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...
Mammalian tissues produce nitric oxide (NO) to modify proteins at heme and sulfhydryl sites, thereby regulating vital cell functions. The majority of NO produced is widely assumed to be neutralized into supposedly inert oxidation products including nitrite (NO2(-)). Here we show that nitrite, also ubiquitous in dietary sources, is remarkably efficient at modifying the same protein sites, and that physiological nitrite concentrations account for the basal levels of these modifications in vivo. We further find that nitrite readily affects cyclic GMP production, cytochrome P450 activities, and heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues. These cellular activities of nitrite, combined with its stability and abundance in vivo, suggest that this anion has a distinct and important signaling role in mammalian biology, perhaps by serving as an endocrine messenger and synchronizing agent. Thus, nitrite homeostasis may be of great importance to NO biology.
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