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 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 micrograms/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 micrograms/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 micrograms/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).(ABSTRACT TRUNCATED AT 250 WORDS)
Casino
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PR
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Kilcoyne
C M
CM
Cannon
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Quyyumi
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Panza
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JA
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D000368:Aged; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D011976:Receptors, Muscarinic; D009599:Nitroprusside; D013373:Substance P; D002784:Cholesterol; D000109:Acetylcholine