Relation of improvement in endothelium-dependent flow-mediated vasodilation after rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome.
The mechanisms by which thiazolidinediones exert beneficial effects on the endothelium are still not clear. We examined the effects of rosiglitazone on the plasma markers of metabolic control (glucose, insulin, adiponectin, resistin, and lipid profiles), markers of inflammation (high-sensitivity C-reactive protein [CRP], interleukin-6, soluble CD40 ligand, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1), and markers of vasoreactivity (asymmetric dimethylarginine [ADMA] and endothelin-1) and analyzed the relations between changes in endothelium-dependent flow-mediated dilation of the brachial artery and changes in these markers to elucidate their roles in mediating the vascular protective effects of rosiglitazone. Of 70 nondiabetic patients who met a modified National Cholesterol Education Program definition of the metabolic syndrome, 35 were randomized to receive rosiglitazone (4 mg/day) and 35 to receive placebo for 8 weeks. At study end, treatment with rosiglitazone had significantly reduced plasma insulin (-25%, p = 0.004) and resistin (-16%, p <0.001), increased adiponectin (164%, p <0.001), low-density lipoprotein cholesterol (16%, p = 0.005), and apolipoprotein-B (14%, p = 0.003), and decreased CRP (-30%, p = 0.005), soluble CD40 ligand (-20%, p = 0.014), ADMA (-16%, p <0.001), and endothelin-1 (-11%, p <0.001) concentrations and systolic and diastolic blood pressures. Rosiglitazone treatment significantly improved flow-mediated dilation (p <0.001) and nitroglycerin-induced vasodilation (p = 0.001) of the right brachial artery. On multivariate analysis, changes in ADMA, endothelin-1, and CRP were independent predictors of improved endothelial reactivity with rosiglitazone. In conclusion, we have, for the first time, demonstrated the independent associations between the improvement in flow-mediated dilation and reductions in ADMA, endothelin-1, and CRP after 8 weeks of treatment with rosiglitazone in nondiabetic patients with the metabolic syndrome. These findings suggest that decreases in ADMA, endothelin-1, and CRP may serve as possible mechanisms for the improvement in endothelial function conferred by rosiglitazone treatment.
Wang
Tzung-Dau
TD
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. tdwang@ha.mc.ntu.edu.tw
Chen
Wen-Jone
WJ
Cheng
Wern-Cherng
WC
Lin
Jong-Wei
JW
Chen
Ming-Fong
MF
Lee
Yuan-Teh
YT
D001120:Arginine / Q000031:analogs & derivatives* / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000187:drug effects*; D016022:Case-Control Studies; D008076:Cholesterol, HDL; D019332:Endothelin-1 / Q000187:drug effects*; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005947:Glucose; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D012044:Regression Analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D008076:Cholesterol, HDL; D019332:Endothelin-1; D045462:Endothelium-Dependent Relaxing Factors; D007328:Insulin; D045162:Thiazolidinediones; D014665:Vasodilator Agents; C487735:dimethylarginine; D000077154:Rosiglitazone; D002097:C-Reactive Protein; D001120:Arginine; D005947:Glucose