title: Rosiglitazone prevents free fatty acid-induced vascular endothelial dysfunction.
abstract: BACKGROUND
  Free fatty acids (FFAs) cause insulin resistance and vascular endothelial dysfunction. The peroxisome proliferator-activated receptor gamma agonist rosiglitazone acts as insulin sensitizer and could exert vasoprotective properties by preservation of endothelium-dependent vasodilation.
  
  
  OBJECTIVE
  We tested the effect of rosiglitazone on FFA-induced endothelial dysfunction of the forearm resistance vessels, insulin sensitivity, asymmetric dimethylarginine (ADMA), and high-sensitivity C-reactive protein concentrations in humans.
  
  
  METHODS
  We conducted a double-blind, randomized, placebo-controlled parallel-group study at a university hospital.
  
  
  METHODS
  Rosiglitazone 8 mg daily or placebo was administered to 16 healthy male subjects for 21 d. On the last day, triglycerides and heparin were infused iv to increase FFA plasma concentrations.
  
  
  METHODS
  Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroglycerine were assessed using strain-gauge plethysmography at baseline, and on d 21 before and after 5 h of triglyceride/heparin infusion.
  
  
  RESULTS
  Forearm blood flow reactivity was not affected by rosiglitazone or placebo. Infusion of triglyceride/heparin substantially increased FFA concentrations (P < 0.001) and reduced endothelium-dependent vasodilation by 38 +/- 17% (P = 0.024). In the face of lower FFA elevation (P = 0.047 vs. controls), endothelium-dependent vasodilation was preserved in subjects receiving rosiglitazone (P = 0.016 vs. placebo). Endothelium-independent vasodilation and C-reactive protein were unchanged, whereas insulin sensitivity and plasma ADMA similarly decreased in both study groups after FFA elevation (both P < 0.05 vs. baseline).
  
  
  CONCLUSIONS
  Rosiglitazone mitigates the increase in FFA after infusion of triglyceride/heparin and prevents FFA-induced endothelial dysfunction. These effects are independent and possibly occur before any changes in insulin sensitivity and ADMA plasma concentrations in healthy subjects.
authors.affiliation: Department of Clinical Pharmacology, Medical University Vienna, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Mittermayer
authors.forename: Georg
authors.initials: G
authors.lastname: Schaller
authors.forename: Johannes
authors.initials: J
authors.lastname: Pleiner
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Krzyzanowska
authors.forename: Stylianos
authors.initials: S
authors.lastname: Kapiotis
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage; D001120:Arginine / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000097:blood*; D005542:Forearm / Q000098:blood supply; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007333:Insulin Resistance; D008297:Male; D008745:Methylation; D005996:Nitroglycerin / Q000008:administration & dosage; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014657:Vasculitis / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D000925:Anticoagulants; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D006493:Heparin; D002097:C-Reactive Protein; D001120:Arginine; D005996:Nitroglycerin; D000109:Acetylcholine