ETOMOXIR, A CARNITINE PALMITOYLTRANSFERASE-I INHIBITOR, PROTECTS HEARTS FROM FATTY ACID-INDUCED ISCHEMIC-INJURY INDEPENDENT OF CHANGES IN LONG-CHAIN ACYLCARNITINE
ETOMOXIR, A CARNITINE PALMITOYLTRANSFERASE-I INHIBITOR, PROTECTS HEARTS FROM FATTY ACID-INDUCED ISCHEMIC-INJURY INDEPENDENT OF CHANGES IN LONG-CHAIN ACYLCARNITINE
复制标题
DOI：
10.1161/01.res.63.6.1036
复制
发表时间：
1988-12-01
影响因子：
20.1
通讯作者：
DAVIES, NJ
中科院分区：
文献类型：
--
作者：
LOPASCHUK, GD;WALL, SR;DAVIES, NJ
已知脂肪酸会增加急性心肌缺血时损伤的严重程度。在这项研究中，我们确定了肉碱棕榈酰基转移酶I抑制剂乙酯2-[6-（4-氯苯氧基）己基]氧酰-2-羧酸乙托莫西尔（Etomoxir）对脂肪酸灌注心脏再灌注恢复的影响。在25分钟的全脑缺血后，再灌注1.2 mM棕榈酸盐和11 mM葡萄糖的离体工作心脏与仅灌注11 mM葡萄糖的心脏相比，表现出功能抑制。低剂量的依托莫西（10-9 M）可降低长链酰基肉碱和长链酰基辅酶A （CoA）水平，但不能防止功能下降。相比之下，高剂量（10-6 M）的依托莫西可以防止棕榈酸盐引起的功能抑制，但不能降低心肌长链酰基肉碱或长链酰基辅酶a水平。在高剂量的依托莫西治疗下，再灌注恢复期间单位功耗氧量降低，再灌注后ATP和肌酸-磷酸水平显著升高。在没有缺血的有氧心脏中，依托莫西（10-6 M）在棕榈酸盐存在和不存在的情况下都增加了葡萄糖氧化，而10-9 M依托莫西没有作用。在这些有氧心脏中，只有低剂量的依托莫西才能降低长链酰基肉碱和长链酰基辅酶a水平。这些数据表明，依托莫西（10-6 M）可促进脂肪酸灌注缺血心脏的功能恢复。这种保护与长链酰基肉碱水平的变化无关，但可能是由于再灌注的心脏增加了葡萄糖的使用，导致单位功耗氧量减少。
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.