ATP synthesis during low-flow ischemia influence of increased glycolytic substrate

• Published in: Circulation (New York, N.Y.) N.Y.), 2000-05, Vol.101 (17), p.2090-2096
• Main Authors: CAVE, A. C, INGWALL, J. S, FRIEDRICH, J, RONGLIH LIAO, SAUPE, K. W, APSTEIN, C. S, EBERLI, F. R
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - biosynthesis; Animals; Biological and medical sciences; Cardiology. Vascular system; Coronary heart disease; Creatine Kinase - metabolism; Disease Models, Animal; Glucose - metabolism; Glucose - physiology; Heart; Hemodynamics; Insulin - physiology; Magnetic Resonance Spectroscopy; Male; Medical sciences; Myocardial Infarction - metabolism; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardium - metabolism; Oxidative Phosphorylation; Oxygen Consumption; Phosphocreatine - metabolism; Rats; Rats, Wistar
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.101.17.2090

Our goals were to (1) simulate the degree of low-flow ischemia and 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 how increased glycolytic substrate alters the energetic profile, function, and recovery of the ischemic myocardium in the isolated blood-perfused rat heart. Hearts had 60 minutes of low-flow ischemia (10% of baseline coronary flow) and 30 minutes of reperfusion with either control or high glucose and insulin (G+I) as substrate. In controls, during ischemia, rate-pressure product and oxygen consumption decreased by 84%. CK velocity decreased by 64%; ATP and phosphocreatine (PCr) concentrations decreased by 51% and 63%, respectively; inorganic phosphate (P(i)) concentration increased by 300%; and free [ADP] did not increase. During ischemia, relative to controls, the G+I group had similar CK velocity, oxygen consumption, and tissue acidosis but increased glycolysis, higher [ATP] and [PCr], and lower [P(i)] and therefore had a greater free energy yield from ATP hydrolysis. Ischemic systolic and diastolic function and postischemic recovery were better. During low-flow ischemia simulating an acute myocardial infarction region, oxidative phosphorylation accounted for 90% of ATP synthesis. The 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, maintained lower [P(i)], and maintained a higher free energy from ATP hydrolysis. This improved energetic profile resulted in better systolic and diastolic function during ischemia and reperfusion. These results support the clinical use of G+I in acute MI.