Gysembergh A, Lemaire S, Piot C, Sportouch C, Richard S, Kloner R A, Przyklenk K
Heart Institute, Good Samaritan Hospital and University of Southern California, Los Angeles, California 90017-2395, USA.
Am J Physiol. 1999 Dec;277(6):H2458-69. doi: 10.1152/ajpheart.1999.277.6.H2458.
Recent evidence revealed biphasic alterations in myocardial concentrations of the second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] with ischemic preconditioning (PC), i.e., increase during brief PC ischemia and decrease early during sustained test occlusion. Our aim was to determine whether an agonist and an antagonist of Ins(1,4,5)P(3) signaling (D-myo-inositol-1,4,5-trisphosphate hexasodium salt [D-myo-Ins(1,4, 5)P3] and 2-aminoethoxydiphenyl borate (2-APB), respectively), given such that they mimic this biphasic profile, would mimic infarct size reduction with PC. To test this concept, isolated, buffer-perfused rabbit hearts received no intervention (control), ischemic PC, D-myo-Ins(1,4,5)P3, D-myo-Ins(1,4,5)P(3) + PC, 2-APB, or 2-APB + PC. All hearts then underwent 30-min coronary occlusion and 2 h reflow, and infarct size was delineated by tetrazolium staining. In addition, the effects of D-myo-Ins(1,4,5)P3 and 2-APB on Ins(1,4,5)P3 signaling were evaluated in isolated fura 2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in all D-myo-Ins(1,4,5)P3- and 2-APB-treated groups versus control (59 and 42-55%, respectively, vs. 80% of myocardium at risk, P < 0.05). Thus pharmacological manipulation of Ins(1,4,5)P3 signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.
最近的证据显示，缺血预处理（PC）可使心肌中第二信使肌醇（1,4,5）-三磷酸[Ins(1,4,5)P3]的浓度发生双相变化，即在短暂的PC缺血期间升高，而在持续的试验性闭塞早期降低。我们的目的是确定，给予能模拟这种双相变化的Ins(1,4,5)P(3)信号激动剂和拮抗剂（分别为D-肌醇-1,4,5-三磷酸六钠盐[D-肌醇-Ins(1,4,5)P3]和2-氨基乙氧基二苯硼酸酯（2-APB）），是否能模拟PC减少梗死面积的作用。为验证这一概念，对离体的、用缓冲液灌注的兔心脏进行如下处理：不干预（对照）、缺血PC、D-肌醇-Ins(1,4,5)P3、D-肌醇-Ins(1,4,5)P(3)+PC、2-APB或2-APB+PC。然后所有心脏均经历30分钟的冠状动脉闭塞和2小时再灌注，并用四氮唑染色法勾勒出梗死面积。此外还在离体的、用fura 2负载的大鼠心肌细胞中评估了D-肌醇-Ins(1,4,5)P3和2-APB对Ins(1,4,5)P3信号的影响。与对照组相比，PC组以及所有用D-肌醇-Ins(1,4,5)P3和2-APB处理的组中的平均梗死面积均减小（分别为59%和42%-55%，而对照组为危险心肌的80%，P<0.05）。因此，对Ins(1,4,5)P3信号进行药理学调控可模拟兔心脏缺血PC所实现的心脏保护作用。
