Br J Pharmacol 2011 Dec;164 (8): 2064-72. [IF:4.925]
Rosiglitazone inhibits vascular K(ATP) channels and coronary vasodilation produced by isoprenaline.
Yu L , Jin X , Yang Y , Cui N , Jiang C .
Department of Biology, Georgia State University, Atlanta, Georgia, USA Harbin Medical University School of Pharmacy, Harbin, Heilongjiang, China.
哈尔滨医科大学药学院，美国佐治亚州立大学
Abstract
BACKGROUND AND PURPOSE Rosiglitazone is an anti-diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. Therefore, the effects of rosiglitazone on the coronary circulation and any potential vascular targets need to be elucidated. Here, we show that the vascular isoform of the ATP-sensitive K(+) (K(ATP) ) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation. EXPERIMENTAL APPROACH The K(IR) 6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell and inside-out patch configurations. The Langendorff heart preparation was used to evaluate rosiglitazone in the coronary circulation of wild-type (WT) and K(IR) 6.1-null (Kcnj8(-/-) ) mice. KEY RESULTS K(IR) 6.1/SUR2B channels in HEK cells were inhibited by rosiglitazone in a membrane-delimited manner. This effect was markedly enhanced by sub-micromolar concentrations of glibenclamide and the IC(50) for rosiglitazone fell to 2μM, a therapeutically achievable concentration. In the Langendorff heart preparation rosiglitazone inhibited, concentration-dependently, the coronary vasodilation induced by isoprenaline, without affecting basal coronary tone. Effects of rosiglitazone on coronary perfusion were attenuated by more than 50% in the Kcnj8(-/-) mice, supporting the involvement of K(ATP) channels in this effect of rosiglitazone on the coronary circulation. CONCLUSIONS AND IMPLICATIONS These results indicate that the vascular K(ATP) channel is one of the targets of rosiglitazone action, through which this drug may compromise coronary responses to circulating vasodilators and perhaps also to metabolic stress.
摘要:
背景和目的：罗格列酮是一种能够提高胰岛素的敏感性和骨骼肌及脂肪组织对葡萄糖摄取能力的抗糖尿病的药物。然而，最近的一些临床试验表明罗格列酮可以增加心血管缺血的风险，尽管其它的研究未能证明这种风险。因此，需要澄清罗格列酮是否对冠脉循环和任何潜在的血管受体有影响。在这里，我们展示了罗格列酮通过对有ATP敏感的钾通道的血管亚型的抑制作用，从而损害冠脉循环的生理的调节作用。实验方法K（IR）6.1/SUR2B通道在HEK293细胞中进行表达，并从内向外对整个细胞的补体配置进行研究。离体心脏制备用于评估罗格列酮在野生型（WT）和K（IR）6.1（Kcnj8（ - / - ））小鼠的冠脉循环状况。
离体心脏制备用于评估罗格列酮在野生型（WT）和K（IR）6.1（Kcnj8（ - / - ））小鼠的冠脉循环状况。主要结果:罗格列酮通过膜分隔的方式抑制HEK细胞的K（IR）6.1/SUR2B通路。当格列本脲和罗格列酮IC（50）的亚微摩尔浓度下跌至2μm的治疗浓度时，这种效应得以显着增强。罗格列酮在浓度依赖性抑制离体心脏制备时，由异丙肾上腺素诱导的冠状动脉舒张不影响基底冠状动脉音。
罗格列酮对Kcnj8（ - / - ）小鼠冠状动脉灌注的影响减少了50％多，从而
支持罗格列酮通过参与K（ATP）通道来对冠脉循环产生影响。结论和启示：这些结果表明，血管K（ATP）通道是罗格列酮的作用靶点之一，通过这种药物可能会影响冠状动脉循环对血管扩张剂的反应，或许也可能是代谢的应激反应。
