Abstract-Diets rich in fruits and vegetables reduce blood pressure (BP) and the risk of adverse cardiovascular events.However, the mechanisms of this effect have not been elucidated. Certain vegetables possess a high nitrate content, and we hypothesized that this might represent a source of vasoprotective nitric oxide via bioactivation. In healthy volunteers, approximately 3 hours after ingestion of a dietary nitrate load (beetroot juice 500 mL), BP was substantially reduced (⌬ max Ϫ10.4/8 mm Hg); an effect that correlated with peak increases in plasma nitrite concentration. The dietary nitrate load also prevented endothelial dysfunction induced by an acute ischemic insult in the human forearm and significantly attenuated ex vivo platelet aggregation in response to collagen and ADP. Interruption of the enterosalivary conversion of nitrate to nitrite (facilitated by bacterial anaerobes situated on the surface of the tongue) prevented the rise in plasma nitrite, blocked the decrease in BP, and abolished the inhibitory effects on platelet aggregation, confirming that these vasoprotective effects were attributable to the activity of nitrite converted from the ingested nitrate. These findings suggest that dietary nitrate underlies the beneficial effects of a vegetable-rich diet and highlights the potential of a "natural" low cost approach for the treatment of cardiovascular disease. Key Words: diet Ⅲ nitric oxide Ⅲ blood pressure Ⅲ hypertension Ⅲ ischemia/reperfusion Ⅲ platelets Ⅲ endothelium P erhaps the largest public health initiative in the Western world has focused on improvement of diet, particularly in those with a high risk of cardiovascular disease. Trials have shown that diets rich in fruits and vegetables reduce blood pressure (BP; Dietary Approaches to Stop Hypertension; DASH, Vegetarian Diet and BP) 1,2 and adverse cardiovascular events. [3][4][5][6][7] These protective effects have previously been attributed to the high antioxidant vitamin content, yet large clinical trials have failed to provide evidence in support of this thesis. 8,9 The greatest protection against coronary heart disease afforded by a change in diet is that associated with the consumption of green leafy vegetables (eg, spinach, lettuce). 6 Such vegetables, also including beetroot, commonly have a high inorganic nitrate (NO 3 Ϫ ) content. 10,11 In humans, after absorption through the stomach wall, Ϸ25% of consumed nitrate enters the enterosalivary circulation where it is reduced to nitrite (NO 2 Ϫ ) by bacterial nitrate reductases from facultative anaerobes on the dorsal surface of the tongue. [12][13][14] This nitrite is swallowed and in the acidic environment of the stomach is reduced to nitric oxide (NO) or re-enters the circulation as nitrite. Indeed, it has been hypothesized that dietary nitrate represents an intravascular source of the pleiotropic, vasoprotective molecule NO, which supplements conventional NO generation by NO synthases (NOS). 15 Endothelium-derived NO is a potent dilator, governs systemic BP, and retards atheroge...

Abstract-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 (in the form of beetroot juice) ingestion. Whether inorganic nitrate underlies these effects and whether the effects of either naturally occurring dietary nitrate or inorganic nitrate supplementation are dose dependent remain uncertain. Using a randomized crossover study design, we show that nitrate supplementation (KNO 3 capsules: 4 versus 12 mmol [nϭ6] or 24 mmol of KNO 3 (1488 mg of nitrate) versus 24 mmol of KCl [nϭ20]) or vegetable intake (250 mL of beetroot juice [5.5 mmol nitrate] versus 250 mL of water [nϭ9]) causes dose-dependent elevation in plasma nitrite concentration and elevation of cGMP concentration with a consequent decrease in blood pressure in healthy volunteers. In addition, post hoc analysis demonstrates a sex difference in sensitivity to nitrate supplementation dependent on resting baseline blood pressure and plasma nitrite concentration, whereby blood pressure is decreased in male volunteers, with higher baseline blood pressure and lower plasma nitrite concentration but not in female volunteers. Our findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation. In addition, our post hoc analyses intimate sex differences in nitrate processing involving the entero-salivary circulation that are likely to be major contributing factors to the lower blood pressures and the vasoprotective phenotype of premenopausal women. (Hypertension. 2010;56:274-281.)Key Words: clinical science Ⅲ diet Ⅲ NO Ⅲ endothelium Ⅲ blood pressure C ardiovascular disease (CVD) is the biggest killer worldwide and is likely to increase in proportion as the non-Western world adopts a Western lifestyle (World Health Organization, fact sheet 317, www.who.int). Hypertension is a major risk factor for CVD and is predicted to reach a global prevalence of 30% by 2025. 1 Because blood pressure (BP) remains elevated in Ϸ50% of all treated hypertensive patients, 2,3 novel and cost-effective therapeutic strategies are urgently required for the treatment of this condition. In this regard, over the last decade, there has been a major initiative in the Western world to increase the public consumption of vegetables (Department of Health United Kingdom, 5 a day, www.nhs.uk/5aday) in part, as a strategy to prevent CVD. 4 This approach has been taken because epidemiological, 5 cohort, 6,7 and trial-based data 8,9 demonstrate that increased consumption of a vegetable-rich diet confers protection from CVD, including hypertension. However, the exact mechanisms of the BP-lowering and protective effects of such a diet remain uncertain.Large-scale clinical trials have failed to show a beneficial cardiovascular effect of several different nut...