Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans.
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.


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 NG-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.
Watanabe
Saiko
S
Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan.
Tagawa
Tatsuya
T
Yamakawa
Ken
K
Shimabukuro
Michio
M
Ueda
Shinichiro
S
D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage; D000959:Antihypertensive Agents / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D008055:Lipids / Q000008:administration & dosage; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D020913:Perindopril / Q000008:administration & dosage; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D000925:Anticoagulants; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D006493:Heparin; D019808:Losartan; D000109:Acetylcholine; D020913:Perindopril