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Nitric Oxide: Reaching Beyond Arginine for Cardiovascular and Muscle Support
By Kelly C. Heim, Ph.D.

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 such as lactic acid. NO-mediated vasodilation promotes blood flow into the working muscles, and studies have positively associated the efficiency of vascular function with exercise performance.2

Vascular relaxation is also critical for cardiovascular health. Aging, dietary fat intake, blood glucose, homocysteine levels and lipid profiles have wellestablished impacts on endothelial production of NO. Thus, NO has emerged as a highly attractive target for cardiovascular support.*

Studies indicate 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 arginine in supplement form.

The endothelium converts arginine to NO via an enzyme called endothelial nitric oxide synthase (eNOS). Only a fraction of an oral arginine dose reaches this point, however. The bioavailability of arginine 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 affected by metabolic factors such as blood glucose.3

L-citrulline is an amino acid precursor of L-arginine. Since it bypasses arginase, it can act as a "Trojan horse" that delivers functional arginine to its site of action. In randomized, double-blind, placebo-controlled trials, citrulline supplementation has promoted arterial flexibility, serum nitric oxide (NO), and its metabolic products relative to placebo.4-6* Research indicates that citrulline increases plasma arginine in a dose-dependent manner and to a greater degree than arginine supplementation.5*

Research suggests that polyphenols (cardioprotective phytonutrients in berries and other fruits) perform a variety of beneficial functions in the arterial wall that complement citrulline.* Polyphenols from grape seed extract, for example, support eNOS activity, and protect NO from another threat—oxidative stress.7,8* Clinical research on CranLoad™, a polyphenol-rich blend of grape seed and cranberry extracts, has demonstrated significant augmentation of blood flow at rest and during exercise.9*

In a pilot trial of elite athletes, consumption of a CranLoad™ containing beverage increased flowmediated dilation (FMD), an indicator of blood flow measured by brachial artery diameter (the vessel where blood pressure is read).* The increase in FMD was significant within 30 minutes and remained elevated for two hours.9* The peak increase in brachial artery diameter was similar to published values for very high doses of L-arginine ranging from 3-21 grams.10* This indicates that a small dose of citrulline has a similar effect to a very high dose of L-arginine.

A significant decrease in blood lactate was also evident in the athletes who consumed CranLoad™.* These findings are consistent with the well-established correlations between blood flow, lactate, and high-intensity athletic performance.

Research on CranLoad™ is part of an ongoing research collaboration between Pure Encapsulations and the Institute of Nutraceuticals and Functional Foods (INAF) and Laval University in Quebec, Canada. This research led to the development of several products, including the newly introduced Nitric Oxide Ultra (capsules), which delivers L-citrulline and CranLoad™ to support NO production and blood flow for cardiovascular health and athletic performance.*

Other nutrients can support NO production and vascular function through alternate mechanisms. Vitamin C , for example, protects NO from degradation and supports production of a critical cofactor known as tetrahydrobiopterin, which is essential for endothelial generation of NO.11* Magnesium supports healthy blood flow by maintaining NO production and calcium channel activity.12* Taurine, an amino acid, promotes arterial flexibility and FMD, as demonstrated in a randomized double-blind crossover trial over a brief, 2-week period.13* Nitric Oxide Ultra (stick packs) provides these functional ingredients, in combination with citrulline and CranLoad™, in convenient singleserving stick packs.*

Both products provide innovative combinations of L-Citrulline with CranLoad™. The combination of these ingredients is prudent because (1) it circumvents the potential limitations of arginine, and (2) it supports multiple aspects of NO production and vascular function.* This multifunctional approach can benefit a broad range of individuals seeking new avenues for cardiovascular support and athletic performance.*

*These statements have not been evaluated by the Food & Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

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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