Elevated non-esterified fatty acids impair nitric oxide independent vasodilation, in humans: evidence for a role of inwardly rectifying potassium channels

To evaluate the role of elevation of non-esterified fatty acids on forearm nitric oxide (NO) dependent and independent relaxation, four studies were performed in the forearms of 14 normals: (1) endothelium-dependent and -independent vasodilations were assessed during acetylcholine (Ach) and sodium nitroprusside (SNP) infusions; (2) flow-mediated vasodilation (FMD) was assessed; (3) bradykinin (BK) was infused during NO and prostaglandin inhibition (NO clamp); (4) blood flow (FBF) was measured during Ouabain, a Na+/K+ ATPase, and BaCl2, rectifying potassium channel (KIR) blockers, respectively. All studies were performed before and after 120 min. Intralipid+heparin (high-NEFA) infusion. Ach-mediated FBF increase was lower at high-NEFA (332±34 vs. 436±44% at 45 μg l forearm−1 min−1; % of ratio infused: control arm P<0.05), while SNP response was similar. FMD did not differ before and during high-NEFA, which induced a blunted response of FBF during BK with or without NO clamp. Ouabain and BaCl2-mediated FBF inhibition was lower (P<0.01) at high-NEFA. During ouabain alone FBF decreased slightly. In conclusion: High-NEFA exerts a negative role on both NO-dependent and independent vasodilations. The decrease in FBF, mediated by KIR inhibition, is blunted by high-NEFA: these substrates interfere with hemodynamic/metabolism coupling, possibly through the inhibition of these channels.