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CLINICAL STUDY: RISK FACTORS

Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress

Kazuya Shinozaki, MD, PhD^*, Atsushi Hirayama, MD, PhD, Yoshihiko Nishio, MD, PhD, Yuichi Yoshida, PhD, Tomohito Ohtani, MD, Tomio Okamura, MD, PhD^*, Masahiro Masada, PhD, Ryuichi Kikkawa, MD, PhD, Kazuhisa Kodama, MD, PhD and Atsunori Kashiwagi, MD, PhD^*,

^* Department of Pharmacology, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
Cardiovascular Division, Osaka Police Hospital, Kitayama-cho, Tennoji-ku Osaka, Japan
Laboratory of Biochemistry, Faculty of Horticulture, Chiba University, Matsudo, Chiba, Japan

Manuscript received May 1, 2001; revised manuscript received August 13, 2001, accepted August 29, 2001.

^* Reprint requests and correspondence: Dr. Atsunori Kashiwagi, Third Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan
kasiwagi{at}belle.shiga-med.ac.jp

OBJECTIVES

We investigated whether abnormal pteridine metabolism is related to coronary endothelial dysfunction in insulin-resistant subjects.

BACKGROUND

Depletion of tetrahydrobiopterin (BH₄) and elevation of the 7,8-dihydrobiopterin (BH₂) (activating and inactivating cofactors of nitric oxide synthase [NOS], respectively) contribute to impairment of NO-dependent vasodilation through reduction of NOS activity as well as increased superoxide anion generation in insulin-resistant rats.

METHODS

Thirty-six consecutive nondiabetic, normotensive and nonobese subjects with angiographically normal coronary vessels were studied. Traditional coronary risk factors, plasma pteridine levels, activities of erythrocyte dihydropteridine reductase (DHPR), the recycling enzyme that converts BH₂ to BH₄ and lipid peroxide (LPO) levels were measured and coronary endothelial function was assessed with graded infusions of acetylcholine (ACh).

RESULTS

When we divided patients into tertiles based on insulin sensitivity, we observed stepwise decreases in the maximal ACh-induced vasodilation and plasma BH₄/7,8-BH₂ ratio, and increases in coronary LPO production as insulin sensitivity decreased. The ACh-induced vasodilation was positively correlated with insulin sensitivity, BH₄/7,8-BH₂ ratio and DHPR activity. Furthermore, BH₄/7,8-BH₂ was inversely correlated with DHPR activity and insulin sensitivity. In multiple stepwise regression analysis, BH₄/BH₂ was independently related to ACh-induced vasodilation and accounted for 39% of the variance. However, no significant correlation existed between other traditional risk factors and BH₄/7,8-BH₂.

CONCLUSIONS

These results indicate that both abnormal pteridine metabolism and vascular oxidative stress are linked to coronary endothelial dysfunction in the insulin-resistant subjects.

Abbreviations and Acronyms   ACh = acetylcholine   Ao = descending aorta   BH2 = 7,8-dihydrobiopterin   BH4 = (6R)-5,6,7,8-tetrahydrobiopterin   BL = borderline   CS = coronary sinus   DHPR = dihydropteridine reductase   eNOS = endothelial nitric oxide synthase   GTP-CH1 = GTP cyclohydrolase I   IR = insulin resistant   IS = insulin sensitive   LPO = lipid peroxide   NO = nitric oxide   NOS = nitric oxide synthase   NTG = nitroglycerin   O2– = superoxide anion   OGTT = oral glucose tolerance test   TBARS = thiobarbituric acid reactive substances   TRAP = total radical-trapping antioxidant parameter   VSAP = vasospastic angina

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