Department of Biology, Georgia State University, Atlanta, GA 30302, USA.
Br J Pharmacol. 2011 Dec;164(8):2064-72. doi: 10.1111/j.1476-5381.2011.01539.x.
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.
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.
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.
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.
罗格列酮是一种改善胰岛素敏感性和葡萄糖摄取的抗糖尿病药物，可作用于骨骼肌和脂肪组织。然而，最近的几项临床试验表明，罗格列酮会增加心血管缺血的风险，尽管其他研究未能显示出这种风险。因此，需要阐明罗格列酮对冠状动脉循环的影响及其任何潜在的血管靶点。在这里，我们发现罗格列酮抑制了血管型三磷酸腺苷敏感钾（K(ATP)）通道，损害了冠状动脉循环的生理调节。
在 HEK293 细胞中表达 K(IR) 6.1/SUR2B 通道，并在全细胞和内面向外贴片配置中进行研究。使用 Langendorff 心脏制备来评估野生型（WT）和 K(IR) 6.1 缺失（Kcnj8(-/-)）小鼠中的罗格列酮对冠状动脉循环的影响。
HEK 细胞中的 K(IR) 6.1/SUR2B 通道以膜局限的方式被罗格列酮抑制。这种作用被亚微摩尔浓度的格列本脲显著增强，罗格列酮的 IC(50)下降至 2µM，达到治疗上可达到的浓度。在 Langendorff 心脏制备中，罗格列酮浓度依赖性地抑制异丙肾上腺素诱导的冠状动脉扩张，而不影响基础冠状动脉张力。罗格列酮对冠状动脉灌注的作用在 Kcnj8(-/-) 小鼠中减弱了 50%以上，这支持了 K(ATP)通道在罗格列酮对冠状动脉循环的这种作用中的参与。
这些结果表明，血管 K(ATP)通道是罗格列酮作用的靶点之一，通过该药物，可能会损害循环血管扩张剂和代谢应激对冠状动脉反应。
