Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
J Mol Cell Cardiol. 2011 Mar;50(3):552-60. doi: 10.1016/j.yjmcc.2010.12.011. Epub 2010 Dec 23.
Murine ventricular and atrial ATP-sensitive potassium (K(ATP)) channels contain different sulfonylurea receptors (ventricular K(ATP) channels are Kir6.2/SUR2A complexes, while atrial K(ATP) channels are Kir6.2/SUR1 complexes). HMR 1098, the sodium salt of HMR 1883 {1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea}, has been considered as a selective sarcolemmal (i.e. SUR2A-dependent) K(ATP) channel inhibitor. However, it is not clear whether HMR 1098 would preferentially inhibit ventricular K(ATP) channels over atrial K(ATP) channels. To test this, we used whole-cell patch clamp techniques on mouse atrial and ventricular myocytes as well as (86)Rb(+) efflux assays and excised inside-out patch clamp techniques on Kir6.2/SUR1 and Kir6.2/SUR2A channels heterologously expressed in COSm6 cells. In mouse atrial myocytes, both spontaneously activated and diazoxide-activated K(ATP) currents were effectively inhibited by 10 μM HMR 1098. By contrast, in ventricular myocytes, pinacidil-activated K(ATP) currents were inhibited by HMR 1098 at a high concentration (100 μM) but not at a low concentration (10 μM). Consistent with this finding, HMR 1098 inhibits (86)Rb(+) effluxes through Kir6.2/SUR1 more effectively than Kir6.2/SUR2A channels in COSm6 cells. In excised inside-out patches, HMR 1098 inhibited Kir6.2/SUR1 channels more effectively, particularly in the presence of MgADP and MgATP (mimicking physiological stimulation). Finally, dose-dependent enhancement of insulin secretion from pancreatic islets and decrease of blood glucose level confirm that HMR 1098 is an inhibitor of Kir6.2/SUR1-composed K(ATP) channels.
鼠心室和心房三磷酸腺苷敏感性钾 (K(ATP)) 通道含有不同的磺酰脲受体（心室 K(ATP) 通道是 Kir6.2/SUR2A 复合物，而心房 K(ATP) 通道是 Kir6.2/SUR1 复合物）。HMR 1098，HMR 1883 的钠盐 {1-[[5-[2-(5-氯邻茴香酰胺基)乙基]-2-甲氧基苯基]磺酰基]-3-甲基硫脲}，被认为是一种选择性肌浆网（即 SUR2A 依赖性）K(ATP) 通道抑制剂。然而，目前尚不清楚 HMR 1098 是否会优先抑制心室 K(ATP) 通道而不是心房 K(ATP) 通道。为了验证这一点，我们使用全细胞膜片钳技术在鼠心房和心室肌细胞上，以及在异源表达于 COSm6 细胞的 Kir6.2/SUR1 和 Kir6.2/SUR2A 通道上进行（86）Rb(+) 外排测定和膜片钳内面向外技术。在鼠心房肌细胞中，10 μM HMR 1098 有效抑制了自发性激活和 diazoxide 激活的 K(ATP) 电流。相比之下，在心室肌细胞中，高浓度（100 μM）而非低浓度（10 μM）的 HMR 1098 抑制了 pinacidil 激活的 K(ATP) 电流。与这一发现一致的是，在 COSm6 细胞中，HMR 1098 抑制（86）Rb(+) 通过 Kir6.2/SUR1 的外排比 Kir6.2/SUR2A 通道更有效。在膜片钳内面向外斑中，HMR 1098 对 Kir6.2/SUR1 通道的抑制作用更强，尤其是在存在 MgADP 和 MgATP（模拟生理刺激）的情况下。最后，来自胰腺胰岛的胰岛素分泌的剂量依赖性增强和血糖水平的降低证实 HMR 1098 是 Kir6.2/SUR1 组成的 K(ATP) 通道抑制剂。
