Blood Pressure With Nitrate Exposure: Back-to-Basics With Fresh Fruits and Vegetables.

Much as the advancements are changing modern medicine, systemic hypertension still remains the largest attributable risk factor for mortality worldwide.1 Each 2 mm Hg increase in systolic blood pressure (BP) increases mortality due to ischemic heart disease and stroke by 7% and 10%, respectively.2 Despite cheap and highly effective pharmacological treatment available, only about half of hypertensives are treated and among those, effective BP control is achieved in only about half.3 Clearly, novel population-based approaches are needed, and more evidence point to go back-to-basics: to reimagine healthy habits, mainly diet. An approach that has been explored in the treatment of hypertension is the delivery of the potent vasodilator, nitric oxide (NO). Endothelial NO generation, achieved through the conventional l-arginine/NO synthase pathway, plays a critical role in sustaining vascular health. However, in most cardiovascular diseases, including hypertension, the levels of endothelial NO are diminished. Increasing evidence suggests that dietary nitrates are key modulators of cardiovascular disease risk reduction through the impact on the vasculature. Apart from being a potent vasodilator, NO is critical in maintaining vascular homeostasis by modulating vascular tone, regulating local cell growth, and protecting the vessel wall against injury. Hypotensive effects of dietary nitrates have been consistently reported in healthy subjects in acute and chronic settings,4 although there is less evidence for these effects in clinical patient groups.5 Proposed mechanisms of actions include endothelial-independent NO availability, which is dependent on the entero-salivary circulation and microbial conversion of dietary nitrate to nitrite in the mouth.6 Accordingly, therapeutic strategies restoring NO levels in hypertension have been explored. However, supplementation with substrate (l-arginine) and other essential cofactors required for healthy NO generation from NO synthase have yielded equivocal results.7 In addition, dietary nitrate provided sustained BP lowering in hypertensive patients in a randomized, double-blind, placebo-controlled study.8 However, NO production from the chemical reduction of inorganic nitrite (NO2−), a phenomenon previously thought to occur only in extreme acidosis,4,9,10 has emerged as a potential pathway for delivery of NO to the blood vessels. Evidence in healthy volunteers suggests nitrite reduction occurs readily within the circulation after elevation of plasma nitrite levels by provision of dietary or oral inorganic nitrate salts.11,12 It is now accepted that a significant proportion of orally ingested inorganic nitrate once absorbed across the upper intestine, is extracted from the blood via the salivary glands and secreted into the oral cavity where it comes into contact with symbiotic bacteria that reduce inorganic nitrate (NO3−) to nitrite.13 On swallowing the saliva, the nitrite then enters the circulation,11,12,14 where it meets mammalian nitrite reductases that convert it to NO resulting in vasodilation15,16 and significant BP lowering.11,12,14 Exploitation of this NO3–NO2–NO (alternative) pathway by supplementation with dietary sources of NO3− (e.g., beetroot juice) is associated with elevations in both plasma nitrite and cyclic guanosine monophosphate (an exquisitely sensitive marker of bioactive NO production)17 with significant BP reductions over 24 hours in healthy volunteers and drug-naive stage 1 patients with hypertension.18 In this issue of the American Journal of Hypertension, Smallwood et al. investigate for the first time the cross-sectional relationship between 24-hour urinary nitrate excretion and BP in the InChianti cohort—a population-based study of mainly older people in Florence, Italy.19 Where the majority of studies have been intervention studies, focusing on the BP lowering effects of nitrate-rich foods and substances, this investigation, evaluated the nitrate-BP link in a population study. They determined 24-hour urinary nitrate excretion by spectrophotometry in 919 participants, and measured supine BP as the mean of 2