IMPAIRED ENDOTHELIUM-DEPENDENT VASCULAR RELAXATION IN PATIENTS WITH HYPERCHOLESTEROLEMIA EXTENDS BEYOND THE MUSCARINIC RECEPTOR

Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation. However, previous human studies have invariably used mu scarinic agents to assess endothelial function. The purpose of this in vestigation was to determine whether impaired endothelium-dependent va sodilation of hypercholesterolemic patients is related to a specific a nd isolated defect of the muscarinic receptor, or to a broader abnorma lity of the endothelial cells. The forearm vascular responses to the e ndothelium-dependent agents acetylch;oline (7.5, 15, and 30 mu g/min) and substance P (1, 2, and 4 pmol/min), and to the direct smooth muscl e dilator sodium nitroprusside (0.8, 1.6, and 3.2 mu g/min) were studi ed in 16 hypercholesterolemic patients (8 men and 8 women; age [mean /- SD] 50 +/- 7 years; serum cholesterol >250 mg/dl) and 16 normal vol unteers (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 plethysmograph y. The vasodilator response to acetylcholine was reduced in hyperchole sterolemic patients compared with normal controls; at the highest dose (30 mu g/min) tile increase in forearm blood flow was 13.5 +/- 7 ml/m in/100 mt in controls and 7.54 +/- 6 in patients (p <0.05). The respon se to substance P was also blunted in hypercholesterolemic patients; a t the highest dose (4 pmol/min), the increase in forearm blood flow wa s 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 flo w responses with acetylcholine and with substance P (r = 0.58; p <0.00 1). No difference was found between the 2 groups in their response to sodium nitroprusside. These findings indicate that impaired endotheliu m-dependent vasodilation in hypercholesterolemia is not due to an isol ated defect of the muscarinic receptor, and suggest either a more gene ralized endothelial abnormality or a defect in the final common pathwa y that regulates the endothelial modulation of vascular tone.