Acute effect of citrulline malate on flow-mediated dilation and serum pharmacodynamics in healthy young males

Johan Grannes¹Nigel A Callender^2,3Adam M Gonzalez⁴Jonny Hisdal^2,3Fredrik T. Vårvik^5,6Thomas Bjørnsen^6,7*

• ¹Department of Sports Science and Physical Education, University of Agder, Kristiansand, Norway
• ²Department of Vascular Surgery, Oslo University Hospital, Oslo, Norway
• ³Universitetet i Oslo Institutt for klinisk medisin, Oslo, Norway
• ⁴Department of Allied Health and Kinesiology, Hofstra University, Hempstead, NY, United States
• ⁵Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway
• ⁶Norwegian Olympic and Paralympic Committee and Confederation of Sports, Oslo, Norway
• ⁷Department of Education and Sports Science, University of Stavanger, Stavanger, Norway

The use of ergogenic compounds has gained increasing popularity among trainees who wish to improve performance and recover faster from their workouts. Among these products is citrulline malate (CitMal), a popular dietary supplement that is suggested to enhance nitric oxide (NO)-mediated vasodilation and muscle blood flow. To evaluate effects on arterial function, flow-mediated dilation (FMD) of the brachial artery during active hyperemia was measured in 12 healthy, recreationally active males (23 ± 3 years) before and after (60-and 120-min post) consuming either 6 g CitMal, 12 g CitMal, or a taste-matched placebo. The study used a randomized, double-blind, placebo-controlled, within-subject counterbalanced crossover design with ≥ 7-day washouts. Repeated measures ANOVA revealed no significant interaction (p = 0.315) or time effect (p=0.649) in corrected FMD% at 60-and 120-min after intake of placebo, 6 g CitMal, and 12 g CitMal. There were also no significant differences (p = 0.301) between doses at any timepoint. A subgroup of six participants completed two additional visits to assess the effect of CitMal ingestion on serum markers involved in NO production. Over 120-min post-consumption, both doses significantly increased peak serum concentrations of citrulline (6 g: 504.7 ± 139.7; 12 g: 881.9 ± 216.7 μM), arginine (6 g: 70.2 ± 20.4; 12 g: 101.8 ± 36.2 μM), and ornithine (6 g: 27.9 ± 14.2; 12 g: 56.5 ± 30.0 μM) from baseline (all p < 0.001), with greater increases following 12 g (all p < 0.05). Likewise, arginine-to-dimethylarginine ratios (SDMA and ADMA) increased from baseline (SDMA, 6 g: 114.1 ± 24.2; 12 g: 166.2 ± 43.7; ADMA, 6 g: 119.2 ± 31.8; 12 g: 169.1 ± 29.1; all p < 0.001), with greater increases following 12 g (p < 0.05). Collectively, these findings suggest that neither 6 g nor 12 g of CitMal significantly enhance FMD within 120 min, despite marked increases in biochemical markers favorable to NO production. These results indicate that acute vascular responses to CitMal may be limited by physiological ceiling effects and that potential vascular benefits may depend on longer-term supplementation, the presence of an exercise stimulus, or populations with impaired endothelial function.