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Role of cardiac ATP-sensitive K^+ channels clarified by Kir6.2-deficient mice

Kir6.2 缺陷小鼠阐明心脏 ATP 敏感 K^ 通道的作用

基本信息

批准号：
11670081
负责人：
NAKAYA Haruaki
金额：
$ 2.24万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

In order to clarify the pathophysioloical significance of sarcolemmal ATP-sensitive K^+ (K_<ATP>) channel in cardiac cells, we conducted functional experiments using Kir6.2-deficient (Kir6.2^<-/->) mice. In open cell-attached patches of ventricular cells of wild type (Kir6.2^<+/+>) but not of Kir6.2^<-/-> mice, single K_<ATP> channel activity with the slope conductance of about 80 pS could be recorded during exposure to an internal solution containing a trace amount of ATP.The ATP-sensitive K^+ current was activated by K^+ channel openers (KCOs) such as pinacidil and cromakalim and the exposure to a glucose-free, dinitrophenol-containing solution in Kir6.2^<+/+> ventricular cells but not in Kir6.2^<-/-> cells. The action potential duration (APD) of Kir6.2^<+/+> ventricular cells but not of Kir6.2^<-/-> cells was shortened by KCOs and metabolic blockade. In anesthetized Kir6.2^<+/+> and Kir6.2^<-/-> mice, coronary artery was occluded for 45 min and reperfused for 120 min, and the infarc … More t size was evaluated by triphenyl tetrazolium chloride staining. For ischemic preconditioning (IP) experiments coronary artery was occluded for three periods of 3 min, each followed by 5 min reperfusion, before the long-term ischemia. IP reduced the infarct size in Kir6.2^<+/+> mice but not in Kir6.2^<-/-> mice. The hearts were removed from Kir6.2^<+/+> and Kir6.2^<-/-> mice, and retrogradely perfused with a physiological solution. Left ventricular pressure was measured using a water-filled balloon inserted into the left ventricle. Global ischemia was produced by stopping the perfusion for 15 min, and then the heart was reperfused for 30 min. During ischemia an increase in the left ventricular end-diastolic pressure was more marked and more rapid in Kir6.2^<-/-> hearts, compared to Kir6.2^<+/+> hearts. The recovery of the left ventricular contractile function during reperfusion was worse in Kir6.2^<-/-> hearts than in Kir6.2^<+/+> hearts. These findings indicate that Kir6.2 is essential for the action potential shortening during the exposure to the metabolic blockade and KCOs. In addition, sarcolemmal K_<ATP> channel is important for the establishment if ischemic preconditioning and the maintenace of mechanical function during ischemia and reperfusion. Less

为了阐明心肌细胞膜ATP敏感性K^+（K_）通道的病理生理意义<ATP>，我们用Kir6.2-缺陷（Kir6.2^<-/->）小鼠进行了功能实验。在野生型（Kir6.2^<+/+>）而非Kir6.2^<-/->小鼠心室肌细胞贴附的开放细胞贴附斑中，<ATP>在暴露于含有微量ATP的内溶液中时，可记录到斜率电导约为80 pS的单个K_通道活动。在Kir6.2^<+/+>心室肌细胞中，ATP敏感性K^+电流可被K^+通道开放剂（KCO）（如吡那地尔和克罗卡林）激活，而在暴露于无葡萄糖、含二硝基酚的溶液中时，Kir6.2 ^<+/->心室肌细胞中的K ^+电流则未被激活。KCOs和代谢阻断可缩短Kir6.2^<+/+>心室肌细胞的动作电位时程（APD），而Kir6.2^<-/->细胞则无此作用。在麻醉的Kir6.2^<+/+>和Kir6.2^<-/->小鼠中，冠状动脉闭塞45 min，再灌注120 min， ...更多信息通过氯化三苯基四唑染色评价T大小。缺血预处理（IP）实验在长期缺血前，先阻断冠状动脉3 min，再灌注5 min。IP减少了Kir6.2^<+/+>小鼠的梗死面积，但在Kir6.2^<-/->小鼠中没有。从Kir6.2^<+/+>和Kir6.2^<-/->小鼠中取出心脏，并用生理溶液逆行灌注。使用插入左心室的充水球囊测量左心室压力。通过停止灌注15 min产生全脑缺血，然后心脏再灌注30 min。在缺血期间，与Kir6.2 ^<+/+>心脏相比，Kir6.2^<-/->心脏的左心室舒张末期压增加更显著且更迅速。Kir6.2^<-/->心脏再灌注时左室收缩功能恢复较Kir6.2 ^<+/+>心脏差。这些发现表明Kir6.2在暴露于代谢阻断剂和KCO期间对动作电位缩短至关重要。此外，肌膜K通道<ATP>对缺血预适应的建立和缺血再灌注过程中机械功能的维持也有重要作用。少