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J Am Coll Cardiol, 2001; 38:1821-1828
© 2001 by the American College of Cardiology Foundation
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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{ddagger}, Yoshihiko Nishio, MD, PhD{dagger}, Yuichi Yoshida, PhD§, Tomohito Ohtani, MD{ddagger}, Tomio Okamura, MD, PhD*, Masahiro Masada, PhD§, Ryuichi Kikkawa, MD, PhD{dagger}, Kazuhisa Kodama, MD, PhD{ddagger} and Atsunori Kashiwagi, MD, PhD*,{dagger}

* Department of Pharmacology, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
{dagger} Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
{ddagger} 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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