Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease
Open accessAbstract
Background—: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. Methods and Results—: Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. Conclusions—: Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00423280.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oral BH4 for 2-6 wk in patients with coronary artery disease did not show improvement and increased BH2 levels.
“A treatment with oral BH4 for 2–6 wk in patients with coronary artery disease did not show improvement; and actually increased BH2 levels (202).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [202]
In most examples, BH4 improves endothelial function, but in some conditions BH4 supplementation is not a practical therapeutic approach.
“In most examples, BH4 is able to improve endothelial function, but the study by Cunnington et al. (202) clearly indicated that in some conditions, BH4 supplementation is not a practical therapeutic approach.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [202]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors
Vásquez-Vivar, J., Kalyanaraman, B., Martásek, P., Hogg, N., Masters, B. S. S., Karoui, H., Tordo, P., & Pritchard, K. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9220 · Cited by 1,484 · see citing works
Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus
Guzik, T. J., Mussa, S., Gastaldi, D., Sadowski, J., Ratnatunga, C., Pillai, R. G., & Channon, K. M. (2002) · Circulation · doi:10.1161/01.cir.0000012748.58444.08 · Cited by 979 · see citing works
Self-citationSuperoxide Generation from Endothelial Nitric-oxide Synthase
Xia, Y., Tsai, A.-L., Berka, V., & Zweier, J. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.40.25804 · Cited by 705 · see citing works
Interactions of Peroxynitrite, Tetrahydrobiopterin, Ascorbic Acid, and Thiols
Kuzkaya, N., Weissmann, N., Harrison, D. G., & Dikalov, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302227200 · Cited by 692 · see citing works
Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.
Stroes, E. S. G., Kastelein, J. J. P., Cosentino, F., Erkelens, W. D., Wever, R. M. F., Koomans, H. A., Lüscher, T. F., & Rabelink, T. J. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119131 · Cited by 588 · see citing works
Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers
Heitzer, T. A., Brockhoff, C. J., Mayer, B., Warnholtz, A., Mollnau, H., Henne, S., Meinertz, T., & Münzel, T. F. (2000) · Circulation Research · doi:10.1161/01.res.86.2.e36 · Cited by 449 · see citing works
Heitzer, T., Krohn, K., Albers, S., & Meinertz, T. (2000) · Diabetologia · doi:10.1007/s001250051551 · Cited by 427 · see citing works
Antoniades, C., Shirodaria, C., Warrick, N., Cai, S., de Bono, J., Lee, J., Leeson, P., Neubauer, S., Ratnatunga, C., Pillai, R., et al. (2006) · Circulation · doi:10.1161/circulationaha.106.612325 · Cited by 365 · see citing works
Self-citationChalupský, K., & Cai, H. “. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409594102 · Cited by 338 · see citing works
Alp, N. J., Mussa, S., Khoo, J. P., Cai, S., Guzik, T. J., Jefferson, A., Goh, N., Rockett, K. A., & Channon, K. M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17786 · Cited by 321 · see citing works
Self-citationVasquez-Vivar, J. M., Pavel Martasek, E., Whitsett, J., Joseph, J., & Kalyanaraman, B. (2002) · Biochemical Journal · doi:10.1042/0264-6021:3620733 · Cited by 287 · see citing works
VÁSQUEZ-VIVAR, J., MARTÁSEK, P., WHITSETT, J., JOSEPH, J., & KALYANARAMAN, B. (2002) · Biochemical Journal · doi:10.1042/bj3620733 · Cited by 287 · see citing works
Antoniades, C., Bakogiannis, C., Leeson, P., Guzik, T. J., Zhang, M.-H., Tousoulis, D., Antonopoulos, A. S., Demosthenous, M., Marinou, K., Hale, A., et al. (2011) · Circulation · doi:10.1161/circulationaha.110.985150 · Cited by 219 · see citing works
Self-citationTetrahydrobiopterin Improves Endothelial Function in Patients with Coronary Artery Disease
Maier, W., Cosentino, F., Lütolf, R. B., Fleisch, M., Seiler, C., Hess, O. M., Meier, B., & Lüscher, T. F. (2000) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200002000-00001 · Cited by 217 · see citing works
Crabtree, M. J., Smith, C. L., Lam, G., Goligorsky, M. S., & Gross, S. S. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00823.2007 · Cited by 213 · see citing works
Self-citationCrabtree, M. J., Tatham, A. L., Hale, A. B., Alp, N. J., & Channon, K. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.041483 · Cited by 210 · see citing works
Self-citationCrabtree, M. J., Tatham, A. L., Al-Wakeel, Y., Warrick, N., Hale, A. B., Cai, S., Channon, K. M., & Alp, N. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m805403200 · Cited by 200 · see citing works
Self-citationAlp, N. J., McAteer, M. A., Khoo, J., Choudhury, R. P., & Channon, K. M. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000115637.48689.77 · Cited by 194 · see citing works
Self-citationSkatchkov, M. P., Sperling, D., Hink, U., Mülsch, A., Harrison, D. G., Sindermann, I., Meinertz, T., & Münzel, T. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9942 · Cited by 188 · see citing works
Antoniades, C., Shirodaria, C., Crabtree, M., Rinze, R., Alp, N., Cunnington, C., Diesch, J., Tousoulis, D., Stefanadis, C., Leeson, P., et al. (2007) · Circulation · doi:10.1161/circulationaha.107.704155 · Cited by 153 · see citing works
Self-citationCosentino, F., Hürlimann, D., Delli Gatti, C., Chenevard, R., Blau, N., Alp, N. J., Channon, K. M., Eto, M., Lerch, P., Enseleit, F., et al. (2008) · Heart · doi:10.1136/hrt.2007.122184 · Cited by 143 · see citing works
Self-citationCrabtree, M. J., Hale, A., & Channon, K. M. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.03.010 · Cited by 131 · see citing works
Self-citationGlobal Improvement of Vascular Function and Redox State With Low-Dose Folic Acid
Shirodaria, C. C., Antoniades, C. A., Lee, J., Jackson, C. E., Robson, M. D., Francis, J. M., Moat, S. J., Ratnatunga, C., Pillai, R. G., Refsum, H., et al. (2007) · Circulation · doi:10.1161/circulationaha.106.679084 · Cited by 131 · see citing works
Self-citationAntoniades, C. A., Bakogiannis, C., Tousoulis, D., Reilly, S. N., Zhang, M.-H., Paschalis, A., Antonopoulos, A. S., Demosthenous, M., Miliou, A., Psarros, C. T., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.927376 · Cited by 124 · see citing works
Self-citationGlobal impairment of brachial, carotid, and aortic vascular function in young smokers
Wiesmann, F., Petersen, S. E., Leeson, P., Francis, J. M., Robson, M. D., Wang, Q., Choudhury, R. P., Channon, K. M., & Neubauer, S. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.08.033 · Cited by 120 · see citing works
Self-citationGao, L., Chalupský, K., Stefani, E., & Cai, H. “. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.07.025 · Cited by 105 · see citing works
Effect of Tetrahydrobiopterin on Endothelial Function in Canine Middle Cerebral Arteries
Tsutsui, M., Milstien, S., & Katušić, Z. S. (1996) · Circulation Research · doi:10.1161/01.res.79.2.336 · Cited by 92 · see citing works
GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease
Antoniades, C. A., Shirodaria, C. C., Assche, T. V., Cunnington, C., Tegeder, I., Lötsch, J., Guzik, T. J., Leeson, P., Diesch, J., Tousoulis, D., et al. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.12.062 · Cited by 79 · see citing works
Self-citationSawabe, K., Wakasugi, K. O., & Hasegawa, H. (2004) · Journal of Pharmacological Sciences · doi:10.1254/jphs.fp0040280 · Cited by 75 · see citing works
Mayahi, L., Heales, S., Owen, D., Casas, J. P., Harris, J., MacAllister, R. J., & Hingorani, A. D. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.142257 · Cited by 49 · see citing works
Sawabe, K., Suetake, Y., Nakanishi, N., Wakasugi, K. O., & Hasegawa, H. (2005) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2005.06.020 · Cited by 21 · see citing works
Sawabe, K., Suetake, Y., Wakasugi, K. O., & Hasegawa, H. (2005) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2005.06.019 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Treating Oxidative Stress in Heart Failure: Past, Present and Future
van der Pol, A., van Gilst, W. H., Voors, A. A., & van der Meer, P. (2018) · European Journal of Heart Failure · doi:10.1002/ejhf.1320 · Cited by 816 · see citing works
Nitric oxide signalling in cardiovascular health and disease
Farah, C., Michel, L. Y. M., & Balligand, J.-L. (2018) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.224 · Cited by 779 · see citing works
Eelen, G., de Zeeuw, P., Treps, L., Harjes, U., Wong, B. W., & Carmeliet, P. (2017) · Physiological Reviews · doi:10.1152/physrev.00001.2017 · Cited by 591 · see citing works
Oxidative Stress and Hypertension
Griendling, K. K., Camargo, L. L., Rios, F. J. O., Alves-Lopes, R., Montezano, A. C. I., & Touyz, R. M. (2021) · Circulation Research · doi:10.1161/circresaha.121.318063 · Cited by 592 · 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
Redox Signaling in Cardiac Physiology and Pathology
Burgoyne, J. R., Mongue‐Din, H., Eaton, P., & Shah, A. M. (2012) · Circulation Research · doi:10.1161/circresaha.111.255216 · Cited by 483 · see citing works
The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor
D’Oria, R., Schipani, R., Leonardini, A., Natalicchio, A., Perrini, S., Cignarelli, A., Laviola, L., & Giorgino, F. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5732956 · Cited by 387 · see citing works
Janaszak-Jasiecka, A., Płoska, A., Wierońska, J. M., Dobrucki, L. W., & Kalinowski, L. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00423-2 · Cited by 358 · see citing works
Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease
Li, H., & Förstermann, U. (2013) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2013.01.006 · Cited by 285 · see citing works
Montezano, A. C. I., & Touyz, R. M. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5302 · Cited by 275 · see citing works
Oxidative stress and the role of redox signalling in chronic kidney disease
Kishi, S., Nagasu, H., Kidokoro, K., & Kashihara, N. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00775-0 · Cited by 283 · see citing works
Kapil, V., Khambata, R. S., Jones, D. A., Rathod, K., Primus, C., Massimo, G., Fukuto, J. M., & Ahluwalia, A. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019240 · Cited by 248 · see citing works
Tetrahydrobiopterin in Cardiovascular Health and Disease
Bendall, J. K., Douglas, G., McNeill, E., Channon, K. M., & Crabtree, M. J. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5566 · Cited by 231 · see citing works
Self-citationThe Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics
Divakaran, S., & Loscalzo, J. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.09.1064 · Cited by 209 · see citing works
Goveia, J., Stapor, P. C., & Carmeliet, P. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404156 · Cited by 199 · see citing works
The eNOS signalosome and its link to endothelial dysfunction
Siragusa, M., & Fleming, I. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-016-1839-0 · Cited by 171 · see citing works
Strasser, B., Gostner, J. M., & Fuchs, D. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000237 · Cited by 173 · see citing works
Lara, J., Ashor, A. W., Oggioni, C., Ahluwalia, A., Mathers, J. C., & Siervo, M. (2016) · European Journal of Nutrition · doi:10.1007/s00394-015-0872-7 · Cited by 163 · see citing works
Oxidative stress in chronic vascular disease: From prediction to prevention
Santilli, F., D’Ardes, D., & Davı̀, G. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.09.003 · Cited by 140 · see citing works
Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling
Alkaitis, M. S., & Crabtree, M. J. (2012) · Current Heart Failure Reports · doi:10.1007/s11897-012-0097-5 · Cited by 139 · see citing works
Self-citationDe Pascali, F., Hemann, C., Samons, K., Chen, C.-A., & Zweier, J. L. (2014) · Biochemistry · doi:10.1021/bi500076r · Cited by 131 · see citing works
Redox regulation of cardiac hypertrophy
Sag, C. M., Santos, C. X. C., & Shah, A. M. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.02.002 · Cited by 124 · see citing works
Roy, R., Wilcox, J., Webb, A. J., & O’Gallagher, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015200 · Cited by 128 · see citing works
Yuyun, M. F., Ng, L. L., & Ng, G. A. (2018) · Microvascular Research · doi:10.1016/j.mvr.2018.03.012 · Cited by 114 · see citing works
Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging
Czibik, G., Mezdari, Z., Altintas, D. M., Bréhat, J., Pini, M., d’Humières, T., Delmont, T., Radu, C., Breau, M., Liang, H., et al. (2021) · Circulation · doi:10.1161/circulationaha.121.054204 · Cited by 111 · see citing works
Varadharaj, S., Kelly, O. J., Khayat, R. N., Kumar, P. S., Ahmed, N., & Zweier, J. L. (2017) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00064 · Cited by 101 · see citing works
Murr, C., Grammer, T. B., Meinitzer, A., Kleber, M. E., März, W., & Fuchs, D. (2014) · Journal of Amino Acids · doi:10.1155/2014/783730 · Cited by 104 · see citing works
Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease
Kraehling, J. R., & Sessa, W. C. (2017) · Circulation Research · doi:10.1161/circresaha.117.303776 · Cited by 98 · see citing works
Ushio‐Fukai, M., Ash, D., Nagarkoti, S., de Chantemèle, E. J. B., Fulton, D. J., & Fukai, T. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8161 · Cited by 96 · see citing works
Godo, S., & Shimokawa, H. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.019 · Cited by 91 · see citing works
Age-related diseases as vicious cycles
Belikov, A. V. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.11.002 · Cited by 92 · see citing works
Crabtree, M. J., Brixey, R., Batchelor, H., Hale, A. B., & Channon, K. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.415992 · Cited by 83 · see citing works
Self-citationSignaling by S-nitrosylation in the heart
Murphy, E., Kohr, M., Menazza, S., Nguyen, T., Evangelista, A., Sun, J., & Steenbergen, C. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.01.003 · Cited by 82 · see citing works
Redox biomarkers in cardiovascular medicine
Galougahi, K. K., Antoniades, C. A., Nicholls, S. J., Channon, K. M., & Figtree, G. A. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv126 · Cited by 83 · see citing works
Self-citationAntiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque
Khambata, R. S., Ghosh, S. M., Rathod, K. S., Thevathasan, T., Filomena, F., Xiao, Q., & Ahluwalia, A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613063114 · Cited by 78 · see citing works
Role of oxidative stress in endothelial insulin resistance
Paneni, F. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i2.326 · Cited by 75 · see citing works
Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)
Boslett, J., Hemann, C., Zhao, Y. J., Lee, H.-C., & Zweier, J. L. (2017) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.239459 · Cited by 69 · see citing works
Novel Insights Regarding Nitric Oxide and Cardiovascular Diseases
Infante, T., Costa, D., & Claudio Napoli, A. (2021) · Angiology · doi:10.1177/0003319720979243 · Cited by 67 · see citing works
Inserte, J., Hernando, V., Vilardosa, Ú., Abad, E., Poncelas, M., & David Garcia-dorado, A. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.112.005975 · Cited by 68 · see citing works
Reyes, L. A., Boslett, J. J., Varadharaj, S., Pascali, F. D., Hemann, C. F., Druhan, L. J., Ambrosio, G., El‐Mahdy, M. A., & Zweier, J. L. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505556112 · Cited by 65 · see citing works
L-arginine, tetrahydrobiopterin, nitric oxide and diabetes
Hoang, H. H., Padgham, S., & Meininger, C. J. (2012) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32835ad1ef · Cited by 61 · see citing works
The role of tetrahydrobiopterin in inflammation and cardiovascular disease
McNeill, E., & Channon, K. M. (2012) · Thrombosis and Haemostasis · doi:10.1160/th12-06-0424 · Cited by 60 · see citing works
Self-citationVaradharaj, S., Porter, K. M., Pleister, A. P., Wannemacher, J., Sow, A., Jarjoura, D. G., Zweier, J. L., & Khayat, R. (2014) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2014.12.012 · Cited by 60 · see citing works
Ong, P. K., Melchior, B., Martins, Y. C., Hofer, A., Orjuela-Sánchez, P., Cabrales, P., Zaniní, G. M., Frangos, J. A., & Carvalho, L. J. M. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003444 · Cited by 58 · see citing works
Promotion of nitric oxide production: mechanisms, strategies, and possibilities
Gonzalez, M., Clayton, S., Wauson, E., Christian, D., & Tran, Q. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1545044 · Cited by 56 · see citing works
Douglas, G., Hale, A., Patel, J., Chuaiphichai, S., Zen, A. A. H., Rashbrook, V. S., Trelfa, L., Crabtree, M. J., McNeill, E., & Channon, K. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy078 · Cited by 49 · see citing works
Self-citationMollace, R., Scarano, F., Bava, I., Carresi, C., Maiuolo, J., Tavernese, A., Gliozzi, M., Musolino, V., Muscoli, S., Palma, E., et al. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106931 · Cited by 48 · see citing works
Tetrahydrobiopterin in energy metabolism and metabolic diseases
Kim, H. K., & Han, J. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104827 · Cited by 47 · see citing works
Alterations in endothelial nitric oxide synthase activity and their relevance to blood pressure
Suvorava, T., Metry, S., Pick, S., & Kojda, G. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115256 · Cited by 48 · see citing works
Carnicer, R., Hale, A., Suffredini, S., Liu, X., Reilly, S. N., Zhang, M. H., Surdo, N. C., Bendall, J. K., Crabtree, M. J., Lim, G. B., et al. (2012) · Circulation Research · doi:10.1161/circresaha.112.274464 · Cited by 46 · see citing works
Self-citationLubrano, V., & Balzan, S. (2019) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-019-03656-y · Cited by 45 · see citing works
Engineer, A., Saiyin, T., Greco, E. R., & Feng, Q. (2019) · Antioxidants · doi:10.3390/antiox8100436 · Cited by 43 · see citing works
Yeo, T. W., Lampah, D. A., Kenangalem, E., Tjitra, E., Price, R. N., Weinberg, J. B., Hyland, Κ., Granger, D. L., & Anstey, N. M. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004667 · Cited by 38 · see citing works
Li, H., Förstermann, U., Xia, N., Kuntić, M., Münzel, T. F., & Daiber, A. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.06.009 · Cited by 38 · see citing works
Maki-Petaja, K. M., Day, L., Cheriyan, J., Hall, F. C., Östör, A. J. K., Shenker, N., & Wilkinson, I. B. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002762 · Cited by 36 · see citing works
Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation
Suvorava, T., Nagy, N., Pick, S., Lieven, O., Rüther, U., Dao, V. T.-V., Fischer, J. W., Weber, M., & Kojda, G. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6059 · Cited by 35 · see citing works
Alexander, L. M., Kutz, J. L., & Kenney, W. L. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00448.2012 · Cited by 35 · see citing works
Hashimoto, T., Sivakumaran, V., Carnicer, R., Zhu, G., Hahn, V. S., Bedja, D., Récalde, A., Duglan, D., Channon, K. M., Casadei, B., et al. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.003208 · Cited by 34 · see citing works
Self-citationExtending the translational potential of targeting NO/ cGMP ‐regulated pathways in the CVS
Papapetropoulos, A., Hobbs, A. J., & Topouzis, S. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12980 · Cited by 34 · see citing works
Reverter, E., Mesonero, F., Seijó, S., Martínez, J., Abraldeṣ, J. G., Peñas, B., Berzigotti, A., Deulofeu, R., Bosch, J., Albillos, A., et al. (2015) · The American Journal of Gastroenterology · doi:10.1038/ajg.2015.185 · Cited by 32 · see citing works
Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling
Whitsett, J., Rangel-Filho, A., Sethumadhavan, S., Celińska, J., Widlansky, M. E., & Vasquez-Vivar, J. M. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.035 · Cited by 32 · see citing works
Pharmacological approaches to coronary microvascular dysfunction
Guarini, G., Huqi, A., Morrone, D., Capozza, P., Todiere, G., & Marzilli, M. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.06.008 · Cited by 30 · see citing works
Shi, Y., Lüscher, T. F., & Camici, G. G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107787 · Cited by 27 · see citing works
Cyclic guanosine monophosphate signalling pathway in pulmonary arterial hypertension
Chen, C.-N., Watson, G., & Zhao, L. (2012) · Vascular Pharmacology · doi:10.1016/j.vph.2012.09.001 · Cited by 26 · see citing works
Cai, Z., Lu, Q., Ding, Y., Wang, Q., Xiao, L., Song, P., & Zou, M. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.305796 · Cited by 26 · see citing works
Mortensen, A., Hasselholt, S., Tveden‐Nyborg, P., & Lykkesfeldt, J. (2013) · Nutrition Research · doi:10.1016/j.nutres.2013.07.006 · Cited by 26 · see citing works
Heikal, L., Starr, A., Hussein, D. A., Prieto‐Lloret, J., Aaronson, P. I., Dailey, L. A., & Nandi, M. (2018) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2018.01.015 · Cited by 26 · see citing works
Pierce, G. L., Jablonski, K., Walker, A. E., Seibert, S. M., DeVan, A. E., Black, S. M., Sharma, S., & Seals, D. R. (2012) · American Journal of Hypertension · doi:10.1038/ajh.2012.70 · Cited by 25 · see citing works
Xie, L., Talukder, M. A. H., Sun, J., Varadharaj, S., & Zweier, J. L. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.06.015 · Cited by 25 · see citing works
Tetrahydrobiopterin and Nitric Oxide Synthase Recouplers
Channon, K. M. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_390 · Cited by 24 · see citing works
Self-citationTetrahydrobiopterin: A Vascular Redox Target to Improve Endothelial Function
Channon, K. M. (2012) · Current Vascular Pharmacology · doi:10.2174/157016112803520819 · Cited by 24 · see citing works
Self-citationImmunometabolic Regulation of Vascular Redox State: The Role of Adipose Tissue
Oikonomou, E. K., & Antoniades, C. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7017 · Cited by 24 · see citing works
Self-citationBH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes
Carnicer, R., Duglan, D., Žiberna, K., Récalde, A., Reilly, S. N., Simon, J. N., Mafrici, S. F., Arya, R., Roselló‐Lletí, E., Chuaiphichai, S., et al. (2021) · Circulation Research · doi:10.1161/circresaha.120.316656 · Cited by 23 · see citing works
Self-citationBenson, M. A., Batchelor, H., Chuaiphichai, S., Bailey, J. D., Zhu, H., Stuehr, D. J., Bhattacharya, S., Channon, K. M., & Crabtree, M. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.493023 · Cited by 23 · see citing works
Self-citationRemote effects on the striatal dopamine system after fluid percussion injury
Huang, E. Y., Tsai, T.-H., Kuo, T., Tsai, J.-J., Tsui, P.-F., Chou, Y., Ma, H.-I., Chiang, Y. H., & Chen, Y.-H. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.03.033 · Cited by 23 · see citing works
Tetrahydrobiopterin Improves Endothelial Function in Cardiovascular Disease: A Systematic Review
Wang, Q., Yang, M., Han, X., & Yu, J. (2014) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2014/850312 · Cited by 23 · see citing works
Lee, I., Kim, S., Nagar, H., Choi, S., Jeon, B. H., Piao, S., & Kim, C. (2020) · Scientific Reports · doi:10.1038/s41598-020-57673-9 · Cited by 23 · see citing works
Somani, Y. B., Soares, R. N., Gosalia, J., Spicuzza, J. M. D., Flanagan, M. P., Basu, S., Kim‐Shapiro, D. B., Murias, J. M., & Proctor, D. N. (2022) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2021-0693 · Cited by 22 · see citing works
Chuaiphichai, S., Starr, A., Nandi, M., Channon, K. M., & McNeill, E. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.08.009 · Cited by 22 · see citing works
Self-citationMechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure
Zeng, Q., Zhou, Q., Liu, W., Wang, Y., Xu, X., & Xu, D. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.636152 · Cited by 22 · see citing works
Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat
Francis, B. N., Hale, A., Channon, K. M., Wilkins, M. R., & Zhao, L. (2014) · Pulmonary Circulation · doi:10.1086/677361 · Cited by 21 · see citing works
Self-citationNO Signaling in the Cardiovascular System and Exercise
Fernandes, T. M., Gomes‐Gatto, C. D. V., Pereira, N. P., Alayafi, Y. R., das Neves, V. J., & de Oliveira, E. M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-4304-8_13 · Cited by 20 · see citing works
Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach
Evers, R. A. F., van Vliet, D., & van Spronsen, F. J. (2019) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12151 · Cited by 20 · see citing works
Chuaiphichai, S., Yu, G. Z., Tan, C., Whiteman, C. A. R., Douglas, G., Dickinson, Y., Drydale, E. N., Appari, M., Zhang, W., Crabtree, M. J., et al. (2021) · Hypertension · doi:10.1161/hypertensionaha.120.17646 · Cited by 19 · see citing works
Self-citationLi, H., Nguyen, H. T., Venkata, S. P. M., Koh, J. Y., Kowluru, A., Li, L., Rossi, N. F., Chen, W., & Wang, J. (2021) · Hypertension · doi:10.1161/hypertensionaha.120.15423 · Cited by 19 · see citing works
Regulatory effects of curcumin on nitric oxide signaling in the cardiovascular system
Abolfazli, S., Mortazavi, P., Kheirandish, A., Butler, A. E., Jamialahmadi, T., & Sahebkar, A. (2023) · Nitric Oxide · doi:10.1016/j.niox.2023.12.003 · Cited by 18 · see citing works
Dikalova, A., Aschner, J. L., Kaplowitz, M. R., Cunningham, G. R., Summar, M. L., & Fike, C. D. (2020) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00280.2019 · Cited by 18 · see citing works
Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL
Maria, R. D., Campolo, J., Frontali, M., Taroni, F., Federico, A., Inzitari, D., Tavani, A., Romano, S., Puca, E., Orzi, F., et al. (2014) · Stroke · doi:10.1161/strokeaha.114.005937 · Cited by 17 · see citing works
Watanabe, T. (2020) · VASA · doi:10.1024/0301-1526/a000903 · Cited by 16 · see citing works
Ma, S., & Ma, C. C.-H. (2014) · Vascular Pharmacology · doi:10.1016/j.vph.2014.08.001 · Cited by 16 · see citing works
Selective Up-Regulation of Arginase-1 in Coronary Arteries of Diabetic Patients
Bagi, Z. A., Fehér, A., Dou, H., & Brosková, Z. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00293 · Cited by 16 · see citing works
Ohashi, A., Mamada, K., Harada, T., Naito, M., Takahashi, T., Aizawa, S., & Hasegawa, H. (2017) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-017-3060-7 · Cited by 16 · see citing works
New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation
Gocht, A., Weyand, M., Ensminger, S. M., & Heim, C. (2017) · The Thoracic and Cardiovascular Surgeon · doi:10.1055/s-0037-1615290 · Cited by 16 · see citing works
The regulation of vascular tetrahydrobiopterin bioavailability
Starr, A., Hussein, D. A., & Nandi, M. (2012) · Vascular Pharmacology · doi:10.1016/j.vph.2012.08.002 · Cited by 16 · see citing works
Tetrahydrobiopterin Protects against Radiation-induced Growth Inhibition in H9c2 Cardiomyocytes
Zhang, Z., Li, Y., Li, R., Zhang, A., Shang, B., Yu, J., & Xie, X. (2016) · Chinese Medical Journal · doi:10.4103/0366-6999.193455 · Cited by 15 · see citing works
Nanoparticle-mediated delivery of tetrahydrobiopterin restores endothelial function in diabetic rats
Kelly, K. A., Heaps, C. L., Wu, G., Labhasetwar, V. D., & Meininger, C. J. (2024) · Nitric Oxide · doi:10.1016/j.niox.2024.04.009 · Cited by 14 · see citing works
Mangge, H., Schnedl, W., Schröcksnadel, S., Geisler, S., Murr, C., & Fuchs, D. (2013) · Pteridines · doi:10.1515/pterid-2013-0002 · Cited by 14 · see citing works
Early ascorbic acid administration prevents vascular endothelial cell damage in septic mice
Madokoro, Y., Kamikokuryo, C., Niiyama, S., Ito, T., Hara, S., Ichinose, H., & Kakihana, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929448 · Cited by 16 · see citing works
Panday, S., Kar, S., & Kavdia, M. (2017) · Microvascular Research · doi:10.1016/j.mvr.2017.07.001 · Cited by 14 · see citing works
- Authors
- Cunnington, C., Van Assche, T., Shirodaria, C., Kylintireas, I., Lindsay, A. C., Lee, J. M., Antoniades, C., Margaritis, M., Lee, R., Cerrato, R., Crabtree, M. J., Francis, J. M., Sayeed, R., Ratnatunga, C., Pillai, R., Choudhury, R. P., Neubauer, S., & Channon, K. M.
- Affiliations
- John Radcliffe Hospital (GB)
- From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
- ORCID
- Venue
- Circulation
- Published
- 2012-03-20
- Volume
- 125
- Issue
- 11
- Pages
- 1356-1366
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC5238935
- OpenAlex
- W1987686985
- Cited by
- 166
- References
- 31
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 3 · 2023: 12 · 2022: 7 · 2021: 12 · 2020: 8 · 2019: 9 · 2018: 12 · 2017: 13 · 2016: 10 · 2015: 19 · 2014: 16 · 2013: 14 · 2012: 16
- FWCI
- 13.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (088291, 090532)
- National Institute for Health and Care Research (NF-SI-0508-10247, IS-BRC-0211-10025)
- British Heart Foundation (RG/07/003/23133, PG/08/119/26263, RG/12/5/29576)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- tetrahydrobiopterin, BH4, dihydrobiopterin, endothelial nitric oxide synthase, coronary artery disease, endothelial function, saphenous vein, internal mammary artery
- MeSH terms
- Administration, Oral, Aged, Biopterins, Coronary Artery Disease, Double-Blind Method, Endothelium, Vascular, Female, Humans, Male, Oxidation-Reduction, Treatment Outcome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
