Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation

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 esogenously 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 mu mol, and from 350+/-35 to 3,850+/-371 mu mol (P < 0.001) vs. saline for both low-and high-dose groups, respectively, Mch-induced vasodilation relative to baseline was reduced by similar to 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 mu mol (P < 0.01); Mch-induced vasodilation was reduced by similar to 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 mu mol, 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.