Skip to main content
SpringerLink
Log in

Effect of L-Citrulline Supplementation on Blood Pressure: a Systematic Review and Meta-Analysis of Clinical Trials

  • Guidelines/Clinical Trials/Meta-Analysis (JB Kostis, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Several interventional studies assessed the impact of dietary supplements on blood pressure. The aim of the present systematic review and meta-analysis was to determine the efficacy of L-citrulline supplementation on blood pressure.

Recent Finding

Pubmed, Scopus, Google Scholar, and ISI Web of Science were comprehensively searched until May 2018 to assess whether L-citrulline reduces blood pressure. Human clinical trials which reported the effect of L-citrulline supplementation on aortic and brachial blood pressure were included. Characteristics of studies and potential sources of heterogeneity were tabulated. A subgroup analysis was performed to attenuate observed inter-study heterogeneity. A total of five interventions were found for meta-analysis. The impact of L-citrulline on brachial systolic (change 0.28 mmHg; 95% CI − 2.87, 2.31 mmHg) and diastolic (change − 1.56 mmHg; 95% CI − 4.32, 1.20 mmHg) blood pressure was not significant. Also, there was no changes in aortic systolic (change 0.22 mmHg; 95% CI − 4.81, 4.38 mmHg) and diastolic (change 0.26 mmHg; 95% CI − 2.27, 2.80 mmHg) blood pressure after L-citrulline supplementation. Participants’ body weight status was a source of observed heterogeneity.

Summary

The present systematic review and meta-analysis suggests that L-citrulline supplementation had no beneficial effect on blood pressure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Balakumar P, Maung UK, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res. 2016;113:600–9.

    Article  Google Scholar 

  2. Pourmasoumi M, Hadi A, Rafie N, Najafgholizadeh A, Mohammadi H, Rouhani MH. The effect of ginger supplementation on lipid profile: a systematic review and meta-analysis of clinical trials. Phytomedicine. 2018;43:28–36.

    Article  CAS  Google Scholar 

  3. Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, Ferdinand KC, Fleg JL, et al. Hypertension across a woman’s life cycle. J Am Coll Cardiol. 2018;71:1797–813.

    Article  Google Scholar 

  4. Sanchez-Gonzalez MA, Koutnik AP, Ramirez K, Wong A, Figueroa A. The effects of short term L-citrulline supplementation on wave reflection responses to cold exposure with concurrent isometric exercise. Am J Hypertens. 2013;26:518–26.

    Article  CAS  Google Scholar 

  5. Adler AJ, Prabhakaran D, Bovet P, Kazi DS, Mancia G, Mungal-Singh V, et al. Reducing cardiovascular mortality through prevention and management of raised blood pressure: a world heart federation roadmap. Glob Heart. 2015;10:111–22.

    Article  Google Scholar 

  6. Dojki FK, Bakris GL. Blood pressure control and cardiovascular/renal outcomes. Endocrinol Metab Clin N Am. 2018;47(1):175–84.

    Article  Google Scholar 

  7. Figueroa A, Alvarez-Alvarado S, Ormsbee MJ, Madzima TA. Impact of L-citrulline supplementation and whole-body vibration training on arterial stiffness and leg muscle function in obese postmenopausal women with high blood pressure. Exp Gerontol. 2015;63:35–40.

    Article  CAS  Google Scholar 

  8. Jourdan M, Nair KS, Carter RE, Schimke J, Ford GC, Marc J, et al. Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet–a pilot study. Clin Nutr. 2015;34:449–56.

    Article  CAS  Google Scholar 

  9. Morita M, Hayashi T, Ochiai M, Maeda M, Yamaguchi T, Ina K, et al. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. Biochem Biophys Res Commun. 2014;454:53–7.

    Article  CAS  Google Scholar 

  10. Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014;103:1019–26.

    Article  CAS  Google Scholar 

  11. •• Kashani BS, Pour PT, Malekmohammad M, Behzadnia N, Sheybani-Afshar F, Fakhri M, et al. Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger syndrome: a clinical trial. J Cardiol. 2014;64:231–5 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  Google Scholar 

  12. •• Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and L-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2015;41:292–7 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  Google Scholar 

  13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.

    Article  CAS  Google Scholar 

  14. • Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions: Wiley; 2011. This is one the most important textbooks in the field of systematic review and meta-analysis. In this book, systematic review and meta-analysis have been explored step by step.

  15. • Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88 This article can help researchers to calculate effect size for clinical trials included in meta-analysis.

    Article  CAS  Google Scholar 

  16. • Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34 This article provided evidence regarding detecting publication bias by statisticl graphs. Detecting publication bias has an important role in validity of the results of a meta-analysis.

    Article  CAS  Google Scholar 

  17. • Sterne J, Bradburn M. Meta-analysis in Stata. In: Egger M, Smith G, Altman D, editors. Systematic reviews in health care. London: BMJ Publishing Group; 2001. p. 347–72. This book explore the procedure of detecting publication bias by Stata. As Stata is considered as one of the mpst important statistical software in meta-analysis, detecting publication bias by this software is necessary.

    Chapter  Google Scholar 

  18. •• Figueroa A, Alvarez-Alvarado S, Jaime SJ, Kalfon R. L-Citrulline supplementation attenuates blood pressure, wave reflection and arterial stiffness responses to metaboreflex and cold stress in overweight men. Br J Nutr. 2016;116:279–85 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  CAS  Google Scholar 

  19. •• Figueroa A, Trivino JA, Sanchez-Gonzalez MA, Vicil F. Oral L-citrulline supplementation attenuates blood pressure response to cold pressor test in young men. Am J Hypertens. 2010;23:12–6 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  CAS  Google Scholar 

  20. •• Gonzales JU, Raymond A, Ashley J, Kim Y. Does l-citrulline supplementation improve exercise blood flow in older adults? Exp Physiol. 2017;102:1661–71 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  CAS  Google Scholar 

  21. •• Ochiai M, Hayashi T, Morita M, Ina K, Maeda M, Watanabe F, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol. 2012;155:257–61 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure.

    Article  Google Scholar 

  22. Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH, Spurgeon HA, et al. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study. Hypertension. 2010;55:799–805.

    Article  CAS  Google Scholar 

  23. Safar ME, Jankowski P. Central blood pressure and hypertension: role in cardiovascular risk assessment. Clin Sci (Lond). 2009;116:273–82.

    Article  Google Scholar 

  24. Pini R, Cavallini MC, Palmieri V, Marchionni N, Di Bari M, Devereux RB, et al. Central but not brachial blood pressure predicts cardiovascular events in an unselected geriatric population: the ICARe dicomano study. J Am Coll Cardiol. 2008;51:2432–9.

    Article  Google Scholar 

  25. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure–lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213–25.

    Article  CAS  Google Scholar 

  26. Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, et al. l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci U S A. 2005;102:13681–6.

    Article  CAS  Google Scholar 

  27. Wu G, Collins JK, Perkins-Veazie P, Siddiq M, Dolan KD, Kelly KA, et al. Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr. 2007;137:2680–5.

    Article  CAS  Google Scholar 

  28. Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Phys. 1981;241:E473–80.

    CAS  Google Scholar 

  29. Merino J, Ferre R, Girona J, Aguas D, Cabre A, Plana N, et al. Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function. Clin Investig Arterioscler. 2015;27:9–16.

    CAS  PubMed  Google Scholar 

  30. Huang T, Larsen KT, Ried-Larsen M, Moller NC, Andersen LB. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: a review. Scand J Med Sci Sports. 2014;24:1–10.

    Article  Google Scholar 

  31. Erdos B, Backes I, McCowan ML, Hayward LF, Scheuer DA. Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. Am J Physiol Heart Circ Physiol. 2015;308:H612–22.

    Article  CAS  Google Scholar 

  32. e Silva Ade S, da Mota MP. Effects of physical activity and training programs on plasma homocysteine levels: a systematic review. Amino Acids. 2014;46:1795–804.

    Article  Google Scholar 

  33. van Guldener C, Nanayakkara PW, Stehouwer CD. Homocysteine and blood pressure. Curr Hypertens Rep. 2003;5:26–31.

    Article  Google Scholar 

  34. Riccioni G, Scotti L, Guagnano MT, Bosco G, Bucciarelli V, Di Ilio E, et al. Physical exercise reduces synthesis of ADMA, SDMA, and L-Arg. Front Biosci (Elite Ed). 2015;7:417–22.

    Article  Google Scholar 

  35. Jira M, Zavodna E, Honzikova N, Novakova Z, Vasku A, Izakovicova Holla L, et al. Association of eNOS gene polymorphisms T-786C and G894T with blood pressure variability in man. Physiol Res. 2011;60:193–7.

    CAS  Google Scholar 

  36. Li J, Cun Y, Tang WR, Wang Y, Li SN, Ouyang HR, et al. Association of eNOS gene polymorphisms with essential hypertension in the Han population in southwestern China. Genet Mol Res. 2011;10:2202–12.

    Article  CAS  Google Scholar 

  37. Zago AS, Park JY, Fenty-Stewart N, Kokubun E, Brown MD. Effects of aerobic exercise on the blood pressure, oxidative stress and eNOS gene polymorphism in pre-hypertensive older people. Eur J Appl Physiol. 2010;110:825–32.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, supported the present study.

Author information

Authors and Affiliations

  1. Students’ Research Committee, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

    Mohammad Sadegh Mirenayat & Hamed Mohammadi

  2. Halal Research Center of IRI, FDA, Tehran, Iran

    Sajjad Moradi

  3. Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Mohammad Hossein Rouhani

Authors
  1. Mohammad Sadegh Mirenayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sajjad Moradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hamed Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Hossein Rouhani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Hossein Rouhani.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Guidelines/Clinical Trials/Meta-Analysis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mirenayat, M.S., Moradi, S., Mohammadi, H. et al. Effect of L-Citrulline Supplementation on Blood Pressure: a Systematic Review and Meta-Analysis of Clinical Trials. Curr Hypertens Rep 20, 98 (2018). https://doi.org/10.1007/s11906-018-0898-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-018-0898-3

Keywords

Search

Navigation