HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal K ATP channels.
HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal K ATP channels.
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HMR 1098 不是异源或肌膜 K ATP 通道的 SUR 同种型特异性抑制剂。
DOI：
10.1016/j.yjmcc.2010.12.011
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发表时间：
2011
影响因子：
5
通讯作者：
Nichols,ColinG
中科院分区：
文献类型：
--
作者：
Zhang,HaiXia;Akrouh,Alejandro;Kurata,HarleyT;Remedi,MariaSara;Lawton,JenniferS;Nichols,ColinG
小鼠心室和心房ATP敏感性钾（KATP）通道含有不同的磺酰脲受体（心室KATP通道为Kir6.2/SUR 2A复合物，心房KATP通道为Kir6.2/SUR 1复合物）。HMR 1098是HMR 1883 {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}的钠盐，被认为是选择性肌膜（即SUR 2A依赖性）Katp通道抑制剂。然而，尚不清楚HMR 1098是否优先抑制心室KATP通道而不是心房KATP通道。为了验证这一点，我们使用了小鼠心房和心室肌细胞的全细胞膜片钳技术，以及COSm 6细胞中异源表达的Kir6.2/SUR 1和Kir6.2/SUR 2A通道的86 Rb+流出测定和切除的内面向外膜片钳技术。在小鼠心房肌细胞中，10μM HMR 1098可有效抑制自发激活和二氮嗪激活的KATP电流。相比之下，在心室肌细胞中，高浓度（100μM）的HMR 1098抑制吡那地尔激活的KATP电流，但低浓度（10μM）的HMR 1098不抑制。与这一发现一致，在COSm 6细胞中，HMR 1098通过Kir6.2/SUR 1比Kir6.2/SUR 2A通道更有效地流出86 Rb+。在切除的由内而外的斑块中，HMR 1098更有效地抑制Kir6.2/SUR 1通道，特别是在MgADP和MgATP（模拟生理刺激）存在的情况下。最后，HMR 1098剂量依赖性地增强胰岛分泌胰岛素和降低血糖水平证实HMR 1098是Kir6.2/SUR 1组成的KATP通道的抑制剂。
Murine ventricular and atrial ATP-sensitive potassium (KATP) channels contain different sulfonylurea receptors (ventricular KATPchannels are Kir6.2/SUR2A complexes, while atrial KATPchannels 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) KATPchannel inhibitor. However, it is not clear whether HMR 1098 would preferentially inhibit ventricular KATPchannels over atrial KATPchannels. To test this, we used whole-cell patch clamp techniques on mouse atrial and ventricular myocytes as well as86Rb+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 KATPcurrents were effectively inhibited by 10μM HMR 1098. By contrast, in ventricular myocytes, pinacidil-activated KATPcurrents were inhibited by HMR 1098 at a high concentration (100μM) but not at a low concentration (10μM). Consistent with this finding, HMR 1098 inhibits86Rb+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 KATPchannels.