Eringa Etto C, Stehouwer Coen D A, Roos Marjon H, Westerhof Nico, Sipkema Pieter
Laboratory for Physiology, Institute for Cardiovascular Research ICaR-VU VU University Medical Center, 1081 BT, Amsterdam, The Netherlands.
Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1134-9. doi: 10.1152/ajpendo.00516.2006. Epub 2007 Jul 10.
Obesity is related to insulin resistance and hypertension, but the underlying mechanisms are unclear. Insulin exerts both vasodilator and vasoconstrictor effects on muscle resistance arteries, which may be differentially impaired in obesity.
To investigate whether vasodilator and vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats and the roles of Akt and endothelial NO synthase (eNOS).
METHODS/RESULTS: Effects of insulin were studied in resistance arteries isolated from cremaster muscles of lean and obese Zucker rats. In arteries of lean rats, insulin increased activity of both NO and endothelin (ET-1), resulting in a neutral effect under basal conditions. In arteries of obese rats, insulin induced endothelin-mediated vasoconstriction (-15 +/- 5% at 1 nM, P < 0.05 vs. lean). Insulin induced vasodilatation during endothelin receptor blockade in arteries of lean rats (20 +/- 5% at 1 nM) but not in those of obese rats. Inhibition of NO synthesis increased vascular tone (by 12 +/- 2%) and shifted insulin-mediated vasoreactivity to vasoconstriction (-25 +/- 1% at 1 nM) in lean rats but had no effect in arteries of obese rats, indicating reduced NO activity. Protein analysis of resistance arteries revealed that insulin-mediated activation of Akt was preserved in obese rats, whereas expression of eNOS was markedly decreased.
Vasodilator but not vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats, and this selective impairment is associated with decreased protein levels of eNOS. These findings provide a new mechanism linking obesity to insulin resistance and hypertension.
肥胖与胰岛素抵抗和高血压相关，但其潜在机制尚不清楚。胰岛素对肌肉阻力动脉具有血管舒张和血管收缩作用，在肥胖状态下这些作用可能会受到不同程度的损害。
研究肥胖大鼠肌肉阻力动脉中胰岛素的血管舒张和血管收缩作用是否受损，以及Akt和内皮型一氧化氮合酶（eNOS）的作用。
方法/结果：在从瘦型和肥胖型 Zucker 大鼠提睾肌分离的阻力动脉中研究胰岛素的作用。在瘦大鼠的动脉中，胰岛素增加一氧化氮（NO）和内皮素（ET-1）的活性，在基础条件下产生中性作用。在肥胖大鼠的动脉中，胰岛素诱导内皮素介导的血管收缩（1 nM 时为-15±5%，与瘦大鼠相比，P<0.05）。在瘦大鼠动脉中，内皮素受体阻断期间胰岛素诱导血管舒张（1 nM 时为 20±5%），而在肥胖大鼠动脉中则无此作用。抑制 NO 合成可增加血管张力（增加 12±2%），并使瘦大鼠胰岛素介导的血管反应性转变为血管收缩（1 nM 时为-25±1%），但对肥胖大鼠动脉无影响，表明 NO 活性降低。阻力动脉的蛋白质分析显示，肥胖大鼠中胰岛素介导的 Akt 激活得以保留，而 eNOS 的表达明显降低。
肥胖大鼠肌肉阻力动脉中胰岛素的血管舒张作用而非血管收缩作用受损，这种选择性损害与 eNOS 蛋白水平降低有关。这些发现提供了一种将肥胖与胰岛素抵抗和高血压联系起来的新机制。
