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Dietary Nitrate: A New Tool in the Treatment and Management of Hypertension?


Learning Objectives:

The main aims of the article are to present the potential therapeutic benefits of dietary nitrate supplementation. To help contextualize, the article will also:

  1. Clarify hypertension via definitions, facts and figures.
  2. Introduce a background, and sources, of dietary nitrates.
  3. Provide research findings from health-based studies.
  4. Explain real world implications.

Introduction to Hypertension - Setting the Scene

Cardiovascular disease (CVD) is the biggest killer worldwide and is likely to increase in proportion as the non-Western world adopts a Western lifestyle (World Health Organization, fact sheet 317, www.who.int/mediacentre/factsheets/fs317/en/ accessed 08/02/2016). Hypertension is a major risk factor for CVD and is predicted to reach a global prevalence of 30% by 2025 (Kearney et al., 2005). As blood pressure (BP) remains elevated in around 50% of all treated hypertensive patients (Cutler et al., 2008; Wang et al., 2007), novel and cost-effective interventions are required for the treatment of this condition. Table 1 (below) shows blood pressure categories with optimal thresholds.

Category

Systolic (mmHg) Diastolic (mmHg)
Optimal BP < 120 < 80
Normal BP < 130 , 85
High normal 130-139 85-89
Stage 1 hypertension (mild) 140-159 90-99
Stage 2 (moderate) 160-179 100-109
Stage 3 (severe) ≥ 180 ≥ 110

Table 1: Categories of blood pressure and hypertension (Williams et al., 2004).

It has been estimated that 40% of the adult population in England and Wales are hypertensive; a figure that increases with age (about a third of them are middle-aged, and about 2/3 in old age) (NICE, 2014). According to the 2006 Health Survey for England (HSE, 2011), the prevalence for hypertension was higher among men (31%) than women (28%) up to the age of 64, and increased with age.

Similarly, the global prevalence of raised blood pressure in adults aged 25 and over was around 40% in 2008. The proportion of the world’s population with high blood pressure, or uncontrolled hypertension, fell modestly between 1980 and 2008. However, because of population growth and aging, the number of people with uncontrolled hypertension rose from 600 million in 1980 to nearly 1 billion in 2008 (WHO, 2016). In more than 95% of cases, the etiology of hypertension is unknown and is called primary / essential or idiopathic hypertension (ACSM, 2006), whereas the secondary hypertension refers to hypertension with a known etiology (etiology is the investigation of the cause of something). As we know, identifiable causes include sleep apnea, drug-induced or drug-related causes, chronic kidney disease, or renovascular disease. Most people with hypertension feel well and are asymptomatic.

Background to Dietary Nitrate

In recent years there has been an increase in the interest in dietary nitrate supplementation (DNS) as an ergogenic aid. Dietary nitrate is commonly found in leafy green vegetables such as arugula leaves, spinach, and especially so in beetroots. Following ingestion, nitrate (NO3-) is converted in the body to nitrite (NO2-) and circulated in the blood. NO2- can be converted into nitric oxide (NO), which is known to play a number of important roles in vascular and metabolic control (Bailey et al. 2009).

Nitrate- nitrite-nitric oxide pathway

Nitric oxide (NO) is one of the most researched molecules both in physiology and medicine, and is known to influence a wide array of physiological processes including: skeletal muscle glucose uptake (Merry et al., 2010), neurotransmission (Garthwaite, 2008),  mitochondrial respiration (Brown, 1994) and skeletal muscle fatigue (Percival et al., 2010). NO is a gaseous physiological signalling molecule that was first recognised as a “nitro-vasodilator” capable of relaxing the vascular endothelium (Furchgott et al., 1980). NO serves as an important signal molecule to promote dilation of blood vessels and reduce vascular resistance (Joannides et al., 1995).  Inorganic nitrate (NO3-) is present in numerous foodstuffs and is abundant in green leafy vegetables and beetroot. Following ingestion, nitrate is converted in the body to nitrite (NO2-) and stored and circulated in the blood. Figure 1 shows a simple overview of the mechanism by which nitrate is broken down into nitrite.

Figure 1: A simple overview of breakdown from nitrate to nitrite.
Figure 1: A simple overview of breakdown from nitrate to nitrite.

In the mouth, facultative anaerobic bacteria on the surface of the tongue reduce NO3 to NO2 (Duncan et al., 1995). This NO2 is swallowed and reduced to NO and other reactive nitrogen intermediates within the stomach (Benjamin et al., 1994; Lundberg et al., 2009). However, it is clear that some NO2  is absorbed to increase circulating plasma (Dejam, Hunter, Schechter, & Gladwin, 2004).

Figure 2 shows a more complex illustration of the breakdown from nitrate to nitrite (often referred as the nitrate- nitrite-nitric oxide pathway), to highlight the numerous mechanisms influenced by dietary nitrate intake.

Figure 2: The pathways of nitric oxide (NO) regeneration in humans
Figure 2: The pathways of nitric oxide (NO) regeneration in humans (adapted from Bailey et al., 2011)


Mechanisms

As formerly termed endothelium-derived relaxing factor by 1998 Physiology or Medicine Nobel Prize recipient Robert F Furchgott (McArdle, Katch, & Katch, 2001), NO spreads through underlying cell membranes to muscle cells within the arterial wall. Here it binds with, and activates the enzyme guanylyl cyclise. This induces arterial smooth muscle relaxation to increase blood flow in neighbouring blood vessels (Balon, 1997; Joyner & Dietz, 1997).

Sources of Dietary Nitrate

NO3 is commonly ingested as part of a healthy diet  (Hord, Tang, & Bryan, 2009) and vegetables account for somewhere in the region of 60-80% of the daily NO3 intake in a western diet, with green leafy vegetables such as lettuce, spinach and beetroot being particularly rich in NO3 (Bryan & Hord, 2010).  Table 2 shows common natural products and their nitrate content. These are typical content values, although it must be stated that they will differ due to regional crop variations, and variety of vegetable, among other reasons.

Nitrate

Content (per kg/fresh veg) Common Vegetables
Very high 2500mg (40mmol) Beetroot (and juice), celery, lettuce, rocket, spinach
High 1000-2500mg (18-40 mmol) Chinese cabbage, celeriac, leek, parsley
Moderate 500-1000 mg (9-18 mmol) Cabbage, dill, turnip, carrot juice
Low 200-500mg (3-9 mmol) Broccoli, carrot, cauliflower, cucumber, pumpkin, V8 veg juice
Very low <200mg (<3 mmol) Asparagus, artichoke, broad beans, peas, tomato, sweet potato/potato, garlic, mushroom

Table 2:  Common natural products and their nitrate content Adapted from Bryan and Hord, 2010.

Recent Research

Leafy GreensRecent epidemiological studies have shown that leafy green vegetables are the most protective in regard to coronary heart disease and ischemic stroke risk (Joshipura et al., 2009; Joshipura et al., 1999) The Dietary Approaches to Stop Hypertension (DASH) studies found dietary intakes rich in fruit and vegetables, and low-fat dairy produce can lower blood pressure in a similar vein to single antihypertensive medication (Appel et al., 1997).

The effects of dietary nitrate supplementation (DNS) have been studied, and have shown positive influences on the cardiovascular system. One study examined the effects of a three day DNS regimen using 8.86 mg/dL per kilogram of bodyweight of sodium nitrate compared to a placebo regimen of equal dosage of sodium chloride (Larsen et al. 2006). The authors found that systolic blood pressure and pulse rate did not change significantly after nitrate supplementation, as compared with placebo supplementation. However, the diastolic blood pressure was on average 3.7 mm Hg lower after nitrate supplementation than after placebo supplementation, and the mean arterial pressure was 3.2 mm Hg lower. From a practical standpoint, this is a positive finding as we know that when the heart is in the diastole phase, it is “at rest” between contractions. So, if the pressure is lower, then it will have a longer refilling time, and therefore the heart will have less stress / work. Similarly, healthy volunteers used beetroot juice as a natural source of nitrate to study the same phenomenon (Webb et al. 2008). Here participants drank 500 mL of either the juice (0.3 mmol nitrate/kg) or water, and blood pressure was monitored repeatedly over a 24 hour period. A reduction in both systolic blood pressure (SBP) (10 mmHg) and diastolic blood pressure (DBP) (8 mmHg) was noted within 3 hours of ingestion - an effect that correlated with maximum elevations in plasma nitrite concentration. A significant blood pressure reduction was still present 24 hours following single administration, therefore underlining the beneficial effects of consuming a dietary rich in leafy green vegetables.

Further research from the health field showed that beetroot juice (BRJ) supplementation can enhance exercise performance in patients with peripheral artery disease (which results in the inability to sufficiently supply blood and oxygen (O2) to the working musculature) (Kenjale et al. 2011). In this small study on a clinical population, acute BRJ supplementation (1500mg/L., 120 min prior to exercise), found that participants tolerated exercise (time to exercise before discomfort from claudication (which is a cramping pain in the leg caused by exercise) increased by ~32 secs (18%). Diastolic blood pressure was lower in the BR group at rest and during cardiopulmonary exercise testing (CPX).

Furthermore, a small unpublished study shows that acute dietary nitrate supplementation produces a reduction in systolic BP of around 3mmHg within 60 minutes of consuming 4mmol/L of nitrate (in this case in the form of a commercially available beetroot juice). With this in mind, and considering research previously published (Kapil et al., 2010) where BP was reduced for 24 hours post-nitrate consumption, shows what a positive effect nitrate consumption has on cardiovascular health.

Practical Implications and Concluding Remarks

We have attempted to discuss increasing dietary nitrate as a means of a novel intervention to reduce blood pressure. By consuming a regular diet of leafy green vegetables we can increase plasma nitrate concentrations, which as we have learned has a lasting (> 24 hours) effect of blood pressure. If we combine the effect from acute dietary nitrate intake with what we know about what physical activity can do for our blood pressure (i.e., a single session of aerobic exercise creates a sustained hypotensive response that lasts up to 24 hours), as per previous work (Hagberg et al., 2000).

Having said this, we are not suggesting that one should purely consume a diet predominately based on leafy green vegetables, as I do not believe we should omit any particular macronutrient from our intake – merely look to avoid any overconsumption of any food stuff. After all, one of the seven deadly sins is gluttony!

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