Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects

Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter. Insulin concentrations fell significantly at week 1 and remained low at weeks 2 and 4 (P<0.001). ROS generation by PMNLs fell to 77.6+/-25.1% of the basal at week 1 and 47.9+/-41.1% at week 4 (P<0.001). ROS generation by MNCs fell to 59.8+/-15.7% of the basal at week 1 and 35.1+/-17.6% at week 4 (P<0.001). 9-HODE and 13-HODE concentrations fell significantly from 787.4+/-52.4 and 713.1+/-44.7 pg/mL to 720.4+/-66.7 (P<0.004) and 675.2+/-65.0 pg/mL (P<0.01) after 4 weeks, respectively. Postischemic dilatation of the brachial artery was measured by ultrasonography. The mean percent dilatation after forearm ischemia before and after troglitazone was 5.5+/-3.01% and 8.75+/-3.37% (P<0.02), respectively. The percent increase in diameter after nitroglycerin was 17.08+/-1.18% before troglitazone, whereas it was 18.9+/-1.91% (P<0.02) after troglitazone. We conclude that troglitazone has a potent and rapid biological inhibitory effect on ROS generation by PMNLs and MNCs and that it inhibits lipid peroxidation significantly. These changes are associated with a significant improvement in postischemic flow-mediated vasodilation in the brachial artery over a relatively short period of 4 weeks.