Rosiglitazone prevents free fatty acid-induced vascular endothelial dysfunction.
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.
Mittermayer
Friedrich
F
Department of Clinical Pharmacology, Medical University Vienna, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Schaller
Georg
G
Pleiner
Johannes
J
Krzyzanowska
Katarzyna
K
Kapiotis
Stylianos
S
Roden
Michael
M
Wolzt
Michael
M
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
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