Impaired endothelium-dependent vascular relaxation in patents with hypercholesterolemia extends beyond the muscarinic receptor

Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation. However, previous human studies have invariably used muscarinic agents to assess endothelial function. The purpose of this investigation was to determine whether impaired endothelium-dependent vasodilation of hypercholesterolemic patients is related to a specific and isolated defect of the muscarinic receptor, or to a broader abnormality of the endothelial cells. The forearm vascular responses to the endothelium-dependent agents acetylcholine (7.5, 15, and 30 μg/min) and substance P (1, 2, and 4 pmol/min), and to the direct smooth muscle dilator sodium nitroprusside (0.8, 1.6, and 3.2 μg/min) were studied in 16 hypercholesterolemic patients (8 men and 8 women; age [mean ± SD] 50 ± 7 years; serum cholesterol >250 mg/dl) and 16 normal volunteers (8 men and 8 women; age 47 ± 8 years; serum cholesterol <200 mg/dl). Drugs were infused into the brachial artery and the response of the forearm vasculature was measured by strain-gauge plethysmography. The vasodilator response to acetylcholine was reduced in hypercholesterolemic patients compared with normal controls; at the highest dose (30 μg/min) the increase in forearm blood flow was 13.5 ± 7 ml/min/100 ml in controls and 7.54 ± 6 in patients (p <0.05). The response to substance P was also blunted in hypercholesterolemic patients; at the highest dose (4 pmol/min), the increase in forearm blood flow was 12.1 ± 5 ml/ min/100 ml in controls and 7.6 ± 4 in patients (p <0.03). A significant correlation was found between the highest blood flow responses with acetylcholine and with substance P (r = 0.58; p <0.001). No difference was found between the 2 groups in their response to sodium nitroprusside. These findings indicate that impaired endothelium-dependent vasodilation in hypercholesterolemia is not due to an isolated defect of the muscarinic receptor, and suggest either a more generalized endothelial abnormality or a defect in the final common pathway that regulates the endothelial modulation of vascular tone.