糖酵解与葡萄糖氧化之间的失衡可能是缺血性心脏有氧再灌注期间高水平脂肪酸产生有害影响的一个原因。

An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts.

作者信息

Lopaschuk G D, Wambolt R B, Barr R L

机构信息

Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, Canada.

出版信息

J Pharmacol Exp Ther. 1993 Jan;264(1):135-44.

PMID:8380856

Abstract

High levels of fatty acids can decrease the recovery of previously ischemic hearts by inhibiting myocardial glucose use during reperfusion. We determined if this was due to a decrease in glycolysis or a decrease in glucose oxidation. Isolated working rat hearts were perfused with either 11 mM [2-3H/U-14C] glucose or 11 mM [2-3H/U-14C] glucose and 1.2 mM palmitate. In aerobically perfused hearts, the presence of fatty acids reduced glucose oxidation rates (from 1576 +/- 154 to 228 +/- 28 nmol/min.g dry weight, P < .05), with a nonsignificant reduction in glycolysis (from 3297 +/- 349 to 2798 +/- 343 nmol/min.g dry weight). If fatty acid perfused hearts were subjected to a 30-min period of ischemic function was 36%. Glucose oxidation rates during reperfusion were markedly lower than glycolytic rates (228 +/- 35 and 3096 +/- 576 nmol/min.g dry weight, respectively, P < .05). Dichloroacetate (1 mM) added during reperfusion significantly improved recovery of mechanical function to 96% of preischemic values. In these hearts, Dichloracetate increased glucose oxidation, while actually decreasing glycolytic rates (values during reperfusion were 501 +/- 136 and 1171 +/- 122 nmol/min.g dry weight, respectively). Insulin (500 microU/ml) added at reperfusion resulted in a small increase in glucose oxidation rates and a significant increase in glycolysis (375 +/- 66 and 4769 +/- 955 nmol/g dry weight.min, respectively). However, the presence of insulin at reperfusion did not improve recovery of function (hearts recovered 52% of preischemic function). We demonstrate that the detrimental effects of high concentrations of fatty acids after ischemia are primarily due to an inhibition of glucose oxidation, and not glycolysis, during the reperfusion period. Furthermore, increasing glucose oxidation during reperfusion has a beneficial effect on functional recovery of hearts.

摘要

高水平脂肪酸可通过抑制再灌注期间心肌对葡萄糖的利用，降低先前缺血心脏的恢复能力。我们确定这是否是由于糖酵解减少或葡萄糖氧化减少所致。将离体工作大鼠心脏用11 mM [2-³H/U-¹⁴C]葡萄糖或11 mM [2-³H/U-¹⁴C]葡萄糖与1.2 mM棕榈酸酯进行灌注。在有氧灌注的心脏中，脂肪酸的存在降低了葡萄糖氧化速率（从1576±154降至228±28 nmol/min·g干重，P <.05），糖酵解有不显著降低（从3297±349降至2798±343 nmol/min·g干重）。如果用脂肪酸灌注的心脏经历30分钟缺血，功能恢复率为36%。再灌注期间的葡萄糖氧化速率明显低于糖酵解速率（分别为228±35和3096±576 nmol/min·g干重，P <.05）。再灌注期间添加二氯乙酸（1 mM）可使机械功能恢复显著提高至缺血前值的96%。在这些心脏中，二氯乙酸增加了葡萄糖氧化，而实际上降低了糖酵解速率（再灌注期间的值分别为501±136和1171±122 nmol/min·g干重）。再灌注时添加胰岛素（500 μU/ml）导致葡萄糖氧化速率略有增加，糖酵解显著增加（分别为375±66和4769±955 nmol/g干重·min）。然而，再灌注时胰岛素的存在并未改善功能恢复（心脏恢复到缺血前功能的52%）。我们证明，缺血后高浓度脂肪酸的有害作用主要是由于再灌注期间葡萄糖氧化受到抑制，而非糖酵解。此外，再灌注期间增加葡萄糖氧化对心脏功能恢复有有益作用。