Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus
Open accessAbstract
Aims/hypothesis Tetrahydrobiopterin is an essential cofactor of nitric oxide synthase, and its deficiency decreases nitric oxide bioactivity. Our aim was to find whether supplementation of tetrahydrobiopterin could improve endothelial dysfunction in diabetic patients.Methods Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine (0.75-3.0 microg x 100 ml(-1) x min(-1)) and to the endothelium-independent vasodilator sodium nitroprusside (0.1-1.0 microg x 100 ml(-1) x min(-1)) before and during concomitant intra-arterial infusion of tetrahydrobiopterin (500 microg/min) were measured by venous occlusion plethysmography in 12 control subjects and 23 patients with Type II (non-insulin-dependent) diabetes mellitus.Results In control subjects, tetrahydrobiopterin had no effect on the dose-response curves to acetylcholine and sodium nitroprusside. In contrast, in diabetic patients, the attenuated endothelium-dependent vasodilation to acetylcholine was considerably improved by concomitant treatment with tetrahydrobiopterin, whereas the endothelium-independent vasodilation was not affected. This beneficial effect of tetrahydrobiopterin in diabetic patients could be completely blocked by N(G)-monomethyl-L-arginine.Conclusion/interpretation These findings suggest the possibility that endothelial dysfunction in Type II diabetes might be related to decreased availability of tetrahydrobiopterin.
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Low levels of BH4 are found in endothelial dysfunction and cardiovascular disease.
“Conversely, low levels of BH4 are found in endothelial dysfunction and cardiovascular disease (421, 429, 440, 550, 560, 858, 899).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [421]
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Cites
Ting, H. H., Timimi, F. K., Boles, K., Creager, S. J., Ganz, P., & Creager, M. A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118394 · Cited by 869 · 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
Oxidation of Tetrahydrobiopterin by Peroxynitrite: Implications for Vascular Endothelial Function
Milstien, S., & Katušić, Z. S. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1422 · Cited by 488 · see citing works
Shinozaki, K., Kashiwagi, A., Nishio, Y., Okamura, T., Yoshida, Y., Masada, M., Toda, N., & Kikkawa, R. (1999) · Diabetes · doi:10.2337/diabetes.48.12.2437 · Cited by 329 · see citing works
Atherosclerosis and the Two Faces of Endothelial Nitric Oxide Synthase
Wever, R. M. F., Lüscher, T. F., Cosentino, F., & Rabelink, T. J. (1998) · Circulation · doi:10.1161/01.cir.97.1.108 · Cited by 292 · see citing works
Pieper, G. M. (1997) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199701000-00002 · Cited by 222 · see citing works
Increased Nitrotyrosine in the Diabetic Placenta: Evidence for oxidative stress
Lyall, F., Gibson, J. L., Greer, I. A., Brockman, D. E., Eis, A., & Myatt, L. (1998) · Diabetes Care · doi:10.2337/diacare.21.10.1753 · Cited by 101 · see citing works
Chen, P. F., Tsai, A., & Wu, K. K. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2579 · Cited by 86 · see citing works
Flagged first, then by citations
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Nitric oxide synthases: regulation and function
Forstermann, U., & Sessa, W. C. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehr304 · Cited by 4,409 · see citing works
Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace
Förstermann, U., & Münzel, T. (2006) · Circulation · doi:10.1161/circulationaha.105.602532 · Cited by 1,957 · see citing works
The clinical implications of endothelial dysfunction
Widlansky, M. E., Gokce, N., Keaney, J. F., & Vita, J. A. (2003) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(03)00994-x · Cited by 1,749 · see citing works
Oxidative Stress and Vascular Disease
Madamanchi, N. R., Vendrov, A., & Runge, M. S. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000150649.39934.13 · Cited by 1,618 · see citing works
Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis
Förstermann, U., Xia, N., & Li, H. (2017) · Circulation Research · doi:10.1161/circresaha.116.309326 · Cited by 1,519 · 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
Mollnau, H., Wendt, M., Szöcs, K., Lassègue, B., Schulz, E., Oelze, M., Li, H., Bodenschatz, M., August, M., Kleschyov, A. L., et al. (2002) · Circulation Research · doi:10.1161/01.res.0000012569.55432.02 · Cited by 676 · see citing works
Self-citationOxidative stress in vascular disease: causes, defense mechanisms and potential therapies
Förstermann, U. (2008) · Nature Clinical Practice Cardiovascular Medicine · doi:10.1038/ncpcardio1211 · Cited by 576 · 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
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 insulin resistance in endothelial dysfunction
Muniyappa, R., & Sowers, J. R. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-012-9229-1 · Cited by 539 · see citing works
Targeting vascular (endothelial) dysfunction
Daiber, A., Steven, S., Weber, A., Shuvaev, V. V., Muzykantov, V. R., Laher, I., Li, H., Lamas, S., & Münzel, T. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13517 · Cited by 501 · see citing works
Zou, M.-H., Shi, C., & Cohen, R. A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214442 · Cited by 494 · see citing works
Is oxidative stress a therapeutic target in cardiovascular disease?
Münzel, T., Gori, T., Bruno, R. M., & Taddei, S. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq396 · Cited by 470 · see citing works
Oxidative stress and diabetic cardiovascular complications
Jay, D., Hitomi, H., & Griendling, K. K. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.06.018 · Cited by 464 · see citing works
Rochette, L., Lorin, J., Zeller, M., Guilland, J.-C., Lorgis, L., Cottin, Y., & Vergely, C. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.07.004 · Cited by 456 · see citing works
Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension
Schulz, E., Jansen, T., Wenzel, P., Daiber, A., & Münzel, T. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1989 · Cited by 430 · see citing works
Thomas, S. R., Witting, P. K., & Drummond, G. R. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2027 · Cited by 383 · 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
eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation
Karbach, S., Wenzel, P., Waisman, A., Munzel, T., & Daiber, A. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113196660748 · Cited by 307 · 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
Crabtree, 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
Alp, 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
Heitzer, T. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00551-2 · Cited by 194 · see citing works
Self-citationCunnington, C., Van Assche, T., Shirodaria, C., Kylintireas, I., Lindsay, A. C., Lee, J. M., Antoniades, C., Margaritis, M., Lee, R., Cerrato, R., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.038919 · Cited by 166 · see citing works
Cosentino, 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
Regulation of Tetrahydrobiopterin Synthesis and Bioavailability in Endothelial Cells
Shi, W., Meininger, C. J., Haynes, T. E., Hatakeyama, K., & Wu, G. (2004) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:41:3:415 · Cited by 137 · see citing works
Wei, R., Ma, S., Wang, C., Ke, J., Yang, J., Li, W., Liu, Y., Hou, W., Feng, X., Wang, G., et al. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00400.2015 · Cited by 137 · see citing works
Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications
Casas, A. I., Dao, V. T.-V., Daiber, A., Maghzal, G. J., Di Lisa, F., Kaludercic, N., Leach, S., Cuadrado, A., Jaquet, V., Seredenina, T., et al. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6433 · Cited by 136 · see citing works
Ihlemann, N., Rask-Madsen, C., Perner, A., Dominguez, H., Hermann, T., Køber, L., & Torp-Pedersen, C. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00008.2003 · Cited by 113 · see citing works
Cai, S. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00460-1 · Cited by 105 · see citing works
Chuaiphichai, S., McNeill, E., Douglas, G., Crabtree, M. J., Bendall, J. K., Hale, A. B., Alp, N. J., & Channon, K. M. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.03089 · Cited by 63 · see citing works
Abudukadier, A., Fujita, Y., Obara, A., Ohashi, A., Fukushima, T., Sato, Y., Ogura, M., Nakamura, Y., Fujimoto, S., Hosokawa, M., et al. (2013) · Diabetes · doi:10.2337/db12-1242 · Cited by 52 · see citing works
WORTHLEY, M., KANANI, R., SUN, Y., SUN, Y., GOODHART, D., CURTIS, M., & ANDERSON, T. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.07.009 · Cited by 25 · see citing works
- Authors
- Heitzer, T., Krohn, K., Albers, S., & Meinertz, T.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- ORCID
- Albers, S.
- Venue
- Diabetologia
- Published
- 2000-10-26
- Volume
- 43
- Issue
- 11
- Pages
- 1435-1438
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2164765386
- Cited by
- 427
- References
- 8
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 10 · 2023: 15 · 2022: 16 · 2021: 10 · 2020: 23 · 2019: 11 · 2018: 9 · 2017: 15 · 2016: 21 · 2015: 11 · 2014: 21 · 2013: 13 · 2012: 27
- FWCI
- 11.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (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
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- tetrahydrobiopterin, endothelial dysfunction, type 2 diabetes, endothelium-dependent vasodilation, nitric oxide, nitric oxide synthase cofactor, acetylcholine, forearm blood flow, L-NMMA, nitric oxide bioavailability
- MeSH terms
- Acetylcholine, Biopterins, Blood Flow Velocity, Diabetes Mellitus, Type 2, Endothelium, Vascular, Enzyme Inhibitors, Female, Forearm, Humans, Infusions, Intra-Arterial, Male, Middle Aged, Nitric Oxide, Nitroprusside, Plethysmography, Vasodilation, Vasodilator Agents, Nitric Oxide Synthase, omega-N-Methylarginine
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