Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite

Abstract

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...

Dietary nitrate supplementation enhances high-intensity running performance in moderate normobaric hypoxia, independent of aerobic fitness

“…Consistent with previous investigations, plasma nitrate and nitrite, and exhaled NO concentrations were significantly elevated following dietary nitrate supplementation [1,2,5,8,55,22,39,38], signifying an increase in the 'substrates' available for NO generation via the nitrate-nitrite-NO pathway [11]. Peak plasma nitrite concentration was 602 % higher in BRJ versus PLA, similar to Arnold et al [38] (775 %) (~ 7 mmol nitrate), but considerably greater than reported by Muggeridge et al [22] (134 %) (~ 5 mmol nitrate) and Vanhatalo et al [8] (150 %) (~ 9.3 mmol).…”

“…These include, but are not restricted to: lower blood pressure [1][2][3], reduced O2 consumption (V O2) during steady-state exercise [4][5][6], attenuated muscle metabolic perturbations [7,8], and enhanced muscle force production [9,10]. These effects are not directly attributable to the nitrate anion, which is relatively inert [11].…”

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

“…Renal NO X excretion is less in sunitinib‐treated rats than in controls,11, 16 which is indicative of reduced NO formation and availability 29. Oral nitrate supplementation has been shown to lower arterial pressure in humans30 and in rats 21, 22. Therefore, we tested whether oral nitrate supplementation lowers arterial pressure in sunitinib‐treated rats.…”

Nitrate pharmacokinetics: Taking note of the difference

“…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). ]…”

“…Its application to modulate physiology and alleviate cardiovascular dysfunction shows particular promise in certain clinical conditions and patient cohorts, including reduction of mean arterial pressure in hypertension [1,2], effective quiescencing of platelet activation/aggregation [3], and reduce risk in conditions where tissue ischemia prevails [4]. However, it is the potential of oral NO 3 -to modify exercise/performance via elevation of plasma nitrite concentration ([NO 2 -]) that has been applied across a range of human test systems, from the effects of walking distance in a sedentary population [5] to enhancing performance in elite athletes [6].…”