Majithiya Jayesh B, Paramar Arvind N, Balaraman R
Pharmacy Department, Faculty of Technology and Engineering, M. S. University of Baroda, Kalabhavan, Baroda-390001, Gujarat, India.
Cardiovasc Res. 2005 Apr 1;66(1):150-61. doi: 10.1016/j.cardiores.2004.12.025.
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.
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.
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.
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.
研究吡格列酮（一种过氧化物酶体增殖物激活受体γ激动剂）治疗对链脲佐菌素（STZ）诱导的糖尿病大鼠血压、内皮功能和氧化应激的影响。
将Sprague-Dawley大鼠随机分为对照组（n = 32）和STZ糖尿病组（n = 32）。大鼠进一步随机接受吡格列酮（10 mg/kg）或安慰剂治疗4周，并执行以下方案。测量血压、血糖水平和体重。分离胸主动脉，记录去甲肾上腺素（PE）在有或无Nω-硝基-L-精氨酸甲酯（L-NAME）存在时的剂量反应曲线。记录乙酰胆碱（Ach）在有或无吲哚美辛、L-NAME和亚甲蓝存在时的剂量反应曲线。进行与张力相关的基础一氧化氮释放实验。评估肝脏、肾脏和主动脉中的脂质过氧化、超氧化物歧化酶、过氧化氢酶和还原型谷胱甘肽。还测量主动脉亚硝酸盐水平。此外，在非糖尿病和STZ糖尿病大鼠的主动脉环中测量了吡格列酮（0.1 μM - 10 mM）存在时PE和Ach的体外作用。在L-NAME存在的情况下，记录吡格列酮诱导的PE收缩环（内皮完整和去内皮）以及KCl收缩环中的舒张情况。
吡格列酮治疗可降低STZ糖尿病大鼠的血压，而对其血糖水平和体重无显著影响。吡格列酮治疗可使STZ糖尿病大鼠中增强的PE诱导收缩和受损的Ach诱导舒张恢复正常。在吡格列酮治疗的STZ糖尿病大鼠中，L-NAME的存在而非吲哚美辛可阻断Ach诱导的舒张。吡格列酮治疗的STZ糖尿病大鼠基础一氧化氮释放显著更高。STZ糖尿病大鼠的氧化应激显著更高，吡格列酮治疗可显著降低氧化应激。吡格列酮治疗可显著降低STZ糖尿病大鼠的高主动脉亚硝酸盐水平。较高浓度（>10 μM）而非较低浓度的吡格列酮存在时，可显著改变PE或Ach的剂量反应曲线。较低浓度而非较高浓度的吡格列酮舒张作用可被去除内皮或L-NAME的存在所阻断。
吡格列酮给药可降低氧化应激，防止一氧化氮分解并增加一氧化氮水平，从而恢复STZ糖尿病大鼠主动脉的内皮功能。因此，从本研究可以得出结论，在STZ糖尿病大鼠中给予吡格列酮可降低血压、预防氧化应激并恢复内皮功能。
