Adjustments in competitive substrate utilization in stunned myocardium during early reperfusion.
Adjustments in competitive substrate utilization in stunned myocardium during early reperfusion.
复制标题
早期再灌注期间顿顿心肌中竞争性底物利用的调整。
DOI：
10.1007/bf00797899
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发表时间：
1995
影响因子：
9.5
通讯作者：
Liedtke,AJ
中科院分区：
文献类型：
--
作者：
Renstrom,B;Liedtke,AJ
本文的目的是陈述和支持一种关于非坏死性心肌缺血间隔后休克和再灌注心肌的中间代谢和底物利用的个人观点。支持这一观点的数据来自于一个完整的，工作的猪心脏准备，包括体外控制区域冠状动脉灌注，在我们的实验室已经使用了近二十年。使用示踪同位素（包括[U-14C]棕榈酸盐、[9,10- 3h]棕榈酸盐、[6-14C]葡萄糖、[5-3H]葡萄糖、[2-14C]丙酮酸盐、[14C]乳酸和[1-14C]醋酸盐）单独或联合对心肌进行稳态标记来表征代谢。在不同的方案中，心肌轻度至中度缺血30-40分钟，然后有氧再灌注40-60分钟。底物利用率和/或氧化率在缺血前、缺血间期以及本综述中强调的有氧再灌注期间随后的代谢调整期间进行常规测量。从这些实验中收集的综合数据表明，在休克状态下，心肌代谢处于快速转变中，有氧氧化的恢复比机械功能更大，首选底物关系的层次转变回到有氧利用，有害两亲体的有益清除，脂肪酸氧化的过度，可能是由于先前缺血应激影响的调节机制的持续改变。在一些再灌注研究中，脂肪酸氧化大约是缺血前的两倍，这在一定程度上取决于灌注液中外源性脂肪酸底物的水平(6)。这种增强部分来自于细胞内储存的脂肪酸释放，主要是三环甘油，如我们所示(8)，部分来自于外源性硫酸的吸收增加，如Saddik和Lopaschuk所示（12）。然而，这种脂肪酸偏好的快速上升并不意味着对竞争性底物施加的正常调节抑制的底物免疫。在单独的研究中，我们提供了恢复心肌过量丙酸对柠檬酸循环的动力学影响(4)。这种竞争性底物使脂肪酸的氧化降低了38%，这不能用清除辅酶a单位来解释，否则将用于脂肪酸活化。从分离制剂中收集的数据来看，脂肪酸氧化的重新出现没有好处，而是对机械恢复产生负性肌力影响（1,7）。然而，在我们使用全血灌注的完整模型中，情况并非如此(6)。我们实验的第二个目标是用葡萄糖、丙酮酸和乳酸作为代表性的类似物，透视碳水化合物底物利用的作用，并定义它们与作为调节底物的脂肪酸的关系。葡萄糖通量和葡萄糖氧化在缺血前受到高度抑制，可能是由于首选使用脂肪酸施加的变抗和产物抑制（2,3,9）。在中度缺血的猪心脏中，局部冠状动脉血流减少60%，糖酵解增加近10倍，甚至葡萄糖氧化也略有增加（2,9）。当在模拟预处理的方案中应用多次短暂缺血预处理时(2)，糖酵解的通量率显着降低。再灌注时，葡萄糖利用和氧化水平降至缺血前的正常水平。
The purpose of this precis is to state and support a personal viewpoint concerning intermediary metabolism and substrate utilization in stunned and reperfused myocardium following an interval of nonnecrotizing myocardial ischemia. The data in support of this viewpoint were derived from an intact, working pig heart preparation which includes extracorporeal control of regional coronary perfusion, and which has been used in our laboratory for almost two decades. Metabolism was characterized using steady-state labeling of myocardium with tracer isotopes including [U-14C]palmitate, [9,10-3H]palmitate, [6-14C] glucose, [5-3H]glucose, [2-14C]pyruvate, [14C]lactate, and [1-14C]acetate either singly or in combination. Myocardium was rendered mild to moderately ischemic for 30–40 min in separate protocols, and then aerobically reperfused for 40–60 min. Rates of substrate utilization and/or oxidation were routinely measured during the preischemic period, the ischemic interval, and as emphasized in this overview the subsequent period of metabolic adjustments during aerobic reperfusion. The composite data compiled from these experiments indicate that in stunned myocardium metabolism is in rapid transition with greater restoration of aerobic oxidation than mechanical function, a hierarchical shift in preferred substrate relationships back toward aerobic utilization with beneficial washout of noxious amphiphiles, and an overshoot in fatty acid oxidation, presumably due to persistent alterations in regulatory mechanisms affected by the preceding ischemic stress.In select reperfusion studies and depending somewhat on the levels of exogenous fatty acid substrate in perfusate, fatty acid oxidation approximately doubled over preischemic values (6). This augmentation occurred in part from fatty acids made available from release of intra cellular stores, principally triacyclglycerols, as we showed (8) and in part from increased uptake of exogenous suostrate as demonstrated by Saddik and Lopaschuk (12). This rapid ascendancy in fatty acid preference, however, does not imply a substrate immunity from the normal regulatory inhibitions imposed by competing substrates. In separate studies we provided to recovering myocardium excess propionate to influence the kinetcs of anaplerotic entrance to the citric acid cycle (4). This competing substrate effected a 38% decrease in the oxidation of fatty acids which was not explained by the scavenging of coenzyme A units otherwise destined for fatty acid activation It has been argued from data collected in isolated preparations that the resurgency in fatty acid oxidation is of no benefit but rather a negative inotropic intluence on mechanical recovery (1, 7). However, in our intact model using whole blood perfusate this was not the case (6).A second objective in our experiments was to place in perspective the role of carbohydrate substrate utilizations using glucose, pyruvate, and lactate as representative analogues and to define their relationships to those of fatty acids as regulated substrates. Glucose flux and glucose oxidation were highly suppressed during preischemia, presumably due to allosteric and product inhibitions imposed by the preferred use of fatty acids (2, 3, 9). In moderately ischemic pig hearts with a 60% reduction in regional coronary flow, glycolysis rose nearly tenfold, and even glucose oxidation was increased slightly (2, 9). When multiple exposures of brief ischemic pretreatments were applied in protocols designed to simulate preconditioning (2), flux rates for glycolysis were significantly reduced. During reperfusion, glucose utilization and oxidation fell toward normal preischemic …