The functional recovery of post-ischemic myocardium requires glycolysis during early reperfusion

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.