It is rocket science – why dietary nitrate is hard to ‘beet’! Part I: twists and turns in the realization of the nitrate–nitrite–NO pathway

Abstract

Dietary nitrate (found in green leafy vegetables, such as rocket, and in beetroot) is now recognized to be an important source of nitric oxide (NO), via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. While this pathway may now seem obvious, its realization followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert but potentially carcinogenic, through N-nitrosamine formation. In Part 1 of a two-part Review on the nitrate-nitrite-NO pathway we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part 2.

An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure

“… Because potassium, nitrate, and other dietary factors can affect BP, the contents of the diets should be carefully described for each study phase and contents should not be varied unless required as part of the study objective. Based on the diets that were used in studies of protocols with demonstrated high reproducibility for classifying subjects as salt sensitive, a dietary potassium intake in the range of 60 to 80 mmol/day could be recommended. …”

“…When testing normotensive subjects with the proposed reference protocol and the physiological levels of salt intake described in Table, the cutoff for classifying someone with salt sensitivity is considered to be a change in MAP of at least 3 to 5 mm Hg in response to the change in salt intake 18,19,21 ; when testing hypertensive subjects, the classification cutoff is generally considered to be a change in MAP of at least 8 to 10 mm Hg. 20,22,23 When ambulatory BP monitors have been 16,17 and other dietary factors can affect BP, the contents of the diets should be carefully described for each study phase and contents should not be varied unless required as part of the study objective. Based on the diets that were used in studies of protocols with demonstrated high reproducibility for classifying subjects as salt sensitive, 18-20 a dietary potassium intake in the range of 60 to 80 mmol/day could be recommended.…”

A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone

“…Inorganic (dietary) nitrate, abundant in green leafy vegetables and beetroot reduces BP in healthy and hypertensive volunteers via the nitrate–nitrite–NO pathway, but not in patients with T2DM, or with their inclusion in a meta‐analysis of 24 h ambulatory BP monitoring . PWV reductions with inorganic nitrate have also been noted in healthy and hypertensive volunteers, but over too short a period for vessel remodelling; these were likely BP‐dependent reductions .…”

Acute interaction between oral glucose (75 g as Lucozade) and inorganic nitrate: Decreased insulin clearance, but lack of blood pressure‐lowering

“…The role of dietary inorganic nitrate (NO 3 − ) as an alternative source of nitric oxide (NO) via the enterosalivary nitrate–nitrite–NO pathway is recognized as a physiological mediator of blood pressure (BP), endothelial function and platelet aggregation . In both healthy individuals and those with chronic cardiovascular conditions, NO 3 − supplementation has been shown to increase exercise capacity .…”