Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway

Abstract

The discovery that dietary (inorganic) nitrate has important vascular effects came from the relatively recent realization of the 'nitrate-nitrite-nitric oxide (NO) pathway'. Dietary nitrate has been demonstrated to have a range of beneficial vascular effects, including reducing blood pressure, inhibiting platelet aggregation, preserving or improving endothelial dysfunction, enhancing exercise performance in healthy individuals and patients with peripheral arterial disease. Pre-clinical studies with nitrate or nitrite also show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness. However, there is a need for good evidence for hard endpoints beyond epidemiological studies. Whilst these suggest reduction in cardiovascular risk with diets high in nitrate-rich vegetables (such as a Mediterranean diet), others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven. Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects. In order to provide simple guidance on nitrate intake from different vegetables, we have developed the Nitrate 'Veg-Table' with 'Nitrate Units' [each unit being 1 mmol of nitrate (62 mg)] to achieve a nitrate intake that is likely to be sufficient to derive benefit, but also to minimize the risk of potential side effects from excessive ingestion, given the current available evidence. The lack of data concerning the long term effects of dietary nitrate is a limitation, and this will need to be addressed in future trials.

Figure 1

Kinetic processes in the handling of dietary nitrate (NO₃^‐) and inorganic nitrite (NO₂^‐) derived from nitrate, from the gut to the circulation to the urinary tract. HNO₂ (nitrous acid), N₂O₃ (dinitrogen trioxide), NO⁺ (nitrosonium ion), RSNO (nitrosothiol), RR'NNO (N‐nitrosamine), eNO (exhaled NO), Vit C (vitamin C), deoxyHb (deoxyhaemoglobin), deoxyMb (deoxymyoglobin), XOR (xanthine oxidoreductase), AO (aldehyde oxidase), ETC (electron transport chain in mitochondria), CA (carbonic anhydrase), ALDH2 (aldehyde dehydrogenase type 2), NOS/eNOS (endothelial nitric oxide synthase), L‐arg* (L‐arginine), *non‐essential amino acid, but also derived from the diet. Nitrate reductase‐possessing bacteria on the posterior third of the tongue and in some urinary tract infections convert nitrate to nitrite. Red and blue arrows represent pathways that are favoured under oxygenated and deoxygenated conditions, respectively