Basics

Dietary Nitric Oxide Precursors and Modulators

It is easy to envision the heart in motion, as the muscular “pump” that sustains life. It is also easy to overlook the fact that arteries, which are also muscular, are in motion too. While the heart beats, the arteries must dilate to enable blood to travel through. This functional capacity of arteries is one of the most important determinants of heart health.

Arterial function is influenced by a variety of factors, mainly the integrity of the vessel lining, or endothelium. A healthy endothelium behaves like Teflon, warding off molecular debris and blood cells that may otherwise “stick.” A healthy endothelium can also efficiently instruct the vessel’s muscle layer to relax. This results in vasodilation, keeping blood pressure within the normal range and ensuring that oxygen and nutrients reach tissues. 

This communication between the endothelium and vascular muscle is made possible by nitric oxide (NO), the most powerful endogenous vasodilator and one of the most important molecules in human physiology. NO is actually a gas made by the endothelium. It lasts for only a few seconds—just long enough to pass into the muscle layer and execute its role. NO keeps the vasculature flexible so it can accommodate abrupt changes in pressure and metabolic demand. NO also defends against fatty deposits and helps keep platelets functioning properly.1

An illustrative example of the importance of vascular flexibility and adaptive dilation is exercise. As soon as the first contraction starts, muscles require greater delivery of oxygen and fuel, with a simultaneous need to remove metabolic wastes. NO-mediated vasodilation promotes blood flow into the working muscles, and studies have positively associated the efficiency of vascular function with exercise performance.2 

Endothelial function is also critical for the prevention and management of cardiovascular disease. Aging, dietary fat intake, high blood glucose, elevated homocysteine levels, sedentary lifestyles and unhealthy lipid profiles have negative impacts on endothelial production of NO.

Nitrates

Nitrates undergo rapid, spontaneous conversion to nitric oxide without requiring an enzyme. They are abundant in beetroot juice and several other plants. Nitrates are also widely used as medications for vascular conditions requiring acute vasodilation (nitroglycerin).

If you can tolerate the taste of the beetroot juice used in clinical trials, an effective dose is 0.1-0.2 mmol/kg (6.4-12.8mg/kg) nitrate, or 436mg for a 150 lb individual. This is comparable to 500 g fresh root. A more appealing option might be a handful of uncooked dark, leafy greens (arugula or spinach are best).

Since nitrates are often unstable during manufacturing, use caution when selecting supplements claiming nitrate from plant extracts. Beet powder is not the same as beet root juice, which has been successfully applied in clinical trials.

Arginine

Epidemiological and clinical evidence indicates that a diet rich in leafy green vegetables and colorful fruits supports endothelial integrity, vascular flexibility, and overall cardiovascular health. Beans, almonds, and cold-water fish such as salmon and mackerel contain high levels of arginine, the immediate precursor of NO. However, the effects of food-derived arginine on vascular function have not been evaluated in studies; instead, clinical research has assessed high doses of isolated arginine.. 

The endothelium converts arginine to NO via an enzyme called endothelial nitric oxide synthase (eNOS). However, only a fraction of an oral arginine remains stable enough to reach this point. Its bioavailability is limited by partial degradation in the gut and liver by an enzyme known as arginase. Studies suggest that arginase activity may vary across different patient groups, and is up-regulated in patients with insulin resistance.3 

Citrulline

Citrulline is an amino acid precursor of arginine. Since it bypasses arginase, it can act as a “Trojan horse” that delivers functional arginine to its site of action. In clinical trials, citrulline supplementation has improved endothelial function and increased serum nitric oxide and its metabolic products relative to placebo.4-6 Research also indicates that citrulline increases plasma arginine in a dose-dependent manner and to a greater degree than arginine supplementation.5

Polyphenols

Research suggests that polyphenols such as flavonoids and proanthocyanidins (cardioprotective phytonutrients in berries and other fruits) perform a variety of beneficial functions in the arterial wall that complement citrulline. Polyphenols from grape seed, for example, support eNOS activity and protection of NO from degradation caused by oxidative stress.7,8 Clinical research demonstrates significant augmentation of blood flow at rest and during exercise.9

Vitamin C and magnesium are also useful in supporting NO signaling. Vitamin C protects NO from degradation and preserves tetrahydrobiopterin, a cofactor that is essential for endothelial generation of NO.11 Magnesium may reduce blood pressure via indirectly supporting NO production and calcium channel activity.12

Interactions

Combinations of nitrates, citrulline and polyphenols support multiple aspects of NO production, potentially improving endothelial function in a synergistic manner. However, caution should be used when adding more potent synergists such as nitrate drugs (nitroglycerine), antihypertensive medications, or sildenafil (Viagra, a cGMP agonist) to the regimen, as these may cause an unsafe drop in blood pressure.

REFERENCES
1. Nitric Oxide (2013) 35:175-185.
2. J Appl Physiol (2010) 109:1394-1403.
3. Circulation Res (2008) 102:95-102.
4. Int J Cardiol (2012) 155:257-261.
5. Br J Clin Pharmacol (2008) 65:51-59.
6. Cardiovasc Drug Rev (2006) 24:275-290.
7. Cell Biol Int (2010) 34:1055-1061. 
8. J Agric Food Chem (2010) 58:4008-4013. 
9. Sports (2013) 1:55-68. 
10. Am J Clin Nutr (2009) 89:77-84. 
11. Nitric Oxide (2014) 36:51-57. 
12. Int J Hypertens (2012) 2012:754250. 
13. Diab Vasc Dis Res (2010) 7:300-310.

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