Menasché P, Kevelaitis E, Mouas C, Grousset C, Piwnica A, Bloch G
Department of Cardiovascular Surgery, Hôpital Lariboisière, Paris, France.
J Thorac Cardiovasc Surg. 1995 Dec;110(6):1606-13; discussion 1613-4. doi: 10.1016/S0022-5223(95)70020-X.
Ischemic preconditioning defines an adaptive endogenous mechanism in which a brief episode of reversible ischemia renders the heart more resistant to a subsequent period of sustained ischemia. Because the cardioprotective effects of ischemic preconditioning might be mediated by an activation of adenosine triphosphate-sensitive potassium channels, this study was designed to assess whether these effects could be duplicated by the preischemic administration of a potassium channel opener. Fifty isolated isovolumic buffer-perfused rat hearts underwent 45 minutes of normothermic potassium arrest followed by 1 hour of reperfusion. They were divided into five equal groups that differed with regard to the preconditioning regimen: Group 1 hearts were left untreated and served a controls; in group 2, preconditioning was achieved with 5 minutes of total global ischemia followed by 5 minutes of buffer reperfusion before cardioplegic arrest; in group 3, the preconditioning stimulus consisted of a 5-minute infusion of the potassium channel opener nicorandil (10 mumol/L) followed by 5 minutes of drug-free buffer perfusion before arrest; group 4 hearts underwent a similar protocol except that the infusion of nicorandil was preceded by that of the potassium channel blocker glibenclamide (10 mumol/L); group 5 hearts were ischemically preconditioned like those of group 2 except that the no-flow preconditioning period was also preceded by a 5-minute infusion of glibenclamide (50 mumol/L). The results demonstrate that ischemic preconditioning significantly improved contractility and reduced contracture during reperfusion, as compared with results in control hearts. These protective effects were duplicated by pretreatment with nicorandil but were abolished when the drug was antagonized by a prior infusion of glibenclamide. Likewise, the glibenclamide-induced blockade of potassium channels largely blunted the beneficial effects of ischemic preconditioning. These data suggest that opening of adenosine triphosphate-sensitive potassium channels substantially contributes to preconditioning-induced cardiac protection in a surgically relevant model of global ischemia and, consequently, that the use of potassium channel openers like nicorandil could be an effective means of enhancing cardioplegic protection.
缺血预处理定义了一种适应性内源性机制，即短暂的可逆性缺血发作可使心脏对随后的持续性缺血期更具耐受性。由于缺血预处理的心脏保护作用可能是由三磷酸腺苷敏感性钾通道的激活介导的，本研究旨在评估钾通道开放剂的缺血前给药是否能复制这些效应。五十个离体的等容缓冲液灌注大鼠心脏先经历45分钟的常温钾停搏，随后再灌注1小时。它们被分为五组，每组数量相等，预处理方案有所不同：第1组心脏未接受处理，作为对照；第2组在心脏停搏前，通过5分钟的全心缺血，随后5分钟的缓冲液再灌注来实现预处理；第3组的预处理刺激包括5分钟输注钾通道开放剂尼可地尔（10 μmol/L），随后在停搏前进行5分钟的无药缓冲液灌注；第4组心脏经历类似方案，但在输注尼可地尔之前先输注钾通道阻滞剂格列本脲（10 μmol/L）；第5组心脏与第2组一样进行缺血预处理，但在无血流预处理期之前也先输注5分钟的格列本脲（50 μmol/L）。结果表明，与对照心脏相比，缺血预处理显著改善了再灌注期间的收缩力并减少了挛缩。尼可地尔预处理可复制这些保护作用，但在药物被预先输注的格列本脲拮抗时则被消除。同样，格列本脲诱导的钾通道阻断在很大程度上减弱了缺血预处理的有益作用。这些数据表明，在与手术相关的全心缺血模型中，三磷酸腺苷敏感性钾通道的开放对预处理诱导的心脏保护有很大贡献，因此，使用像尼可地尔这样的钾通道开放剂可能是增强心脏停搏保护的有效手段。
