Endothelial dysfunction is increasingly recognized as an early and important feature of vascular disease. Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia, although it is unknown whether this defect is selective for some pathways of nitric oxide production or indicates a more generalized abnormality of endothelial function. The aim of this study was to further elucidate the nature of endothelial dysfunction in human hypercholesterolemia by comparing vascular responses of agonists that use different signal transduction pathways to activate production of nitric oxide.Methods and ResultsForearm flow was measured in 12 hypercholesterolemic patients (total cholesterol, 286±35 mg/dL [mean±SD]) aged 50±11 years and in 12 healthy subjects (total cholesterol, 173±27 mg/dL) aged 48±7 years using strain-gauge plethysmography and brachial artery drug infusions. The endothelium-dependent vasodilators used were acetylcholine (7.5, 15, and 30 μg/min), which uses a pertussis toxin-sensitive signal transduction pathway, and bradykinin (100, 200, and 400 ng/min), which uses a pertussis toxininsensitive signal transduction pathway to activate nitric oxide production. Sodium nitroprusside (0.8, 1.6, and 3.2 μg/min) was used to test endothelium-independent vasodilation. The maximum flow in response to acetylcholine was markedly impaired in patients compared with healthy subjects (8.0±5.1 versus 17.5±7.7 mL · min−1· 100 mL−1,P= .002). However, the maximum forearm flow in response to bradykinin was similar in the two groups (13.0±4.5 versus 16.2±5.5 mL · min−1100 mL−1,P= .14), as was the maximum flow in response to sodium nitroprusside (7.0±2.8 versus 8.4±2.2 mL · min−1· 100 mL−1,P= .13).NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, reduced the maximum forearm vasodilation induced by bradykinin to the same extent in patients and in healthy subjects (-29±8% versus −32±6% reduction in peak flow,P= .80), with similar maximum flows in response to bradykinin (9.2±4.0 versus 10.4±2.6 mL · min−1· 100 mL−1,P= .35).ConclusionsHypercholesterolemic patients are capable of normal nitric oxide bioavailability in response to bradykinin. Impairment of microvascular endothelial vasodilator function in human hypercholesterolemia is selective, and the defect occurs at the level of the acetylcholine receptor or its signal transduction pathway.