Jeremy R W, Ambrosio G, Pike M M, Jacobus W E, Becker L C
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
J Mol Cell Cardiol. 1993 Mar;25(3):261-76. doi: 10.1006/jmcc.1993.1033.
Glycolysis normally provides only a small fraction of myocardial ATP production, but ATP from glycolysis may be preferentially used to support membrane activities such as ion pumping. Since ion homeostasis is disturbed during ischemia, glycolysis may be particularly important in the recovery of postischemic myocardium. This hypothesis was investigated in isovolumic, isolated rabbit hearts, perfused with 16 mM glucose, 5 mM pyruvate or 5 mM acetate. Global left ventricular function (rate-pressure product, RPP) and unidirectional ATP synthesis rate (P(i)-->ATP flux, 31P NMR) were measured before and after 20 min global ischemia. Control hearts with intact glycolysis were compared with hearts which had glycolysis inhibited by iodoacetate (150 microM), 2-deoxyglucose (10 mM) or prior glycogen depletion. In normal hearts, inhibition of glycolysis had no effect on function when pyruvate or acetate was present as as a carbon substrate. In post-ischemic hearts, reperfusion with glucose (n = 7) resulted in moderate recovery of function to about 65% of pre-ischemic levels after 1 h reperfusion. Administration of iodoacetate at the onset of reperfusion to hearts receiving pyruvate or acetate resulted in much worse functional recovery and a marked rise in left ventricular end-diastolic pressure (LVEDP). With pyruvate (n = 7), RPP recovered to 27% of pre-ischemic levels, while mean LVEDP increased to 34 mmHg (vs 16 mmHg with glucose); with acetate (n = 6), RPP returned to 31% of pre-ischemic levels, while mean LVEDP rose to 32 mmHg. The ratio of P(i)-->ATP flux to atoms of oxygen consumed (P:O ratio) was 2.14 +/- 0.36 in hearts reperfused with iodoacetate and pyruvate, consistent with partial mitochondrial uncoupling. However, if inhibition of glycolysis with iodoacetate was delayed until after 30 min reperfusion, recovery of hearts reperfused with pyruvate was similar to hearts perfused with glucose, and there was no evidence of mitochondrial uncoupling (P:O ratio = 2.95 +/- 0.33). Inhibition of glycolysis during reperfusion with 2-deoxyglucose yielded results similar to reperfusion with iodoacetate. The worst recovery was observed in hearts with combined glycolytic inhibition by pre-ischemic glycogen depletion and iodoacetate during reperfusion (RPP = 13% of pre-ischemic levels). These findings indicate that glycolysis plays a crucial role during early reperfusion in the functional and metabolic recovery of post-ischemic myocardium.
糖酵解通常仅提供心肌ATP生成的一小部分，但糖酵解产生的ATP可能优先用于支持诸如离子泵浦等膜活动。由于缺血期间离子稳态受到干扰，糖酵解在缺血后心肌的恢复中可能尤为重要。本假说在离体兔等容心脏中进行了研究，这些心脏用16 mM葡萄糖、5 mM丙酮酸或5 mM乙酸盐灌注。在全心缺血20分钟前后测量整体左心室功能（速率 - 压力乘积，RPP）和单向ATP合成速率（P(i)→ATP通量，31P NMR）。将糖酵解完整的对照心脏与用碘乙酸盐（150 microM）、2 - 脱氧葡萄糖（10 mM）抑制糖酵解或预先糖原耗竭的心脏进行比较。在正常心脏中，当丙酮酸或乙酸盐作为碳底物存在时，糖酵解的抑制对功能没有影响。在缺血后心脏中，用葡萄糖再灌注（n = 7）导致1小时再灌注后功能适度恢复至缺血前水平的约65%。在接受丙酮酸或乙酸盐的心脏再灌注开始时给予碘乙酸盐导致功能恢复差得多，并且左心室舒张末期压力（LVEDP）显著升高。对于丙酮酸（n = 7），RPP恢复至缺血前水平的27%，而平均LVEDP升至34 mmHg（与葡萄糖灌注时的16 mmHg相比）；对于乙酸盐（n = 6），RPP恢复至缺血前水平的31%，而平均LVEDP升至32 mmHg。在用碘乙酸盐和丙酮酸再灌注的心脏中，P(i)→ATP通量与消耗的氧原子之比（P:O比）为2.14±0.36，与部分线粒体解偶联一致。然而，如果用碘乙酸盐抑制糖酵解延迟至再灌注30分钟后，用丙酮酸再灌注的心脏恢复情况与用葡萄糖灌注的心脏相似，并且没有线粒体解偶联的证据（P:O比 = 2.95±0.33）。用2 - 脱氧葡萄糖在再灌注期间抑制糖酵解产生的结果与用碘乙酸盐再灌注相似。在缺血前糖原耗竭和再灌注期间用碘乙酸盐联合抑制糖酵解的心脏中观察到最差的恢复情况（RPP = 缺血前水平的13%）。这些发现表明，糖酵解在缺血后心肌的早期再灌注期间对功能和代谢恢复起着关键作用。
