***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Abstract —Single dose administration of dietary inorganic nitrate acutely reduces blood pressure ( BP ) in normotensive healthy volunteers , via bioconversion to the vasodilator nitric oxide . We assessed whether dietary nitrate might provide sustained BP lowering in patients with hypertension . We r and omly assigned 68 patients with hypertension in a double-blind , placebo-controlled clinical trial to receive daily dietary supplementation for 4 weeks with either dietary nitrate ( 250 mL daily , as beetroot juice ) or a placebo ( 250 mL daily , as nitrate-free beetroot juice ) after a 2-week run-in period and followed by a 2-week washout . We performed stratified r and omization of drug-naive ( n=34 ) and treated ( n=34 ) patients with hypertension aged 18 to 85 years . The primary end point was change in clinic , ambulatory , and home BP compared with placebo . Daily supplementation with dietary nitrate was associated with reduction in BP measured by 3 different methods . Mean ( 95 % confidence interval ) reduction in clinic BP was 7.7/2.4 mm Hg ( 3.6–11.8/0.0–4.9 , P<0.001 and P=0.050 ) . Twenty-four-hour ambulatory BP was reduced by 7.7/5.2 mm Hg ( 4.1–11.2/2.7–7.7 , P<0.001 for both ) . Home BP was reduced by 8.1/3.8 mm Hg ( 3.8–12.4/0.7–6.9 , P<0.001 and P<0.01 ) with no evidence of tachyphylaxis over the 4-week intervention period . Endothelial function improved by ≈20 % ( P<0.001 ) , and arterial stiffness was reduced by 0.59 m/s ( 0.24–0.93 ; P<0.01 ) after dietary nitrate consumption with no change after placebo . The intervention was well tolerated . This is the first evidence of durable BP reduction  with dietary nitrate supplementation in a relevant patient group . These findings suggest a role for dietary nitrate as an affordable , readily-available , adjunctive treatment in the management of patients with hypertension ( funded by The British Heart Foundation ) . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT01405898 Background — The endothelial nitric oxide synthase cofactor tetrahydrobiopterin ( BH4 ) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans . Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states . We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease . Methods and Results — Forty-nine patients with coronary artery disease were r and omized to receive low-dose ( 400 mg/d ) or high-dose ( 700 mg/d ) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery .  Vascular function was quantified by magnetic resonance imaging before and after treatment , along with plasma BH4 levels . Vascular superoxide , endothelial function , and BH4 levels were determined in segments of saphenous vein and internal mammary artery . Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein ( but not internal mammary artery ) but also increased levels of the oxidation product dihydrobiopterin ( BH2 ) , which lacks endothelial nitric oxide synthase cofactor activity . There was no effect of BH4 treatment on vascular function or superoxide production . Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue . Conclusions — Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4 . Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00423280 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more 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 r and omized crossover study design , we show that nitrate supplementation ( KNO3 capsules : 4 versus 12 mmol [ n=6 ] or 24 mmol of KNO3 ( 1488 mg of nitrate ) versus 24 mmol of KCl [ n=20 ] ) or vegetable intake ( 250 mL of beetroot juice [ 5.5 mmol nitrate ] versus 250 mL of water [ n=9 ] ) 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 Nitric oxide ( NO ) was implicated in the regulation of mobilization and function of circulating angiogenic cells ( CACs ) . The supposedly inert anion nitrate , abundant in vegetables , can be stepwise reduced in vivo to form nitrite , and consecutively NO , representing an alternative to endogenous NO formation by NO synthases . This study investigated whether inorganic dietary nitrate influences mobilization of CACs . In a r and omized double-blind fashion , healthy volunteers ingested 150 ml water with 0.15 mmol/kg ( 12.7 mg/kg ) of sodium nitrate , an amount corresponding to 100 - 300 g of a nitrate-rich vegetable , or water alone as control . Mobilization of CACs was determined by the number of CD34(+)/KDR(+ ) and CD133(+)/KDR(+ ) cells using flow cytometry and the mobilization markers stem cell factor ( SCF ) and stromal cell-derived factor-1a ( SDF-1α ) were determined in plasma via ELISA . Nitrite and nitrate were measured using high-performance liquid chromatography and reductive gas-phase chemiluminescence , respectively . NOS-dependent vasodilation was measured as flow-mediated vasodilation . Further mechanistic studies were performed in mice after intravenous application of nitrite together with an NO scavenger to identify the role of nitrite and NO in CAC mobilization . Nitrate ingestion led to a rise in plasma nitrite together with an acute increase in CD34(+)/KDR(+ ) and CD133(+)/KDR(+)-CACs along with increased NOS-dependent vasodilation . This was paralleled by an increase in SCF and SDF-1α and the maximal increase in plasma nitrite correlated with CD133(+)/KDR(+)-CACs ( r=0.73 , P=0.016 ) . In  mice , nitrate given per gavage and direct intravenous injection of nitrite led to CAC mobilization , which was abolished by the NO scavenger cPTIO , suggesting that nitrite mediated its effect via formation of NO . Dietary inorganic nitrate acutely mobilizes CACs via serial reduction to nitrite and NO . The nitrate-nitrite-NO pathway could offer a novel nutritional approach for regulation of vascular regenerative processes Diets rich in green , leafy vegetables have been shown to lower blood pressure ( BP ) and reduce the risk of cardiovascular disease .  Green , leafy vegetables and beetroot are particularly rich in inorganic nitrate . Dietary nitrate supplementation , via sequential reduction to nitrite and NO , has previously been shown to lower BP and improve endothelial function in healthy humans . We sought to determine if supplementing dietary nitrate with beetroot juice , a rich source of nitrate , will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes ( T2DM ) . Twenty-seven patients , age 67.2±4.9 years ( 18 male ) , were recruited for a double-blind , r and omized , placebo-controlled crossover trial . Participants were r and omized to begin , in either order , a 2-week period of supplementation with 250ml beetroot juice daily ( active ) or 250ml nitrate-depleted beetroot juice ( placebo ) . At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring , tests of macro- and microvascular endothelial function , and a hyperinsulinemic isoglycemic clamp were performed . After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged : 134.6±8.4mmHg versus 135.1±7.8mmHg ( mean±SD ) , placebo vs active-mean difference of -0.5mmHg ( placebo-active ) , p=0.737 ( 95 % CI -3.9 to 2.8 ) . There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity . Supplementation of the diet with 7.5mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration , but did not lower BP , improve endothelial function , or improve insulin sensitivity in individuals with T2DM BACKGROUND Through effects on nitric oxide ( NO ) bioavailability , endothelial function is improved after the intake of beetroot juice-which is rich in inorganic nitrate- , but decreased after the intake of a meal . OBJECTIVE The objective of this study was to examine if beetroot juice could counteract the impairment of endothelial function associated with the ingestion of a mixed meal . METHODS Twenty healthy overweight and slightly obese men with a BMI between 28 and 35 kg/m(2 ) received in r and om order a mixed meal providing 56.6 g of fat with beetroot juice or a control drink . The beetroot juice ( 140 mL ) provided approximately 500 mg dietary nitrate .  Flow-mediated dilation ( FMD ) of the brachial artery was measured before and 2 h after meal consumption . Blood was sample d at regular intervals . RESULTS Postpr and ial changes in serum triacylglycerol ( TAG ) ( P = 0.69 ) , plasma glucose ( P = 0.84 ) and insulin ( P = 0.67 ) concentrations were comparable between the meals . After consumption of beetroot juice , the postpr and ial impairment in FMD following a st and ardized mixed meal was improved ( P = 0.030 ) compared with the control drink ( -0.37 ± 2.92 % versus -1.56 ± 2.90 % ) . Following beetroot juice consumption , plasma concentrations of the circulating NO pool were higher at T60 , T120 , and T240 ( P < 0.001 at all time points ) . CONCLUSION In healthy overweight and slightly obese men a single dose of beetroot juice attenuates the postpr and ial impairment of FMD following a mixed meal , possibly through increases in plasma NO concentrations Peripheral arterial disease ( PAD ) results in a failure to adequately supply blood and oxygen ( O(2 ) ) to working tissues and presents as claudication pain during walking . Nitric oxide ( NO ) bioavailability is essential for vascular health and function . Plasma nitrite ( NO(2)(- ) ) is a marker of vascular NO production but may also be a protected circulating " source " that can be converted to NO during hypoxic conditions , possibly aiding perfusion . We hypothesized that dietary supplementation of inorganic nitrate in the form of beetroot ( BR ) juice would increase plasma NO(2)(- ) concentration , increase exercise tolerance , and decrease gastrocnemius fractional O(2 ) extraction , compared with placebo ( PL ) . This was a r and omized , open-label , crossover 
    Output:
    
Conclusions Inorganic nitrate and beetroot supplementation was associated with beneficial effects on EF .
These effects appear to be reduced in older subjects and in subjects with greater cardiometabolic risk