The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.
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SUBMITTER: Khalaf D
PROVIDER: S-EPMC6683098 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.
Khalaf David D Krüger Marcus M Wehland Markus M Infanger Manfred M Grimm Daniela D
Nutrients 20190722 7
Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increa ...[more]
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Project description:Enhanced arginase-induced arginine consumption is believed to play a key role in the pathogenesis of sickle cell disease-induced end organ failure. Enhancement of arginine availability with L-arginine supplementation exhibited less consistent results; however, L-citrulline, the precursor of L-arginine, may be a promising alternative. In this study, we determined the effects of L-citrulline compared to L-arginine supplementation on arginine-nitric oxide (NO) metabolism, arginine availability and microcirculation in a murine model with acutely-enhanced arginase activity. The effects were measured in six groups of mice (n = 8 each) injected intraperitoneally with sterile saline or arginase (1000 IE/mouse) with or without being separately injected with L-citrulline or L-arginine 1 h prior to assessment of the microcirculation with side stream dark-field (SDF)-imaging or in vivo NO-production with electron spin resonance (ESR) spectroscopy. Arginase injection caused a decrease in plasma and tissue arginine concentrations. L-arginine and L-citrulline supplementation both enhanced plasma and tissue arginine concentrations in arginase-injected mice. However, only the citrulline supplementation increased NO production and improved microcirculatory flow in arginase-injected mice. In conclusion, the present study provides for the first time in vivo experimental evidence that L-citrulline, and not L-arginine supplementation, improves the end organ microcirculation during conditions with acute arginase-induced arginine deficiency by increasing the NO concentration in tissues.
| S-EPMC4516994 | biostudies-literature
Project description:It has been reported that supplementing certain amino acids has therapeutic effects on ulcerative colitis (UC). We intend to explore whether citrulline (Cit) supplementation has protective effects on UC. Fifteen male Wistar rats were divided into normal control group (NC group), UC group and UC+Cit group, with five rats in each group. The UC model was established by TNBS/ethanol method. Rats in UC+Cit group were intragastrically administered with Cit for 7 consecutive days after modeling. All rats were sacrificed after 7 days. Blood samples were collected to detect the number of monocytes. Colon tissues were taken for HE staining. Immunohistochemistry staining for CD68 and p-STAT3 were performed to detect the infiltration of monocytes and the phosphorylation of STAT3 in colon tissues. The concentrations of MCP-1, IL-6 and IL-17A and the protein expression of p-STAT3 in colon tissues were measured by ELISA and western blot methods, respectively. The body weight of UC group rats decreased significantly after 7 days (p<0.05). However, the weight loss of UC+Cit group rats was not statistically significant (p>0.05). The number of peripheral blood monocytes in UC+Cit group was significantly lower than that in UC group (p<0.05), and the infiltration of CD68-positive monocytes in the colon tissue of UC+Cit group was significantly reduced than that in UC group. The concentrations of MCP-1, IL-6 and IL-17A and the expression of p-STAT3 in colon tissues of UC+Cit group rats were significantly lower than those in UC group (both p<0.05). Our study suggests that Cit supplementation may be a potential therapy for UC.
| S-EPMC7567373 | biostudies-literature
Project description:Increased blood pressure (BP), vascular dysfunction and inflammation are involved in the etiology of cardiovascular disease (CVD). Although several dietary components such as polyphenols and L-citrulline may help to control BP, their combined impact on ambulatory BP in individuals at risk of CVD remains unknown. The objective of this research was to investigate the short-term impact of supplementation with a combination of polyphenol extract and L-citrulline on ambulatory BP, endothelial function and inflammation. In a randomized double-blind parallel trial, 73 men and women with prehypertension were supplemented with a placebo (cellulose, n = 34, Plac) or 548 mg/day of polyphenols and 2 g/day of L-citrulline (n = 35, Suppl) for 6 weeks. The primary outcome of this study was the difference between groups in 24-h ambulatory diastolic BP (DBP) at week six. Secondary outcomes were a difference between groups at week six in ambulatory systolic BP (SBP), casual BP, serum lipids and high-sensitivity C-reactive protein (hs-CRP) concentrations and skin advanced glycation end products (AGEs). Potential interaction of treatment with sex was examined. Suppl had no impact on mean ambulatory SBP and DBP (p > 0.10 vs. placebo). Daytime and 24-h SBP were reduced with Suppl in women (p ? 0.01), but not in men (p ? 0.27). A non-significant reduction in AGEs was observed after Suppl compared to Plac among all participants (p = 0.07) and there was no difference in the concentrations of blood lipids (p > 0.20) or CRP (p = 0.36) between treatments at week six. Therefore, supplementation with polyphenol extract and L-citrulline for 6 weeks has no impact on ambulatory BP, blood lipids and CRP in adults with prehypertension. However, the polyphenol extract/L-citrulline supplement may reduce ambulatory SBP in women, but not in men. These preliminary results need further research efforts towards further documenting this sex-dependent BP response to supplementation with polyphenols and L-citrulline.
| S-EPMC7912201 | biostudies-literature
Project description:NEW FINDINGS:What is the central question of this study? Does short-term supplementation with l-citrulline in order to increase l-arginine improve exercise blood flow and peripheral dilatation responses to exercise in older adults? What is the main finding and its importance? l-Citrulline increased femoral blood flow by 11% and vascular conductance by 14% during lower-limb exercise in older men, whereas no changes were observed in older women. This modest improvement in bulk muscle blood flow in older men has implications for altering muscle metabolism that may result in enhanced exercise tolerance in older adults. l-Citrulline (Cit) increases l-arginine (Arg), the primary substrate for nitric oxide biosynthesis. We tested the hypothesis that muscle blood flow during exercise would be enhanced by Cit supplementation in older adults. Femoral artery blood flow was measured during calf exercise using Doppler ultrasound, and vascular conductance (FVC) was calculated in 25 older adults (13 women and 12 men) before and after 14 days of Cit (6 g day-1 ) and placebo (maltodextrin) in a randomized, double-blind, crossover study. Plasma [Arg] and resting blood pressure were also measured before and after each condition. Women and men were analysed separately because of significant sex-by-condition interactions for the change in exercise blood flow and FVC. Plasma [Arg] was increased by 30 and 35% after Cit (P < 0.01) in women and men, respectively, with no change after placebo. Citrulline lowered diastolic blood pressure in men (75 ± 9 versus 71 ± 6 mmHg, P = 0.02), but this variable remained unchanged in women. Blood flow and FVC during exercise at higher workloads were increased after Cit in men (flow, 521 ± 134 versus 584 ± 166 ml min-1 , P = 0.04; FVC, 5.0 ± 1.5 versus 5.8 ± 1.7 m, min mmHg-1 , P = 0.01) but were not different after placebo. These variables were not altered by Cit in women. Adjusting for baseline diastolic blood pressure removed (P = 0.10) the difference in FBF and FVC following Cit in men. These results indicate that l-citrulline has a modest effect of improving muscle blood flow during submaximal exercise in older men.
| S-EPMC5999519 | biostudies-literature
Project description:Several amino acids (AA) are known to regulate key metabolic pathways that are crucial for immune responses. In particular, arginine (ARG) appears to have important roles regarding immune modulation since it is required for macrophage responses and lymphocyte development. Moreover, citrulline (CIT) is a precursor of arginine, and it was reported as an alternative to ARG for improving macrophage function in mammals. The present study aimed to explore the effects of dietary ARG and CIT supplementation on the gilthead seabream (Sparus aurata) immune status. Triplicate groups of fish (23.1 ± 0.4 g) were either fed a control diet (CTRL) with a balanced AA profile, or the CTRL diet supplemented with graded levels of ARG or CIT (i.e., 0.5 and 1% of feed; ARG1, CIT1, ARG2, and CIT2, respectively). After 2 and 4 weeks of feeding, fish were euthanized and blood was collected for blood smears, plasma for humoral immune parameters and shotgun proteomics, and head-kidney tissue for the measurement of health-related transcripts. A total of 94 proteins were identified in the plasma of all treatments. Among them, components of the complement system, apolipoproteins, as well as some glycoproteins were found to be highly abundant. After performing a PLS of the expressed proteins, differences between the two sampling points were observed. In this regard, component 1 (61%) was correlated with the effect of sampling time, whereas component 2 (18%) seemed associated to individual variability within diet. Gilthead seabream fed ARG2 and CIT2 at 4 weeks were more distant than fish fed all dietary treatments at 2 weeks and fish fed the CTRL diet at 4 weeks. Therefore, data suggest that the modulatory effects of AA supplementation at the proteome level were more effective after 4 weeks of feeding and at the higher inclusion level (i.e., 1% of feed). The bactericidal activity increased in fish fed the highest supplementation level of both AAs after 4 weeks. Peripheral monocyte numbers correlated positively with nitric oxide, which showed an increasing trend in a dose-dependent manner. The colony-stimulating factor 1 receptor tended to be up-regulated at the final sampling point regardless of dietary treatments. Data from this study point to an immunostimulatory effect of dietary ARG or CIT supplementation after 4 weeks of feeding in the gilthead seabream, particularly when supplemented at a 1% inclusion level.
| S-EPMC7419597 | biostudies-literature
Project description:Background:Experimental evidence indicates that oral L-citrulline (L-Cit) may reduce resting blood pressure (BP) as well as BP responses to exercise and cold exposure (non-resting). However, results from human intervention trials are inconsistent. This study aims to summarize the clinical evidence regarding the effects of L-Cit supplementation on brachial systolic blood pressure (SBP), brachial diastolic blood pressure (DBP), in addition to aortic SBP and aortic DBP at rest and non-resting conditions. Methods:Multiple databases including PubMed, Embase, Cochrane library, Web of Science, and Clinical Trials were searched systematically. Randomized controlled trials of human participants were quantitatively meta-analyzed. Results:Fourteen trials contained in eight studies were available for quantitative syntheses for brachial BP. Results showed that L-Cit supplementation significantly reduced both brachial SBP (-?4.490?mmHg, 95% CI: -?7.332 to -?1.648, P?=?0.002) and brachial DBP (-?3.629?mmHg, 95% CI: -?5.825 to -?1.434, P?=?0.001). Nine of the trials were meta-analyzed for aortic BP which showed that L-Cit intervention significantly reduced aortic SBP (-?6.763?mmHg, 95% CI: -?10.991 to -?2.534, P?=?0.002), but not aortic DBP (-?3.396?mmHg, 95% CI: -?7.418 to 0.627, P?=?0.098). The observed reducing effects of L-Cit appeared stronger for non-resting than for resting brachial SBP (P for difference?=?0.044). Conclusion:L-Cit supplementation significantly decreased non-resting brachial and aortic SBP. Brachial DBP was significantly lowered by L-Cit regardless of resting status. Given the relatively small number of available trials in the stratified analyses and the potential limitations of these trials, the present findings should be interpreted cautiously and need to be confirmed in future well-designed trials with a larger sample size.
| S-EPMC6933755 | biostudies-literature
Project description:Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. The pathogenesis of this syndrome is not fully understood and believed to result from several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. NO deficiency in MELAS syndrome is likely to be multifactorial in origin with the decreased availability of the NO precursors, arginine and citrulline, playing a major role. In this study we used stable isotope infusion techniques to assess NO production in children with MELAS syndrome and healthy pediatric controls. We also assessed the effect of oral arginine and citrulline supplementations on NO production in children with MELAS syndrome. When compared to control subjects, children with MELAS syndrome were found to have lower NO production, arginine flux, plasma arginine, and citrulline flux. In children with MELAS syndrome, arginine supplementation resulted in increased NO production, arginine flux, and arginine concentration. Citrulline supplementation resulted in a greater increase of these parameters. Additionally, citrulline supplementation was associated with a robust increase in citrulline concentration and flux and de novo arginine synthesis rate. The greater effect of citrulline in increasing NO production is due to its greater ability to increase arginine availability particularly in the intracellular compartment in which NO synthesis takes place. This study, which is the first one to assess NO metabolism in children with mitochondrial diseases, adds more evidence to the notion that NO deficiency occurs in MELAS syndrome, suggests a better effect for citrulline because of its greater role as NO precursor, and indicates that impaired NO production occurs in children as well as adults with MELAS syndrome. Thus, the initiation of treatment with NO precursors may be beneficial earlier in life. Controlled clinical trials to assess the therapeutic effects of arginine and citrulline on clinical complications of MELAS syndrome are needed.
| S-EPMC4818739 | biostudies-literature
Project description:AimsOral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects.MethodsIn a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (C(max), T(max), C(min), AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects.ResultsL-Citrulline dose-dependently increased AUC and C(max) of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the C(min) of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 +/- 8 (baseline) to 278 +/- 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 +/- 10 to 125 +/- 15 micromol mmol(-1) creatinine (P = 0.01, 95% CI 8, 58) and from 38 +/- 3.3 to 50 +/- 6.7 nmol mmol(-1) creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD.ConclusionOur data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.
| S-EPMC2291275 | biostudies-literature
Project description:BackgroundPlasma citrulline (CIT) concentration is considered to be a reliable marker of functional enterocyte mass, primarily in humans. However, information about CIT levels along with related metabolites, arginine (ARG), nitric oxide (NO), and ammonia in neonatal calves are lacking.ObjectivesTo compare plasma CIT, ARG, NO, and whole blood ammonia concentrations in neonatal calves with acute diarrhea with those in healthy calves and to assess their possible relationships with diarrhea-related criteria.AnimalsSeventy neonatal calves (60 with acute diarrhea and 10 healthy).MethodsObservational case-control study. Diarrheic calves were classified into subgroups on the basis of etiology, severity of diarrhea, degree of dehydration, and systemic inflammatory response syndrome (SIRS) status. Plasma CIT and ARG concentrations were measured by liquid chromatography/tandem mass spectrometry.ResultsPlasma CIT (median [range]: 67.5 [61.9-75.4] vs 30.1 [15.0-56.1] μmol/L) and ARG (170.7 [148.5-219.5] vs 106.1 [54.4-190.7] μmol/L) were lower and plasma NO (4.42 [3.29-5.58] vs 6.78 [5.29-8.92] μM) and blood ammonia concentrations (28.7 [26.1-36.9] vs 59.8 [34.6-99.5] μmol/L) were higher in the neonatal calves with diarrhea (P < .001). Plasma CIT (β = -0.29, P = .02), ARG (β = -0.33, P = .01), NO (β = 0.55, P < .001), and blood ammonia (β = 0.63, P <.001) were affected by SIRS status. Except for ammonia (0.52), the effects sizes for severity of diarrhea and degree of dehydration were small (ηp2 ≤ 0.45) for CIT, ARG, and NO.Conclusions and clinical importanceThe changes in these variables might have diagnostic, prognostic, and therapeutic value in diarrheic neonatal calves.
| S-EPMC6430905 | biostudies-literature
Project description:L-citrulline and L-arginine supplementation has been shown to have several beneficial effects on the cardiovascular system. Nitric oxide (NO) protects against the progression of atherosclerosis and is synthesized by nitric oxide synthase (NOS), which converts L-arginine (L-Arg) into L-citrulline (L-Cit). Our previous study revealed that chronic administration of a combination of L-Cit and L- Arg has a better therapeutic effect on high cholesterol-induced atherosclerosis in rabbits. We investigated how L-Arg and L-Cit affect endothelial function, aging and atherosclerosis. Following a 3-day stimulation of human umbilical venous endothelial cells (HUVECs) with high glucose (HG: 22 mM) and L-Arg (300 μM), L-Cit (300 μM) or L-Arg plus L-Cit (LALC: each 150 μM) supplementation, endothelial senescence and function were evaluated. These amino acids were also administered to dyslipidemic type 2 diabetic (ZDFM) rats fed a high cholesterol diet. They were fed L-Arg or L-Cit or LALC for four weeks. Aortic senescence was investigated by measuring senescence-associated ß-galactosidase (SA-ß-gal), telomerase activity, DNA damage and p16INK4a protein expression. Only L-Cit and LALC supplementation retarded the HG-induced endothelial senescence, as evaluated by SA-ß-gal activity, a widely used marker of cellular senescence, p16INK4a expression, a senescence-related protein, and DNA damage. Under HG conditions, L-Cit and LCLA restored telomerase activity to levels observed under normal glucose (NG) conditions. Under HG conditions, L-Cit decreased ROS production, as measured by CM-H2DCFDA and the expression of p67phox, a major component of NADPH oxidase. Under HG conditions, L-Cit and LALC increased NO production, as measured by DAF-2AM. Endothelial NO synthase (eNOS) and phosphorylated eNOS were decreased under HG conditions and L-Cit and LALC significantly increased these levels. Arginase 2 protein expression increased under the HG conditions, and L-Cit and LALC significantly attenuated this effect. In ZDFM rats, SA-ß-gal activity was detected on the aortic endothelial surface; however, L-Cit and LALC reduced these levels. L-Cit and LALC both decreased the proportion of senescent cells. Furthermore, treatment with LALC for 4 weeks increased plasma NO production. Therefore conclusively, L-citrulline supplementation rescued NO levels better than L-arginine supplementation by inhibiting ROS production and arginase 2 protein expression. Consequently, L-Cit and LCLA supplementation retaeded HG-induced endothelial senescence.
| S-EPMC5802914 | biostudies-literature