Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in rabbit heart
Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in rabbit heart
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DOI：
10.1152/ajpheart.1999.277.6.h2458
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发表时间：
1999-12-01
影响因子：
4.8
通讯作者：
Przyklenk, K
中科院分区：
文献类型：
--
作者：
Gysembergh, A;Lemaire, S;Przyklenk, K
最近的证据显示，心肌第二信使肌醇(1,4,5)-三磷酸[Ins(1,4,5)P-3]浓度在缺血预处理（PC）时呈双相变化，即在短暂的PC缺血时升高，在持续的试验阻断中早期降低。我们的目的是确定Ins(1,4,5)P-3信号[d -肌醇-1,4,5-三磷酸六钠盐[d -肌醇（1,4,5）P-3]和2-氨基乙氧基二苯硼酸盐（2-APB）]的激动剂和拮抗剂是否会模拟PC的梗死面积缩小，因为它们分别模拟了这种双相特征。为了验证这一概念，分离的、缓冲灌注的兔心脏接受不干预（对照）、缺血PC、D-myo-Ins(1,4,5)P-3、D-myo-Ins(1,4,5)P-3 + PC、2-APB或2-APB + PC。然后对所有心脏进行30分钟冠状动脉闭塞和2小时血流灌注，并通过四氮唑染色划定梗死面积。此外，我们在离体负载fura 2的大鼠心肌细胞中评估了D-myo-Ins(1,4,5)P-3和2-APB对Ins(1,4,5)P-3信号传导的影响。与对照组相比，PC和所有D-myo-Ins(1,4,5)P-3和2- apb治疗组的平均梗死面积减小（分别为59%和42-55%，80%的心肌处于危险状态，P < 0.05）。因此，Ins(1,4,5)P-3信号的药理学操作模拟了兔心脏缺血PC的心脏保护作用。
Recent evidence revealed biphasic alterations in myocardial concentrations of the second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P-3] 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)P-3] 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)P-3, 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)P-3 and 2-APB on Ins(1,4,5)P-3 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)P-3- 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)P-3 signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.