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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2376.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid–Induced Acute Endothelial Dysfunction in Humans

Saiko Watanabe; Tatsuya Tagawa; Ken Yamakawa; Michio Shimabukuro; Shinichiro Ueda

From the Department of Clinical Pharmacology and Therapeutics (S.W., T.T., K.Y., S.U.) and the Second Department of Internal Medicine (M.S.), University of the Ryukyus School of Medicine, Okinawa, Japan.

Correspondence to Dr Shinichiro Ueda, Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara, Okinawa, 903-0215 Japan. E-mail suedano9{at}dream.com

Objective— An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction.

Methods and Results— Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the coinfusion of vitamin C or N^G-monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (P=0.0096) without L-NMMA, but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction.

Conclusions— Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels.

We investigated the involvement of the RAS on FFA-induced endothelial dysfunction. An ACE inhibitor or an ARB prevented FFA-induced endothelial dysfunction. Our results suggest that elevated FFAs, which are frequently seen in patients with insulin resistance, cause endothelial dysfunction via RAS activation and presumably the resultant oxidative stress in humans.

Key Words: fatty acids • endothelium • angiotensin II • insulin resistance • nitric oxide

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