Alex H. Liu

Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial.

There is mounting evidence that specific dietary polyphenols can enhance vascular health by augmenting nitric oxide. Our aim was to investigate the acute effects of chlorogenic acid, an important dietary phenolic acid present in coffee (400 mg, equivalent to 2 cups of coffee), on nitric oxide status, endothelial function, and blood pressure. Healthy men and women (n = 23) were recruited to a randomized, double-blind, placebo-controlled, crossover trial. Chlorogenic acid resulted in significantly higher plasma concentrations of chlorogenic acid (P < 0.001). Relative to control, the mean post-treatment systolic blood pressure (-2.41 mmHg, 95% CI: -0.03, -4.78; P = 0.05) and diastolic blood pressure (-1.53 mmHg, 95% CI: -0.05, -3.01; P = 0.04) were significantly lower with chlorogenic acid. Markers of nitric oxide status (P > 0.10) and the measure of endothelial function (P = 0.60) were not significantly influenced. Chlorogenic acid can lower blood pressure acutely, an effect that, if sustained, would benefit cardiovascular health.

Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers

An increase in nitrate intake can augment circulating nitrite and nitric oxide. This may lead to lower blood pressure and improved vascular function. Green leafy vegetables, such as spinach, are rich sources of nitrate. We aimed to assess the acute effects of a nitrate-rich meal containing spinach on arterial stiffness and blood pressure in healthy men and women. Twenty-six participants aged 38-69years were recruited to a randomized controlled cross-over trial. The acute effects of two energy-matched (2000kJ) meals, administered in random order, were compared. The meals were either high nitrate (220mg of nitrate derived from spinach [spinach]) or low nitrate [control]. Outcome measurements were performed pre-meal and at specific time points up to 210min post meal. Spinach resulted in an eightfold increase in salivary nitrite and a sevenfold increase in salivary nitrate concentrations from pre-meal (P<0.001) to 120min post meal. Spinach compared with control resulted in higher large artery elasticity index (P<0.001), and lower pulse pressure (P<0.001) and systolic blood pressure (P<0.001). Post meal carotid-femoral pulse wave velocity (P=0.07), augmentation index (P=0.63), small artery elasticity index (P=0.98) and diastolic blood pressure (P=0.13) were not significantly altered by spinach relative to control. Therefore, consumption of a nitrate-rich meal can lower systolic blood pressure and pulse pressure and increase large artery compliance acutely in healthy men and women. If sustained, these effects could contribute to better cardiovascular health.

Absence of an effect of high nitrate intake from beetroot juice on blood pressure in treated hypertensive individuals: a randomized controlled trial

BACKGROUND Dietary nitrate, which is in green leafy vegetables and beetroot, decreases blood pressure through the enterosalivary nitrate-nitrite-nitric oxide pathway in healthy individuals. Whether similar effects would occur in individuals with treated hypertension and, therefore, at increased risk of cardiovascular disease is unclear. OBJECTIVE We assessed whether increased dietary nitrate intake by using beetroot juice for 1 wk lowers blood pressure in treated hypertensive men and women. DESIGN Participants (n = 27) were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effect of 1-wk intake of nitrate-rich beetroot juice was compared with 1-wk intake of nitrate-depleted beetroot juice (placebo). The primary outcome was blood pressure assessed by measuring home blood pressure during the intervention and 24-h ambulatory blood pressure on day 7 of the intervention. Other outcomes included nitrate metabolism assessed by measuring nitrate and nitrite in plasma, saliva, and urine. RESULTS Relative to the placebo, 1-wk intake of nitrate-rich beetroot juice resulted in a 3-fold increase in plasma nitrite and nitrate, a 7-fold increase in salivary nitrite, an 8-fold higher salivary nitrate, and a 4-fold increase in both urinary nitrite and nitrate (P < 0.001). However, no differences in home blood pressure and 24-h ambulatory blood pressure were observed with 1-wk intake of nitrate-rich beetroot juice in comparison with the placebo. CONCLUSION An increase in dietary nitrate intake may not be an effective short-term approach to further lower blood pressure in treated hypertensive subjects.

Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women.

BACKGROUND Endothelial nitric oxide (NO) is fundamental to cardiovascular health. Dietary nitrate and nitrate from endothelial derived NO metabolism provides a significant contribution to the circulating NO pool through the nitrate-nitrite-NO pathway. A critical step in this pathway is the reduction of nitrate to nitrite by the oral microbiota. We aimed to assess the effects of antibacterial mouthwash use on markers of nitrate-nitrite-NO metabolism and blood pressure in treated hypertensive men and women. METHODS Fifteen treated hypertensive men and women (mean age 65 years) were recruited to a randomized controlled cross-over trial. The effects of 3-day use of antibacterial mouthwash on oral nitrate to nitrite reduction, salivary and plasma nitrate and nitrite, plasma cyclic guanosine monophosphate (cGMP) and systolic and diastolic blood pressure were compared to control (water). RESULTS Relative to control, 3-day antibacterial mouthwash use resulted in decreased oral nitrate to nitrite reduction (P = 0.02), decreased salivary nitrite (P = 0.01) and increased salivary nitrate (P < 0.001), and there was a trend toward a decrease in plasma nitrite concentration (P = 0.09). Use of antibacterial mouthwash over 3 days also resulted in higher systolic blood pressure (2.3mm Hg; 95% CI: 0.5, 4.0; P = 0.01), but not diastolic blood pressure (P = 0.4) or plasma cGMP (P = 0.7), relative to control. CONCLUSIONS Interruption of the nitrate-nitrite-NO pathway through the use of antibacterial mouthwash was paralleled by a small elevation of systolic blood pressure in treated hypertensive men and women.

Short-term effects of nitrate-rich green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure

Evidence for a beneficial effect of dietary nitrate, through the nitrate-nitrite-NO pathway, on measures of cardiovascular function in healthy individuals is accumulating. It is less clear whether increased dietary nitrate intake from green leafy vegetables would have similar beneficial vascular effects in those at increased risk of developing hypertension. Our aim was to assess the effects of short-term regular consumption of increased nitrate from green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure. Thirty-eight men and women ages 30-70 years with systolic blood pressure 120 to 139 mm Hg were recruited to a randomized controlled crossover trial. The effects of a 7-day high-nitrate diet intervention (increased nitrate intake by at least 300 mg/day from green leafy vegetables) were compared to a 7-day low-nitrate diet intervention. Outcome measures included pre- and postintervention salivary and plasma nitrate and nitrite concentrations; ambulatory, home, and office blood pressure; augmentation index; and carotid-femoral pulse wave velocity. The high-nitrate diet intervention resulted in at least a fourfold increase in salivary and plasma nitrate and nitrite (P<0.001). Ambulatory, home, and office blood pressure and arterial stiffness were not different between the high-nitrate diet and the low-nitrate diet. Increasing dietary nitrate intake in those with high-normal blood pressure and at increased risk of hypertension may not be an effective short-term strategy to lower blood pressure.

Short-Term Effects of a High Nitrate Diet on Nitrate Metabolism in Healthy Individuals

Dietary nitrate, through the enterosalivary nitrate-nitrite-NO pathway, can improve blood pressure and arterial stiffness. How long systemic nitrate and nitrite remain elevated following cessation of high nitrate intake is unknown. In 19 healthy men and women, the time for salivary and plasma nitrate and nitrite to return to baseline after 7 days increased nitrate intake from green leafy vegetables was determined. Salivary and plasma nitrate and nitrite was measured at baseline [D0], end of high nitrate diet [D7], day 9 [+2D], day 14 [+7D] and day 21 [+14D]. Urinary nitrite and nitrate was assessed at D7 and +14D. Increased dietary nitrate for 7 days resulted in a more than fourfold increase in saliva and plasma nitrate and nitrite (p < 0.001) measured at [D7]. At [+2D] plasma nitrite and nitrate had returned to baseline while saliva nitrate and nitrite were more than 1.5 times higher than at baseline levels. By [+7D] all metabolites had returned to baseline levels. The pattern of response was similar between men and women. Urinary nitrate and nitrate was sevenfold higher at D7 compared to +14D. These results suggest that daily ingestion of nitrate may be required to maintain the physiological changes associated with high nitrate intake.

Nitrate, the oral microbiome, and cardiovascular health: a systematic literature review of human and animal studies

Background Dietary nitrate is an important source of nitric oxide (NO), a molecule critical for cardiovascular health. Nitrate is sequentially reduced to NO through an enterosalivary nitrate-nitrite-NO pathway that involves the oral microbiome. This pathway is considered an important adjunct pathway to the classical l-arginine-NO synthase pathway. Objective The objective of this study was to systematically assess the evidence for dietary nitrate intake and improved cardiovascular health from both human and animal studies. Design A systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by using key search terms in Medline and EMBASE databases and defined inclusion and exclusion criteria. Results Thirty-seven articles on humans and 14 articles on animals were included from 12,541 screened references. Data on the effects of dietary nitrate on blood pressure, endothelial function, ischemic reperfusion injury, arterial stiffness, platelet function, and cerebral blood flow in both human and animal models were identified. Beneficial effects of nitrate on vascular health have predominantly been observed in healthy human populations, whereas effects in populations at risk of cardiovascular disease are less clear. Few studies have investigated the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. In animal studies, there is evidence that nitrate improves blood pressure and endothelial function, particularly in animal models with reduced NO bioavailability. Nitrate dose seems to be a critical factor because there is evidence of cross-talk between the 2 pathways of NO production. Conclusions Evidence for a beneficial effect in humans at risk of cardiovascular disease is limited. Furthermore, there is a need to investigate the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. Further animal studies are required to elucidate the mechanisms behind the observed effects.

Vegetable-derived bioactive nitrate and cardiovascular health

Vegetable derived nitrate is now recognised as an important bioactive phytochemical with cardioprotective properties. Nitrate, through the recently described enterosalivary nitrate-nitrite-nitric oxide (NO) pathway, increases NO, a molecule pivotal for cardiovascular health. Clinical trials have observed that dietary nitrate has similar effects to NO when supplied exogenously. These effects include reduced blood pressure and improvements in other markers of vascular health such as endothelial function, arterial stiffness, ischemia reperfusion injury, blood flow, and platelet aggregation. Few observational studies, however, have examined dietary nitrate intake and long term cardiovascular health outcomes. This represents a significant gap in the literature. There is also a lingering concern about a possible carcinogenic effect of nitrate intake. Additionally, a number of potential factors that could impact nitrate to nitrite to NO reduction have been identified. This review will provide an overview of the evidence to date that nitrate, through its effects on endogenous NO and vascular health, is an important bioactive cardioprotective component of a diet rich in vegetables.