Blockade of ischaemic preconditioning in dogs by the novel ATP dependent potassium channel antagonist sodium 5-hydroxydecanoate.
Blockade of ischaemic preconditioning in dogs by the novel ATP dependent potassium channel antagonist sodium 5-hydroxydecanoate.
复制标题
新型 ATP 依赖性钾通道拮抗剂 5-羟基癸酸钠可阻断狗的缺血预处理。
作者：
J. Auchampach;G. Grover;G. Gross
客观化
其目的是：(1)确定新的缺血选择性ATP依赖性钾(KATP)通道拮抗剂5-羟基癸酸钠(5-HD)是否阻断犬的缺血预适应；(2)确定冠脉内小剂量格列本脲(一种经典的磺脲类KATP通道拮抗剂)是否可以阻断不依赖全身代谢效应的缺血预适应。
方法
巴比妥钠麻醉犬冠状动脉左回旋支结扎60min，再灌注5h。预适应的方法是阻断左回旋支5min，然后在60min阻断前再灌流10min。5-HD(150微克·kg~(-1)×min~(-1))或赋形剂在有或没有预适应的情况下，从60min闭塞前15分钟开始，通过冠脉内输注到缺血区超过20min。格列本脲(3微克·kg~(-1)×min~(-1))在预适应或非预适应犬冠脉内注入左回旋动脉5分钟或前5分钟。用放射性微球测量跨壁心肌血流量，用三苯基四氮唑染色测定心肌梗死面积，并以危险区域的百分比表示。
结果
在血流动力学变量、心肌血流量、危险区域或血糖方面，两组之间没有差异。冠脉内注射5-HD、冠脉内注射格列本脲或冠脉内注射格列本脲后，冠脉内5-HD或冠脉内注射格列本脲均可完全阻断冠脉内5-HD或冠脉内注射格列本脲对心肌梗死面积的影响。在缺乏研究剂量的预适应的情况下，5-HD和格列本脲均不影响梗塞面积。
结论
这些结果进一步支持了心肌KATP通道激活参与犬缺血预适应机制的假说。
OBJECTIVE
The aims were: (1) to determine if a new ischaemia selective ATP dependent potassium (KATP) channel antagonist, sodium 5-hydroxydecanoate (5-HD), blocks ischaemic preconditioning in dogs; (2) to determine whether a small intracoronary dose of glibenclamide, a classical sulphonylurea KATP channel antagonist, could block ischaemic preconditioning independent of systemic metabolic effects.
METHODS
Barbitone anaesthetised dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 5 h of reperfusion. Preconditioning was produced by a single 5 min left circumflex occlusion followed by 10 min of reperfusion prior to the 60 min occlusion period. 5-HD (150 micrograms.kg-1 x min-1) or vehicle was given by intracoronary infusion into the ischaemic region over 20 min, beginning 15 min prior to the 60 min occlusion period in the presence or absence of preconditioning. Glibenclamide (3 micrograms.kg-1 x min-1) was given by intracoronary infusion into the left circumflex artery during the 5 min preconditioning period or during the first 5 min of occlusion in preconditioned or non-preconditioned dogs. Transmural myocardial blood flow was measured by radioactive microspheres and infarct size determined by triphenyltetrazolium staining and expressed as a percent of the area at risk.
RESULTS
There were no differences in haemodynamic variables, myocardial blood flow, area at risk, or blood glucose between groups. Infarct size was markedly reduced in preconditioned dogs compared to control animals, at 7(SEM 2)% v 29(4)%, p < 0.05 The reduction in infarct size by preconditioning was blocked completely by intracoronary 5-HD, or by intracoronary glibenclamide given during preconditioning or during the first 5 min of the prolonged occlusion period. Neither 5-HD nor glibenclamide affected infarct size in the absence of preconditioning at the doses studied.
CONCLUSIONS
These results further strengthen the hypothesis that activation of myocardial KATP channels is involved in the mechanism of ischaemic preconditioning in dogs.