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Simvastatin, capillary permeability, and acetylcholine‐mediated vasomotion in atherosclerotic, hypercholesterolemic men
Author(s) -
Dell'Omo Giulia,
Bandinelli Simona,
Penno Giuseppe,
Pedrinelli Roberto,
Mariani Mario
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.109787
Subject(s) - simvastatin , medicine , sodium nitroprusside , endocrinology , vascular permeability , acetylcholine , vasomotion , vasodilation , endothelium , lipoprotein , cholesterol , nitric oxide
Objectives The aim of this study was to test the effect of high‐dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial‐mediated vasodilator responses in patients with hypercholesterolemic atherosclerosis. Methods The transcapillary albumin escape rate (TERalb, the 1‐hour decline rate of intravenous 125 I‐albumin, a measure of macromolecular permeability of capillary endothelium) and forearm vasodilatation (venous plethysmography) to intraarterial acetylcholine and sodium nitroprusside (7.5, 15, 30 μg/min and 0.8, 1.6, and 3.2 μg/min respectively, 5 minutes at each rate) to account for endothelium‐dependent and independent mechanisms, were measured at baseline and after 1‐month simvastatin (40 mg once daily) in 16 hypercholesterolemic (low‐density lipoprotein cholesterol >130 mg/dL), atherosclerotic men. Thirteen healthy, untreated subjects were the controls. Results Baseline TERalb was higher and responsiveness to both acetylcholine and sodium nitroprusside was depressed in patients compared with controls. One‐month high‐dose simvastatin reduced low‐density lipoprotein cholesterol by 39%, normalized TERalb, and improved local vasomotor responses to acetylcholine, without modifying those to sodium nitroprusside. Changes in TERalb and acetylcholine‐mediated vasodilatation were dissociated and unrelated to lipid modifications. Conclusions Low‐density lipoprotein cholesterol reduction through 1 month of high‐dose simvastatin normalized the exaggerated transvascular albumin leakage of patients with hypercholesterolemic atherosclerosis, perhaps by restoring an exaggerated endothelial permeability, apparently through mechanisms independent of circulating lipids. Improvements in acetylcholine‐mediated vasomotion were also evident, but were dissociated from TERalb, demonstrating a heterogeneous behavior of the 2 indices of endothelial function in response to high‐dose statin treatment. (Clin Pharmacol Ther 2000;68:427‐34.) Clinical Pharmacology & Therapeutics (2000) 68 , 427–434; doi: 10.1067/mcp.2000.109787