BASIC RESEARCH

Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia

Y Fukuda, H Teragawa, K Matsuda, T Yamagata, H Matsuura and K Chayama

First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734–8551, Japan

Correspondence to:
Correspondence to:
Dr Yukihiro Fukuda, First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734–8551, Japan;
yfukuda{at}hiroshima-u.ac.jp

Objective: To examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients.

Design: Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine (ACh).

Setting: Tertiary cardiology centre.

Patients: 18 patients with angiographically normal coronary arteries, of whom nine had hypercholesterolaemia and nine had noromocholesterolaemia.

Interventions: ACh (3 and 30 µg/min) was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 (1 mg/min) before and after infusion of L-N^G-monomethyl-L-arginine (L-NMMA) (40 µmol/min for five minutes).

Main outcome measures: Diameter of the epicardial coronary arteries and coronary blood flow.

Results: In hypercholesterolaemic patients, BH4 attenuated the ACh induced decrease in coronary diameter (p < 0.05) and restored the ACh induced increase in coronary blood flow (p < 0.05). In normocholesterolaemic patients, BH4 did not affect the ACh induced changes in coronary diameter or coronary blood flow. In both groups, L-NMMA decreased the baseline coronary diameter (p < 0.05) and baseline coronary blood flow (p < 0.05). In hypercholesterolaemic patients, L-NMMA inhibited both the BH4 mediated attenuation of the ACh induced decrease in coronary diameter (p < 0.05) and the BH4 mediated enhancement of the ACh induced increase in coronary blood flow (p < 0.01).

Conclusions: Intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients.

Keywords: coronary artery; tetrahydrobiopterin; nitric oxide; hypercholesterolaemia

Abbreviations: ACh, acetylcholine; BH4, tetrahydrobiopterin; L-NMMA, L-N^G-monomethyl-L-arginine

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Crabtree, M. J., Tatham, A. L., Al-Wakeel, Y., Warrick, N., Hale, A. B., Cai, S., Channon, K. M., Alp, N. J. (2009). Quantitative Regulation of Intracellular Endothelial Nitric-oxide Synthase (eNOS) Coupling by Both Tetrahydrobiopterin-eNOS Stoichiometry and Biopterin Redox Status: INSIGHTS FROM CELLS WITH TET-REGULATED GTP CYCLOHYDROLASE I EXPRESSION. J. Biol. Chem. 284: 1136-1144 [Abstract] [Full Text]  
• Cosentino, F, Hurlimann, D, Delli Gatti, C, Chenevard, R, Blau, N, Alp, N J, Channon, K M, Eto, M, Lerch, P, Enseleit, F, Ruschitzka, F, Volpe, M, Luscher, T F, Noll, G (2008). Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia. Heart 94: 487-492 [Abstract] [Full Text]  
• Worthley, M. I., Kanani, R. S., Sun, Y.-H., Sun, Y., Goodhart, D. M., Curtis, M. J., Anderson, T. J. (2007). Effects of tetrahydrobiopterin on coronary vascular reactivity in atherosclerotic human coronary arteries. Cardiovasc Res 76: 539-546 [Abstract] [Full Text]  
• Whitsett, J., Picklo, M. J. Sr, Vasquez-Vivar, J. (2007). 4-Hydroxy-2-Nonenal Increases Superoxide Anion Radical in Endothelial Cells via Stimulated GTP Cyclohydrolase Proteasomal Degradation. Arterioscler. Thromb. Vasc. Bio. 27: 2340-2347 [Abstract] [Full Text]  
• Hattori, Y., Hattori, S., Wang, X., Satoh, H., Nakanishi, N., Kasai, K. (2007). Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice. Arterioscler. Thromb. Vasc. Bio. 27: 865-870 [Abstract] [Full Text]  
• Moens, A. L., Kass, D. A. (2006). Tetrahydrobiopterin and Cardiovascular Disease. Arterioscler. Thromb. Vasc. Bio. 26: 2439-2444 [Abstract] [Full Text]  
• Stevens, L.-M., Fortier, S., Aubin, M.-C., El-Hamamsy, I., Maltais, S., Carrier, M., Perrault, L. P. (2006). Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass.. Eur. J. Cardiothorac. Surg. 30: 464-471 [Abstract] [Full Text]  
• Teragawa, H, Fukuda, Y, Matsuda, K, Ueda, K, Higashi, Y, Oshima, T, Yoshizumi, M, Chayama, K (2004). Relation between C reactive protein concentrations and coronary microvascular endothelial function. Heart 90: 750-754 [Abstract] [Full Text]  
• Alp, N. J., Channon, K. M. (2004). Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease. Arterioscler. Thromb. Vasc. Bio. 24: 413-420 [Abstract] [Full Text]  
• Alp, N. J., McAteer, M. A., Khoo, J., Choudhury, R. P., Channon, K. M. (2004). Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice. Arterioscler. Thromb. Vasc. Bio. 24: 445-450 [Abstract] [Full Text]  
• Werner, E. R., Gorren, A. C.F., Heller, R., Werner-Felmayer, G., Mayer, B. (2003). Tetrahydrobiopterin and Nitric Oxide: Mechanistic and Pharmacological Aspects. Exp. Biol. Med. 228: 1291-1302 [Abstract] [Full Text]  
• Zheng, J.-S., Yang, X.-Q., Lookingland, K. J., Fink, G. D., Hesslinger, C., Kapatos, G., Kovesdi, I., Chen, A. F. (2003). Gene Transfer of Human Guanosine 5'-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension. Circulation 108: 1238-1245 [Abstract] [Full Text]