ATP synthesis during low-flow ischemia - Influence of increased glycolyticsubstrate

Background-Our goals were to (1) simulate the degree of low-flow ischemia a nd mixed anaerobic and aerobic metabolism of an acutely infarcting region; (2) define changes in anaerobic glycolysis, oxidative phosphorylation, and the creatine kinase (CK) reaction velocity; and (3) determine whether and h ow increased glycolytic substrate alters the energetic profile, function, a nd recovery of the ischemic myocardium in the isolated blood-perfused rat h eart. Methods and Results-Hearts had 60 minutes of low-flow ischemia (10% of base line coronary flow) and 30 minutes of reperfusion with either control or hi gh glucose and insulin (G+I) as substrate. In controls, during ischemia, ra te-pressure product and oxygen consumption decreased by 84%. CK velocity de creased by 64%; ATP and phosphocreatine (PCr) concentrations decreased by 5 1% and 63%, respectively; inorganic phosphate (P-i) concentration increased by 300%; and free [ADP] did not increase. During ischemia, relative to con trols, the G+I group had similar CK velocity, oxygen consumption, and tissu e acidosis but increased glycolysis, higher [ATP] and [PCr], and lower [P-i ] and therefore had a greater free energy yield from ATP hydrolysis. Ischem ic systolic and diastolic function and postischemic recovery were better. Conclusions-During low-flow ischemia simulating an acute myocardial infarct ion region, oxidative phosphorylation accounted for 90% of ATP synthesis. T he CK velocity fell by 66%, and CK did not completely use available PCr to slow ATP depletion. G+I, by increasing glycolysis, slowed ATP depletion, ma intained lower [P-i], and maintained a higher free energy from ATP hydrolys is. This improved energetic profile resulted in better systolic and diastol ic function during ischemia and reperfusion. These results support the clin ical use of G+I in acute MI.