Relationship between protective effects of rosiglitazone on endothelium and endogenous nitric oxide synthase inhibitor in streptozotocin-induced diabetic rats and cultured endothelial cells.
BACKGROUND
Previous investigations have indicated that the level of asymmetric dimethylarginine (ADMA) is increased in diabetic patients and animals, and rosiglitazone has a protective effect on the endothelium. In the present study, we tested the relationship between protective effects of rosiglitazone and ADMA in streptozotocin (STZ)-induced diabetic rats and cultured endothelial cells.


METHODS
Blood samples were collected from carotid artery. Vasodilator responses to acetylcholine (ACh) in the isolated aortic rings were measured, and serum concentrations of glucose, lipid, nitrite/nitrate, ADMA and tumour necrosis factor-alpha (TNF-alpha) were determined. Cultured endothelial cells were treated with ADMA, and the concentrations of intercellular adhesion molecule (ICAM-1), TNF-alpha, and the activity of nuclear factor-kappaB (NF-kappaB) were determined.


RESULTS
Vasodilator responses to ACh were decreased markedly and the serum concentrations of TNF-alpha, nitrite/nitrate and ADMA were increased significantly in diabetic rats. Rosiglitazone (3, 10 or 30 mg/kg) produced a significant reduction of the inhibition of vasodilator responses to ACh, but had no effect on the serum concentrations of glucose, lipid, nitrite/nitrate and ADMA in diabetic rats. ADMA (30 microM) significantly increased the activity of NF-kappaB and elevated the levels of ICAM-1 and TNF-alpha, and pre-treatment with rosiglitazone (10 or 30 microM) markedly inhibited the increased activity of NF-kappaB and reduced the elevated levels of TNF-alpha and ICAM-1 induced by ADMA in cultured endothelial cells.


CONCLUSIONS
Rosiglitazone improves endothelial function in diabetic rats, which is related to the reduction of the inflammatory response induced by ADMA.
Wang
Shan
S
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
Jiang
Jun-Lin
JL
Hu
Chang-Ping
CP
Zhang
Xiao-Jie
XJ
Yang
Dong-Liang
DL
Li
Yuan-Jian
YJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004730:Endothelium, Vascular / Q000201:enzymology*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
D007004:Hypoglycemic Agents; D009566:Nitrates; D009573:Nitrites; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C487735:dimethylarginine; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D001120:Arginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine