Hypercholesterolemia impairs vasodilation in forearm resistance vessels in humans. This study compared vascular reactivity in 11 normal subjects and 13 hypercholesterolemic patients (serum LDL cholesterol 111±7 vs. 211±19 mg/dl). Vascular reactivity was assessed using methacholine (endothelium-derived relaxant) and nitroprusside (direct smooth muscle stimulant). Basal and reactive hyperemic forearm blood flow was similar between groups, but the maximal vasodilatory response to methacholine was reduced in hypercholesterolemic subjects. Similarly, nitroprusside-induced vasodilation was also impaired. Vasoconstrictive responses to phenylephrine were comparable between groups. These findings suggest that hypercholesterolemia reduces the effect of nitrovasodilators and endothelium-derived relaxing factor on vascular smooth muscle in resistance vessels. The study concludes that hypercholesterolemia impairs vascular function in the absence of atherosclerosis, potentially contributing to atherosclerosis development. The impaired vasodilation may result from endothelial dysfunction, smooth muscle abnormalities, or structural changes in the vessels. The study highlights the importance of vascular function in hypercholesterolemia and suggests that early treatment may prevent atherosclerosis by preserving vascular function.Hypercholesterolemia impairs vasodilation in forearm resistance vessels in humans. This study compared vascular reactivity in 11 normal subjects and 13 hypercholesterolemic patients (serum LDL cholesterol 111±7 vs. 211±19 mg/dl). Vascular reactivity was assessed using methacholine (endothelium-derived relaxant) and nitroprusside (direct smooth muscle stimulant). Basal and reactive hyperemic forearm blood flow was similar between groups, but the maximal vasodilatory response to methacholine was reduced in hypercholesterolemic subjects. Similarly, nitroprusside-induced vasodilation was also impaired. Vasoconstrictive responses to phenylephrine were comparable between groups. These findings suggest that hypercholesterolemia reduces the effect of nitrovasodilators and endothelium-derived relaxing factor on vascular smooth muscle in resistance vessels. The study concludes that hypercholesterolemia impairs vascular function in the absence of atherosclerosis, potentially contributing to atherosclerosis development. The impaired vasodilation may result from endothelial dysfunction, smooth muscle abnormalities, or structural changes in the vessels. The study highlights the importance of vascular function in hypercholesterolemia and suggests that early treatment may prevent atherosclerosis by preserving vascular function.