(Circulation. 2000;101:2090.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
ATP Synthesis During Low-Flow Ischemia
Influence of Increased Glycolytic Substrate
From the Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, and the NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital (J.S.I., J.F.), Boston, Mass.
Correspondence to Carl S. Apstein, MD, 715 Albany St, Room X720, Boston, MA 02118. E-mail capstein{at}acs.bu.edu
Background—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.
Methods and Results—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 (Pi) 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 [Pi] and therefore had a greater free energy yield from ATP hydrolysis. Ischemic systolic and diastolic function and postischemic recovery were better.
Conclusions—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 [Pi], 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.
Key Words: creatine kinase • glucose • insulin • ischemia • metabolism
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