Xiang Lusha, Dearman Jennifer, Abram Sean R, Carter Cory, Hester Robert L
Dept. of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MI 39216-4505, USA.
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1658-66. doi: 10.1152/ajpheart.01206.2007. Epub 2008 Feb 22.
Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)-mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS are responsible for the increased TP-mediated vasoconstriction in OZRs, resulting in impaired functional vasodilation. Eleven-week-old male lean Zucker rats (LZRs) and OZRs were fed normal rat chow or chow containing rosiglitazone (5 mg.kg(-1).day(-1)) for 2 wk. In another set of experiment, LZRs and OZRs were treated with 2 mM tempol (drinking water) for 7-10 days. After the treatments, spinotrapezius muscles were prepared, and arcade arteriolar diameters were measured following muscle stimulation and arachidonic acid (AA) application (10 muM) in the absence and presence of the TP antagonist SQ-29548 (1 muM). OZRs exhibited higher insulin, glucose, triglyceride, and superoxide levels and increased NADPH oxidase activity compared with LZRs. Functional and AA-induced vasodilations were impaired in OZRs. Rosiglitazone treatment improved insulin, glucose, triglyceride, and superoxide levels as well as NADHP oxidase activity in OZRs. Both rosiglitazone and tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 treatment improved vasodilatory responses in nontreated OZRs with no effect in LZRs or treated OZRs. These results suggest that insulin resistance and the resultant increased ROS impair functional dilation in OZRs by increasing TP-mediated vasoconstriction.
患有代谢综合征的个体表现出胰岛素抵抗以及对运动的功能性血管舒张反应减弱。我们已经表明，肥胖 Zucker 大鼠（OZR）的功能性血管舒张受损与血栓素受体（TP）介导的血管收缩增强有关。我们推测，胰岛素抵抗、高血糖/高血脂以及由此产生的活性氧（ROS）是导致 OZR 中 TP 介导的血管收缩增加的原因，从而导致功能性血管舒张受损。11 周龄的雄性瘦 Zucker 大鼠（LZR）和 OZR 分别喂食普通大鼠饲料或含罗格列酮（5 mg·kg⁻¹·d⁻¹）的饲料，持续 2 周。在另一组实验中，LZR 和 OZR 用 2 mM Tempol（饮用水）处理 7 - 10 天。处理后，制备斜方肌，在不存在和存在 TP 拮抗剂 SQ - 29548（1 μM）的情况下，在肌肉刺激和应用花生四烯酸（AA，10 μM）后测量弓状小动脉直径。与 LZR 相比，OZR 表现出更高的胰岛素、葡萄糖、甘油三酯和超氧化物水平以及增加的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性。OZR 的功能性和 AA 诱导的血管舒张受损。罗格列酮治疗改善了 OZR 的胰岛素、葡萄糖、甘油三酯和超氧化物水平以及 NADHP 氧化酶活性。罗格列酮和 Tempol 治疗均改善了 OZR 的血管舒张反应，而对 LZR 无影响。SQ - 29548 治疗改善了未处理的 OZR 的血管舒张反应，对 LZR 或处理过的 OZR 无影响。这些结果表明，胰岛素抵抗以及由此产生的 ROS 增加通过增强 TP 介导的血管收缩损害了 OZR 的功能性扩张。
