title: Elevated non-esterified fatty acids impair nitric oxide independent vasodilation, in humans: evidence for a role of inwardly rectifying potassium channels.
abstract: 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 BaCl(2), rectifying potassium channel (K(IR)) 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 microg 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 BaCl(2)-mediated FBF inhibition was lower (P<0.01) at high-NEFA. During ouabain alone FBF decreased slightly.
  
  
  CONCLUSIONS
  High-NEFA exerts a negative role on both NO-dependent and independent vasodilations. The decrease in FBF, mediated by K(IR) inhibition, is blunted by high-NEFA: these substrates interfere with hemodynamic/metabolism coupling, possibly through the inhibition of these channels.
authors.affiliation: Department of Clinical and Experimental Medicine, Cattedra di Malattie del Metabolismo, University of Padova, Via Giustiniani 2, 35128 Padua, Italy.
authors.forename: Saula Vigili
authors.initials: SV
authors.lastname: de Kreutzenberg
authors.forename: Massimo
authors.initials: M
authors.lastname: Puato
authors.forename: Edward
authors.initials: E
authors.lastname: Kiwanuka
authors.forename: Stefano
authors.initials: S
authors.lastname: Del Prato
authors.forename: Paolo
authors.initials: P
authors.lastname: Pauletto
authors.forename: Leone
authors.initials: L
authors.lastname: Pasini
authors.forename: Antonio
authors.initials: A
authors.lastname: Tiengo
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001783:Blood Flow Velocity; D001920:Bradykinin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D024661:Potassium Channels, Inwardly Rectifying; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D010042:Ouabain; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine; D001920:Bradykinin