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The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.

ABSTRACT: 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 increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (Km) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the "l-arginine paradox".

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]

PMID: 31336573

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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.

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.

Project description:New findingsWhat 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.

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.

Dataset Information

The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.

Publications

The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.

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