Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism
Open accessAbstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • L‐Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS). • NO improves endothelial function by elevating cyclic guanosine monophosphate. • However, oral L‐arginine treatment in humans is hampered by extensive metabolism. WHAT THIS STUDY ADDS • Oral L‐citrulline supplementation raises plasma L‐arginine concentration and augments NO‐dependent signalling in a dose‐dependent manner. • L‐Citrulline may thus be an alternative to L‐arginine in patients with impaired NOS activity. AIMS: Oral 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. METHODS: In 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. RESULTS: L‐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 µmol 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. CONCLUSION: Our 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.
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Oral citrulline supplementation has been shown to be more effective in increasing arginine and activation of nitric oxide synthase (NOS) as well as various biomarkers of nitric oxide.
“Due to this and its non-competitive uptake for cell transport [542], oral citrulline supplementation has been shown to be more effective in increasing arginine [543, 544] and activation of nitric oxide synthase (NOS) [544] as well as various biomarkers of nitric oxide [545].”
From ISSN exercise & sports nutrition review update: research & recommendations (2018) · cites this paper as [543]
The Results and Discussion report that oral L-citrulline raised plasma L-arginine more effectively than the tested L-arginine regimens at the highest dose. They also report an improved arginine/ADMA ratio and increased NO-related markers, but do not directly demonstrate activation of NOS. The biomarkers clause is cited separately to [545]. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrevious experiments demonstrated increased nitric oxide production in vivo.
“and increased nitric oxide production in vivo (Churchward-Venne et al. 2014; Schwedhelm et al. 2007).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
Citrulline has the potential to increase plasma nitrate and nitric oxide availability.
“Citrulline, the end product of arginine-mediated nitric oxide production, has shown the potential to increase plasma nitrate and NO availability (Schwedhelm et al. 2007; Morita et al. 2014).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
Citrulline increases both plasma arginine and cGMP and is free of side effects.
“increases both plasma arginine and cGMP (Schwedhelm et al. 2007) and is free of side effects.”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
Supplementation of older adults with citrulline elevated plasma arginine concentrations for up to 6 h.
“supplementation of older adults with citrulline elevated plasma arginine concentrations for up to 6 h (Moinard et al. 2015; Schwedhelm et al. 2007)”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
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Cites
Corretti, M. C., Anderson, T. J., Benjamin, E. J., Celermajer, D. S., Charbonneau, F., Creager, M. A., Deanfield, J. E., Drexler, H., Gerhard‐Herman, M. D., Herrington, D. M., et al. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01746-6 · Cited by 4,606 · see citing works
Böger, R. H., Bode-Böger, S. M., Szuba, A., Tsao, P. S., Chan, J. R., Tangphao, O., Blaschke, T. F., & Cooke, J. P. (1998) · Circulation · doi:10.1161/01.cir.98.18.1842 · Cited by 1,181 · see citing works
Self-citationPollock, J. S., Förstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M., & Murad, F. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.23.10480 · Cited by 979 · see citing works
Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns
Chace, D. H., Kalas, T. A., & Naylor, E. W. (2003) · Clinical Chemistry · doi:10.1373/clinchem.2003.022178 · Cited by 621 · see citing works
Almost all about citrulline in mammals
Curis, E., Nicolis, I., Moinard, C., Osowska, S., Zerrouk, N., Bénazeth, S., & Cynober, L. (2005) · Amino Acids · doi:10.1007/s00726-005-0235-4 · Cited by 571 · see citing works
The role of nitric oxide in cardiovascular diseases
NASEEM, K. (2005) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2004.09.003 · Cited by 557 · see citing works
Asymmetrical Dimethylarginine: The Über Marker?
Cooke, J. P. (2004) · Circulation · doi:10.1161/01.cir.0000126823.07732.d5 · Cited by 396 · see citing works
Endothelial function and nitric oxide: clinical relevance
Vallance, P. J., & Chan, N. N. (2001) · Heart · doi:10.1136/heart.85.3.342 · Cited by 389 · see citing works
Böger, R. H. (2004) · The Journal of Nutrition · doi:10.1093/jn/134.10.2842s · Cited by 363 · see citing works
Self-citationAsymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease
Kielstein, J. T., Böger, R. H., BODE-BÖGER, S. M., SCHÄFFER, J., BARBEY, M., Koch, K. M., & Frölich, J. C. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v103594 · Cited by 360 · see citing works
Self-citationEnzymes of Arginine Metabolism
Morris, S. M. (2004) · Journal of Nutrition · doi:10.1093/jn/134.10.2743s · Cited by 357 · see citing works
Schulman, S. P., Becker, L. C., Kass, D. A., Champion, H. C., Terrin, M. L., Forman, S., Ernst, K. V., Kelemen, M. D., Townsend, S. N., Capriotti, A., et al. (2006) · JAMA · doi:10.1001/jama.295.1.58 · Cited by 357 · see citing works
The Clinical Pharmacology of L-Arginine
Böger, R. H., & Bode‐Böger, S. M. (2001) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.41.1.79 · Cited by 331 · see citing works
Self-citationCynober, L. A. (2002) · Nutrition · doi:10.1016/s0899-9007(02)00780-3 · Cited by 303 · see citing works
Plasma Membrane Transporters for Arginine
Closs, E. I., Simon, A., Vékony, N., & Rotmann, A. (2004) · Journal of Nutrition · doi:10.1093/jn/134.10.2752s · Cited by 297 · see citing works
Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension
Perticone, F., Sciacqua, A., Maio, R., Perticone, M., Maas, R., Böger, R. H., Tripepi, G., Sesti, G., & Zoccali, C. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.04.040 · Cited by 269 · see citing works
Self-citationBöger, R. H., Bode‐Böger, S. M., Thiele, W., Creutzig, A., Alexander, K., & Frölich, J. C. (1998) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(98)00375-1 · Cited by 263 · see citing works
Self-citationL‐arginine‐induced vasodilation in healthy humans:pharmacokinetic–pharmacodynamic relationship
Bode‐Böger, S. M., Böger, R. H., Galland, A., Tsikas, D., & Frölich, J. C. (1998) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1998.00803.x · Cited by 258 · see citing works
Self-citationDetermination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay
Schulze, F., Wesemann, R., Schwedhelm, E., Sydow, K., Albsmeier, J., Cooke, J. P., & Böger, R. H. (2004) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2004.257 · Cited by 252 · see citing works
Self-citationAsymmetric dimethylarginine (ADMA): A novel risk marker in cardiovascular medicine and beyond
Böger, R. H. (2006) · Annals of Medicine · doi:10.1080/07853890500472151 · Cited by 236 · see citing works
Self-citationTherapeutic Use of Citrulline in Cardiovascular Disease
Romero, M. J., Platt, D. H., Caldwell, R. B., & Caldwell, R. W. (2006) · Cardiovascular Drug Reviews · doi:10.1111/j.1527-3466.2006.00275.x · Cited by 231 · see citing works
Sydow, K. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00617-x · Cited by 215 · see citing works
Piatti, P., Monti, L. D., Valsecchi, G., Magni, F., Setola, E., Marchesi, F., Galli-Kienle, M., Pozza, G., & Alberti, K. G. M. M. (2001) · Diabetes Care · doi:10.2337/diacare.24.5.875 · Cited by 208 · see citing works
Oral L-arginine improves endothelial function in healthy individuals older than 70 years
Bode‐Böger, S. M., Muke, J., Surdacki, A., Brabant, G. E., Böger, R. H., & Frölich, J. C. (2003) · Vascular Medicine · doi:10.1191/1358863x03vm474oa · Cited by 198 · see citing works
Self-citationDetermination of a reference value for NG, NG‐dimethyl‐L‐arginine in 500 subjects
Schulze, F., Maas, R., Freese, R., Schwedhelm, E., Silberhorn, E., & Böger, R. H. (2005) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2005.01561.x · Cited by 154 · see citing works
Self-citationSplanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man.
Castillo, L., deRojas-Walker, T., Chapman, T. E., Vogt, J., Burke, J. F., Tannenbaum, S. R., & Young, V. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.1.193 · Cited by 133 · see citing works
Walker, H. A., McGing, E., Fisher, I. B., Böger, R. H., Bode‐Böger, S. M., Jackson, G., Ritter, J. M., & Chowienczyk, P. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01380-8 · Cited by 112 · see citing works
Self-citationBöger, R. H., Bode‐Böger, S. M., Phivthong‐ngam, L., Brandes, R. P., Schwedhelm, E., Mügge, A., Böhme, M., Tsikas, D., & Frölich, J. C. (1998) · Atherosclerosis · doi:10.1016/s0021-9150(98)00145-2 · Cited by 103 · see citing works
Self-citationAsymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase
Böger, R. H., Vallance, P. J., & Cooke, J. P. (2003) · Atherosclerosis Supplements · doi:10.1016/s1567-5688(03)00027-8 · Cited by 96 · see citing works
Self-citationWaugh, W. H., Daeschner, C. W., Files, B., McConnell, M. E., & Strandjord, S. E. (2001) · PubMed Central · Cited by 95 · see citing works
Tsikas, D., Sandmann, J., Savva, A., Lueßen, P., Böger, R. H., Gutzki, F., Mayer, B., & Frölich, J. C. (2000) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)00142-0 · Cited by 85 · see citing works
Self-citationBöger, G. I., Rudolph, T. K., Maas, R., Schwedhelm, E., Dumbadze, E., Bierend, A., Benndorf, R. A., & Böger, R. H. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.02.051 · Cited by 80 · see citing works
Self-citationYılmaz, M. İ., Sağlam, M., Çağlar, K., Çakır, E., Özgürtaş, T., Sönmez, A., Eyileten, T., Yenicesu, M., Açıkel, C., Oğuz, Y., et al. (2005) · Transplantation · doi:10.1097/01.tp.0000183750.22675.be · Cited by 79 · see citing works
Blum, A., Hathaway, L., Mincemoyer, R., Schenke, W. H., Kirby, M., Csákó, G., Waclawiw, M. A., Panza, J. A., & Cannon, R. O. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(99)00553-7 · Cited by 77 · see citing works
Bednarz, B., Jaxa-Chamiec, T., Maciejewski, P., Szpajer, M., Janik, K., Gniot, J., Kawka‐Urbanek, T., Drozdowska, D., Gessek, J., & Laskowski, H. (2005) · PubMed · Cited by 64 · see citing works
Li, C., Huang, W., Harris, M. B., Goolsby, J. M., & Venema, R. C. (2005) · Biochemical Journal · doi:10.1042/bj20041005 · Cited by 58 · see citing works
Böger, R. H., Tsikas, D., Bode‐Böger, S. M., Phivthong‐ngam, L., Schwedhelm, E., & Frölich, J. C. (2004) · Nitric Oxide · doi:10.1016/j.niox.2004.07.008 · Cited by 56 · see citing works
Self-citationAsymmetric dimethylarginine (ADMA) modulates endothelial function - therapeutic implications
Böger, R. H. (2003) · Vascular Medicine · doi:10.1191/1358863x03vm501ed · Cited by 55 · see citing works
Self-citationCitrulline Is an Effective Arginine Precursor in Enterally Fed Neonatal Piglets
Urschel, K. L., Shoveller, A. K. K., Uwiera, R. R. E., Pencharz, P. B., & Ball, R. O. (2006) · Journal of Nutrition · doi:10.1093/jn/136.7.1806 · Cited by 52 · see citing works
Wang, J., Sim, A. S., Wang, X. L., & Wilcken, D. E. L. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6271-8 · Cited by 37 · see citing works
Böger, G. I., Maas, R., Schwedhelm, E., Bierend, A., Benndorf, R. A., Kastner, M., Steenpaß, A., & Böger, R. H. (2004) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(04)92228-0 · Cited by 20 · see citing works
Self-citationArginine Therapy for Acute Myocardial Infarction
Abumrad, N. N., & Barbul, A. (2006) · JAMA · doi:10.1001/jama.295.18.2138-b · Cited by 12 · see citing works
Hampton, T. (2006) · JAMA · doi:10.1001/jama.295.11.1238 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Böger GI, Rudolph T, Maas R, Schwedhelm E, Dumbardze E, Bierend A, Benndorf R, Böger RH. Improvement of endothelium-dependent vasodilation by simvastatin is enabled by combination with L-arginine in patients with elevated ADMA levels. J Am Coll Cardiol 2007; 49: 2274-82.
- Cooke JP. ADMA -the Über-marker? Circulation 2004; 109: 1813-8.
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Kerksick, C. M., Wilborn, C. D., Roberts, M. D., Smith-Ryan, A., Kleiner, S. M., Jäger, R., Collins, R., Cooke, M., Davis, J. N., Galvan, E., et al. (2018) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-018-0242-y · Cited by 945 · see citing works
Arginase: an emerging key player in the mammalian immune system
Munder, M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00291.x · Cited by 701 · see citing works
Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans
Wu, G., Meininger, C. J., McNeal, C. J., Bazer, F. W., & Rhoads, J. M. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-74180-8_10 · Cited by 311 · see citing works
Arginine and Endothelial Function
Gambardella, J., Khondkar, W., Morelli, M. B., Wang, X., Santulli, G., & Trimarco, V. (2020) · Biomedicines · doi:10.3390/biomedicines8080277 · Cited by 254 · see citing works
l-Citrulline Supplementation: Impact on Cardiometabolic Health
Allerton, T. D., Proctor, D. N., Stephens, J. M., Dugas, T. R., Spielmann, G., & Irving, B. A. (2018) · Nutrients · doi:10.3390/nu10070921 · Cited by 235 · see citing works
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Wijnands, K. A. P., Castermans, T. M. R., Hommen, M., Meesters, D. M., & Poeze, M. (2015) · Nutrients · doi:10.3390/nu7031426 · Cited by 208 · see citing works
Luiking, Y. C., Poeze, M., Ramsay, G., & Deutz, N. E. P. (2008) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2007.25765 · Cited by 203 · see citing works
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Cave, M. C., Hurt, R. T., Frazier, T. H., Matheson, P. J., Garrison, R. N., McClain, C. J., & McClave, S. A. (2008) · Nutrition in Clinical Practice · doi:10.1177/011542650802300116 · Cited by 191 · see citing works
Citrulline: From metabolism to therapeutic use
Bahri, S., Zerrouk, N., Aussel, C., Moinard, C., Crenn, P. P., Curis, E., Chaumeil, J., Cynober, L., & Sfar, S. (2012) · Nutrition · doi:10.1016/j.nut.2012.07.002 · Cited by 175 · see citing works
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Albaugh, V. L., Pinzon‐Guzman, C., & Barbul, A. (2016) · Journal of Surgical Oncology · doi:10.1002/jso.24490 · Cited by 173 · see citing works
Holguín, F., COMHAIR, S. A. A., Hazen, S. L., Powers, R. W., Khatri, S. S., Bleecker, E. R., Busse, W. W., Calhoun, W. J., Castro, M., Fitzpatrick, A. M., et al. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201207-1270oc · Cited by 166 · see citing works
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Figueroa, A., Wong, A., Jaime, S. J., & Gonzales, J. U. (2017) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000340 · Cited by 147 · see citing works
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Morita, M., Hayashi, T., Ochiai, M., Maeda, M., Yamaguchi, T., Ina, K., & Kuzuya, M. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.10.029 · Cited by 140 · see citing works
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Bailey, S. J., Blackwell, J. R., Lord, T., Vanhatalo, A., Winyard, P. G., & Jones, A. M. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00192.2014 · Cited by 136 · see citing works
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Kaore, S. N., Amane, H. S., & Kaore, N. M. (2012) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2012.01059.x · Cited by 97 · see citing works
The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine
Meldrum, D. R., Gambone, J. C., Morris, M. A., Meldrum, D. A. N., Esposito, K., & Ignarro, L. J. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.03.093 · Cited by 95 · see citing works
Bailey, S. J., Blackwell, J. R., Williams, E. R., Vanhatalo, A., Wylie, L. J., Winyard, P. G., & JONES, A. M. (2016) · Nitric Oxide · doi:10.1016/j.niox.2016.06.008 · Cited by 95 · see citing works
Szlas, A., Kurek, J. M., & Krejpcio, Z. (2022) · Nutrients · doi:10.3390/nu14050961 · Cited by 94 · see citing works
Safety and Effectiveness of Arginine in Adults
McNeal, C. J., Meininger, C. J., Reddy, D., Wilborn, C., & Wu, G. (2016) · Journal of Nutrition · doi:10.3945/jn.116.234740 · Cited by 93 · see citing works
Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review
Rashid, J., Kumar, S. S., Job, K. M., Liu, X., Fike, C. D., & Sherwin, C. M. T. (2020) · Pediatric Drugs · doi:10.1007/s40272-020-00384-5 · Cited by 92 · see citing works
Park, S., Son, W., & Kwon, O. (2015) · Journal of Exercise Rehabilitation · doi:10.12965/jer.150254 · Cited by 90 · see citing works
L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
Aguayo, E., Martínez‐Sánchez, A., Fernández-Lobato, B., & Alacid, F. (2021) · Applied Sciences · doi:10.3390/app11073293 · Cited by 92 · see citing works
Sureda, A., Córdova, A., Ferrer, M. D., Tauler, P., Pérez, G., Tur, J. A., & Pons, A. (2009) · Free Radical Research · doi:10.1080/10715760903071664 · Cited by 85 · see citing works
Lüneburg, N., Xanthakis, V., Schwedhelm, E., SULLIVAN, L. M., Maas, R., Anderssohn, M., Riederer, U., Glazer, N. L., Vasan, R. S., & Böger, R. H. (2011) · Journal of Nutrition · doi:10.3945/jn.111.148197 · Cited by 84 · see citing works
Self-citationAsymmetric Dimethylarginine, Endothelial Dysfunction and Renal Disease
Aldamiz-Echevarria, L. J., & Andrade, F. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms130911288 · Cited by 83 · see citing works
El‐Hattab, A. W., Emrick, L., Hsu, J. W.-C., Chanprasert, S., Almannai, M., Craigen, W. J., Jahoor, F., & Scaglia, F. (2016) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2016.01.010 · Cited by 83 · see citing works
Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension
Tain, Y., Sheen, J., Chen, C., Yu, H., Tiao, M., Kuo, H.-C., & Huang, L. (2014) · Free Radical Research · doi:10.3109/10715762.2014.895341 · Cited by 81 · see citing works
Agarwal, U., Didelija, I. C., Yuan, Y., Wang, X., & Marini, J. C. (2017) · Journal of Nutrition · doi:10.3945/jn.116.240382 · Cited by 81 · see citing works
Figueroa, A., Trivino, J. A., Sanchez-Gonzalez, M. A., & Vicil, F. (2010) · American Journal of Hypertension · doi:10.1038/ajh.2009.195 · Cited by 79 · see citing works
Cutrufello, P. T., Gadomski, S. J., & Zavorsky, G. S. (2015) · Journal of Sports Sciences · doi:10.1080/02640414.2014.990495 · Cited by 79 · see citing works
Whole-body vibration training in obese subjects: A systematic review
Zago, M., Capodaglio, P., Ferrario, C., Tarabini, M., & Galli, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0202866 · Cited by 79 · see citing works
McCarty, M. F., & DiNicolantonio, J. J. (2015) · AGE · doi:10.1007/s11357-015-9823-8 · Cited by 79 · see citing works
Gonzalez, A. M., Townsend, J. R., Pinzone, A. G., & Hoffman, J. R. (2023) · Nutrients · doi:10.3390/nu15030660 · Cited by 89 · see citing works
Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects
Alvares, T., Conte-Junior, C., Silva, J., & Paschoalin, V. M. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-54 · Cited by 76 · see citing works
Figueroa, A., Wong, A., Hooshmand, S., & Sanchez‐Gonzalez, M. A. (2012) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e3182733794 · Cited by 76 · see citing works
L-Citrulline increases nitric oxide and improves control in obese asthmatics
Holguín, F., Grasemann, H., Sharma, S., Winnica, D., Wasil, K., Smith, V. L., Cruse, M. H., Perez, N., Coleman, E., Scialla, T. J., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.131733 · Cited by 74 · see citing works
Álvares, T. S., Conte, C. A., Paschoalin, V. M. F., Silva, J. T., Meirelles, C. D. M., Bhambhani, Y. N., & Gomes, P. S. C. (2012) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h11-144 · Cited by 71 · see citing works
Weckman, A. M., McDonald, C. R., Baxter, J. B., Fawzi, W. W., Conroy, A. L., & Kain, K. C. (2019) · Advances in Nutrition · doi:10.1093/advances/nmz015 · Cited by 72 · see citing works
Trexler, E. T., Persky, A. M., Ryan, E. D., Schwartz, T. A., Stoner, L. R., & Smith‐Ryan, A. E. (2019) · Sports Medicine · doi:10.1007/s40279-019-01091-z · Cited by 74 · see citing works
Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?
Hsu, C., & Tain, Y. (2020) · Antioxidants · doi:10.3390/antiox10010033 · Cited by 67 · see citing works
Maric, S., Restin, T., Muff, J. L., Camargo, S. M. R., Guglielmetti, L. C., Holland-Cunz, S. G., Crenn, P. P., & Vuille-dit-Bille, R. N. (2021) · Nutrients · doi:10.3390/nu13082794 · Cited by 68 · see citing works
Strobel, J., Mieth, M., Endreß, B., Auge, D., König, J., Fromm, M. F., & Maas, R. (2012) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2012.06.002 · Cited by 66 · see citing works
Self-citationThe Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and Its Vasculature
Visser, M., Paulus, W. J., Vermeulen, M. A. R., Richir, M. C., Davids, M., Wisselink, W., de Mol, B. A. J. M., & van Leeuwen, P. A. M. (2010) · European Journal of Heart Failure · doi:10.1093/eurjhf/hfq158 · Cited by 66 · see citing works
Nutritional Recommendations for Physique Athletes
Roberts, B. M., Helms, E. R., Trexler, E. T., & Fitschen, P. J. (2020) · Journal of Human Kinetics · doi:10.2478/hukin-2019-0096 · Cited by 67 · see citing works
Uyanga, V. A., Amevor, F. K., Liu, M., Cui, Z., Zhao, X., & Lin, H. (2021) · Nutrients · doi:10.3390/nu13113782 · Cited by 66 · see citing works
Wong, A., Alvarez‐Alvarado, S., Jaime, S. J., Kinsey, A. W., Spicer, M. T., Madzima, T. A., & Figueroa, A. (2015) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2015-0465 · Cited by 65 · see citing works
Impact of Arginine Nutrition and Metabolism during Pregnancy on Offspring Outcomes
Hsu, C., & Tain, Y. (2019) · Nutrients · doi:10.3390/nu11071452 · Cited by 64 · see citing works
Bourdon, A., Parnet, P., Nowak, C., Tran, N.-T., Winer, N., & Darmaun, D. (2016) · Journal of Nutrition · doi:10.3945/jn.115.221267 · Cited by 63 · see citing works
Rhim, H. C., Kim, S. J., Park, J., & Jang, K.-M. (2020) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2020.02.003 · Cited by 61 · see citing works
The Role of Amino Acids in Endothelial Biology and Function
Li, M., Wu, Y., & Ye, L. (2022) · Cells · doi:10.3390/cells11081372 · Cited by 63 · see citing works
Lee, Y., Su, Y., Liu, T., Tsai, C., Chang, C., & Yu, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02911 · Cited by 59 · see citing works
Churchward-Venne, T. A., Cotie, L. M., MacDonald, M. J., Mitchell, C. J., Prior, T., Baker, S. K., & Phillips, S. M. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00096.2014 · Cited by 58 · see citing works
Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage.
Barzal, J., Szczylik, C. A., Rzepecki, P., Jaworska, M., & Anuszewska, E. (2014) · Acta Biochimica Polonica · doi:10.18388/abp.2014_1823 · Cited by 58 · see citing works
Figueroa, A., Alvarez‐Alvarado, S., Ormsbee, M. J., Madzima, T. A., Campbell, J. C., & Wong, A. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.01.046 · Cited by 58 · see citing works
Rhim, H. C., Kim, M. S., Park, Y.-J., Choi, W. S., Park, H. K., Kim, H. G., Kim, A., & Paick, S. H. (2019) · The Journal of Sexual Medicine · doi:10.1016/j.jsxm.2018.12.002 · Cited by 57 · see citing works
Tain, Y., & Hsu, C. (2022) · Antioxidants · doi:10.3390/antiox11030511 · Cited by 57 · see citing works
Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs
Fike, C. D., Dikalova, A., Kaplowitz, M. R., Cunningham, G. R., Summar, M. L., & Aschner, J. L. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2014-0351oc · Cited by 57 · see citing works
Baumgardt, S. L., Paterson, M. R., Leucker, T. M., Fang, J., Zhang, D. X., Bosnjak, Z. J., Warltier, D. C., Kersten, J. R., & Ge, Z. (2016) · Circulation Heart Failure · doi:10.1161/circheartfailure.115.002424 · Cited by 57 · see citing works
Effects of pomegranate extract on blood flow and running time to exhaustion
Trexler, E. T., Smith‐Ryan, A. E., Melvin, M. N., Roelofs, E. J., & Wingfield, H. L. (2014) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2014-0137 · Cited by 56 · see citing works
Tain, Y., Huang, L., Lee, C., Chan, J. Y. H., & Hsu, C. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.114.121384 · Cited by 55 · see citing works
Arginine behaviour after arginine or citrulline administration in older subjects
Moinard, C., Maccario, J., Walrand, S., Lasserre, V., Marc, J., Boirie, Y., & Cynober, L. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515004638 · Cited by 55 · see citing works
Does l ‐citrulline supplementation improve exercise blood flow in older adults?
Gonzales, J. U., Raymond, A., Ashley, J., & Kim, Y. (2017) · Experimental Physiology · doi:10.1113/ep086587 · Cited by 55 · see citing works
Amino Acids in Circulatory Function and Health
Durante, W. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-45328-2_3 · Cited by 55 · see citing works
A critical review of citrulline malate supplementation and exercise performance
Gough, L. A., Sparks, S. A., McNaughton, L. R., Higgins, M. F., Newbury, J. W., Trexler, E. T., Faghy, M. A., & Bridge, C. A. (2021) · European Journal of Applied Physiology · doi:10.1007/s00421-021-04774-6 · Cited by 58 · see citing works
Obesity-related Asthma: A Pathobiology-based Overview of Existing and Emerging Treatment Approaches
Althoff, M. D., Gaietto, K. M., Holguín, F., & Forno, E. (2024) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202406-1166so · Cited by 55 · see citing works
Chapman, J. C., Liu, Y., Zhu, L., & Rhoads, J. M. (2012) · Pediatric Research · doi:10.1038/pr.2012.137 · Cited by 52 · see citing works
Endogenous flux of nitric oxide: Citrulline is preferred to Arginine
Bahadoran, Z., Mirmiran, P., Kashfi, K., & Ghasemi, A. (2020) · Acta Physiologica · doi:10.1111/apha.13572 · Cited by 51 · see citing works
Nitric oxide, aging and aerobic exercise: Sedentary individuals to Master's athletes
Shannon, O. M., Clifford, T., Seals, D. R., Craighead, D. H., & Rossman, M. J. (2022) · Nitric Oxide · doi:10.1016/j.niox.2022.06.002 · Cited by 51 · see citing works
Wijnands, K. A. P., Meesters, D. M., van Barneveld, K. W. Y., Visschers, R. G. J., Briedé, J. J., Vandendriessche, B., van Eijk, H. M. H., Bessems, B. A. F. M., Hoven, N. T., von Wintersdorff, C. J. H., et al. (2015) · Nutrients · doi:10.3390/nu7075217 · Cited by 51 · see citing works
Pretreatment With Citrulline Improves Gut Barrier After Intestinal Obstruction in Mice
Batista, M. A., Nicoli, J. R., Martins, F. S., Machado, J. A. N., Arantes, R. M. E., Quirino, I. E. P., Correia, M. I. T. D., & Cardoso, V. N. (2011) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607111414024 · Cited by 51 · see citing works
Yabuki, Y., Shioda, N., Yamamoto, Y., Shigano, M., Kumagai, K., Morita, M., & Fukunaga, K. (2013) · Brain Research · doi:10.1016/j.brainres.2013.05.011 · Cited by 51 · see citing works
Mitochondria: Role of citrulline and arginine supplementation in MELAS syndrome
El‐Hattab, A. W., Emrick, L., Chanprasert, S., Craigen, W. J., & Scaglia, F. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.12.009 · Cited by 51 · see citing works
Ham, D. J., Gleeson, B. G., Chee, A., Baum, D. M., Caldow, M. K., Lynch, G. S., & Koopman, R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141572 · Cited by 50 · see citing works
Oral supplementation with L‐homoarginine in young volunteers
Atzler, D., Schönhoff, M., Cordts, K., Ortland, I., Hoppe, J., Hummel, F. C., Gerloff, C. P., Jaehde, U., Jagodzinski, A., Böger, R. H., et al. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13068 · Cited by 50 · see citing works
Self-citationMartínez-Sánchez, A., Ramos-Campo, D. J., Fernández-Lobato, B., Rubio-Arias, J. A., Alacid, F., & Aguayo, E. (2017) · Food & Nutrition Research · doi:10.1080/16546628.2017.1330098 · Cited by 50 · see citing works
l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice
Romero, M. J., Yao, L., Sridhar, S., Bhatta, A., Dou, H., Ramesh, G., Brands, M. W., Pollock, D. M., Caldwell, R. B., Cederbaum, S. D., et al. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00480 · Cited by 49 · see citing works
A Urologist's Guide to Ingredients Found in Top-Selling Nutraceuticals for Men's Sexual Health
Cui, T., Kovell, R. C., Brooks, D. C., & Terlecki, R. P. (2015) · The Journal of Sexual Medicine · doi:10.1111/jsm.13013 · Cited by 49 · see citing works
Morita, M., Sakurada, M., Watanabe, F., Yamasaki, T., Doi, H., Ezaki, H., Morishita, K., & Miyake, T. (2013) · Immunology Endocrine & Metabolic Agents - Medicinal Chemistry · doi:10.2174/18715222113139990008 · Cited by 49 · see citing works
Suzuki, T., Morita, M., Hayashi, T., & Kamimura, A. (2016) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2016.1230007 · Cited by 49 · see citing works
- Authors
- Schwedhelm, E., Maas, R., Freese, R., Jung, D., Lukacs, Z., Jambrecina, A., Spickler, W., Schulze, F., & Böger, R. H.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Schwedhelm, Edzard
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2007-10-22
- Volume
- 65
- Issue
- 1
- Pages
- 51-59
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC2291275
- OpenAlex
- W2162463567
- Cited by
- 494
- References
- 43
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 22 · 2023: 47 · 2022: 42 · 2021: 48 · 2020: 42 · 2019: 30 · 2018: 27 · 2017: 24 · 2016: 32 · 2015: 33 · 2014: 27 · 2013: 16 · 2012: 16
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- citrulline, L-arginine, nitric oxide, nitric oxide synthase, asymmetric dimethylarginine, flow-mediated dilation, endothelial function, cyclic GMP, urinary nitrate, arginase, oral supplementation, pharmacokinetics, pharmacodynamics, dose-response relationship, nitric oxide metabolism, endothelium-dependent vasodilation
- MeSH terms
- Administration, Oral, Arginine, Citrulline, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Nitric Oxide, Placebos, Vasodilation, Cross-Over Studies, Nitric Oxide Synthase
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