Fryer R M, Schultz J E, Hsu A K, Gross G J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Am J Physiol. 1998 Dec;275(6):H2009-15. doi: 10.1152/ajpheart.1998.275.6.H2009.
Ischemic preconditioning (IPC) confers cardioprotection against a prolonged ischemic insult. Tyrosine kinase (TK) inhibitors have been shown to attenuate IPC; however, it is unclear whether TK is involved in the initiation of and/or the maintenance of this phenomenon. Thus the hypothesis that TK acts primarily during the initiation of IPC was examined in a rat model of myocardial infarction. Hearts were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. IPC was elicited by three 5-min occlusions interspersed with 5 min of reperfusion before the prolonged occlusion period. Genistein, a nonspecific TK inhibitor, was administered before or during the final 2 min of the first or third occlusion period of IPC. Daidzein, an inactive structural analog of genistein, and lavendustin A, a more specific TK inhibitor, were also tested in this model. IPC markedly reduced infarct size expressed as a percentage of the area at risk compared with control (56.3 +/- 2.8 to 7.1 +/- 2.0%). This cardioprotection was attenuated by genistein pretreatment (5 mg/kg: 34.7 +/- 2.2%, 10 mg/kg: 33.5 +/- 5.9%). However, genistein administered during the first or third occlusion period of IPC did not significantly attenuate cardioprotection (10.3 +/- 2.9% and 6.4 +/- 2.0%). Lavendustin A (1. 0 mg/kg) pretreatment also attenuated IPC (30.1 +/- 2.2%), whereas daidzein (5 mg/kg) had no effect (7.9 +/- 2.4%). These results suggest that activation of a TK is involved in the initiation but not the maintenance of IPC in the rat myocardium.
缺血预处理（IPC）可赋予心脏对长时间缺血损伤的保护作用。酪氨酸激酶（TK）抑制剂已被证明可减弱IPC；然而，尚不清楚TK是否参与这一现象的启动和/或维持。因此，在大鼠心肌梗死模型中检验了TK主要在IPC启动过程中起作用的假说。心脏接受30分钟冠状动脉闭塞和2小时再灌注。在长时间闭塞期之前，通过穿插5分钟再灌注的三次5分钟闭塞来诱导IPC。在IPC的第一次或第三次闭塞期的最后2分钟之前或期间给予非特异性TK抑制剂染料木黄酮。染料木黄酮的无活性结构类似物大豆苷元和更特异性的TK抑制剂拉芬斯汀A也在此模型中进行了测试。与对照组相比，IPC显著降低了以危险区域面积百分比表示的梗死面积（从56.3±2.8降至7.1±2.0%）。染料木黄酮预处理减弱了这种心脏保护作用（5mg/kg：34.7±2.2%，10mg/kg：33.5±5.9%）。然而，在IPC的第一次或第三次闭塞期给予染料木黄酮并没有显著减弱心脏保护作用（分别为10.3±2.9%和6.4±2.0%）。拉芬斯汀A（1.0mg/kg）预处理也减弱了IPC（30.1±2.2%），而大豆苷元（5mg/kg）则无作用（7.9±2.4%）。这些结果表明，TK的激活参与大鼠心肌IPC的启动，但不参与其维持。
