Department of Cardiology B, Arhus University Hospital, Skejby, 8200 Arhus N, Denmark.
Exp Physiol. 2010 Jan;95(1):140-52. doi: 10.1113/expphysiol.2009.049452. Epub 2009 Aug 28.
We have found that cardioprotection by l-glutamate mimics protection by classical ischaemic preconditioning (IPC). We investigated whether the effect of IPC involves amino acid transamination and whether IPC modulates myocardial glutamate metabolism. In a glucose-perfused, isolated rat heart model subjected to 40 min global no-flow ischaemia and 120 min reperfusion, the effects of IPC (2 cycles of 5 min ischaemia and 5 min reperfusion) and continuous glutamate (20 mm) administration during reperfusion on infarct size and haemodynamic recovery were studied. The effect of inhibiting amino acid transamination was evaluated by adding the amino acid transaminase inhibitor amino-oxyacetate (AOA; 0.025 mm) during reperfusion. Changes in coronary effluent, interstitial (microdialysis) and intracellular glutamate (GLUT) concentrations were measured. Ischaemic preconditioning and postischaemic glutamate administration reduced infarct size to the same extent (41 and 40%, respectively; P < 0.05 for both), without showing an additive effect. Amino-oxyacetate abolished infarct reduction by IPC and glutamate, and increased infarct size in both control and IPC hearts in a dose-dependent manner. Ischaemic preconditioning increased GLUT before ischaemia (P < 0.01) and decreased the release of glutamate during the first 10 min of reperfusion (P = 0.03). A twofold reduction in GLUT from the preischaemic state to 45 min of reperfusion (P = 0.0001) suggested increased postischaemic glutamate utilization in IPC hearts. While IPC and AOA changed haemodynamics in accordance with infarct size, glutamate decreased haemodynamic recovery despite reduced infarct size. In conclusion, ischaemic cardioprotection of the normal and IPC-protected heart depends on amino acid transamination and activity of the malate-aspartate shuttle during reperfusion. Underlying mechanisms of IPC include myocardial glutamate metabolism.
我们发现，L-谷氨酸模拟保护经典缺血预处理（IPC）。我们研究了 IPC 的效果是否涉及氨基酸转氨基作用，以及 IPC 是否调节心肌谷氨酸代谢。在葡萄糖灌注的离体大鼠心脏模型中，进行 40 分钟的全流量缺血和 120 分钟的再灌注，研究了 IPC（2 个 5 分钟缺血和 5 分钟再灌注循环）和再灌注期间连续谷氨酸（20mm）给药对梗死面积和血流动力学恢复的影响。通过在再灌注期间添加氨基酸转氨基酶抑制剂氨基氧乙酸（AOA；0.025mm）来评估抑制氨基酸转氨基作用的效果。测量冠状动脉流出物、间质（微透析）和细胞内谷氨酸（GLUT）浓度的变化。缺血预处理和缺血后谷氨酸给药均使梗死面积减少到相同程度（分别为 41%和 40%；两者均 P<0.05），无叠加作用。AOA 消除了 IPC 和谷氨酸对梗死的减少作用，并以剂量依赖的方式增加了对照和 IPC 心脏的梗死面积。缺血预处理增加了缺血前的GLUT（P<0.01），并减少了再灌注的前 10 分钟期间谷氨酸的释放（P=0.03）。从缺血前状态到再灌注 45 分钟时GLUT减少了两倍（P=0.0001），表明 IPC 心脏的再灌注后谷氨酸利用增加。尽管梗死面积减少，但 IPC 和 AOA 改变了与梗死面积一致的血流动力学，而谷氨酸降低了血流动力学恢复。总之，正常和 IPC 保护的心脏的缺血性心脏保护依赖于再灌注期间的氨基酸转氨基作用和苹果酸天冬氨酸穿梭的活性。IPC 的潜在机制包括心肌谷氨酸代谢。
