Grover G J, Dzwonczyk S, Sleph P G, Sargent C A
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
J Pharmacol Exp Ther. 1993 May;265(2):559-64.
Previous studies have indicated that the ATP-sensitive potassium channels blocker glibenclamide (glyburide) can abolish preconditioning in canine models of myocardial ischemia. Recently, an isolated rat heart model of preconditioning has been developed that may be ideal for studying the mechanisms of preconditioning. In the present study, we determined the effect of glyburide on preconditioning in isolated rat hearts. Rat hearts were isolated and retrogradely perfused with oxygenated Krebs'-Henseleit solution. They were then subjected to four periods of total global ischemia of 5-min duration, separated by 5-min reperfusion. The hearts were then subjected to 30-min global ischemia followed by 30-min reperfusion and contractile function and lactate dehydrogenase release determined. Non-preconditioned hearts sustained severe damage. Glyburide (1-100 microM) pretreatment had no effect on the severity of 30-min global ischemia and 30-min reperfusion. Preconditioning caused significant improvements in reperfusion contractile function (25-fold increase in left ventricular developed pressure) and reductions in reperfusion lactate dehydrogenase release and reperfusion end diastolic pressure (contracture). Glyburide had modest preischemic cardiodepressant and vasoconstrictor effects at 1-30 microM, whereas 100 microM caused a 50% reduction in preischemic coronary flow. Despite these effects, none of these concentrations of glyburide affected the efficacy of preconditioning. These studies indicate that preconditioning in isolated rat hearts does not occur via a glyburide- (and thus presumably ATP-sensitive potassium channel) sensitive mechanism.
以往的研究表明，ATP敏感性钾通道阻滞剂格列本脲（优降糖）可消除犬心肌缺血模型中的预处理作用。最近，已建立了一种孤立大鼠心脏预处理模型，这可能是研究预处理机制的理想模型。在本研究中，我们确定了格列本脲对孤立大鼠心脏预处理的影响。将大鼠心脏分离出来，用含氧的克氏-亨氏溶液逆行灌注。然后使其经历4个持续5分钟的全心缺血期，期间间隔5分钟的再灌注。接着使心脏经历30分钟的全心缺血，随后30分钟的再灌注，并测定收缩功能和乳酸脱氢酶释放情况。未预处理的心脏遭受了严重损伤。格列本脲（1 - 100微摩尔）预处理对30分钟全心缺血和30分钟再灌注的严重程度没有影响。预处理显著改善了再灌注收缩功能（左心室舒张末压增加25倍），并减少了再灌注时乳酸脱氢酶的释放以及再灌注末期舒张压（挛缩）。格列本脲在1 - 30微摩尔时具有适度的缺血前心肌抑制和血管收缩作用，而100微摩尔可使缺血前冠状动脉血流量减少50%。尽管有这些作用，但这些浓度的格列本脲均未影响预处理的效果。这些研究表明，孤立大鼠心脏中的预处理并非通过格列本脲敏感机制（因此推测也不是ATP敏感性钾通道敏感机制）发生。
