Diep Quy N, El Mabrouk Mohammed, Cohn Jeffrey S, Endemann Dierk, Amiri Farhad, Virdis Agostino, Neves Mario Fritsch, Schiffrin Ernesto L
Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Montreal, Quebec, Canada.
Circulation. 2002 May 14;105(19):2296-302. doi: 10.1161/01.cir.0000016049.86468.23.
Pioglitazone and rosiglitazone, thiazolidinedione peroxisome proliferator-activated receptor-gamma (PPARgamma) activators, reduce blood pressure (BP) in some hypertensive models by unclear mechanisms. We tested the hypothesis that pioglitazone or rosiglitazone would prevent BP elevation and vascular dysfunction in angiotensin (Ang) II-infused rats by direct vascular effects.
Sprague-Dawley rats received Ang II (120 ng x kg(-1) x min(-1) SC) with or without pioglitazone (10 mg x kg(-1) x d(-1)) or rosiglitazone (5 mg x kg(-1) x d(-1)) for 7 days. Systolic BP, elevated in Ang II-infused rats (176+/-5 mm Hg) versus controls (109+/-2 mm Hg, P<0.01), was reduced by pioglitazone (134+/-2 mm Hg) or rosiglitazone (123+/-2 mm Hg). In mesenteric small arteries studied in a pressurized myograph, media/lumen ratio was increased (P<0.05) and acetylcholine-induced relaxation impaired in Ang II-infused rats (P<0.05); both were normalized by the thiazolidinediones. In Ang II-infused rats, vascular DNA synthesis (by 3H-thymidine incorporation); expression of cell cycle proteins cyclin D1 and cdk4, angiotensin II type 1 receptors, vascular cell adhesion molecule-1, and platelet and endothelial cell adhesion molecule; and nuclear factor-kappaB activity were increased. These changes were abrogated by pioglitazone or rosiglitazone.
Thiazolidinedione PPAR-gamma activators attenuated the development of hypertension, corrected structural abnormalities, normalized cell growth, and improved endothelial dysfunction induced by Ang II and prevented upregulation of angiotensin II type 1 receptors, cell cycle proteins, and proinflammatory mediators. Thiazolidinediones may be useful in the prevention and/or treatment of hypertension, particularly when it is associated with insulin resistance or diabetes mellitus.
吡格列酮和罗格列酮作为噻唑烷二酮类过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，可通过不明机制降低某些高血压模型中的血压（BP）。我们检验了这样一个假设，即吡格列酮或罗格列酮可通过直接的血管效应预防血管紧张素（Ang）II灌注大鼠的血压升高和血管功能障碍。
将Sprague-Dawley大鼠分为两组，一组接受Ang II（120 ng·kg⁻¹·min⁻¹皮下注射），另一组在接受Ang II的基础上分别给予吡格列酮（10 mg·kg⁻¹·d⁻¹）或罗格列酮（5 mg·kg⁻¹·d⁻¹），持续7天。与对照组（109±2 mmHg，P<0.01）相比，Ang II灌注大鼠的收缩压升高（176±5 mmHg），而吡格列酮（134±2 mmHg）或罗格列酮（123±2 mmHg）可使其降低。在压力肌动描记仪上研究的肠系膜小动脉中，Ang II灌注大鼠的中膜/管腔比值增加（P<0.05），乙酰胆碱诱导的舒张功能受损（P<0.05）；而噻唑烷二酮类药物可使其恢复正常。在Ang II灌注大鼠中，血管DNA合成（通过³H-胸腺嘧啶掺入法检测）、细胞周期蛋白cyclin D1和cdk4、血管紧张素II 1型受体、血管细胞黏附分子-1以及血小板和内皮细胞黏附分子的表达以及核因子κB活性均增加。这些变化被吡格列酮或罗格列酮消除。
噻唑烷二酮类PPARγ激动剂可减轻高血压的发展，纠正结构异常，使细胞生长正常化，改善Ang II诱导的内皮功能障碍，并防止血管紧张素II 1型受体、细胞周期蛋白和促炎介质的上调。噻唑烷二酮类药物可能对高血压的预防和/或治疗有用，尤其是在与胰岛素抵抗或糖尿病相关的情况下。
