‐rich diets reduce blood pressure and risk of ischaemic stroke and ischaemic heart disease. Whilst the cardioprotective effects of a fruit and vegetable-­‐rich diet are unequivocal, the exact mechanisms of this effect remain uncertain. Recent evidence has highlighted the possibility that dietary nitrate, an inorganic anion found in large quantities in vegetables (particularly green leafy vegetables), might have a role to play. This beneficial activity lies in the processing in vivo of nitrate to nitrite (a process that has been traditionally viewed as detrimental) and thence to the pleiotropic molecule nitric oxide. Ingestion of dietary (inorganic) nitrate elevates circulating and tissue levels of nitrite via bioconversion in the entero-­‐salivary circulation. In addition, nitrite is a potent vasodilator in humans; an effect thought to underlie the blood pressure lowering effects of dietary nitrate ingestion. In a series of randomized, cross-­‐over, placebo controlled studies in healthy and hypertensive subjects (n=6-­‐20), I show that single-­‐dose supplementation with either inorganic nitrate capsules (4-­‐24 mmol KNO3) or dietary nitrate (as beetroot juice, 3.3-­‐5.5 mmol nitrate) elevated plasma nitrite levels and reduced blood pressure in a dose-­‐dependent manner. In a separate study, interruption of the entero-­‐salivary circulation with antiseptic mouthwash use for 7 days reduced plasma nitrite levels and elevated blood pressure significantly. Stratification of results by sex revealed important differences in the entero-­‐salivary circulation of nitrate to nitrite that had consequences on resting blood pressure and response to nitrate supplementation. 6 In conclusion, these studies challenge the current dogma that inorganic nitrate is only detrimental, and on the contrary suggests that dietary nitrate is important for cardiovascular health. It may be that sufficient supply of nitrate through the diet together with functioning, oral microflora is essential for normal cardiovascular homeostasis and may be a contributing factor to the lower blood pressure and vasoprotective phenotype of pre-­‐menopausal women. Lastly, the importance of the oral microflora to maintain plasma nitrite levels intimates that oral hygiene treatments may disturb nitrite/nitric oxide homeostasis with potential deleterious effects.