Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.

Abstract-The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus.Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase C␤ as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase C␤ would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase C␤ inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 g/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (Pϭ0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase C␤ prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase C␤ activation. (Circ Res. 2002;90:107-111.)Key Words: protein kinase C Ⅲ nitric oxide Ⅲ hyperglycemia Ⅲ endothelium Ⅲ diabetes V ascular disease is the principal cause of morbidity and mortality in patients with diabetes mellitus. 1 Diabetes mellitus is associated with changes in endothelial cell function that augur the development of atherosclerosis. An important early change, decreased bioavailability of endothelium-derived nitric oxide, is linked to many of the pathological features of atherosclerosis including upregulation of leukocyte adhesion molecules, platelet activation, and an increased propensity for vasoconstriction. 2,3 Previous studies have demonstrated decreased endothelium-dependent vasodilation, a physiological marker of decreased bioavailability of nitric oxide in both conduit arteries and resistance vessels in experimental models of diabetes and humans with type 1 and type 2 diabetes. 4 -6 The central importance of hyperglycemia to the development of cardiovascular disease in diabetes mellitus is becoming increasingly evident. Population studies have revealed that an incremental risk of cardiovascular disease is associated with higher levels of blood glucose, beginning in the upper normal range. 7 Hyperglycemia, per se, impairs vasodilator function in animals and healthy humans, similar to that which occurs in patients with diabetes. 8,9 This cannot be attributed to downregulation of endothelial nitric oxide synthase (eNOS), since glucose inc...