Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning
Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning
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DOI：
10.1124/jpet.104.074476
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Wong, TM
中科院分区：
文献类型：
--
作者：
Cao, CM;Xia, Q;Wong, TM
我们验证了高电导钙活化钾（K-Ca）通道参与缺血损伤预处理的心脏保护的假设。在缺血/再灌注的离体灌注大鼠心脏中，缺血预处理（IPC）对梗死面积和乳酸脱氢酶（LDH）释放的影响在缺血前30分钟（而不是在缺血过程中）被1mum paxilline （K-Ca通道抑制剂）所消除。在代谢抑制和缺氧（MI/A）的分离心室肌细胞中，MI/A预处理可提高其活力，而在MI/A前给予Pax可消除这种作用。与IPC类似，10 muM NS1619(1,3-二氢-1-[2-羟基-5-（三氟甲基）苯基]-5-三氟甲基- 2hbenzimidazol -2-one；NS)， K-Ca通道的打开剂，减少梗死面积和LDH释放，Pax的作用减弱。阻断和激活K-Ca通道的有害和保护作用分别伴随着左心室收缩功能的受损和改善。此外，NS的作用不受100mum 5-羟癸酸（K-ATP通道抑制剂）的影响。100mum二氮氧化物（K-ATP通道的活化剂）的作用也没有被Pax改变。此外，在离体大鼠心脏和心肌细胞中，用20mum白术皂苷打开线粒体通透性过渡孔（mPTP）可消除IPC或NS的有益作用。0.2 mg环孢素A抑制mPTP开放可降低心肌梗死面积和LDH释放，改善心肌收缩功能，Pax不减弱这一作用。总之，该研究提供了K-Ca通道触发IPC的心脏保护的证据，其中包括mPTP。
We tested the hypothesis that the high-conductance calcium-activated potassium (K-Ca) channel is involved in the cardioprotection of preconditioning with ischemic insults. In the isolated perfused rat heart subjected to ischemia/reperfusion, effects of ischemic preconditioning (IPC) on infarct size and lactate dehydrogenase (LDH) release were abolished by 1 muM paxilline (Pax), an inhibitor of the K-Ca channel, administered 30 min before, but not during, ischemia. In isolated ventricular myocytes subjected to metabolic inhibition and anoxia (MI/A), preconditioning with MI/A increased their viability, and the effect was abolished by administering Pax before MI/A. Like IPC, 10 muM NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5- trifluoromethyl-2Hbenzimidazol-2-one; NS), an opener of K-Ca channels, reduced infarct size and LDH release, effects attenuated by Pax. The harmful and protective effects of blockade and activation of the K-Ca channel were accompanied by impaired and improved left ventricular contractile functions, respectively. In addition, the effect of NS was not altered by 100 muM 5-hydroxydecanoate, an inhibitor of the K-ATP channel. Neither was the effect of 100 muM diazoxide, an activator of the K-ATP channel, altered by Pax. Furthermore, opening of the mitochondrial permeability transition pore (mPTP) with 20 muM atractyloside abolished the beneficial effects of IPC or NS in the isolated rat heart and myocyte. Inhibition of mPTP opening with 0.2 muM cyclosporin A decreased the infarct size and LDH release and improved the contractile function, effects not attenuated by Pax. In conclusion, the study provides evidence that the K-Ca channel triggers cardioprotection of IPC, which involves mPTP.