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Citrus Bergamot and L-Citrulline for Nitric Oxide Boosting in Athletes

Citrus Bergamot Citrus Bergamot
Kaneka
 
EuroMedica

Nitric oxide (NO) is a natural signaling molecule made by the human body. It plays a major signaling role in vascular relaxation, and elevated levels are associated with several physiological functions involving blood pressure regulation, cardiovascular health, mitochondria production, calcium transport, oxidative stress and skeletal muscle repair.1 Specifically, the endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, resulting in vasodilation and increased blood flow. However, NO declines steadily with increasing age in healthy humans.2 In the coronary circulation of aging adults a loss of 75 percent of endothelium-derived NO was shown in 70 to 80-year-old patients compared to young, healthy 20-year-olds.3 Consequently, there is value in taking steps to improve NO levels, and this article will examine the effects of citrus bergamot and L-citrulline (NOMax) in doing just that.

The Value in Promoting NO Production

Let’s start with a general understanding of the value of in promoting NO production, which offers benefits for athletic performance, sexual health and cardiovascular health.

• Athletic performance: NO can impact “muscular pump,” a term used in bodybuilding circles to describe the sensation of tight congestion, or swelling, of your muscles with blood coursing through them during your weight training session.4

• Sexual health: NO is necessary for achieving and sustaining an erection.5-6

• Cardiovascular health: The cardioprotective roles of NO include regulation of blood pressure and vascular tone, inhibition of platelet aggregation and leukocyte adhesion, and prevention smooth muscle cell proliferation.7

Citrus Bergamot

Known as “bergamot,” Citrus bergamia is a small citrus plant that grows in the southern coast of the Calabria region of Italy where the juice of this fruit was traditionally recognized by the local population as a remedy for “fatty arteries” and heart problems.8 Bergamot juice has a particularly high content and a unique composition of flavonoid polyphenols. Overwhelming scientific evidence indicates that these polyphenols are responsible for the majority of bergamot’s pharmacological effects,9 among which is increasing NO levels. Specific research has been conducted on Bergamot Polyphenolic Fraction (BPF, by HP Ingredients), a proprietary bergamot extract, and will be reviewed in this article.

BPF and NO

First of all, six aglyconic flavonoids have been identified in BPF: naringenin, hesperedin, eriodictyol, diosmetin, apigenin and luteolin.10 Now consider that the citrus flavonoid hesperedin has been shown to stimulate the production of NO,11 and some of these same flavonoids have also been shown to help maintain NO levels.12 So how does this this translate to the use of BPF in humans?

This was the subject of a randomized, placebo-controlled study13 conducted to evaluate the effects of a four-week BPF supplementation (650 mg twice a day for four weeks) on serum (NO), a naturally occurring analogue of L-arginine (involved in NO production) known as asymmetric dimethyl-arginine (ADMA), indices of endothelial function and maximal oxygen uptake (VO2max) of 30 athletes. Results were significant differences between pre- and post-intervention baseline NO levels were observed after BPF supplementation, and higher post-intervention baseline NO level was observed after BPF compared with placebo. Moreover, BPF increased baseline NO concentration (ΔNO). The positive correlation was observed between baseline post-intervention NO concentration and maximal oxygen uptake and also between ΔNO and ΔVO2max in response to BPF supplementation. There was an association between a higher value of endothelial function and higher VO2max after BPF compared with lower values of placebo. In conclusion, these findings suggest that an increase in NO release in response to BPF supplementation may play a central role in cardiovascular adaptive mechanisms and enhanced exercise performance in athletes.

L-arginine and NO

The amino acid L-arginine is a precursor (building material) for the synthesis of NO.14 Supplemental sources of L-arginine appear to augment NO production,15 with the result being a measurable increase in blood flow16 (i.e., vasodilatation). Dietary supplements containing L-arginine have certainly been marketed with the purpose of increasing vasodilation, thereby elevating blood flow to the exercising muscle and enhancing the metabolic response to exercise. Studies have indeed shown that L-arginine supplementation increased blood volume,17 and increased the rate V02 response (the capacity of an individual’s body to transport and use oxygen during exercise) the onset of moderate-intensity exercise in humans.18 Likewise, L-arginine supplementation has shown benefit in the treatment of erectile dysfunction (ED).19-20

The combination of BPF and L-arginine

So, what happens when BPF is combined with L-arginine? This was assessed in a study conducted in rats to examine the results of supplementation with a combination of BPF and L-arginine on physical performance associated with increased NO. Measurements included total movements, distance traveled, activity time and average speed. Results clearly demonstrated that the combination was more effective than supplementation with the component ingredients alone, compared to the control group.

L-citrulline and NO

Despite that L-arginine supplementation promotes NO levels, it may not be the best way to approach NO production as an NO precursor. Consider that the amino acid L-citrulline is a precursor of arginine (it is combined with aspartic acid to form arginosuccinic acid, which later is metabolized into the amino acid arginine). Many of L-citrulline’s functions stem primarily from its ability to increase plasma levels of arginine endogenously (in the human body).21 A particularly interesting feature of L-citrulline is that it increases plasma L-arginine levels better than taking L-arginine itself.22 The reason for this is that if you keep supplementing with L-arginine, the body will start making less L-arginine since it’s getting enough from dietary sources (the supplement). If, on the other hand, you supplement with L-citrulline, the body can use it to make more L-arginine. This is the basis to the use of citrulline for increasing NO—and why L-citrulline may be better at increasing NO levels then L-arginine. So, what does the human research show?

To answer this question, a double-blind, randomized, placebo-controlled cross-over study23 was conducted to assess the metabolic conversion of L-citrulline to L-arginine in 20 healthy volunteers, and the bottom-line effects. Results showed that L-citrulline dose-dependently increased plasma L-arginine concentration more effectively than L-arginine (P < 0.01). Moreover, urinary nitrate (nitric oxide precursor) about 35 percent. In conclusion, the data from this study showed that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signaling in a dose-dependent manner.

Another human clinical study24 assessed the efficacy of supplementation with 800 mg/day L-citrulline on NO. Results were that, compared with baseline values, NO increased by about 65 percent in eight weeks. In another study, L-citrulline helped improve erection hardness score in men with mild erectile dysfunction,25 an additional indication of improvements of NO.

NoMax and NO

So, what do we know so far? We know that BPF effectively increases NO. We know that a combination of BPF and L-arginine is more effective at boosting NO than either nutraceutical separately. But we also know that L-citrulline is more effective than L-arginine in both increasing L-arginine levels and NO levels. So, what would happen with a combination of BPF and L-citrulline? Would that be better than a combination of BPF and L-citrulline? All indications suggest that the answer is yes. There is such a nutraceutical blend with the proprietary name NOMax (by HP Ingredients), which is currently being used as part of a randomized, placebo-controlled human clinical study. Specifically, there are three arms of the study:

• Dose 1 – 500 mg BPF + 1,000 mg L-citrulline
• Dose 2 – 1,000 mg BPF + 2,000 mg L-citrulline
• Placebo

The study is not yet complete at the time of this writing but, given the prior research, I anticipate some very promising results.

Conclusion

NO is an important signaling molecule made by the human body, which offers benefits for athletic performance, sexual health and cardiovascular health. Research shows that the citrus bergamot extract known as BPF is effective at stimulating NO levels, while the amino acids L-arginine and L-citrulline are effective as precursors for NO—although L-citrulline is more effective. While research also shows that the combination of BPF and L-arginine is more effective for physical performance than either nutraceutical alone, the results of a new study will show if the combination of BPF and L-citrulline may be even more effective at promoting healthy NO levels.

References:

1 Feil R, Kleppisch T. NO/cGMP-dependent modulation of synaptic transmission. Handb Exp Pharmacol. 2008;(184):529-60.

2 Torregrossa AC, Aranke M, Bryan NS. Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly. J Geriatr Cardiol. 2011 Dec; 8(4): 230–242.

3 Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990 Feb; 81(2):491-7.

4 Andrich V. Osmotic anabolic signaling. Built Magazine 2007 (in press).

5 Yetik-Anacak G, Sorrentino R, Linder AE, Murat N. Gas what: NO is not the only answer to sexual function. Br J Pharmacol. 2015 Mar;172(6):1434-54.

6 Andersson KE. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev. 2011 Dec;63(4):811-59.

7 Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med. 2005 Feb-Apr;26(1-2):33-65.

8 Walker R, Janda E, Mollace V. Chapter 84: The Use of Bergamot-derived Polyphenol Fraction in Cardiometabolic Risk Prevention and its Possible Mechanisms of Action. In Watson RR, Preedy VR, Zibadi S. Polyphenols in Human Health and Disease. Volume 2. 2014:1087-110.

9 Jandaa E, Lascalaa A, Martinoa C, Ragusab S, Nuceraa S, Walkera R, Gratteria S, Mollacea V. Molecular mechanisms of lipid- and glucose-lowering activities of bergamot flavonoids. PharmaNutrition. 2016; 4S:S8–S18.

10 Janda E, Salerno R, Martino C, et al. Qualitative and quantitative analysis of the proautophagic activity of Citrus flavonoids from Bergamot Polyphenol Fraction. Data Brief. 2018 May 31;19:1327-1334.

11 Rizza S, Muniyappa R, Iantorno M, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011 May;96(5):E782-92.

12 Rendeiro C, Dong H, Saunders C, et al. Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: a randomised, controlled, double-masked, cross-over intervention study. Br J Nutr. 2016 Dec;116(12):1999-2010.

13 Mollace R, Gliozzi M, Tavernese A, Musolino V, et al. Bergamot Polyphenolic Fraction supplementation improves metabolic balance, endothelial function and maximal oxygen uptake in athletes. J Sports Med Ther. 2018; 3: 053-061.

14 Tapiero H, Mathe G, Couvreur P, et al. I. Arginine. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (France) 2002; 56(9):439-45.

15 Nonami Y. The role of nitric oxide in cardiac surgery. Surgery Today (JAPAN) 1997; 27(7):583-92.

16 Cheng JW, Baldwin SN, Balwin SN. L-arginine in the management of cardiovascular diseases. Annals of Pharmacotherapy 2001; 35(6):755-64.

17 Alvares TS, Conte CA, Paschoalin VM, Silva JT, Meirelles Cde M, Bhambhani YN, Gomes PS. Acute I­arginine supplementation increases muscle blood vol­ume but not strength performance. Appl Physiol Nutr Metab. 2012 Feb;37(1):115-26.

18 Koppa K, Taes YE, Pottier A, Boone J, Bouckaert J, Derave W. Dietary arginine supplementation speeds pulmonary V02 kinetics during cycle exercise. Med Sci Sports Exerc. 2009 Aug;41 (8):1626-32.

19 Chen J, Wollman Y, Chernichovsky T, laina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind randomized, placebo-controlled study. BJU Int., 1999;83(3):269-73.

20 Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dys­function. Intl J lmpot Res, 1994;6:33-5.

21 Dhanakoti SN, Brosnan JT, Herzberg GR, Brosnan ME. Renal arginine synthesis: studies in vitro and in vivo. Am J Physiol 1990; 259:E437-E442.

22 Yearick ES, Nadeau RG. Serum amino acid response to isocaloric test meals. Am J Clin Nutr 1967; 20: 338-344.

23 Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, and Böger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9.

24 Morita M, Sakurada M, Watanabe F, Yamasaki T, Doi H, Ezaki H, Morishita K, Miyakex T. Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina. Immunol Endocr Metab Agents Med Chem. 2013 Sep;13(3):214-220.

25 Cormio L, De Siati M, Lorusso F, Selvaggio O, Mirabella L, Sanguedolce F, Carrieri G. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology 2011;77:119-22.

Gene Bruno, MS, MHS, the provost for Huntington University of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at gene.bruno@hchs.edu.