Lopaschuk G D, Wall S R, Olley P M, Davies N J
Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Circ Res. 1988 Dec;63(6):1036-43. doi: 10.1161/01.res.63.6.1036.
Fatty acids are known to increase the severity of injury during acute myocardial ischemia. In this study, we determined the effects of a carnitine palmitoyltransferase I inhibitor, ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir) on reperfusion recovery of fatty acid perfused hearts. Following a 25-minute period of global ischemia, isolated working hearts reperfused with 1.2 mM palmitate, 11 mM glucose exhibited depressed function compared to hearts perfused with 11 mM glucose alone. A low dose of Etomoxir (10(-9) M) decreased long chain acylcarnitine and long chain acyl-coenzyme A (CoA) levels but did not prevent depressed function. In contrast, a high dose of Etomoxir (10(-6) M) prevented the palmitate-induced depression of function but did not decrease myocardial long chain acylcarnitine or long chain acyl-CoA levels. At this high dose of Etomoxir, oxygen consumption per unit work was decreased during reperfusion recovery, and ATP and creatine-phosphate levels were significantly higher after reperfusion. In aerobic hearts not subjected to ischemia, Etomoxir (10(-6) M) increased glucose oxidation both in the presence and absence of palmitate, while 10(-9) M Etomoxir had no effect. In these aerobic hearts, only the low dose of Etomoxir decreased long chain acylcarnitine and long chain acyl-CoA levels. These data demonstrate that Etomoxir (10(-6) M) increases functional recovery of fatty acid perfused ischemic hearts. This protection is unrelated to changes in levels of long chain acylcarnitines but may be due to increased glucose use by the reperfused heart, resulting in decreased oxygen consumption per unit work.
已知脂肪酸会加重急性心肌缺血期间的损伤严重程度。在本研究中，我们测定了肉碱棕榈酰转移酶I抑制剂2-[6-(4-氯苯氧基)己基]环氧乙烷-2-羧酸乙酯（依托莫昔）对脂肪酸灌注心脏再灌注恢复的影响。在25分钟的全心缺血期后，与仅用11 mM葡萄糖灌注的心脏相比，用1.2 mM棕榈酸酯和11 mM葡萄糖再灌注的离体工作心脏功能受到抑制。低剂量的依托莫昔（10^(-9) M）可降低长链酰基肉碱和长链酰基辅酶A（CoA）水平，但不能预防功能抑制。相比之下，高剂量的依托莫昔（10^(-6) M）可预防棕榈酸酯诱导的功能抑制，但不会降低心肌长链酰基肉碱或长链酰基辅酶A水平。在这个高剂量的依托莫昔下，再灌注恢复期间单位功的耗氧量降低，再灌注后ATP和磷酸肌酸水平显著更高。在未经历缺血的有氧心脏中，无论有无棕榈酸酯存在，依托莫昔（10^(-6) M）均可增加葡萄糖氧化，而10^(-9) M的依托莫昔则无此作用。在这些有氧心脏中，只有低剂量的依托莫昔可降低长链酰基肉碱和长链酰基辅酶A水平。这些数据表明，依托莫昔（10^(-6) M）可增加脂肪酸灌注的缺血心脏的功能恢复。这种保护作用与长链酰基肉碱水平的变化无关，但可能是由于再灌注心脏对葡萄糖的利用增加，导致单位功的耗氧量降低。
