Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans

Abstract

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...

Nitrate pharmacokinetics: Taking note of the difference

“…With a burgeoning awareness of the potential importance of NO 3 -in sport and exercise, an ever-increasing variety of NO 3 -fortified products are becoming commercialised, ranging from sport bars and lozenges to BR capsules. Importantly, NO 3 -salts (in solution or via capsule) are readily available for both oral and intravenous administration and ] ratio, as defined in Table 1) was relatively consistent (1.0-1.2) and is in keeping with the work of most using BR [11][12][13][14], but inconsistent with Webb et al hrs, and a plasma t½ of >6 hrs is found irrespective of KNO 3 dose (4 -24 mmol).…”

“…In addition, taken together there is good evidence that time to peak NO 3 -may depend on the source of NO 3 -, although there are notable exceptions [11]. In general, a KNO 3 solution/capsule and NO 3 -containing gel (SiS Go+Nitrate) appear to exhibit an earlier peak (~1hr) when compared with BR at a similar loading dose.…”

“…Of those utilising a similar BR source, in one or two repeated tests there is an apparent split between those exhibiting high relative yield [12][13][14] and those finding significantly lower yield [3,11]. In these examples, volume of NO 3 -administration does not appear to be the cause of the discrepancy, neither does this appear to be methodological (since all studies essentially use ozonebased chemiluminescence to measure plasma NO metabolites). ]…”

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

“…In contrast, where large falls in systolic pressure have been reported, the groups studied have been much younger. The subjects in Webb et al's study 26 were 25.5 ± 4.5 years old; the subjects in Kapil et al's study 27 were 22.5 ± 0.9 years old.…”

“…[22][23][24] It has previously been shown that dietary nitrate supplementation, via sequential reduction of nitrate to nitrite and nitric oxide, can lower blood pressure and improve endothelial function in healthy humans. [25][26][27][28][29] Inorganic nitrate from the diet may have numerous other beneficial effects including improving exercise tolerance, ameliorating ischaemia-reperfusion injury, inhibition of platelet aggregation, protection against gastrointestinal infection, and protection against gastric ulceration (for review see 30 ). Furthermore, Lundberg and Weitzberg's group has shown that, in endothelial nitric oxide synthase (eNOS) knockout mice, supplementation of the diet with inorganic nitrate improved glucose tolerance and ameliorated other features of the metabolic syndrome.…”