Song J, Walsh M F, Igwe R, Ram J L, Barazi M, Dominguez L J, Sowers J R
Department of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Diabetes. 1997 Apr;46(4):659-64. doi: 10.2337/diab.46.4.659.
The insulin-sensitizing compound troglitazone has evolved into a promising therapeutic agent for type II diabetes. It improves insulin sensitivity and lipoprotein metabolic profiles and lowers blood pressure in humans and rodents. Because troglitazone has insulin-like effects on a number of tissues, we hypothesized that it may reduce vascular tone through stimulation of endothelial-derived nitric oxide (NO) production or by diminution of vascular smooth muscle cell (VSMC) intracellular calcium ([Ca2+]i). Our results show that troglitazone decreases norepinephrine-induced contractile responses in the rat tail artery, an effect not reversed by the NO inhibitor L-nitroarginine methyl ester (L-NAME). In contrast, troglitazone significantly inhibited L-type Ca2+ currents in freshly dissociated rat tail artery and aortic VSMCs and in cultured VSMCs. The data suggest that troglitazone attenuates vascular contractility via a mechanism involving VSMC [Ca2+]i but independent from endothelial generation of NO. Because insulin has been shown to affect vascular tone by both of these mechanisms, troglitazone only partially mimics insulin action in this tissue.
胰岛素增敏化合物曲格列酮已发展成为一种有前景的II型糖尿病治疗药物。它可改善人类和啮齿动物的胰岛素敏感性、脂蛋白代谢谱并降低血压。由于曲格列酮对多种组织具有胰岛素样作用，我们推测它可能通过刺激内皮源性一氧化氮（NO）生成或降低血管平滑肌细胞（VSMC）细胞内钙浓度（[Ca2+]i）来降低血管张力。我们的结果表明，曲格列酮可降低去甲肾上腺素诱导的大鼠尾动脉收缩反应，一氧化氮抑制剂L-硝基精氨酸甲酯（L-NAME）不能逆转这一效应。相反，曲格列酮可显著抑制新鲜分离的大鼠尾动脉和主动脉VSMC以及培养的VSMC中的L型钙电流。数据表明，曲格列酮通过一种涉及VSMC [Ca2+]i但独立于内皮源性一氧化氮生成的机制减弱血管收缩性。由于胰岛素已被证明可通过这两种机制影响血管张力，曲格列酮在该组织中仅部分模拟胰岛素作用。
