Pioglitazone, a PPARgamma agonist, restores endothelial function in aorta of streptozotocin-induced diabetic rats.
OBJECTIVE
To study the effect of pioglitazone (a PPAR gamma agonist) treatment on blood pressure, endothelial function, and oxidative stress in streptozotocin (STZ)-induced diabetic rats.


METHODS
Sprague-Dawley rats were randomized into control (n=32) and STZ-diabetic (n=32) groups. Rats were further randomized to receive pioglitazone (10 mg/kg) or placebo for 4 weeks, and the following protocols were carried out. Blood pressure, blood glucose level, and body weight were measured. Thoracic aorta was isolated and the dose-response curve of phenylephrine (PE) in the presence or absence of Nomega-nitro-L-arginine-methyl ester (L-NAME) was recorded. The dose-response curve of acetylcholine (Ach) in the presence or absence of indomethacin, L-NAME, and methylene blue was recorded. Tone-related basal nitric oxide release experiments were carried out. Lipid peroxidation, superoxide dismutase, catalase, and reduced glutathione were estimated in liver, kidney, and aorta. Aortic nitrite levels were also measured. Further, in vitro effects of PE and Ach in the presence of pioglitazone (0.1 M-10 mM) were measured in aortic rings of nondiabetic and STZ-diabetic rats. Pioglitazone-induced relaxations were recorded in PE-contracted rings (with intact and denuded endothelium) in the presence of L-NAME and in KCl-contracted rings.


RESULTS
Pioglitazone treatment reduced blood pressure without having any significant effect on blood glucose level and body weight of STZ-diabetic rats. Enhanced PE-induced contraction and impaired Ach-induced relaxations in STZ-diabetic rats were restored to normal by pioglitazone treatment. The presence of L-NAME but not indomethacin blocked Ach-induced relaxation in pioglitazone-treated STZ-diabetic rats. Basal nitric oxide release was significantly higher in pioglitazone-treated STZ-diabetic rats. Oxidative stress was significantly higher in STZ-diabetic rats and pioglitazone treatment significantly reduced it. High aortic nitrite levels of STZ-diabetic rats were significantly reduced by pioglitazone treatment. The presence of pioglitazone at higher concentrations (>10 muM), but not at lower concentrations, significantly changed the dose-response curve of PE or Ach. Pioglitazone relaxations at lower concentrations but not at higher concentrations were blocked by endothelium removal or by the presence of L-NAME.


CONCLUSIONS
Pioglitazone administration reduced oxidative stress, which prevented the breakdown of nitric oxide and increased nitric oxide levels, thereby restoring the endothelial function in aorta of STZ-diabetic rat. Hence, from the present study it can be concluded that pioglitazone administration in STZ-diabetic rats lowers blood pressure, protects against oxidative stress, and restores endothelial function.
Majithiya
Jayesh B
JB
Pharmacy Department, Faculty of Technology and Engineering, M. S. University of Baroda, Kalabhavan, Baroda-390001, Gujarat, India. jayeshbm@yahoo.com
Paramar
Arvind N
AN
Balaraman
R
R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists*; D010656:Phenylephrine / Q000494:pharmacology; D000077205:Pioglitazone; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D047495:PPAR gamma; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D000077205:Pioglitazone; D007213:Indomethacin