L-Citrulline (Blood Flow)

Background: Acute and chronic hyperglycemia in patients with type 2 diabetes mellitus (T2DM) causes endothelial dysfunction and arterial stiffness, contributing to early mortality from cardiovascular disease (CVD). Although L-citrulline (CIT) supplementation improves endothelial function in older women and decreases fasting glucose in those with T2DM, whether it improves vascular function and blood glucose during acute hyperglycemic states in T2DM is unknown. Methods: We randomized 16 patients with T2DM (age 62 ± 6 years) to consume either CIT (6 g/day) or placebo for 4 weeks. Brachial artery flow-mediated dilation (FMD), brachial and aortic blood pressure, aortic and leg arterial stiffness (pulse wave velocity, PWV), and blood glucose concentration were assessed in the fasted state and 60 min following glucose ingestion (during acute hyperglycemia). Results: Four weeks of L-citrulline supplementation improved FMD, femoral-ankle PWV, aortic systolic blood pressure, and blood glucose concentration in the fasted state compared to placebo (all p < 0.05). During acute hyperglycemia, CIT supplementation increased FMD and reduced femoral-ankle PWV, aortic systolic BP, and glucose levels compared to placebo (all p < 0.05). Conclusions: CIT supplementation is beneficial to improve vascular function and glucose levels during chronic and acute hyperglycemia in middle-aged and older adults with T2DM.

BACKGROUND: Patients with type 2 diabetes (T2D) develop vascular complications due to arginine deficiency-induced microvascular endothelial dysfunction, which is related to the loss of muscle strength (MS) associated with aging. Thus, increased nitric oxide (NO)-mediated vasodilation may improve MS. We investigated the impact of the NO precursor citrulline on microvascular function (endothelial and muscle reactivity) and MS in T2D patients. METHODS: Sixteen participants with T2D (53-72 years, nine females) were randomized to citrulline supplementation (CITS, 6 g/day) or placebo for 4 weeks prior to an 8-week washout period, followed by the opposite supplement for 4 weeks in a crossover trial. Endothelial function (log-transformed reactive hyperemia index, LnRHI), forearm muscle reactivity (near-infrared spectroscopy-derived tissue oxygen index (TOI) reperfusion indices), plasma arginine levels (ARG), and handgrip strength (HGSrel) and calf MS (CMSrel) adjusted for body weight were measured at baseline and 4 weeks for each condition. RESULTS: CITS increased the LnRHI (∆0.11 ± 0.16 vs. ∆-0.08 ± 0.24, p < 0.05), TOI range (∆2.6 ± 3.3 vs. ∆-1.5 ± 4.8%, p < 0.01), TOI hyperemic response (∆1.2 ± 1.4 vs. ∆-0.6 ± 2.8%, p < 0.05), TOI 2 min area under the curve (∆154 ± 187 vs. ∆-41 ± 194%/s, p < 0.01), ARG (∆43 ± 28 vs. ∆1 ± 16μM/L, p < 0.001), CMS (∆1.5 ± 2.8 vs. ∆-0.3 ± 1.2 kg, p < 0.05), and CMSrel (∆0.02 ± 0.03 vs. ∆-0.01 ± 0.02 kg/kg, p < 0.01) compared to placebo. The improvements in LnRHI and CMSrel were correlated (r = 0.37, p < 0.05). CONCLUSIONS: This study showed that CITS improves microvascular endothelial function, muscle microvascular reactivity, and calf muscle strength in middle-aged and older patients with T2D.

Background: The dietary supplement citrulline might increase nitric oxide levels, leading to vasodilation and improved blood flow, potentially benefiting athletes' aerobic exercise performance. However, rapid oxidative impairment of the L-arginine/nitric oxide (NO) pathway limits these effects. This is countered by Bergamot Polyphenolic Fraction Gold® (BPFG), a strong natural antioxidant. To investigate L-citrulline + BPFG supplementation's effects, we performed a randomized, double-blind, placebo-controlled pilot trial on athletic performance and blood flow in trained athletes (cyclists). Methods: Random assignment of 90 male athletes resulted in nine different groups: placebo for Group 1, BPFG at 500 and 1000 mg daily for Groups 2 and 3, L-citrulline at 1000 and 2000 mg/daily for Groups 4 and 5, and the combination product of BPFG plus citrulline (N.O. Max) for Groups 6-9. Baseline and 3-month pre- and post-exercise biochemical, reactive vasodilation (RHI), and maximal oxygen consumption measurements were taken for all subjects. Results: Three months of the combination of BPFG and L-citrulline (N.O. Max) produced a significant synergistic effect, markedly increasing NO (p < 0.001 vs. placebo) release and RHI (p < 0.001 vs. placebo). Cardiorespiratory fitness improved significantly with the BPFG and L-citrulline combination, resulting in substantially higher VO2 max, VT1, VT2, and peak power and a significantly lower heart rate (p < 0.01 vs. placebo). No harmful adverse effects were observed. Conclusions: N.O. Max supplementation, providing beneficial effects on the antioxidant state and preserving the vascular endothelium might be a supplementation strategy to improve athletic performance and potentiate results. Given the small sample size, this study serves as a pilot, and further research is needed to validate these findings on a larger scale.

PURPOSE: 7 days L-citrulline supplementation has been reported to improve blood pressure, V. O2 kinetics, gastrointestinal (GI) perfusion and endurance cycling performance through increasing arterial blood flow. In situations where blood volume is compromised (e.g., hyperthermia/hypohydration), L-citrulline may improve thermoregulation and exercise performance by redistributing blood flow to aid heat loss and/or muscle function. This study assessed 7 days L-citrulline supplementation on running performance in the heat, whilst mildly hypohydrated. METHODS: 13 endurance runners (2 female, 31 ± 8 y, V. O2peak 60 ± 6 mL/kg/min) participated in a randomised crossover study with 7 days L-citrulline (CIT; 6 g/d) or placebo (maltodextrin powder; PLA) supplementation. Participants completed a 50 min running 'preload' at 65% V. O2peak (32 °C, 50% relative humidity) to induce hyperthermia and hypohydration before a 3 km running time trial (TT). Body mass and blood samples were collected at baseline, pre-preload, post-preload and post-TT, whilst core and skin temperature, heart rate and perceptual responses were collected periodically throughout. RESULTS: TT performance was not different between trials (CIT 865 ± 142 s; PLA 892 ± 154 s; P = 0.437). Core and skin temperature and heart rate (P ≥ 0.270), hydration (sweat rate, plasma volume, osmolality) indices (P ≥ 0.216), GI damage (P ≥ 0.260) and perceptual responses (P ≥ 0.610) were not different between trials during the preload and TT. CONCLUSIONS: 7 days of L-citrulline supplementation had no effect on 3 km running performance in the heat or any effects on thermoregulation or GI damage in trained runners in a hypohydrated state. © 2024. The Author(s).

Endothelial dysfunction decreases exercise limb blood flow (BF) and muscle oxygenation. Acute L-Citrulline supplementation (CIT) improves muscle tissue oxygen saturation index (TSI) and deoxygenated hemoglobin (HHb) during exercise. Although CIT improves endothelial function (flow-mediated dilation [FMD]) in hypertensive women, the impact of CIT on exercise BF and muscle oxygenation (TSI) and extraction (HHb) are unknown. We examined the effects of CIT (10 g/day) and a placebo for 4 weeks on blood pressure (BP), arterial vasodilation (FMD, BF, and vascular conductance [VC]), and forearm muscle oxygenation (TSI and HHb) at rest and during exercise in 22 hypertensive postmenopausal women. Compared to the placebo, CIT significantly (p < 0.05) increased FMD (Δ-0.7 ± 0.6% vs. Δ1.6 ± 0.7%) and reduced aortic systolic BP (Δ3 ± 5 vs. Δ-4 ± 6 mmHg) at rest and improved exercise BF (Δ17 ± 12 vs. Δ48 ± 16 mL/min), VC (Δ-21 ± 9 vs. Δ41 ± 14 mL/mmHg/min), TSI (Δ-0.84 ± 0.58% vs. Δ1.61 ± 0.46%), and HHb (Δ1.03 ± 0.69 vs. Δ-2.76 ± 0.77 μM). Exercise BF and VC were positively correlated with improved FMD and TSI during exercise (all p < 0.05). CIT improved exercise artery vasodilation and muscle oxygenation via increased endothelial function in hypertensive postmenopausal women. The effect of microencapsulated watermelon rind (Citrullus lanatus) and beetroot (Beta vulgaris L.) ingestion on ischemia/reperfusion-induced endothelial dysfunction: a randomised clinical trial. Volino-Souza M(1)(2), Oliveira GV(1)(3), Tavares AC(1)(4), Souza K(1)(4), Alvares T(1)(4). Author information: (1)Nutrition and Exercise Metabolism Research Group, Multidisciplinary Center UFRJ-Macaé, Federal University of Rio de Janeiro, Macaé, Rio de Janeiro, Brazil. [email protected]. (2)Postgraduate Program in Food Science, Chemistry Institute, Federal University of Rio de Janeiro, RJ, Brazil. (3)Medical Science Institute, Multidisciplinary Center UFRJ-Macaé, Federal University of Rio de Janeiro, Macaé, Brazil. (4)Food and Nutrition Institute, Multidisciplinary Center UFRJ-Macaé, Federal University of Rio de Janeiro, Macaé, Brazil. Endothelial dysfunction is commonly associated with a cardiovascular

6. Food Funct. 2023 Aug 29;14(17):7959-7968. doi: 10.1039/d3fo02612d. The effect of microencapsulated watermelon rind (Citrullus lanatus) and beetroot (Beta vulgaris L.) ingestion on ischemia/reperfusion-induced endothelial dysfunction: a randomised clinical trial. Volino-Souza M(1)(2), Oliveira

BACKGROUND: Citrulline may amplify the effects of L-arginine and nitric oxide concentration, which may augment vasodilation and blood flow, thereby enhancing aerobic exercise performance. The purpose of this randomized, double-blind, placebo-controlled crossover study was to investigate effects of L-citrulline + Glutathione on aerobic exercise performance and blood flow in well-trained men. METHODS: Twenty-five males (Mean ± SD; Age: 22.2 ± 2.4 yrs; Height: 177.0 ± 4.8 cm; Weight: 75.3 ± 6.9 kg) were randomly assigned to the L-citrulline + Glutathione (Setria Performance Blend: SPB; L-citrulline [2 g] + glutathione [200 mg], 6 capsules) or placebo (PL; 3.1 g cellulose, 6 capsules) group. Participants performed a maximal oxygen consumption treadmill test to determine peak velocity (PV) and returned after eight days of ingesting either PL or SPB. Three timed treadmill runs to exhaustion (TTE) were performed at 90%, 100%, and 110% PV. Brachial artery blood flow and vessel diameter were assessed using ultrasound at 1-hr prior to exercise (1hrPrEX), after each exercise bout, immediately post-exercise (immediate PEX), and 30 minutes post exercise (30minPEX) at visits 2 and 4. Blood analytes were assessed via venous blood draws at visit 1, visit 3, and 1hrPEX, immediate PEX, and 30minPEX at visits 2 and 4. After a 14-day washout, participants repeated the same procedures, ingesting the opposite treatment. Separate repeated measures ANOVAs were performed for TTE, vessel diameter, blood flow, and blood analytes. RESULTS: Blood flow was significantly augmented 30minPEX (p = 0.04) with SPB in comparison with PL. L-citrulline and L-arginine plasma concentrations were significantly elevated immediately PEX (p = 0.001) and 30-minPEX (p = 0.001) following SPB in comparison to PL. CONCLUSION: Acute ingestion of SPB after eight days may enhance blood flow, L-citrulline, and L-arginine plasma concentrations after high-intensity exercise, which may enhance performance. CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/ct2/show/nct04090138], identifier [NCT04090138].

In sports nutrition, nitric oxide (NO•) precursors such as L-citrulline are widely used to enhance NO• bioavailability, which is considered an ergogenic aid. Our study aimed to examine the effect of short-term L-citrulline supplementation on respiratory muscles' performance, fatigue, and oxygenation in older adults. Fourteen healthy older males took 6 g of L-citrulline or a placebo for seven days in a double-blind crossover design. Pulmonary function via spirometry (i.e., forced expired volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio)), fractional exhaled nitric oxide (NO•), maximal inspiratory pressure (MIP), rate of perceived exertion, and sternocleidomastoid muscle oxygenation (i.e., oxyhemoglobin (Δ[O2Hb]) and de-oxyhemoglobin (Δ[HHb]), total hemoglobin concentration (Δ[tHb]), and tissue saturation index (TSI%)) were evaluated at baseline, after seven days of L-citrulline supplementation, and after incremental resistive breathing to task failure of the respiratory muscles. The exhaled NO• value was only significantly increased after the supplementation (26% p < 0.001) in the L-citrulline condition. Pulmonary function, MIP, rate of perceived exertion, and sternocleidomastoid muscle oxygenation were not affected by the L-citrulline supplementation. In the present study, although short-term L-citrulline supplementation increased exhaled NO•, no ergogenic aids were found on the examined parameters at rest and after resistive breathing to task failure in older adults.

Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: Setria®) or placebo (PL) for 4 weeks. Brachial artery flow-mediated dilation (FMD), aortic stiffness (pulse wave velocity, PWV), brachial and aortic BP reactivity to CPT, and serum fasting blood glucose (FBG), ARG, and ARG/ADMA ratio were measured. Baseline FBG was higher in CIT+GSH vs. PL. FMD increased after CIT+GSH vs. PL (p < 0.05). CIT and CIT+GSH increased ARG/ADMA (p < 0.05), but did not affect aortic PWV. CIT+GSH attenuated the brachial and aortic systolic BP and mean arterial pressure (MAP) responses to CPT vs. PL and CIT (p < 0.05). The improvements in FMD were related to baseline FMD (r = -0.39, p < 0.05) and aortic MAP response to CPT (r = -0.33, p < 0.05). This study showed that CIT+GSH improved FMD and attenuated systolic BP and MAP reactivity in PMW. Although CIT increased ARG/ADMA, it did not improve FMD in healthy PMW.

BACKGROUND: Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans. METHODS: We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity. RESULTS: nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (-3.3% [-6.5, -0.01], P=0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced -4.3% [-8.5, -0.1], P=0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms. CONCLUSIONS: Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.

BACKGROUND: Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation. METHODS: Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially. RESULTS: L-Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L-citrulline plus L-arginine administration as compared with the control. CONCLUSION: Our data show for the first time that a combination of oral L-citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans.

Glutamine is purported to inhibit recycling of citrulline to arginine and to limit nitric oxide release in vitro. However, vasoactive effects of glutamine have not been clearly demonstrated in vivo. During hyperammonemia, impaired cerebrovascular reactivity to CO(2) is related to glutamine accumulation. We tested the hypotheses that 1) glutamine infusion in the absence of hyperammonemia impairs cerebrovascular CO(2) reactivity and 2) arginine infusion preserves CO(2) reactivity during glutamine infusion and during hyperammonemia. Pentobarbital sodium-anesthetized rats were equipped with a closed cranial window for measuring pial arteriolar diameter. Intravenous infusion of 3 mmol. kg(-1). h(-1) of L-glutamine for 6 h produced threefold increases in plasma and cerebrospinal fluid concentrations. Dilation to hypercapnia was reduced by 45% compared with that of a time control group at 6 h but not at 3 h of glutamine infusion. Coinfusion of 2 mmol. kg(-1). h(-1) of L-arginine with glutamine maintained the hypercapnic vasodilation at the control value. Infusion of ammonium acetate at a rate known to produce threefold increases in cortical tissue glutamine concentration resulted in no significant hypercapnic vasodilation. Coinfusion of arginine with ammonium acetate maintained hypercapnic vasodilation at 60% of the control value. Arginine infusion did not augment hypercapnic vasodilation in a control group. We conclude that glutamine modulates cerebrovascular CO(2) reactivity in vivo. Glutamine probably acts by limiting arginine availability because the vascular inhibitory effect required >3 h to develop and because arginine infusion counteracted the vascular effect of both endogenously and exogenously produced increases in glutamine.

BACKGROUND AND PURPOSE: N-Methyl-D-aspartate (NMDA) produces dilatation of cerebral arterioles that is dependent on production of nitric oxide (NO). In these experiments we examined the hypothesis that cerebral vasodilatation in response to NMDA is mediated by the neuronal isoform of NO synthase. METHODS: We measured diameters of cerebral arterioles (baseline diameter, 89 +/- 7 microns) using a closed cranial window in anesthetized rabbits that received either vehicle (10 mL/kg IP peanut oil) or 7-nitroindazole (7-NI; 50 mg/kg IP). 7-NI is reported to be a selective inhibitor of neuronal NO synthase. RESULTS: Two hours after administration of 7-NI, activity of brain NO synthase (measured by conversion of L-arginine to L-citrulline) was reduced by 33% compared with vehicle (24 +/- 1 versus 16 +/- 3 pmol/min per milligram protein; n = 7; P < .05). Dilatation of cerebral arterioles in response to NMDA (100 and 300 mumol/L) was inhibited by 30% to 40% by 7-NI compared with responses in the presence of vehicle (23 +/- 6% versus 14 +/- 5% and 30 +/- 4% versus 21 +/- 5%, respectively; P < .05 for both concentrations; n = 10). In contrast, vasodilatation in response to acetylcholine (1 mumol/L) was similar in vehicle- and 7-NI-treated animals (17 +/- 5% versus 21 +/- 4%; P > .05). CONCLUSIONS: These findings suggest that vasodilatation in response to NMDA is mediated by neuronally derived NO. 7-NI appears to produce selective inhibition of brain NO synthase but not endothelial NO synthase.

BACKGROUND: Many human studies report that nitric oxide (NO) improves sport performance. This is because NO is a potential modulator of blood flow, muscle energy metabolism, and mitochondrial respiration during exercise. L-Citrulline is an amino acid present in the body and is a potent endogenous precursor of L-arginine, which is a substrate for NO synthase. Here, we investigated the effect of oral L-citrulline supplementation on cycling time trial performance in humans. METHODS: A double-blind randomized placebo-controlled 2-way crossover study was employed. Twenty-two trained males consumed 2.4 g/day of L-citrulline or placebo orally for 7 days. On Day 8 they took 2.4 g of L-citrulline or placebo 1 h before a 4-km cycling time trial. Time taken to complete the 4 km cycle, along with power output/VO2 ratio (PO/VO2), plasma nitrite and nitrate (NOx) and amino acid levels, and visual analog scale (VAS) scores, was evaluated. RESULTS: L-Citrulline supplementation significantly increased plasma L-arginine levels and reduced completion time by 1.5 % (p < 0.05) compared with placebo. Moreover, L-citrulline significantly improved subjective feelings of muscle fatigue and concentration immediately after exercise. CONCLUSIONS: Oral L-citrulline supplementation reduced the time take to complete a cycle ergometer exercise trial. TRIAL REGISTRATION: Current Controlled Trials UMIN000014278.

BACKGROUND: Postmenopausal women are at increased risk of developing cardiovascular, muscular, and metabolic dysfunction due to hormonal changes associated with aging. Citrulline, a non-essential amino acid and precursor to nitric oxide, has gained interest as a potential dietary supplement for improving vascular health, muscle function, and metabolic parameters in this population. OBJECTIVE: This systematic review aims to evaluate the effects of citrulline supplementation, administered directly or via watermelon products, on cardiovascular, muscular, and metabolic outcomes in postmenopausal women. METHODS: A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases to identify randomized controlled trials (RCTs) investigating citrulline supplementation in postmenopausal women. Studies were included if they reported outcomes related to blood pressure, arterial stiffness, endothelial function, muscle strength or mass, metabolic parameters, and safety. Study quality was assessed using the Cochrane Risk of Bias Tool 2. Due to heterogeneity in study designs and reported outcomes, results were synthesized narratively. RESULTS: Twelve RCTs involving 360 postmenopausal women were included. all conducted in the United States, with study durations ranging from 4 to 8 weeks and participant ages between 50 and 75 years. Seven studies reported blood pressure outcomes, with most showing reductions in systolic blood pressure and mean arterial pressure. Five studies examined arterial stiffness, with mixed findings on pulse wave velocity and augmentation index. Four studies assessed endothelial function, two of which demonstrated significant improvements in flow-mediated dilation. Muscle function outcomes were investigated in two studies, suggesting improvements only when citrulline was combined with resistance training. Six studies assessed metabolic parameters, with no consistent effects observed on body weight, glucose, insulin, or lipid profiles. Across all studies, no adverse effects related to citrulline supplementation were reported. CONCLUSION: Citrulline supplementation may offer benefits for blood pressure regulation (up to 9 mmH

Gonzalez, AM and Trexler, ET. Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. J Strength Cond Res 34(5): 1480-1495, 2020-L-citrulline, a nonessential amino acid found primarily in watermelon, has recently garnered much attention for its potential to augment L-arginine bioavailability, nitric oxide production, and exercise performance. Over the past decade, L-citrulline has received considerable scientific attention examining potentially ergogenic properties for both aerobic and anaerobic exercise performance. Thus, the purpose of this article is to summarize the theoretical rationale behind L-citrulline supplementation and to comprehensively review the available scientific evidence assessing the potential ergogenic value of L-citrulline supplementation on vascular function and exercise performance in humans. In addition, research that has investigated the potential synergistic effects of L-citrulline with other dietary ingredients (e.g., arginine, antioxidants, nitrates, and branched-chain amino acids) is reviewed. Oral L-citrulline and citrulline malate supplementation have shown to increase plasma citrulline and arginine concentrations, along with total nitrate and nitrite concentrations. Although blood flow enhancement is a proposed mechanism for the ergogenic potential of L-citrulline, evidence supporting acute improvements in vasodilation and skeletal muscle tissue perfusion after supplementation is scarce and inconsistent. Nevertheless, several studies have reported that L-citrulline supplementation can enhance exercise performance and recovery. Given the positive effects observed from some investigations, future studies should continue to investigate the effects of both acute and chronic supplementation with L-citrulline and citrulline malate on markers of blood flow and exercise performance and should seek to elucidate the mechanism underlying such effects.