Kelly C. Heim, Ph.D
It is one of the simplest molecules in physiology. It was named “Molecule of the Year” in 1992 and has been the subject of over 15,000 scientific publications in the last decade. Its promise as a molecular target has captured academic and pharmaceutical research interest around the globe. The mere mention of its name turns the heads of doctors and patients, gracing headlines of cardiology journals and fitness magazines alike. In light of its recent rise in popularity, it is not surprising that many health professionals are curious about nitric oxide.
If you completed your medical or health education prior to 1987, nitric oxide was probably never mentioned in your physiology curriculum. The identification and biological characterization of an elusive vasodilating molecule, tentatively named Endothelium Derived Relaxing Factor, was a difficult task 30 years ago. The molecule’s real identity, unveiled by the American biochemist Robert F. Furchgott in 1986, was astonishingly simple—it consisted of a single nitrogen and oxygen atom bound together. Dr. Furchgott and two other American scientists won the 1998 Nobel Prize for their collective discoveries of nitric oxide (NO) as a medically relevant molecule in the body.
NO has since been acclaimed as the most powerful and indispensable vasodilator the body makes. It is a curiously ephemeral gas synthesized by the endothelium—the inner lining of the blood vessel—with a half-life of 3-5 seconds. As soon as it is made, NO diffuses into the arterial muscle layer, causing it to relax. This results in rapid vasodilation. Since the heart pumps blood in powerful pulses, this allows blood to flow without abrupt increases in pressure.
Arterial dilation is critical during exercise because working muscles require rapid oxygen and nutrient delivery.  This metabolic demand increases drastically upon the first muscle contraction. By virtue of NO, blood flows quickly and easily, delivering fuel and oxygen while removing lactate and other waste products. Accordingly, human clinical studies have positively associated healthy NO signaling with delayed fatigue and improved athletic performance.1
Aging, dietary fat intake, blood glucose homeostasis and lipid profiles can significantly affect endothelial NO production. The foundation of an efficient NO system is a diet rich in leafy green vegetables and colorful fruits, which provide essential cofactors and phytochemicals that allow NO to last longer and to function efficiently.  Legumes and certain fish such as salmon and mackerel are rich sources of arginine, the immediate precursor of NO. However, higher doses are needed to emulate the effects shown in human studies. The majority of the current pharmacological knowledge has emerged from clinical trials evaluating 2-20 grams in supplement form.*
Arginine is converted to NO via an enzyme in the artery wall, known as endothelial nitric oxide synthase (eNOS). When taken orally, however, much of the arginine never reaches the endothelium. Its bioavailability is compromised by 30-70% due to degradation by arginase, an enzyme in the intestine and liver. According to recent studies, arginase activity may be high in certain patient groups, and is affected by blood glucose and other metabolic factors.2
Citrulline, the amino acid precursor of arginine, bypasses this obstacle. Since citrulline is resistant to arginase, it acts as a “Trojan horse” that carries bioactive arginine to the vessel wall, where eNOS converts it to NO.  Randomized, double-blind, placebo-controlled trials have demonstrated that citrulline elevates plasma arginine more effectively than arginine supplements.3 Support for arterial flexibility and other cardiovascular health measurements have been statistically significant for citrulline relative to placebo.3-5*
While effective as a single agent, citrulline is only part of a multifactorial picture. Through cooperative mechanisms, other nutrients support both NO production and stability. Once NO is made, antioxidants such as vitamin C and phytonutrients protect it from oxidation. Vitamin C additionally maintains levels of an essential NO biosynthetic cofactor known as tetrahydrobiopterin.6 Magnesium, which plays diverse roles in cardioprotection, supports NO production and calcium channel function to promote blood flow.7 The amino acid taurine, which supports healthy NO production and blood flow, was effective in a human clinical study after only 2 weeks of supplementation.8*
Research suggests that polyphenols—phytonutrients found in fruits, red wine and certain vegetables, execute unique and important protective functions in the vasculature. Polyphenols from grape seed extract promote eNOS activity and may protect NO from free radicals that normally destroy it.9,10 A unique blend of polyphenols from grape seed and cranberry extracts (CranLoad™) significantly augments blood flow, both at rest and during exercise.11*
In a pilot study of elite athletes, a CranLoad™ containing beverage increased flow-mediated dilation (FMD), an indicator of blood flow measured by brachial artery diameter.  Significant increases in FMD were evident within 30 minutes and were sustained for 2 hours.11 The mean peak increase in brachial artery diameter was similar to published values for high-dose L-arginine supplementation (3-21 grams).12 A reduction in blood lactate was also significant in the athletes following consumption of CranLoad™.*
Since NO signaling depends on a wide range of nutritional factors, a multimodal, evidence-based approach is prudent. A plant-based diet is the most important recommendation to patients requiring support for vascular health. L-citrulline supplementation, in conjunction with vitamin C, magnesium, taurine and/or polyphenols, offers a spectrum of beneficial effects that include NO production, function and arterial health that can benefit cardiovascular patients and athletes alike.*
Learn more about nitric oxide, cardiovascular health and athletic performance in Dr. Kelly Heim’s recent webinar:
Kelly C. Heim, Ph.D. Nutritional Pharmacologist Pure Encapsulations


  1. Bailey SJ, Winyard PG, Vanhatalo A, et al. J Appl Physiol (2010) 109:1394-1403.
  2. Romero MJ, Platt DH, Tawfik HE, et al. Circulation Res (2008) 102:95-102.
  3. Schwedhelm E, Maas R, Freese R, et al. Br J Clin Pharmacol (2008) 65:51-59.
  4. Ochiai M, Hayashi T, Morita M, et al. Int J Cardiol (2012) 155:257-261.
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  7. Cunha AR, Umbelino B, Correia ML, Neves MF. Int J Hypertens (2012) 2012:754250.
  8. Moloney MA, Casey RG, O’Donnell DH, et al. Diab Vasc Dis Res (2010) 7:300-310.
  9. Feng Z, Wei RB, Hong Q, Cui SY, Chen XM. Cell Biol Int (2010) 34:1055-1061.
  10. Caton PW Pothecary MR, Lees DM, et al. J Agric Food Chem (2010) 58:4008-4013.
  11. Labonté K, Couillard C, Motard-Bélanger, A, et al. Sports (2013) 1:55-68.
  12. Bai Y, Sun L, Yang T, Sun K, Chen J, Hui R. Am J Clin Nutr (2009) 89:77-84.

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

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.**This blog was written by an outside source. This blog does not necessarily reflect the views or positions of Natural Partners.