Uchiyama Yuka, Otani Hajime, Okada Takayuki, Uchiyama Takamichi, Ninomiya Hideki, Kido Masakuni, Imamura Hiroji, Nakao Shinichi, Shingu Koh
Department of Anesthesiology, Kansai Medical University, Moriguchi City, Japan.
J Thorac Cardiovasc Surg. 2003 Jul;126(1):148-59. doi: 10.1016/s0022-5223(03)00236-8.
Mitochondrial K(ATP) channel activation is an essential component of ischemic preconditioning. These channels are selectively opened by diazoxide and may be up-regulated by adenosine and nitric oxide. Therefore, pharmacological preconditioning with diazoxide in combination with adenosine and a nitric oxide donor (triple-combination pharmacological preconditioning) may enhance cardioprotection.
Isolated and perfused rat hearts underwent ischemic preconditioning with 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion before 5 minutes of oxygenated potassium cardioplegia and 35 minutes of ischemia. Pharmacological preconditioning was performed by adding adenosine, diazoxide, and a nitric oxide donor S-nitroso-N-acetyl-penicillamine each alone or in combinations for 25 minutes followed by 10 minutes washout before cardioplegic arrest. Only triple-combination pharmacological preconditioning conferred significant cardioprotection as documented by highly improved left ventricular function and limited creatine kinase release during reperfusion that was comparable to that afforded by ischemic preconditioning. Mitochondrial K(ATP) channel activity assessed by flavoprotein oxidation was increased by diazoxide, but no further increase in flavoprotein oxidation was obtained by ischemic preconditioning and triple-combination pharmacological preconditioning. Significant activation of protein kinase C-epsilon was observed in only ischemic preconditioning and triple-combination pharmacological preconditioning. Pretreatment with the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate or the protein kinase C inhibitor chelerythrine abrogated activation of protein kinase C-epsilon and cardioprotection afforded by ischemic preconditioning and triple-combination pharmacological preconditioning.
Integrated pharmacological preconditioning is not simply mediated by enhanced mitochondrial K(ATP) channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial K(ATP) channel activation, and nitric oxide.
线粒体ATP敏感性钾通道（mitochondrial K(ATP) channel）激活是缺血预处理的重要组成部分。这些通道可被二氮嗪选择性打开，且可能被腺苷和一氧化氮上调。因此，二氮嗪联合腺苷及一氧化氮供体进行药物预处理（三联药物预处理）可能增强心脏保护作用。
分离并灌注的大鼠心脏在进行5分钟氧合钾停搏液灌注及35分钟缺血前，先经历3个循环的5分钟缺血及5分钟再灌注的缺血预处理。通过单独或联合添加腺苷、二氮嗪及一氧化氮供体S-亚硝基-N-乙酰青霉胺进行25分钟的药物预处理，随后在停搏前冲洗10分钟。只有三联药物预处理赋予了显著的心脏保护作用，表现为左心室功能显著改善以及再灌注期间肌酸激酶释放受限，这与缺血预处理所提供的保护相当。通过黄素蛋白氧化评估的线粒体K(ATP)通道活性被二氮嗪增加，但缺血预处理和三联药物预处理并未使黄素蛋白氧化进一步增加。仅在缺血预处理和三联药物预处理中观察到蛋白激酶C-ε的显著激活。用线粒体K(ATP)通道抑制剂5-羟基癸酸或蛋白激酶C抑制剂白屈菜红碱预处理可消除缺血预处理和三联药物预处理所提供的蛋白激酶C-ε激活及心脏保护作用。
综合药物预处理并非简单地由增强的线粒体K(ATP)通道激活介导，而是可能通过腺苷、线粒体K(ATP)通道激活和一氧化氮的协同相互作用促进的蛋白激酶C信号放大来介导。
