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

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.