A major cause of death and disability in patients with diabetes mellitus is atherosclerosis. Endothelial dysfunction is an important, if not primary, factor in atherogenesis. Among the substances normally synthesized and released by the endothelium is nitric oxide. Endothelium-dependent vasorelaxation, mediate by nitric oxide, is impaired in experimental models of diabetes and in patients with insulin-dependent (IDDM) and non-insulin- dependent diabetes mellitus (NIDDM). Reactive oxygen species, such as superoxide anions, inactivate nitric oxide in experimental models of diabetes and may contribute to alterations in vasomotor reactivity. This proposal plans to examine the effect of acute and chronic administration of the antioxidants, vitamin C and vitamin E, on vasodilator reactivity in peripheral and coronary vessels of patients with diabetes mellitus (both IDDM and NIDDM) and healthy, age-matched control subjects. To determine whether acute and long-term treatment with antioxidant vitamins favorably affects nitric oxide-mediated vasodilation, coronary artery endothelial function will be assessed by intracoronary infusion of acetylcholine in patients with diabetes mellitus undergoing cardiac catheterization. Acute studies will be performed prior to and immediately following intracoronary administration of vitamin C or placebo. Long-term studies will be obtained six months following randomization to vitamins E and C, or corresponding placebo. In addition, peripheral conduit artery endothelial function will be studied noninvasively by vascular ultrasound in healthy subjects and patients with IDDM and NIDDM. Acute studies will be performed prior to and 2 hours after administration of oral vitamin C. Long-term studies will be performed six months following randomization to vitamin C and E or placebo. It is anticipated that results from these studies will give mechanistic insight into a cause of abnormal endothelial function in diabetes mellitus, and yield a treatment strategy that may reduce morbidity and mortality from atherosclerosis in this population.
