Optimizing Nitric Oxide Production for Exercise Performance & Vascular Function: A Narrative Review on the Combination of Glutathione and Citrulline Short Review
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Keywords
Antioxidants, Sports Nutrition, Nitric Oxide, Flow Mediated Dilation
Abstract
Introduction: Citrulline has been thoroughly researched and well documented to increase plasma arginine levels, boosting nitric oxide (NO) synthesis via the nitric oxide synthase (NOS) pathway. While glutathione, a key antioxidant, protects NO from oxidative degradation and helps maintain vascular signaling integrity. When taken together, these nutrients may offer enhanced and/or sustained NO bioavailability, supporting vascular function, recovery, and exercise performance more effectively than citrulline alone.
Methods: A literature review was conducted to explore the relationships between glutathione, citrulline, NO, and vascular health. Three databases, PubMed, ScienceDirect, and Google Scholar and eight search terms were used to find relevant articles.
Results: Four double-blind placebo controlled human clinical trials found the combination of glutathione and l-citrulline to be more effective in enhancing and sustaining NO production levels and flow mediated dilation (vasodilation) better than citrulline alone (P<0.03).
Conclusions: Collectively, these studies support the functional synergy between citrulline and glutathione in promoting NO-related health and performance outcomes offering a promising nutritional strategy for athletes, aging individuals, and those seeking cardiovascular support.
References
2. Jin RC, Loscalzo J. Vascular Nitric Oxide: Formation and Function. J Blood Med. Aug 1 2010;2010(1):147-162. doi:10.2147/jbm.S7000
3. Gonzalez AM, Townsend JR, Pinzone AG, Hoffman JR. Supplementation with Nitric Oxide Precursors for Strength Performance: A Review of the Current Literature. Nutrients. Jan 28 2023;15(3)doi:10.3390/nu15030660
4. Gamonales JM, Rojas-Valverde D, Muñoz-Jiménez J, Serrano-Moreno W, Ibáñez SJ. Effectiveness of Nitrate Intake on Recovery from Exercise-Related Fatigue: A Systematic Review. Int J Environ Res Public Health. Sep 23 2022;19(19)doi:10.3390/ijerph191912021
5. Lancaster JR, Jr. Nitric oxide: a brief overview of chemical and physical properties relevant to therapeutic applications. Future Sci OA. Aug 2015;1(1):Fso59. doi:10.4155/fso.15.59
6. Marini JC, Didelija IC, Castillo L, Lee B. Plasma arginine and ornithine are the main citrulline precursors in mice infused with arginine-free diets. J Nutr. Aug 2010;140(8):1432-7. doi:10.3945/jn.110.125377
7. Morris SM, Jr. Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr. 2002;22:87-105. doi:10.1146/annurev.nutr.22.110801.140547
8. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. Jan 2008;65(1):51-9. doi:10.1111/j.1365-2125.2007.02990.x
9. Theodorou AA, Zinelis PT, Malliou VJ, et al. Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance. Nutrients. Sep 22 2021;13(10)doi:10.3390/nu13103311
10. Glenn JM, Gray M, Wethington LN, Stone MS, Stewart RW, Jr., Moyen NE. Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females. Eur J Nutr. Mar 2017;56(2):775-784. doi:10.1007/s00394-015-1124-6
11. Gasmi A, Nasreen A, Lenchyk L, et al. An Update on Glutathione's Biosynthesis, Metabolism, Functions, and Medicinal Purposes. Curr Med Chem. 2024;31(29):4579-4601. doi:10.2174/0109298673251025230919105818
12. Averill-Bates DA. The antioxidant glutathione. Vitam Horm. 2023;121:109-141. doi:10.1016/bs.vh.2022.09.002
13. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. Feb-Apr 2009;30(1-2):1-12. doi:10.1016/j.mam.2008.08.006
14. Weschawalit S, Thongthip S, Phutrakool P, Asawanonda P. Glutathione and its antiaging and antimelanogenic effects. Clin Cosmet Investig Dermatol. 2017;10:147-153. doi:10.2147/ccid.S128339
15. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr. Dec 9 2005;2(2):38-44. doi:10.1186/1550-2783-2-2-38
16. Baldelli S, Ciccarone F, Limongi D, Checconi P, Palamara AT, Ciriolo MR. Glutathione and Nitric Oxide: Key Team Players in Use and Disuse of Skeletal Muscle. Nutrients. Sep 30 2019;11(10)doi:10.3390/nu11102318
17. Prasad A, Andrews NP, Padder FA, Husain M, Quyyumi AA. Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. J Am Coll Cardiol. Aug 1999;34(2):507-14. doi:10.1016/s0735-1097(99)00216-8
18. McKinley-Barnard S, Andre T, Morita M, Willoughby DS. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. J Int Soc Sports Nutr. 2015;12:27. doi:10.1186/s12970-015-0086-7
19. Hwang P, Morales Marroquín FE, Gann J, et al. Eight weeks of resistance training in conjunction with glutathione and L-Citrulline supplementation increases lean mass and has no adverse effects on blood clinical safety markers in resistance-trained males. J Int Soc Sports Nutr. Jun 27 2018;15(1):30. doi:10.1186/s12970-018-0235-x
20. Cabre HE, Greenwalt CE, Gould LM, Smith-Ryan AE. The effects of L-Citrulline and Glutathione on Endurance performance in young adult trained males. J Int Soc Sports Nutr. Dec 2023;20(1):2206386. doi:10.1080/15502783.2023.2206386
21. Figueroa A, Maharaj A, Kang Y, et al. Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women. Nutrients. Mar 23 2023;15(7)doi:10.3390/nu15071557
22. Königstein K, Dipla K, Zafeiridis A. Training the Vessels: Molecular and Clinical Effects of Exercise on Vascular Health-A Narrative Review. Cells. Oct 30 2023;12(21)doi:10.3390/cells12212544
23. Halliwill JR, Buck TM, Lacewell AN, Romero SA. Postexercise hypotension and sustained postexercise vasodilatation: what happens after we exercise? Experimental Physiology. 2013;98(1):7-18. doi:https://doi.org/10.1113/expphysiol.2011.058065
24. Gonzalez AM, Yang Y, Mangine GT, Pinzone AG, Ghigiarelli JJ, Sell KM. Acute Effect of L-Citrulline Supplementation on Resistance Exercise Performance and Muscle Oxygenation in Recreationally Resistance Trained Men and Women. J Funct Morphol Kinesiol. Jun 22 2023;8(3)doi:10.3390/jfmk8030088
25. Bailey SJ, Blackwell JR, Lord T, Vanhatalo A, Winyard PG, Jones AM. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol (1985). Aug 15 2015;119(4):385-95. doi:10.1152/japplphysiol.00192.2014
26. Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res. May 2010;24(5):1215-22. doi:10.1519/JSC.0b013e3181cb28e0
27. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Jan 2007;87(1):315-424. doi:10.1152/physrev.00029.2006
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