title: Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.
abstract: We have recently shown that insulin-resistant obese subjects exhibit impaired endothelial function. Here, we test the hypothesis that elevation of circulating FFA to levels seen in insulin-resistant subjects can impair endothelial function. We studied leg blood flow responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) or the endothelium-independent vasodilator sodium nitroprusside during the infusion of saline and after raising systemic circulating FFA levels exogenously via a low- or high-dose infusion of Intralipid plus heparin or endogenously by an infusion of somatostatin (SRIF) to produce insulinopenia in groups of lean healthy humans. After 2 h of infusion of Intralipid plus heparin, FFA levels increased from 562+/-95 to 1,303+/-188 micromol, and from 350+/-35 to 3,850+/-371 micromol (P < 0.001) vs. saline for both low- and high-dose groups, respectively. Mch-induced vasodilation relative to baseline was reduced by approximately 20% in response to the raised FFA levels in both groups (P < 0.05, saline vs. FFA, ANOVA). In contrast, similar FFA elevation did not change leg blood flow responses to sodium nitroprusside. During the 2-h SRIF infusion, insulin levels fell, and FFA levels rose from 474+/-22 to 1,042+/-116 micromol (P < 0.01); Mch-induced vasodilation was reduced by approximately 20% (P < 0.02, saline vs. SRIF, ANOVA). Replacement of basal insulin levels during SRIF resulted in a fall of FFA levels from 545+/-47 to 228+/-61 micromol, and prevented the impairment of Mch-induced vasodilation seen with SRIF alone. In conclusion, (a) elevated circulating FFA levels cause endothelial dysfunction, and (b) impaired endothelial function in insulin-resistant humans may be secondary to the elevated FFA concentrations observed in these patients.
authors.affiliation: Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202, USA.
authors.forename: H O
authors.initials: HO
authors.lastname: Steinberg
authors.forename: M
authors.initials: M
authors.lastname: Tarshoby
authors.forename: R
authors.initials: R
authors.lastname: Monestel
authors.forename: G
authors.initials: G
authors.lastname: Hook
authors.forename: J
authors.initials: J
authors.lastname: Cronin
authors.forename: A
authors.initials: A
authors.lastname: Johnson
authors.forename: B
authors.initials: B
authors.lastname: Bayazeed
authors.forename: A D
authors.initials: AD
authors.lastname: Baron
mesh_terms: D000328:Adult; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000502:physiology*; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007866:Leg / Q000098:blood supply; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology; D014664:Vasodilation
chemical_list: D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D016210:Methacholine Chloride; D009599:Nitroprusside; D013004:Somatostatin