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Rosiglitazone Prevents Free Fatty Acid-Induced Vascular Endothelial Dysfunction

Department of Clinical Pharmacology (F.M., G.S., J.P., M.W.), and Clinical Institute for Medical and Chemical Laboratory Diagnostics (S.K.), Medical University Vienna, A-1090 Vienna, Austria; Department of Internal Medicine I (K.K.), Rudolfstiftung Hospital, A-1030 Vienna, Austria; and 1st Medical Department (M.R.), Hanusch Hospital, A-1140 Vienna, Austria

Address all correspondence and requests for reprints to: Michael Wolzt, Medical University Vienna, Department of Clinical Pharmacology, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.wolzt{at}meduniwien.ac.at.

Context: Free fatty acids (FFAs) cause insulin resistance and vascular endothelial dysfunction. The peroxisome proliferator-activated receptor 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.

Design and Setting: We conducted a double-blind, randomized, placebo-controlled parallel-group study at a university hospital.

Patients and Interventions: 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.

Main Outcome Measures: 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.