ZD0947, a sulphonylurea receptor modulator, detects functional sulphonylurea receptor subunits in murine vascular smooth muscle ATP-sensitive K+ channels.
ZD0947, a sulphonylurea receptor modulator, detects functional sulphonylurea receptor subunits in murine vascular smooth muscle ATP-sensitive K+ channels.
复制标题
ZD0947 是一种磺酰脲受体调节剂，可检测小鼠血管平滑肌 ATP 敏感 K 通道中的功能性磺酰脲受体亚基。
DOI：
10.1016/j.ejphar.2017.02.023
复制
发表时间：
2017
影响因子：
5
通讯作者：
Teramoto N
中科院分区：
文献类型：
--
作者：
Yamamoto T;Takahara K;Uchida K;Teramoto N
为了鉴定小鼠门静脉天然ATP敏感性K+通道（KATP通道）的功能性磺脲受体（SUR.x）亚基，研究了SUR.x调节剂ZD 0947对新鲜分散的小鼠门静脉肌细胞自发性门静脉收缩、宏观膜电流和单位电流（采用膜片钳技术）的影响。ZD 0947以浓度依赖性方式可逆性降低小鼠门静脉的自发收缩（Ki=293 nM）。额外应用格列本脲（300 nM）可拮抗3 µM ZD 0947引起的松弛，但格列齐特（100-300 nM）则不能拮抗。在常规全细胞配置中，100 µM ZD 0947在−60 mV的保持电位下引发内向格列本脲敏感性电流，证明对K+具有选择性（即KATP电流）。在−60 mV下，30 µM或100 µM ZD 0947引起的膜电流峰值幅度小于100 µM吡那地尔引起的膜电流峰值幅度。在细胞附着模式下，100 µM ZD 0947激活格列本脲敏感性K+通道，其电导（35 pS）与HEK 293细胞中表达并被100 µM ZD 0947激活的重组Kir6.1/SUR 2B通道相似。这些结果表明，ZD 0947通过激活KATP通道引起显著的血管舒张，基于其药理学选择性，SUR 2B可能是小鼠门静脉KATP通道中SUR.x的主要功能亚基。
In order to identify functional sulphonylurea receptor (SUR.x) subunits of native ATP-sensitive K+channels (KATPchannels) in mouse portal vein, the effects of ZD0947, a SUR.x modulator, were investigated on spontaneous portal vein contractions, macroscopic membrane currents and unitary currents recorded (using patch-clamp techniques) in freshly dispersed mouse portal vein myocytes. Spontaneous contractions in mouse portal vein were reversibly reduced by ZD0947 in a concentration-dependent manner (Ki=293 nM). The relaxation elicited by 3 µM ZD0947 was antagonized by the additional application of glibenclamide (300 nM), but not gliclazide (100–300 nM). In the conventional whole-cell configuration, 100 µM ZD0947 elicited inward glibenclamide-sensitive currents at a holding potential of −60 mV that demonstrated selectivity for K+(i.e. KATPcurrents). The peak amplitude of the membrane current elicited by 30 µM or 100 µM ZD0947 was smaller than that elicited by 100 µM pinacidil at −60 mV. In the cell-attached mode, 100 µM ZD0947 activated glibenclamide-sensitive K+channels with a conductance (35 pS) similar to that of recombinant Kir6.1/SUR2B channels that were expressed in HEK293 cells and activated by 100 µM ZD0947. These results demonstrate that ZD0947 caused a significant vascular relaxation through the activation of KATPchannels and that SUR2B may be the major functional subunit of SUR.x in mouse portal vein KATPchannels, based on its pharmacological selectivity.