Citrulline Research Analysis

L-Citrulline is an amino acid. It is turned into L-arginine in the kidneys after supplementation, which means L-citrulline supplementation is a more effective method of increasing L-arginine levels in the body than L-arginine supplementation.

Keywords: health fitness nutrition supplements science information details

2011 Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases

«SODs play a critical role in inhibiting oxidative inactivation of nitric oxide, thereby preventing peroxynitrite formation and endothelial and mitochondrial dysfunction.»

«Excessive reactive oxygen species Revised abstract, especially superoxide anion (O₂^•−), play important roles in the pathogenesis of many cardiovascular disease, including hypertension and atherosclerosis. Superoxide dismutases (SODs) are the major antioxidant defense systems against O₂^•−, which consist of three isoforms of SOD in mammals: the cytoplasmic Cu/ZnSOD (SOD1), the mitochondrial MnSOD (SOD2), and the extracellular Cu/ZnSOD (SOD3), all of which require catalytic metal (Cu or Mn) for their activation. Recent evidence suggests that in each subcellular location, SODs catalyze the conversion of O₂^•− H₂O₂, which may participate in cell signaling. In addition, SODs play a critical role in inhibiting oxidative inactivation of nitric oxide, thereby preventing peroxynitrite formation and endothelial and mitochondrial dysfunction. The importance of each SOD isoform is further illustrated by studies from the use of genetically altered mice and viral-mediated gene transfer. Given the essential role of SODs in cardiovascular disease, the concept of antioxidant therapies, that is, reinforcement of endogenous antioxidant defenses to more effectively protect against oxidative stress, is of substantial interest. However, the clinical evidence remains controversial. In this review, we will update the role of each SOD in vascular biologies, physiologies, and pathophysiologies such as atherosclerosis, hypertension, and angiogenesis. Because of the importance of metal cofactors in the activity of SODs, we will also discuss how each SOD obtains catalytic metal in the active sites. Finally, we will discuss the development of future SOD-dependent therapeutic strategies. Antioxid. Redox Signal. 15, 1583–1606.»

2013 Insulin-Mediated Activation of the L-Arginine Nitric Oxide Pathway in Man, and Its Impairment in Diabetes

In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (Forearm blood flow) (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [3H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics.

2015 Frequency and Circadian Timing of Eating May Influence Biomarkers of Inflammation and Insulin Resistance Associated with Breast Cancer Risk

Each 10 percent increase in the proportion of calories consumed in the evening was associated with a 3 percent increase in CRP. Conversely, eating one additional meal or snack per day was associated with an 8 percent reduction in CRP.

2015 Synergistic effects of nitric oxide and exercise on revascularisation in the infarcted ventricle in a murine model of myocardial infarction

«It has been shown that density of microvessels decreases in the left ventricular after myocardial infarction (MI). The change of angiogenic and angiostatic factors as the main factors in revascularisation after exercise training in area at risk is not determined yet in MI. Therefore, the aim of the present study was the effect of exercise training and L-arginine supplementation on area at risk angiogenesis in myocardial infarction rat. Four weeks after surgery (Left Anterior Descending Coronary artery Ligation), myocardial infarction rats were divided into 4 groups: Sedentary rats (Sed-MI); L-arginine supplementation (La-MI); Exercise training (Ex-MI) and Exercise + L-arginine (Ex+La). Exercise training (ET) lasted for 10 weeks at 17 m/min for 10-50 min day⁻¹. Rats in the L-arginine-treated groups drank water containing 4 % L-arginine. After ET and L-arginine supplementation, ventricular function was evaluated and angiogenic and angiostatic indices were measured at ~1 mm from the edge of scar tissue (area at risk). Statistical analysis revealed that gene expression of VEGF as an angiogenic factor, angiostatin as an angiostatic factor and caspase-3 at area at risk decrease significantly in response to exercise training compared to the sedentary group. The capillary and arteriolar density in the Ex groups were significantly higher than those of the Sed groups. Compared to the Ex-MI group, the Ex+La group showed a markedly increase in capillary to fiber ratio. No significant differences were found in infarct size among the four groups, but cardiac function increased in response to exercise. Exercise training increases revascularization at area at risk by reduction of angiostatin. L-arginine supplementation causes additional effects on exercise-induced angiogenesis by preventing more reduction of VEGF gene expression in response to exercise. These improvements, in turn, increase left ventricular systolic function and decrease mortality in myocardial infarction rats.»

2017 Effects of Beetroot Juice Supplementation on Cardiorespiratory Endurance in Athletes. A Systematic Review

"Athletes use nutritional supplementation to enhance the effects of training and achieve improvements in their athletic performance. Beetroot juice increases levels of nitric oxide (NO), which serves multiple functions related to increased blood flow, gas exchange, mitochondrial biogenesis and efficiency, and strengthening of muscle contraction. These biomarker improvements indicate that supplementation with beetroot juice could have ergogenic effects on cardiorespiratory endurance that would benefit athletic performance. The aim of this literature review was to determine the effects of beetroot juice supplementation and the combination of beetroot juice with other supplements on cardiorespiratory endurance in athletes. A keyword search of DialNet, MedLine, PubMed, Scopus and Web of Science databases covered publications from 2010 to 2016. After excluding reviews/meta-analyses, animal studies, inaccessible full-text, and studies that did not supplement with beetroot juice and adequately assess cardiorespiratory endurance, 23 articles were selected for analysis. The available results suggest that supplementation with beetroot juice can improve cardiorespiratory endurance in athletes by increasing efficiency, which improves performance at various distances, increases time to exhaustion at submaximal intensities, and may improve the cardiorespiratory performance at anaerobic threshold intensities and maximum oxygen uptake (VO_2max). Although the literature shows contradictory data, the findings of other studies lead us to hypothesize that supplementing with beetroot juice could mitigate the ergolytic effects of hypoxia on cardiorespiratory endurance in athletes. It cannot be stated that the combination of beetroot juice with other supplements has a positive or negative effect on cardiorespiratory endurance, but it is possible that the effects of supplementation with beetroot juice can be undermined by interaction with other supplements such as caffeine."

2001 Nitric oxide and angiogenesis.

«The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.»

2003 NO and angiogenesis.

«Angiogenesis requires the elaboration of endothelium-derived nitric oxide (NO). Angiogenic factors induce the release of NO from endothelial cells, which mediates a multiplicity of processes involved in angiogenesis. These NO-modulated processes include endothelial cell survival, proliferation, migration, and interaction with the extracellular matrix. Derangements of the NO synthase pathway impair angiogenesis. Accordingly, the competitive inhibitor of the NOS pathway asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of angiogenesis. By contrast, agents which increase NO synthesis, such as low dose statins, enhance angiogenesis. Modulation of the NO synthase pathway could become a new therapeutic avenue for angiogenesis-related disorders.»

2004 L-lysine decreases nitric oxide production and increases vascular resistance in lungs isolated from lipopolysaccharide-treated neonatal pigs.

«Nitric oxide (NO) production may depend on the uptake of L-arginine (L-arg), the substrate for NO synthase in inflammatory lung diseases. The cellular transport of L-arg occurs via the cationic amino acid transporters (CAT), and L-lysine (L-lys) competitively inhibits CAT. Neonatal pigs were treated with lipopolysaccharide (LPS) or vehicle for 4 h. LPS increased exhaled NO (exNO; 0.026 +/- 0.003 to 0.046 +/- 0.003 nmol. kg(-1). min(-1); p < 0.005) and decreased mean systemic arterial blood pressure (89 +/- 4 to 67 +/- 4 mm Hg; p < 0.05), whereas vehicle did not affect exNO or mean systemic arterial blood pressure. The lung were then isolated and perfused; exNO was greater in lung from LPS-treated animals (0.08 +/- 0.01 nmol/kg/min) than in lung from vehicle-treated animals (0.05 +/- 0.01 nmol. kg(-1). min(-1); p < 0.05). The addition of L-arg (0.3 mM) significantly (p < 0.05) increased exNO production in both groups of lung (mean increase 0.04 +/- 0.01 nmol. kg(-1). min(-1) LPS-treated lung, p < 0.05; mean increase 0.02 +/- 0.01 nmol. kg(-1). min(-1) vehicle-treated lung); however, L-arg decreased pulmonary vascular resistance (PVR) only in LPS-treated lung (mean decrease 0.03 +/- 0.01 mm Hg. ml(-1). kg(-1). min(-1), p < 0.05). L-lys caused a dose-dependent decrease in exNO production and a dose-dependent increase in PVR in LPS-treated lung. L-lys decreased exNO only at 30 mM and had no effect on PVR in vehicle-treated lung. In four lung each from vehicle- and LPS-treated animals, reverse transcriptase-PCR demonstrated CAT-2 mRNA only in LPS-treated animals. These results suggest that the increased NO production in the lung from LPS-treated animals depends on the uptake of vascular L-arg.»

2015 Can skin exposure to sunlight prevent liver inflammation?

«Liver inflammation contributes towards the pathology of non-alcoholic fatty liver disease (NAFLD). Here we discuss how skin exposure to sunlight may suppress liver inflammation and the severity of NAFLD. Following exposure to sunlight-derived ultraviolet radiation (UVR), the skin releases anti-inflammatory mediators such as vitamin D and nitric oxide. Animal modeling studies suggest that exposure to UVR can prevent the development of NAFLD. Association studies also support a negative link between circulating 25-hydroxyvitamin D and NAFLD incidence or severity. Clinical trials are in their infancy and are yet to demonstrate a clear beneficial effect of vitamin D supplementation. There are a number of potentially interdependent mechanisms whereby vitamin D could dampen liver inflammation, by inhibiting hepatocyte apoptosis and liver fibrosis, modulating the gut microbiome and through altered production and transport of bile acids. While there has been a focus on vitamin D, other mediators induced by sun exposure, such as nitric oxide may also play important roles in curtailing liver inflammation.»

2018 Acute ingestion of beetroot juice increases exhaled nitric oxide in healthy individuals.

"After beetroot consumption, average values of the natural log of FENO50 (lnFENO50) increased by 21.3% (Cohen's d = 1.54, p < .001) 45 minutes after consumption and by 20.3% (Cohen's d = 1.45, p < .001) 90 min after consumption. On the other hand, only very small increases in FENO50 were observed after consumption of the control liquid (less than 1% increase). A small subset (n = 4) of participants completed an extended protocol lasting over 3 hours, where elevated levels of FENO50 persisted. No significant changes in cardiovascular measures were observed with this small single dose of beetroot juice."

2018 Ageing: Is there a role for arachidonic acid and other bioactive lipids? A review.

Ageing is inevitable. Recent studies suggest that it could be delayed. Low-grade systemic inflammation is seen in type 2 diabetes mellitus, hypertension and endothelial dysfunction that are common with increasing age. In all these conditions, an alteration in arachidonic acid (AA) metabolism is seen in the form of increased formation of pro-inflammatory eicosanoids and decreased production of anti-inflammatory lipoxins, resolvins, protectins and maresins and decreased activity of desaturases. Calorie restriction, exercise and parabiosis delay age-related changes that could be related to enhanced proliferation of stem cells, decrease in inflammation and transfer of GDF-11 (growth differentiation factor-11) and other related molecules from the young to the old, increase in the formation of lipoxin A4, resolvins, protectins and maresins, hydrogen sulfide (H2S) and nitric oxide (NO); inhibition of ageing-related hypothalamic or brain IKK-β and NF-kB activation, decreased gonadotropin-releasing hormone (GnRH) release resulting in increased neurogenesis and consequent decelerated ageing. This suggests that hypothalamus participates in ageing process. N-acylethanolamines (NAEs) and lipid-derived signalling molecules can be tuned favorably under dietary restriction to extend lifespan and/or prevent advanced age associated diseases in an mTOR dependent pathway manner. Sulfur amino acid (SAA) restriction increased hydrogen sulfide (H2S) production and protected tissues from hypoxia and tissue damage. Anti-inflammatory metabolites formed from AA such as LXA4, resolvins, protectins and maresins enhance production of NO, CO, H2S; suppress NF-kB expression and alter mTOR expression and thus, may aid in delaying ageing process. Dietary restriction and exercise enhance AA metabolism to form LXA4, resolvins, protectins and maresins that have anti-inflammatory actions. AA and their metabolites also influence stem cell biology, enhance neurogenesis to improve memory and augment autophagy to prolong life span. Thus, AA and other PUFAs and their anti-inflammatory metabolites inhibit inflammation, augment stem cell proliferation, restore to normal lipid-derived signaling molecules and NO and H2S production, enhance autophagy and prolong life span.

2018 Blue light exposure decreases systolic blood pressure, arterial stiffness, and improves endothelial function in humans.

«Blue light exposure significantly decreased systolic blood pressure and increased heart rate as compared to control. In parallel, blue light significantly increased forearm blood flow, flow-mediated dilation, circulating nitric oxide species and nitroso compounds while it decreased forearm vascular resistance and pulse wave velocity.»

2019 Post-exercise hypotension and skeletal muscle oxygenation is regulated by nitrate-reducing activity of oral bacteria.

«Post-exercise hypotension (PEH) is a common physiological phenomenon leading to lower blood pressure after acute exercise, but it is not fully understood how this intriguing response occurs. This study investigated whether the nitrate-reducing activity of oral bacteria is a key mechanism to trigger PEH. Following a randomized, double blind and crossover design, twenty-three healthy individuals (15 males/8 females) completed two treadmill trials at moderate intensity. After exercise, participants rinsed their mouth with antibacterial mouthwash to inhibit the activity of oral bacteria or a placebo mouthwash. Blood pressure was measured before, 1h and 2 h after exercise. The microvascular response to a reactive hyperaemia test, as well as blood and salivary samples were taken before and 2 h after exercise to analyse nitrate and nitrite concentration and the oral microbiome. As expected, systolic blood pressure (SBP) was lower (1 h: -5.2 ± 1.0 mmHg; P < 0.001); 2 h: -3.8 ± 1.1 mmHg, P = 0.005) after exercise compared to baseline in the placebo condition. This was accompanied by an increase of circulatory nitrite 2 h after exercise (2h: 100 ± 13 nM) compared to baseline (59 ± 9 nM; P = 0.013). Additionally, an increase in the peak of the tissue oxygenation index (TOI) during the reactive hyperaemia response was observed after exercise (86.1 ± 0.6%) compared to baseline levels (84.8 ± 0.5%; P = 0.010) in the placebo condition. On the other hand, the SBP-lowering effect of exercise was attenuated by 61% at 1 h in the recovery period, and it was fully attenuated 2 h after exercise with antibacterial mouthwash. This was associated with a lack of changes in circulatory nitrite (P > 0.05), and impaired microvascular response (peak TOI baseline: 85.1 ± 3.1%; peak TOI post-exercise: 84.6 ± 3.2%; P > 0.05). Diversity of oral bacteria did not change after exercise in any treatment. These findings show that nitrite synthesis by oral commensal bacteria is a key mechanism to induce the vascular response to exercise over the first period of recovery thereby promoting lower blood pressure and greater muscle oxygenation.»

1994 ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia.

"We tested the hypothesis that dilatation of cerebral arterioles during hypoxia is mediated by activation of ATP-sensitive K+ channels. The diameter of pial arterioles was measured through a closed cranial window in anesthetized rabbits. Topical application of aprikalim (10(-6) mol/L), a direct activator of ATP-sensitive K+ channels, dilated pial arterioles by 18 +/- 3% (mean +/- SEM). Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K+ channels, virtually abolished aprikalim-induced vasodilatation. When arterial PO2 was reduced from 129 +/- 3 to 25 +/- 1 mm Hg, the diameter of cerebral arterioles increased by 66 +/- 9% (P < .05). Glibenclamide inhibited dilatation of pial arterioles during hypoxia by 46 +/- 5% (P < .05). In contrast, vasodilatation in response to sodium nitroprusside was not altered by glibenclamide. Topical application of adenosine (10(-4) mol/L) increased arteriolar diameter by 21 +/- 4%. Glibenclamide did not affect adenosine-induced vasodilatation. These findings suggest that dilatation of cerebral arterioles in response to hypoxia is mediated, in part, by activation of ATP-sensitive K+ channels."

Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability

Highlights
• Oral l-citrulline plus l-arginine rapidly raises plasma l-arginine levels.
• Combined administration causes a significantly greater increase in plasma NOx and cGMP.
• Blood flow is also significantly increased by l-citrulline plus l-arginine.
• This study proposes a novel strategy to rapidly potentiate NO–cGMP dependent reactions.
• This approach may have clinical utility in the regulation of cardiovascular function.